Navigating gastrointestinal challenges in genetic myopathies: Diagnostic insights and future directions

Abstract

BACKGROUND

Gastrointestinal (GI) manifestations are prevalent in genetic myopathies, posing significant diagnostic and management challenges.

AIM

To synthesize evidence on the diagnostic approaches, management strategies, patient perspectives, and future research directions regarding GI symptoms in genetic myopathies.

METHODS

A systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. We searched PubMed, Scopus, EMBASE, and Web of Science from inception to December 2024. Eligible studies reported GI manifestations in genetic myopathies, including clinical evaluations, imaging, physiological tests, histopathology, and genetic analyses. Inclusion criteria encompassed original research studies, review articles, case reports, and clinical guidelines published in peer-reviewed journals. Exclusion criteria included conference abstracts without full-text availability and non-peer-reviewed sources. Two independent reviewers screened studies and extracted data. They assessed methodological quality using the Newcastle-Ottawa Scale for observational studies, A MeaSurement Tool to Assess Systematic Reviews for systematic reviews, and the Joanna Briggs Institute checklist for case reports. A systematic narrative synthesis was employed to summarize the findings.

RESULTS

A total of 234 studies met the inclusion criteria. GI manifestations varied widely, with dysphagia, gastroesophageal reflux, abdominal pain, constipation, diarrhea, and fecal incontinence being the most frequently reported symptoms. The included studies highlighted a multidisciplinary diagnostic approach incorporating clinical assessment, imaging, physiological testing, histopathology, and genetic testing. Management strategies ranged from dietary interventions and rehabilitative therapies to pharmacological treatments and surgical procedures. Patient perspectives underscored the significant impact of GI symptoms on quality of life, social interactions, and emotional well-being. The main limitations of the included studies were high heterogeneity in study design, small sample sizes, and the potential risk of bias due to limited methodological rigor in some reports.

CONCLUSION

This review underscores the complexity of GI manifestations in genetic myopathies and the need for a comprehensive, multidisciplinary management approach. Future research should focus on elucidating molecular mechanisms, identifying biomarkers, and developing targeted therapies to improve patient outcomes. The findings have implications for both clinical practice and public health, emphasizing the necessity of early diagnosis and personalized management strategies.

Key Words: Genetic myopathies; Gastrointestinal manifestations; Diagnostic approaches; Multidisciplinary management; Patient perspectives; Future directions; Quality of life

Core Tip: Gastrointestinal (GI) manifestations in genetic myopathies are frequently overlooked yet significantly impact patient outcomes. This systematic review highlights the prevalence, diagnostic challenges, and management strategies for GI dysfunction in conditions like Duchenne muscular dystrophy, Becker muscular dystrophy, and mitochondrial myopathies. The study underscores the role of imaging, motility testing, and genetic evaluation in guiding care. Additionally, it explores the influence of genetic and environmental modifiers on symptom variability. A multidisciplinary approach integrating gastroenterology, neurology, and nutrition is essential for improving quality of life. Future research should focus on targeted therapies and molecular mechanisms to optimize patient management.

INTRODUCTION

Genetic myopathies are a group of inherited muscle disorders caused by genetic defects in the contractile fibers of the muscle, their membrane, or supporting proteins, leading to structural and functional abnormalities. These conditions vary widely in severity and presentation but typically involve progressive muscle weakness, atrophy, and impaired motor function[1]. The etiology of genetic myopathies depends on the specific condition but generally involves mutations in genes encoding structural proteins, enzymes involved in energy production, or proteins responsible for muscle regulation. These mutations disrupt normal muscle function, leading to the characteristic symptoms of the disorder[2]. Genetic myopathies are classified into muscular dystrophies, congenital myopathies, metabolic myopathies, myotonic disorders, and mitochondrial myopathies[3]. Although individually rare, collectively, these disorders impose a significant burden on affected individuals and their families[4]. The prevalence of genetic myopathies varies, with estimates ranging between 1:5000 and 1:50000, depending on the specific disorder and population[5].

Muscle weakness is the hallmark of genetic myopathies and can significantly impair daily activities such as walking, climbing stairs, and lifting objects. It may be generalized or localized, affecting specific muscle groups[6]. Prolonged muscle tightness and contractures can restrict joint mobility and flexibility, leading to skeletal deformities[7]. In severe cases, respiratory muscle weakness can result in breathing difficulties and life-threatening complications[8]. The impact of genetic myopathies extends beyond skeletal muscle involvement, affecting multiple organ systems. As smooth muscle shares some structural similarities with skeletal muscle, genetic myopathies can also affect the gastrointestinal (GI) tract, leading to symptoms such as dysphagia, gastroesophageal reflux disease (GERD), constipation, and intestinal pseudo-obstruction[9]. GI manifestations in genetic myopathies are often underrecognized but significantly impact patients' quality of life, nutrition, and overall health[10].

Myopathies effects often extend beyond skeletal muscles to affect other organs or tissues as well. As smooth muscles share skeletal muscles with some common structural features, myopathies can impact the GI tract, leading to symptoms such as dysphagia, reflux, and constipation[11]. In some cases, individuals with myopathies may experience swallowing difficulties due to weakened or impaired muscles in the esophagus, leading to dysphagia[12]. Additionally, muscle weakness can affect the coordination of the digestive system, potentially causing issues such as GERD or constipation[13]. These GI symptoms can significantly impact the quality of life for individuals with myopathies, requiring management and support from healthcare professionals[14].

This review aims to explore the GI manifestations observed in genetic myopathies systematically. By elucidating the connection between inherited muscle disorders and GI symptoms such as dysphagia, GERD, constipation, diarrhea, and intestinal pseudo-obstruction, this review underscores the importance of recognizing and addressing these complications in clinical practice. Additionally, it highlights the necessity of a multidisciplinary approach involving specialists from neurology, gastroenterology, and nutrition to provide comprehensive care for affected individuals, thereby improving their overall well-being.

MATERIALS AND METHODS

This systematic review follows a comprehensive, multidisciplinary approach to investigating GI manifestations in genetic myopathies. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ensuring methodological rigor and transparency.

A systematic literature search was performed using four electronic databases: (1) PubMed; (2) Scopus; (3) EMBASE; and (4) Web of Science. The search strategy combined Medical Subject Headings terms and free-text keywords related to genetic myopathies and GI manifestations. Boolean operators (AND, OR, NOT) were applied to refine the search. The following are examples of search terms used: ("Genetic myopathies" OR "muscular dystrophy" OR "mitochondrial myopathies" OR "congenital myopathies" OR "metabolic myopathies" OR "limb-girdle muscular dystrophy" OR "Duchenne muscular dystrophy" OR "Becker muscular dystrophy") AND ("Gastrointestinal manifestations" OR "dysphagia" OR "gastroparesis" OR "intestinal pseudo-obstruction" OR "malabsorption" OR "constipation" OR "gastroesophageal reflux disease" OR "abdominal pain" OR "bowel dysfunction"). The search was limited to studies published in peer-reviewed journals. The study design was not restricted, allowing the inclusion of primary research studies, review articles, case reports, and clinical guidelines.

Inclusion and exclusion criteria

Studies were included if they met the following criteria: (1) Focused on GI manifestations in genetic myopathies; (2) Provided original research findings, review articles, case reports, or clinical guidelines; (3) Published in peer-reviewed journals or reputable scientific sources; and (4) Available in full-text and written in English.

Studies were excluded if they met the following criteria: (1) Irrelevant to genetic myopathies or GI manifestations; (2) Duplicate publications from the same dataset without additional findings; (3) Conference abstracts without full-text availability; and (4) Non-peer-reviewed sources, including preprints, editorials, and letters.

Study selection

Screening and selection were performed in two phases: (1) Title and abstract screening: Two independent reviewers (Reviewer 1 and Reviewer 2) screened all retrieved articles based on the eligibility criteria; and (2) Full-text review: Articles that met the initial screening criteria were retrieved and reviewed in full text by the same two reviewers.

Discrepancies in study selection were resolved through discussion or, if necessary, consultation with a third reviewer. A PRISMA flow diagram (Figure 1) illustrates the study selection process.

Figure 1 The flow chart of the included studies.

Statistical analysis

Two independent reviewers performed data extraction using a standardized form. Extracted data included study characteristics (design, sample size, country of origin), patient demographics (age, sex, genetic diagnosis), GI symptoms and complications, diagnostic approaches and imaging modalities used, management strategies and interventions, and patient perspectives and quality-of-life impact.

To assess the methodological quality and risk of bias, we applied validated tools based on study design. Newcastle-Ottawa Scale was used for observational studies. A MeaSurement Tool to Assess Systematic Reviews was used for systematic reviews, while Joanna Briggs Institute’s checklist was used for case reports. Studies were graded for quality, and those with a high risk of bias were excluded from the final analysis. Discrepancies in study selection, data extraction, and quality assessment were resolved by consensus or consultation with a third reviewer.

A systematic narrative synthesis was used to analyze findings, identifying common themes, trends, and gaps in the literature. Results were categorized based on GI symptoms, disease subtypes, and diagnostic and management strategies. Areas of consensus and controversies were discussed, and future research priorities were highlighted. Limitations of the included studies, such as risk of bias, small sample sizes, and variability in study design, were also considered in the analysis. Since this study is based on previously published literature, ethical approval and patient consent were not required. However, ethical considerations included ensuring accuracy, transparency, and appropriate attribution of sources in reporting findings.

RESULTS

Figure 1 shows the study's flow chart. A total of 10 studies and 10 case reports met the inclusion criteria, describing GI manifestations in children with various types of genetic myopathies, including Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy (LGMD), myotonic dystrophy (DM) [type 1 (DM1) and DM type 2 ‎‎(DM2)], nemaline myopathy, and mitochondrial disorders such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and Kearns-Sayre syndrome. The included studies highlighted a multimodal diagnostic strategy for assessing GI dysfunction in genetic myopathies, incorporating clinical evaluation, imaging studies, physiological tests, histopathology, and genetic testing. Symptoms such as dysphagia, reflux, constipation, and pseudo-obstruction were commonly assessed via patient-reported outcomes and physical examination findings. Table 1 summarizes studies on GI manifestations in genetic myopathies[15-24]. The included studies primarily focused on DMD and other neuromuscular disorders, with a particular emphasis on dysphagia, motility disorders, and metabolic complications. Jaffe et al[15] demonstrated that DMD patients had higher rates of dysphagia, choking, and heartburn compared to controls, emphasizing the impact of oropharyngeal muscle weakness. Hilbert et al[16] found that 55% of DM1 patients had swallowing difficulties, while 53% of DM2 patients reported severe constipation. In addition, Tieleman et al[17] reported significant dysphagia, abdominal pain, and constipation in DM2 patients, suggesting GI involvement similar to DM1.

Table 1 Summary of studies on gastrointestinal disorders in genetic myopathies.

Ref.	Study title	Population	GI manifestations	Methods	Key findings
Jaffe et al[15], 1990	Symptoms of upper gastrointestinal dysfunction in Duchenne muscular dystrophy: Case-control study	55 DMD patients, 55 controls	Dysphagia, choking, heartburn, vomiting	Case-control study, questionnaire-based assessment	DMD patients had significantly more GI symptoms than controls, especially oropharyngeal dysfunction
Lo Cascio et al[18], 2016	Gastrointestinal Dysfunction in Patients with Duchenne Muscular Dystrophy	33 DMD patients (12-41 years)	Constipation, delayed gastric emptying, prolonged oro-cecal transit time	Questionnaires, gastric emptying time, colonic transit studies	DMD patients had prolonged gastric emptying and colonic transit times, indicating severe GI dysmotility
Lee et al[23], 2020	Relationship between Eating and Digestive Symptoms and Respiratory Function in Advanced Duchenne Muscular Dystrophy Patients	180 advanced DMD patients	Constipation, swallowing difficulty, aspiration	Questionnaires, respiratory function tests	GI symptoms correlated with respiratory function, not age, indicating progressive neuromuscular decline
Borrelli et al[24], 2005	Evolution of gastric electrical features and gastric emptying in children with Duchenne and Becker muscular dystrophy	20 children with DMD/BMD	Delayed gastric emptying, dysrhythmias	Electrogastrography, ultrasonography	DMD patients showed worsening gastric motility over time, BMD patients had milder symptoms
Kansu et al[21], 2023	The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study	589 children with elevated transaminases	Liver dysfunction, metabolic abnormalities	CPK testing, genetic analysis	DMD/BMD diagnosed in 47% of male patients with isolated hypertransaminasemia
Tang et al[22], 2022	Hepatic Steatosis Assessment as a New Strategy for the Metabolic and Nutritional Management of Duchenne Muscular Dystrophy	48 DMD patients	Metabolic syndrome, hepatic steatosis	Liver ultrasound, metabolic assessment	Total 40% of DMD patients had significant hepatic steatosis, increasing with disease progression
Kraus et al[19], 2016	Constipation in Duchenne Muscular Dystrophy: Prevalence, Diagnosis, and Treatment	120 DMD patients (5-30 years)	Functional constipation	Questionnaire, Bristol stool form scale, abdominal radiographs	Total 46.7% had functional constipation, often underdiagnosed and undertreated
Nart et al[20], 2023	Life-threatening bowel complications in adults with Duchenne muscular dystrophy: a case series	Adults with DMD	Colonic pseudo-obstruction, sigmoid volvulus	Case series, clinical review	Emphasized surgical risks and role of home parenteral nutrition
Hilbert et al[16], 2017	High frequency of gastrointestinal manifestations in myotonic dystrophy type 1 and type 2	913 DM1 and 180 DM2 patients	Dysphagia, constipation, cholecystectomy	Patient-reported surveys, medical records	DM1 had higher rates of swallowing issues, while DM2 had more constipation
Tieleman et al[17], 2008	Gastrointestinal involvement is frequent in Myotonic Dystrophy type 2	29 DM2 patients, 29 DM1 patients, 87 controls	Dysphagia, abdominal pain, constipation	Questionnaires, colon transit study	GI dysfunction was as common in DM2 as in DM1, with slow colonic transit in 24%

BMD: Becker muscular dystrophy; DM: Myotonic dystrophy; DMD: Duchenne muscular dystrophy; GI: Gastrointestinal.

Other studies show significant GI dysmotility and constipation in patients with genetic myopathies. Lo Cascio et al[18] used objective motility tests to show delayed gastric emptying, prolonged oro-cecal transit, and slow colonic transit times in DMD patients, independent of symptom perception. In addition, Kraus et al[19] found that 46.7% of DMD patients had functional constipation, yet many remained undiagnosed and undertreated. Furthermore, Nart et al[20] described life-threatening colonic pseudo-obstruction and sigmoid volvulus in older DMD patients, highlighting the risks of advanced GI dysmotility. Metabolic and liver dysfunction are also common in genetic myopathies[20]. Kansu et al[21] showed that 47% of children with isolated hyper-transaminasemia had underlying DMD/BMD, reinforcing liver enzyme abnormalities as a potential early marker of muscle disease. In addition, Tang et al[22] reported 40% of DMD patients had hepatic steatosis, which worsened with disease progression and steroid use. These findings underscore the underrecognized role of GI dysfunction in genetic myopathies, emphasizing the need for early screening, dietary interventions, and multidisciplinary care.

Table 2 shows different case reports highlighting severe GI complications[25-34]. The case reports illustrated severe and often life-threatening GI manifestations, reinforcing the importance of early detection and intervention in patients with genetic myopathies. Acute gastric dilation and gastroparesis were observed in some patients with genetic myopathies. Dhaliwal et al[25] described a DMD patient with a gigantic stomach due to severe gastroparesis, managed conservatively. Barohn et al[26] documented gastric hypomotility and smooth muscle degeneration in a DMD patient with fatal acute gastric dilation.

Table 2 Summary of case reports on gastrointestinal disorders in genetic myopathies.

Ref.	Title of case report	Condition	Gastrointestinal manifestations	Management	Outcome
Dhaliwal et al[23], 2019	Gigantic Stomach: A Rare Manifestation of Duchenne Muscular Dystrophy	DMD	Severe gastric dilation, gastroparesis	Conservative management	Resolved without surgery
Barohn et al[24], 1988	Gastric Hypomotility in Duchenne’s Muscular Dystrophy	DMD	Acute gastric dilation, intestinal pseudo-obstruction	Autopsy study, gastric emptying tests	Found smooth muscle degeneration
Xie et al[34], 2020	Transaminitis in a Three-year-old Boy with Duchenne Muscular Dystrophy	DMD	Elevated liver enzymes, metabolic dysfunction	Enzyme tests, genetic sequencing	Diagnosed early, no liver damage found
Walsh et al[25], 2011	Progressive dysphagia in limb-girdle muscular dystrophy type 2B	Limb-girdle muscular dystrophy 2B	Progressive dysphagia for solids and liquids	Videofluoroscopy, genetic analysis	Confirmed Dysferlin mutations as the cause
Yoo et al[26], 2022	Clinical Course of Dysphagia in Patients with Nemaline Myopathy	Nemaline myopathy	Swallowing difficulties, aspiration risk	Tube feeding, dysphagia therapy	Improved swallowing over time
Glaser et al[27], 2015	Myotonic dystrophy as a cause of colonic pseudoobstruction: not just another constipated child	Myotonic dystrophy	Chronic intestinal pseudo-obstruction	Colectomy	Successful surgical outcome
Bayoumy et al[28], 2022	Sigmoid Volvulus in Myotonic Dystrophy Type I (Steinert Disease)	DM1 (Steinert disease)	Sigmoid volvulus	Endoscopic decompression	Resolved with conservative management
Dindyal et al[30], 2014	MELAS syndrome presenting as an acute surgical abdomen	MELAS syndrome	Toxic megacolon	Total colectomy	Diagnosis confirmed postoperatively
Sartoretti et al[29], 1996	Intestinal non-rotation and pseudoobstruction in myotonic dystrophy: case report and review of the literature	DM	Acute abdomen, ileus, aspiration pneumonia	Conservative therapy	Avoided surgery, symptoms controlled
Shaker et al[31], 1992	Manometric characteristics of cervical dysphagia in a patient with the Kearns-Sayre syndrome	Kearns-Sayre syndrome	Dysphagia, upper esophageal sphincter dysfunction	Manometry	Confirmed pharyngeal and esophageal dysmotility

DM: Myotonic dystrophy; DMD: Duchenne muscular dystrophy; MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

Walsh et al[27] and Yoo et al[28] described cases with severe dysphagia and aspiration risk. Walsh et al[27] identified progressive dysphagia for solids and liquids in LGMD2B, confirmed via videofluoroscopy and genetic testing. Meanwhile, Yoo et al[28] reported swallowing difficulties and aspiration risks in nemaline myopathy, demonstrating the potential for improvement with dysphagia rehabilitation. On the other hand, Glaser et al[29], Bayoumy et al[30], and Sartoretti et al[31] described patients with different types of genetic myopathies who developed intestinal pseudo-obstruction and surgical emergencies. Glaser et al[29] presented a case of chronic intestinal pseudo-obstruction in DM, requiring colectomy for symptom relief. Bayoumy et al[30] described a 32-year-old woman with MD1 who developed sigmoid volvulus, successfully treated with endoscopic decompression. Sartoretti et al[31] reported a case of intestinal non-rotation and acute pseudo-obstruction in DM, which was managed conservatively, avoiding unnecessary surgery. Mitochondrial disorders and GI dysfunction were also observed in some patients with genetic myopathies. Dindyal et al[32] described MELAS syndrome presenting as toxic megacolon, necessitating emergency colectomy. Shaker et al[33] used manometric studies to confirm pharyngeal and esophageal dysmotility in a patient with Kearns-Sayre syndrome. These case reports highlight the unpredictable and often severe nature of GI complications in myopathies, reinforcing the need for close monitoring, early intervention, and tailored management strategies.

Previous studies and case reports suggest that GI symptoms may precede neuromuscular diagnoses, particularly in disorders affecting smooth muscle function. Dysphagia and motility disorders are prevalent across all genetic myopathies, with a high burden in DMD, DM (DM1 and DM2), and nemaline myopathy. Constipation and severe dysmotility syndromes are common but often underdiagnosed and undertreated. Metabolic and hepatic complications are increasingly recognized in muscular dystrophies, requiring further research into their pathophysiology. Severe GI complications, such as acute gastric dilation, pseudo-obstruction, and volvulus, can be life-threatening and necessitate prompt intervention. The diagnostic evaluation involved clinical assessment, imaging studies [X-rays, ultrasound, computed tomography (CT)/magnetic resonance imaging (MRI)], physiological tests (manometry, pH monitoring, gastric emptying studies, anorectal manometry), histological analysis (endoscopic biopsy, muscle biopsy), and genetic testing [next-generation sequencing (NGS) panels].

Managing GI manifestations in genetic myopathies requires an individualized, multidisciplinary approach. Nutritional interventions such as tube feeding and dietary modifications were commonly recommended for dysphagia and malnutrition. Swallowing therapy and speech-language interventions improved feeding ability in patients with oropharyngeal dysphagia. Pharmacological treatments, including prokinetic agents, laxatives, and proton pump inhibitors (PPIs), were widely used to address delayed gastric emptying, constipation, and reflux, respectively. Severe cases required gastrostomy tube placement, colectomy, or endoscopic decompression for pseudo-obstruction and volvulus.

GI symptoms significantly affect quality of life, social interactions, and emotional well-being. Dysphagia and motility disorders contributed to nutritional deficiencies, requiring enteral feeding in advanced cases. Chronic constipation and pseudo-obstruction led to recurrent hospitalizations, reducing independence in daily activities. Many patients reported anxiety, embarrassment, and social withdrawal due to incontinence or feeding difficulties.

The findings highlight several critical gaps in understanding and managing GI dysfunction in genetic myopathies. Further research is needed to elucidate the role of smooth muscle dysfunction, autonomic nervous system involvement, and neuromuscular signaling in GI dysmotility. Identifying molecular or imaging biomarkers could improve early detection and monitoring. Investigating gene therapy, neuromodulation techniques, and pharmacological innovations may lead to better treatment outcomes. Establishing evidence-based recommendations for GI assessment and management protocols across different myopathy subtypes is necessary.

This review underscores the diverse and often severe nature of GI dysfunction in genetic myopathies, emphasizing the need for early screening, standardized diagnostic protocols, and a multidisciplinary management approach. Future research should focus on elucidating molecular mechanisms, identifying biomarkers, and developing targeted therapies to enhance patient outcomes and quality of life.

DISCUSSION

Types of genetic myopathies

Many types of genetic myopathies may involve the GI tract. Table 3 summarizes the main features of these myopathies. Muscular dystrophies involve various types of muscular dystrophies, such as DMD, BMD, and LGMD, which may exhibit GI manifestations[35]. DMD is the most common form of childhood muscular dystrophy, affecting approximately 1 in 3500 to 1 in 9300 male live births globally. This translates to a prevalence of 1-9 cases per 100000 individuals. DMD is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene located on the X chromosome[36]. The dystrophin gene is one of the largest in the human genome, making it susceptible to various mutations. Deletions and duplications within the gene are the most common mutations, accounting for around 70%-80% of DMD cases. Point mutations (changes in single nucleotides) occur in 20%-30% of cases[37]. While most cases are due to inherited mutations, around 33% of DMD diagnoses arise from new mutations (not inherited from parents) occurring in the sperm or egg cell. Germline mosaicism (where only some of the egg or sperm cells have the mutation) can also contribute to DMD, even if parents do not have the condition[38].

Table 3 Overview of each type of genetic myopathy, including prevalence rates, age, sex, genetic bases, key clinical features, diagnostic approaches, and management strategies.

Type of myopathy	Prevalence	Age of onset	Sex	Most affected races	Genetic basis	Key clinical features	Diagnostic approaches	Management strategies
DMD	1 in 3500 to 1 in 9300 male births globally	Early childhood	Males	All races, more common in certain populations such as Caucasian and African American	X-linked recessive genetic disorder caused by mutations in the dystrophin gene located on the X chromosome. Mutations include deletions, duplications, and point mutations	Muscle weakness, delayed motor milestones, dysphagia, GERD, delayed gastric emptying, constipation, pseudo-obstruction	Magnetic resonance imaging for smooth muscle atrophy, gastric emptying scintigraphy, genetic testing for dystrophin mutations	Swallowing therapy, proton pump inhibitors, dietary modifications, fundoplication for severe GERD
Becker muscular dystrophy	1–6 per 100000 individuals	Adolescence or early adulthood	Males	All races, more common in certain populations such as Caucasian and African American	Milder allelic form of DMD, also caused by mutations in the dystrophin gene, typically in-frame deletions, duplications, or small insertions, allowing some functional dystrophin protein to be produced	Similar to DMD but milder and later onset; dysphagia, GERD, delayed gastric emptying, fatty liver disease	Upper GI series, abdominal ultrasound for hepatomegaly, genetic testing	Nutritional support, laxatives for constipation, hepatoprotective agents
LGMD	1 in 14500–123000 globally	Varies (typically adolescence or adulthood)	Both sexes	All races	A heterogeneous group of disorders categorized into autosomal dominant (LGMD1) and autosomal recessive (LGMD2) forms involving mutations in various genes such as Lamin A/C, Calpain 3, and Dysferlin. Over 50 genetic loci were identified as potential contributors	Weakness in shoulder and pelvic girdle muscles, dysphagia, constipation, elevated liver enzymes	Esophageal manometry, liver ultrasound	Dietary fiber, biofeedback therapy for bowel dysfunction
Congenital myopathies	1.62 per 100000 globally (higher in children)	Present at birth or infancy	Both sexes have a higher prevalence in children	All races	A diverse group of disorders present at birth or infancy, caused by mutations in over 40 genes with various inheritance patterns, including ACTA1, RYR1, and Dynamin 2	Muscle hypotonia, delayed motor milestones, feeding difficulties, dysphagia, GERD, constipation, recurrent respiratory infections	Muscle biopsy, barium swallow, upper GI endoscopy	Feeding therapy, nutritional support, reflux management, respiratory care
Metabolic myopathies	1 in 5000 to 1 in 50000 individuals	Varies (childhood or adulthood)	Both sexes	All races	Caused by gene mutations affecting carbohydrate or fat metabolism within muscle cells, leading to disorders such as McArdle disease (PYGM gene) and Tarui disease (PFKM gene)	Exercise intolerance, muscle cramps, recurrent abdominal pain, nausea, diarrhea, fatty liver, hypoglycemia, hepatomegaly	Genetic panels, metabolic tests (e.g., carnitine palmitoyltransferase or very long-chain acyl-CoA dehydrogenase), gastric motility studies	Dietary adjustments, enzyme replacement (e.g., pancreatic enzymes), glucose infusions for hypoglycemia
Mitochondrial myopathies	1 in 5000 to 1 in 10000	Varies (childhood or adulthood)	Both sexes	All races	Result from mutations in genes involved in mitochondrial function and energy production, including MT-TL1 (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome), MT-TK (myoclonic epilepsy with ragged red fibers syndrome), and sea urchin retroposon family 1 (Leigh syndrome). Inheritance can be autosomal recessive or matrilineal (mitochondrial DNA mutations)	Dysphagia, diarrhea, gastroparesis, pancreatitis, pseudo-obstruction, hepatopathy, malabsorption	Muscle biopsy, genetic testing for mitochondrial DNA mutations, gastric motility studies	Prokinetic agents, pancreatic enzyme replacement, nutritional supplementation
Myotonic disorders	1 in 8000 to 1 in 20000 globally	Typically adulthood	Both sexes	All races	This includes DM Type 1 (DM1) and Type 2 (DM2), caused by expanded CTG repeats in the DMPK gene and CCTG repeats in the ZNFN213 gene, respectively. Autosomal dominant inheritance pattern	Dysphagia, GERD, constipation, paralytic ileus, diarrhea, megacolon, sigmoid volvulus, anal incontinence	Radiologic studies for motility, manometry, genetic testing for DMPK and ZNFN213 genes	Swallowing therapy, dietary modifications, management of motility disorders, surgical interventions for volvulus or megacolon

DM: Myotonic dystrophy; DMD: Duchenne muscular dystrophy; DMPK: Dystrophia myotonica protein kinase; GERD: Gastroesophageal reflux disease; GI: Gastrointestinal; LGMD: Limb-girdle muscular dystrophy.

BMD is a milder allelic form of DMD. It is less common than DMD, with a worldwide prevalence estimated at around 1-6 cases per 100000 individuals. This translates to 0.1-1.8 cases per 10000 male births. BMD shares the same genetic basis as DMD, with mutations occurring in the same dystrophin gene on the X chromosome. However, the type and severity of the mutations in the dystrophin gene differ between the two conditions[39]. In BMD, mutations are typically in-frame deletions, duplications, or small insertions. These mutations partially preserve the gene's reading frame, allowing some functional dystrophin protein to be produced. In contrast, DMD often results from out-of-frame mutations (deletions or duplications that disrupt the reading frame) or large deletions, leading to little or no functional dystrophin production[40]. BMD usually manifests later than DMD, typically in adolescence or early adulthood, compared to early childhood in DMD. BMD progresses slower and generally presents with milder symptoms compared to DMD. Individuals with BMD may experience progressive muscle weakness, fatigue, and difficulty with mobility, but the course and severity can vary considerably[41]. While muscle weakness can eventually impact different bodily functions, the life expectancy for individuals with BMD is generally longer compared to those with DMD. Similar to DMD, around 30% of BMD cases occur due to new mutations in the sperm or egg cell, and germline mosaicism can also contribute to the condition[42].

LGMD is a heterogeneous group of genetic muscle disorders characterized by progressive weakness primarily affecting the shoulder and pelvic girdle muscles. Determining the prevalence of LGMD is challenging due to its diverse forms and overlap with other muscle disorders. Estimates suggest a range of 1 in 14500 to 1 in 123000 individuals globally[43]. LGMD exhibits a complex genetic landscape, with multiple genes involved and different inheritance patterns. Broadly, LGMDs are categorized into two main types based on inheritance: (1) Autosomal dominant (LGMD1); and (2) Autosomal recessive (LGMD2)[44]. LGMD1 forms are less common, accounting for around 5%-10% of LGMD cases, and are caused by mutations in a single gene. Only one copy of the mutated gene from either parent is sufficient to cause the condition[45]. LGMD2 forms are more frequent, making up around 90% of LGMD cases. They require inheritance of two copies of the mutated gene, one from each parent. Over 50 genetic loci have been identified as potential contributors to various LGMD subtypes[46]. Each subtype can have its own specific gene and mutation responsible for the disease. Some frequently involved genes include Lamin A/C (LMNA), Calpain 3 (CAPN3), and Dysferlin (DYSF). CAPN3 is responsible for LGMD2A, the most common subtype. DYSF is associated with LGMD2B, another prevalent form, while LMNA is involved in LGMD1B, a dominant form[47]. The specific gene responsible for an individual's LGMD depends on the specific type and family history. New gene discoveries are ongoing, and further research is needed to fully understand the complete spectrum of genes and mutations contributing to LGMD[45].

Congenital myopathies are a diverse group of structural muscle disorders present at birth or infancy, with different types of varying presentations. Muscle fiber architectural abnormalities are the hallmark of congenital myopathies. According to predominant structural pathological muscle abnormalities, these myopathies are divided into five subgroups: (1) Core myopathies (the most common form of congenital myopathies); (2) Nemaline myopathies; (3) Centronuclear myopathies; (4) Congenital fiber type disproportion myopathy; and (5) Myosin storage myopathy[44]. Early symptoms can be subtle and overlap with other conditions[48]. They have a pooled prevalence of around 1.62 per 100000 individuals, with a higher prevalence in children (around 2.76 per 100000)[49]. Like other muscular dystrophies, their genetic basis is complex and heterogeneous, involving mutations in over 40 genes with various inheritance patterns. Broadly, the inheritance patterns can be categorized as autosomal dominant (20%), autosomal recessive (most common, around 60%-70% of cases), and X-linked (less frequent)[50]. These mutations disrupt proteins essential for muscle development and function, leading to various types of congenital myopathies with varying symptoms like weakness, stiffness, and respiratory problems. Common mutations observed in these types of myopathies include alpha-actine(ACTA1) gene mutations, which are responsible for the common type “nemaline myopathy “with characteristic muscle weakness and stiffness[51]. Another mutation is the RYR1 gene mutation, which causes “central core myopathy”, leading to muscle weakness and hypotonia. Dynamin 2 (DNM2) gene mutations are associated with “centronuclear myopathy”, characterized by muscle weakness, respiratory problems, and intellectual disability. While genetic testing can help identify the specific type and inheritance pattern, in many cases, new gene discoveries continue to be made. Not all cases have a currently known genetic cause[52].

Metabolic myopathies are a diverse group of genetic muscle disorders characterized by abnormalities in the metabolism of carbohydrates or fats within muscle cells. These disorders can lead to muscle weakness, cramping, pain, and fatigue during exercise or even at rest[53]. The prevalence of metabolic myopathies varies depending on the specific type, but they are generally considered rare conditions. Estimates suggest a prevalence ranging from 1 in 5000 to 1 in 50000 individuals, with a higher likelihood of being diagnosed in adults than children[54]. The genetic basis of metabolic myopathies is also diverse, with mutations in multiple genes responsible for different metabolic myopathy types. These mutations typically affect enzymes crucial for metabolizing carbohydrates or fats for energy production or protein transporters, which are responsible for transporting essential molecules across the cell membrane[55]. The specific inheritance pattern can vary depending on the involved gene and can be autosomal recessive, autosomal dominant, or X-linked. Fatty acid oxidation disorders (FAOD) and glycogen storage diseases (GSDs) are common examples of metabolic myopathies[56]. GSDs are a group of disorders characterized by glycogen accumulation (a form of stored glucose) in muscle cells. Several subtypes of GSDs, including GSD type V (McArdle disease) and GSD type VII (Tarui disease), are caused by mutations in the PYGM and PFKM genes, respectively[57]. FAODs result from defects in the enzymes responsible for breaking down fatty acids for energy production. Deficiencies in enzymes such as carnitine palmitoyltransferase (CPT) or very long-chain acyl-CoA dehydrogenase (VLCAD) can lead to FAODs[58].

Mitochondrial myopathies are a group of genetic disorders that primarily affect mitochondria, which are the energy-producing structures within cells. These disorders result from mutations in genes involved in mitochondrial function and energy production[59]. Mitochondrial myopathies can affect various organs and tissues, but they primarily impact skeletal muscles, leading to muscle weakness, exercise intolerance, and other symptoms. Estimating the exact prevalence of mitochondrial myopathies is challenging due to ‎the heterogeneity of the clinical presentations, the varying degrees of severity‎, and the difficult diagnosis due to symptoms overlapping with other ‎disorders, leading to underdiagnosis.‎ However, the prevalence of mitochondrial myopathies is expected to be around 1 in 5000 to 1 in 10000 individuals, making them relatively rare conditions[60]. However, the exact prevalence can vary depending on the specific subtype of mitochondrial myopathy and the population being studied. While the overall number might seem low, it's important to remember that ‎mitochondrial disorders are among the most common genetic diseases[61].‎ Mitochondrial myopathies have a diverse genetic basis. They can be caused by mutations in genes located in either the nuclear DNA or the mitochondrial DNA (mtDNA). Nuclear DNA mutations are inherited in an autosomal recessive or autosomal dominant manner, while mtDNA mutations are typically inherited from the mother and follow a matrilineal pattern. The maternal inheritance has varying degrees of penetrance, expression of the disease, and clinical severity within families[62].

Several subtypes of mitochondrial myopathies are associated with specific gene mutations. Some of the commonly known forms include MELAS syndrome, myoclonic epilepsy with ragged red fibers (MERRF) syndrome, and Leigh syndrome. MELAS syndrome is often caused by a mutation in the MT-TL1 gene, which produces a transfer RNA molecule involved in protein synthesis within mitochondria[60]. MERRF syndrome is typically caused by mutations in the MT-TK gene, leading to impaired mitochondrial protein synthesis[63]. Leigh syndrome can have multiple genetic causes, with mutations occurring in genes involved in mitochondrial energy production, such as the sea urchin retroposon family 1, NADH dehydrogenase Fe-S protein 1, and adenosine triphosphate (ATP) 6 genes[64]. In addition to these specific subtypes, there are many other less common forms of mitochondrial myopathies, each with its own genetic basis. Diagnosis of mitochondrial myopathies involves a combination of clinical evaluation, biochemical testing, muscle biopsies, and genetic testing. Genetic testing can help identify specific mutations and confirm the diagnosis[65].

Myotonic disorders (myotonic dystrophies) are a group of inherited neuromuscular diseases characterized ‎by muscle stiffness, weakness, and wasting. Unlike most muscular dystrophies, which ‎primarily cause muscle wasting and weakness, myotonic disorders often manifest ‎with muscle stiffness and impaired relaxation after contraction (myotonia)[66].‎ Estimating the true prevalence of myotonic disorders is challenging due to ‎the heterogeneity of presentations and severity and frequent mis/or underdiagnosis. ‎However, estimates suggest a combined prevalence of ‎1 in 8000 to 1 in 20000 ‎individuals ‎globally, with specific types having variable frequencies[67]. DM1 is considered the most common form, with a prevalence of around 1 in 8000 ‎individuals worldwide. It is caused by an expanded CTG repeat mutation in the ‎ dystrophia myotonica protein kinase (DMPK) gene on chromosome 19. This repeat expands in length across generations, leading to progressive ‎worsening of symptoms. The number of CTG repeats is directly associated with the disorder's severity and age of onset[68]. DM2 is less common than ‎DM1, with the exact prevalence unknown, and could be around 1 in 30000 to 1 in 100000 individuals, ‎but potentially could be as frequent as DM1 in specific ‎populations like Finland and Germany. It is caused by an expansion of CCTG repeats ‎in the ZNFN213 gene on chromosome 3. Similar to DM1, the number of CCTG repeats correlates with the severity and age of onset[69]. DM2 also follows an autosomal dominant inheritance pattern. This mutation also tends to expand with each generation. Both ‎DM1 and DM2 follow an autosomal dominant inheritance pattern. This means that ‎inheriting only one copy of the mutated gene from a parent is sufficient to cause the ‎disorder[70]. However, the severity of symptoms can vary significantly due to factors like ‎the length of the repeat expansion and other genetic modifiers.‎ The complex interplay of repeat expansions, other genetic factors, and ‎environmental triggers contribute to the diverse clinical presentations and ‎disease progression[71].‎ Diagnosis of myotonic disorders involves a combination of clinical evaluation, family history assessment, electromyography to detect myotonia, and genetic testing to confirm the presence of the specific genetic mutation[72]. Management of myotonic disorders is primarily focused on symptom relief and optimizing quality of life. Treatment may involve physical therapy to manage muscle weakness and stiffness, medication to address symptoms such as myotonia and cardiac abnormalities, and regular monitoring of potential complications in organs such as the heart and respiratory system[73].

Molecular changes in genetic myopathies

DMD is primarily caused by mutations in the dystrophin gene, leading to the dystrophin protein's absence or dysfunction. However, the pathophysiology of DMD involves a complex interplay of molecular events beyond dystrophin deficiency. The absence or deficiency of the dystrophin protein, a critical component of the dystrophin-glycoprotein complex responsible for maintaining muscle membrane integrity, is the hallmark molecular abnormality in DMD[74]. Dystrophin deficiency compromises the stability of muscle fibers, making them susceptible to damage and degeneration. Transcriptomic studies have revealed widespread dysregulation of gene expression in DMD muscle tissue[75]. The upregulation of genes associated with inflammation, fibrosis, and muscle regeneration coexists with the downregulation of genes involved in muscle structure and function. This dysregulated gene expression contributes to the progressive loss of muscle mass and function in DMD[76]. Apart from dystrophin, DMD is associated with abnormal expression and localization of various proteins involved in muscle physiology. Disruptions in the expression and function of sarcolemmal proteins, cytoskeletal components, and signaling molecules contribute to muscle fiber fragility and impaired contractile function[77]. Dysregulation of signaling pathways plays a pivotal role in DMD pathogenesis. Aberrant activation of pathways such as nuclear factor-kappa B (NF-κB), transforming growth factor-beta (TGF-β), and Wnt/β-catenin signaling exacerbates DMD-associated inflammation, fibrosis, and degeneration. Conversely, impaired signaling cascades involved in muscle regeneration and repair further compromise muscle function[78]. Molecular changes in DMD have profound downstream effects on cellular processes such as inflammation, fibrosis, oxidative stress, and mitochondrial dysfunction. Chronic inflammation and fibrosis exacerbate muscle damage, while oxidative stress and mitochondrial dysfunction contribute to energy imbalance and impaired muscle function[79].

BMD is characterized by distinct molecular changes contributing to disease pathogenesis and progression. BMD arises from mutations in the dystrophin gene, producing truncated or partially functional dystrophin protein. Unlike DMD, where mutations lead to the absence of dystrophin, BMD mutations allow for some dystrophin production[77]. The severity of BMD is influenced by the extent of dystrophin deficiency and the specific mutation involved. Mutations in the dystrophin gene lead to aberrant expression and function of the dystrophin protein[80]. While dystrophin is produced in BMD, it is often reduced in quantity and compromised in function. This partial dystrophin expression contributes to muscle fiber instability and degeneration, albeit to a lesser extent than in DMD[41]. Transcriptomic analyses have revealed dysregulated gene expression patterns in BMD muscle tissue. The altered gene expression in muscle structure, metabolism, and signaling pathways contributes to disease pathogenesis. However, gene expression changes in BMD are typically less pronounced than those observed in DMD, reflecting the milder clinical phenotype[76]. Dysregulation of protein-protein interactions and signaling pathways is crucial in BMD pathogenesis. Abnormalities in the dystrophin-associated protein complex disrupt sarcolemmal integrity and intracellular signaling, contributing to muscle weakness and degeneration. Dysregulated signaling pathways such as NF-κB and TGF-β exacerbate inflammation, fibrosis, and muscle wasting in BMD[81]. Molecular changes in BMD have downstream effects on cellular processes such as inflammation, fibrosis, oxidative stress, and muscle regeneration. These processes contribute to disease progression, albeit at a slower rate compared to DMD. Additionally, compensatory mechanisms and enhanced muscle regeneration may partially mitigate the deleterious effects of molecular changes in BMD[82].

LGMD is a condition that causes disruptions in the normal functioning of muscle cells. These disruptions are usually caused by mutations in genes crucial for muscle structure, repair, and contraction[43]. These mutations can affect genes that encode important proteins like dystrophin, sarcoglycans, DYSF, calpain, or laminin, leading to compromised muscle fiber stability, impaired muscle membrane integrity, and abnormal calcium homeostasis[83]. LGMD2A is caused by mutations in the CAPN3 gene, impacting a crucial protein in maintaining muscle structure. LGMD2B, on the other hand, is caused by mutations in the DYSF gene, which affects a protein involved in membrane repair and signaling pathways in muscle cells[84]. Finally, LGMD1B results from mutations in LMNA genes, which affect muscle cell gene expression and function by affecting proteins essential for maintaining the nuclear envelope. These disruptions increase the likelihood of muscle damage, impaired muscle regeneration, and, ultimately, progressive muscle wasting and weakness[85]. Inflammatory processes and oxidative stress also contribute to developing LGMD, worsening muscle damage. The specific molecular mechanisms that cause the different subtypes of LGMD can vary, reflecting the diverse genetic causes and underlying pathways involved[86]. Understanding these molecular changes is crucial for developing targeted therapies and interventions to halt or slow the progression of LGMD.

Congenital myopathies arise from mutations affecting genes encoding proteins crucial for skeletal muscle structure, function, and regulation. Mutations in genes such as ACTA1, RYR1, MTM1, and selenoprotein N have been implicated in various forms of congenital myopathies, including nemaline myopathy, central core disease, myotubular myopathy, and congenital fiber-type disproportion[87]. Molecular studies have revealed diverse mechanisms contributing to muscle dysfunction, including disruption of sarcomere organization, impaired calcium handling, defective protein synthesis, and altered oxidative metabolism[88]. Dysregulation of signaling pathways involved in muscle development, such as the RhoA-ROCK pathway, has also been implicated in the pathogenesis of congenital myopathies[2]. Furthermore, advances in NGS technologies have facilitated the identification of novel disease-associated genes and variants, expanding our understanding of the genetic landscape of congenital myopathies[89].

Metabolic myopathies typically result from mutations affecting genes encoding enzymes critical for energy production, including those involved in glycolysis, glycogen metabolism, and fatty acid oxidation[86]. For example, enzyme deficiencies such as CPT and VLCAD lead to FAODs. In contrast, enzyme defects like glycogen phosphorylase or branching enzymes cause GSDs[90]. Molecular studies have uncovered various pathogenic mechanisms contributing to muscle dysfunction in metabolic myopathies, including impaired energy production, mitochondrial dysfunction, oxidative stress, and altered cellular signaling[91]. Disrupted metabolic pathways result in an inadequate supply of ATP, leading to muscle weakness, cramping, pain, and fatigue during exercise or even at rest. Additionally, aberrant lipid accumulation, mitochondrial abnormalities, and altered redox homeostasis contribute to muscle damage and inflammation[92].

Mitochondrial myopathies arise from mutations affecting genes encoding proteins involved in mitochondrial function, including those required for oxidative phosphorylation, mitochondrial protein synthesis, and mtDNA maintenance[61]. Molecular studies have revealed diverse mechanisms contributing to muscle dysfunction in mitochondrial myopathies, including impaired ATP production, mitochondrial respiratory chain dysfunction, oxidative stress, and mtDNA mutations[93]. These molecular changes lead to energy depletion, mitochondrial dysfunction, and cellular damage, particularly in tissues with high energy demands, such as skeletal muscle. Additionally, mitochondrial dysfunction triggers secondary processes such as inflammation, apoptosis, and oxidative damage, exacerbating muscle pathology[94].

Myotonic disorders, including DM1 and DM2, are caused by expanded repeat sequences in specific genes, leading to toxic RNA gain-of-function effects. In DM1, an expanded CTG repeat in the DMPK gene on chromosome 19 leads to the accumulation of mutant DMPK mRNA containing CUG repeats[95]. This expanded RNA forms toxic RNA foci, sequestering RNA-binding proteins such as muscleblind-like 1 and disrupting their normal cellular functions. The expanded CUG repeats are also processed into toxic microRNA-like molecules, further contributing to RNA toxicity[96]. In DM2, an expanded CCTG repeat in the cellular nucleic acid protein (CNBP) gene on chromosome 3 leads to the accumulation of mutant CNBP mRNA containing CCUG repeats. Like DM1, the expanded CCUG repeats form toxic RNA aggregates that sequester muscle blind-like proteins, impairing their splicing regulation functions[97]. Furthermore, dysregulation of alternative splicing and gene expression contributes to disease pathogenesis in myotonic disorders[98]. Molecular studies have also identified downstream cellular pathways affected by RNA toxicity, including dysregulation of ion channels, muscle development, and metabolism. Additionally, impaired insulin signaling and mitochondrial dysfunction have been implicated in the metabolic abnormalities observed in myotonic disorders[99].

Similarities and dissimilarities between skeletal and GI smooth muscles

The structure and bio-physiology of GI smooth muscles are finely tuned to orchestrate digestion, absorption, and waste elimination processes within the GI tract. These muscles are vital in maintaining GI function and overall digestive health[100]. Structurally, GI smooth muscles consist of spindle-shaped cells with a single nucleus, organized into two main layers: (1) The inner circular layer; and (2) The outer longitudinal layer. These layers work in tandem to facilitate peristalsis and other digestive processes. Additionally, specialized cells known as Interstitial Cells of Cajal serve as pacemakers, coordinating rhythmic contractions throughout the GI tract[101]. Various stimuli, including neural, hormonal, and mechanical signals, initiate smooth muscle contraction in the GI tract. Intracellular calcium concentration is crucial in triggering muscle contraction by activating the interaction between actin and myosin filaments[102]. The enteric nervous system, embedded within the GI tract wall, regulates smooth muscle activity, coordinating peristalsis, secretion, and blood flow. Neurotransmitters such as acetylcholine, serotonin, nitric oxide, and hormones like gastrin and motilin modulate smooth muscle contraction and relaxation, fine-tuning GI function[103]. Pacemaker activity generated by Cells of Cajal produces slow electrical waves propagating through GI smooth muscles, orchestrating rhythmic contractions. These slow waves are subject to modulation by neural and hormonal inputs, regulating the frequency and strength of contractions. GI smooth muscles demonstrate plasticity and adaptability, adjusting their contractile activity in response to changes in luminal contents and functional demands[104]. Functionally, GI smooth muscles perform crucial roles in digestion, absorption, and waste elimination. Peristalsis, coordinated contractions of smooth muscles, propels luminal contents forward through the digestive tract, facilitating digestion and absorption[105]. Alternating contractions and relaxations of smooth muscles facilitate the mixing of luminal contents with digestive enzymes, aiding in nutrient absorption. Additionally, smooth muscles regulate sphincter control, controlling the flow of luminal contents between different digestive compartments. Basal tone in GI smooth muscles helps maintain luminal patency and prevent reflux of contents between digestive compartments[106].

Skeletal and GI smooth muscles share similarities and differences, as shown in Table 4. Both types of muscles are excitable tissues. They can respond to stimuli and generate electrical signals (action potentials) that trigger contraction. Both types of muscles contain actin and myosin filaments, the primary contractile proteins responsible for muscle contraction. Both have sarcoplasmic reticulum, a specialized network that stores calcium ions (Ca²⁺), essential for initiating muscle contraction[107]. Both types of muscles contract through the sliding filament mechanism, where actin and myosin filaments slide past each other to generate force and produce muscle contraction. Skeletal and smooth muscles rely on calcium ions for muscle contraction. Increasing intracellular calcium concentration triggers muscle contraction by activating the interaction between actin and myosin filaments[108]. While the nervous system plays a significant role in regulating skeletal muscle contraction through motor neurons, GI smooth muscles also receive innervation from the autonomic nervous system, particularly the enteric nervous system, which modulates muscle activity and peristalsis[103]. Hormonal signals can influence both skeletal and GI smooth muscles. Hormones such as adrenaline and noradrenaline can affect the contractility of skeletal muscles, while GI hormones like gastrin and motilin regulate the activity of smooth muscles in the digestive tract[109].

Table 4 Skeletal vs gastrointestinal smooth muscle: Similarities and dissimilarities.

Feature	Skeletal muscle	Gastrointestinal smooth muscle
Excitable tissue	Yes	Yes
Contractile proteins	Actin and myosin	Actin and myosin
Sarcoplasmic reticulum	Yes	Yes
Contraction mechanism	Sliding filament	Sliding filament
Calcium dependence	Yes	Yes
Control	Voluntary	Involuntary
Innervation	Motor neurons	Autonomic nervous system
Hormonal regulation	Yes	Yes
Attachment to bone	Yes	No
Fiber nuclei	Multinucleated	Uninucleated
Fiber arrangement	Bundles of striated (striped) fibers	Sheets or layers of non-striated fibers
Contraction speed	Fast and powerful	Slow and sustained
Contraction pattern	Brief bursts	Tonic (sustained)
Dominant respiration	Anaerobic	Aerobic
Regeneration	Limited	Better capacity
Fatigue resistance	Susceptible	Highly resistant
Main control system	Central nervous system	Enteric nervous system

On the other hand, there are many differences between the two types of muscles. For example, the skeletal muscles are under voluntary control and attached to bones, which can be consciously controlled to move. In contrast, GI smooth muscles are under involuntary control, and their contractions are not consciously regulated[110]. Meanwhile, skeletal muscles comprise multinucleated muscle fibers organized into distinct bundles, whereas GI smooth muscles consist of spindle-shaped cells with a single nucleus arranged in sheets or layers. Skeletal muscles typically contract rapidly and with greater force, enabling quick movements such as running or jumping[111]. GI smooth muscles contract more slowly, sustainably, and rhythmically, facilitating processes like peristalsis and mixing of digestive contents. Skeletal muscle relies primarily on anaerobic respiration for short bursts of activity, while smooth muscle primarily uses aerobic respiration for sustained contractions[105]. Skeletal muscle has limited regeneration abilities, while smooth muscle has a better capacity for self-repair. In addition, skeletal muscles exhibit varying degrees of fatigue during sustained activity due to the accumulation of metabolic by-products[112]. In contrast, GI smooth muscles are highly resistant to fatigue and can sustain prolonged contractions without significant energy depletion. Lastly, skeletal muscle contraction is primarily controlled by neural signals from the central nervous system, allowing for precise and coordinated movements[113]. GI smooth muscles can exhibit spontaneous contractions independent of neural input, driven by pacemaker cells and local neurotransmitters within the enteric nervous system[114].

General mechanisms of GI manifestations in genetic myopathies

The GI tract plays a crucial role in digestion, nutrient absorption, and waste elimination, which are regulated by neurogenic and myogenic factors. Proper gut motility, driven by coordinated contractions of smooth muscle cells lining the GI tract, is essential for the consumption and digestion of food, absorption of water and nutrients, and excretion of waste products[115]. Disruption of the autonomic or enteric nervous system, responsible for inducing smooth muscle contractions or dysfunction in the contractile network of smooth muscle cells, can significantly impact GI tract function. Consequences of such dysfunction include aspiration of food bolus into the lungs, retention of digesting material in the gut lumen, dehydration, fecal incontinence, and other complications[11]. Severe impairment disrupts daily activities and affects mental and emotional well-being. Maintaining the integrity of the neurogenic and myogenic regulatory systems governing GI tract motility is crucial for overall GI health and quality of life[116].

Genetic myopathies can present with various GI manifestations, impacting digestion, absorption, and waste elimination. The mechanisms underlying GI manifestations in genetic myopathies can be multifactorial and involve both structural and functional abnormalities of smooth muscles within the GI tract (Table 5). Smooth muscles play a crucial role in regulating the movement and function of the digestive system, including peristalsis, sphincter control, and mixing of food contents[83]. In genetic myopathies, mutations affecting the structure or function of smooth muscle cells can lead to abnormalities in GI motility and function. One key mechanism is the impairment of contractility in smooth muscle cells[117]. Genetic mutations may disrupt smooth muscles' normal contractile machinery, leading to muscle tone, coordination, and relaxation abnormalities. This can result in dysphagia (difficulty swallowing), GERD, gastroparesis, bloating, abdominal pain, constipation, diarrhea, and intestinal pseudo-obstruction, which are common GI manifestations observed in genetic myopathies[118]. Another mechanism is the involvement of skeletal muscle abnormalities in the muscles responsible for the voluntary control of the GI tract, such as the muscles of the pelvic floor and the external anal sphincter. Dysfunction in these muscles can lead to fecal incontinence and difficulty with bowel movements[119]. Impaired abdominal wall movement due to weak abdominal muscles can hinder the effectiveness of pushing stool during defecation. Weak muscles of mastication cause difficulty chewing and swallowing, leading to inadequate food intake and potential malnutrition[120].

Table 5 Mechanism of gastrointestinal manifestations in genetic myopathies.

Mechanism	Description
Smooth muscle dysfunction	Genetic mutations affecting smooth muscle cells can lead to contraction, coordination, and relaxation abnormalities, resulting in dysphagia, gastroesophageal reflux disease, gastroparesis, bloating, abdominal pain, constipation, diarrhea, and intestinal pseudo-obstruction
Skeletal muscle abnormalities	Dysfunction in skeletal muscles involved in voluntary control of the GI tract, such as pelvic floor muscles and the external anal sphincter, can cause fecal incontinence and difficulty with bowel movements. Weak abdominal muscles can hinder effective stool pushing during defecation. Weak masticatory muscles can lead to difficulty chewing and swallowing
Smooth muscle innervation and neuromuscular transmission	Genetic mutations can affect smooth muscle innervation and disrupt neuromuscular transmission in the enteric nervous system, leading to dysregulation of smooth muscle activity and symptoms such as diarrhea or constipation
Abnormal regulatory pathways	Disruption of neurotransmitters, hormones, and signaling pathways that regulate smooth muscle cells in the GI tract can result in abnormal smooth muscle contraction and relaxation patterns, contributing to GI symptoms
Systemic manifestations	Genetic myopathies can be associated with systemic abnormalities, such as metabolic disturbances and endocrine dysfunction, which indirectly impact the GI tract and contribute to GI symptoms, including impaired gut motility and nutrient absorption
Malabsorption	Chronic GI problems in genetic myopathies can lead to malabsorption of essential nutrients, resulting in deficiencies of vitamins, minerals, and electrolytes, which further impact overall health and exacerbate symptoms

GI: Gastrointestinal.

Additionally, abnormalities in smooth muscle innervation and neuromuscular transmission can contribute to GI dysfunction in genetic myopathies. The enteric nervous system, which controls GI motility and secretion, may be affected by genetic mutations, leading to dysregulation of smooth muscle activity, and causing symptoms like diarrhea or constipation[121]. Furthermore, various neurotransmitters, hormones, and signaling pathways regulate smooth muscle cells in the GI tract. Disruption of these regulatory mechanisms due to genetic mutations can result in aberrant smooth muscle contraction and relaxation patterns, further contributing to GI symptoms[122]. Furthermore, certain genetic myopathies are associated with systemic manifestations, including metabolic abnormalities and endocrine dysfunction. These systemic abnormalities can indirectly impact the GI tract and contribute to GI symptoms[123]. For example, disturbances in energy metabolism or hormonal imbalances can affect gut motility and nutrient absorption[124]. Chronic GI problems in genetic myopathies can lead to malabsorption of essential nutrients due to impaired digestion and absorption. This can result in deficiencies of vitamins, minerals, and electrolytes, further impacting overall health and exacerbating some symptoms[125]. It is important to note that the specific mechanisms of GI involvement can vary depending on the type and subtype of genetic myopathy. Different genetic mutations can lead to distinct pathophysiological processes, resulting in varying GI manifestations[117]. The mechanism of GI manifestations in genetic myopathies involves complex interactions between genetic factors, smooth muscle dysfunction, neuromuscular abnormalities, and dysregulation of regulatory pathways within the GI tract[126]. Understanding these mechanisms is crucial for developing targeted therapies aimed at improving GI function and quality of life in individuals with genetic myopathies.

Genetic and environmental modifiers of GI symptoms in genetic myopathies

GI symptoms in genetic myopathies exhibit significant variability among patients, even individuals with the same genetic mutation. This variability suggests that additional genetic modifiers, environmental factors, and lifestyle influences play a critical role in shaping the severity and presentation of GI manifestations. Understanding these modifiers is essential for developing personalized treatment strategies and improving patient outcomes (Table 6)[127].

Table 6 Genetic and environmental modifiers of gastrointestinal symptoms in genetic myopathies.

Modifier type	Key influences	Impact on GI symptoms	Clinical implications
Genetic modifiers	Modifier genes (e.g., laminin alpha 2-chain gene, Lamin A/C, Calpain 3, Dysferlin)	Alters smooth muscle integrity and neuromuscular transmission in the gut	Genetic screening may help predict GI severity and guide therapy
	MtDNA mutations (mtDNA heteroplasmy)	Variable energy deficits affecting intestinal motility and absorption	Mitochondrial-targeted therapies and dietary modifications
	Epigenetic changes (DNA methylation, histone modifications)	May regulate neuromuscular gene expression, impacting gut function	Potential target for gene modulation therapy
Gut microbiota	Dysbiosis (loss of beneficial bacteria, increase in pathogenic bacteria)	Worsens constipation, diarrhea, bloating, and inflammation	Probiotics, microbiome-targeted interventions (e.g., fecal microbiota transplantation)
Nutritional status	Protein intake, fiber intake, vitamin deficiencies (e.g., B12, D, Mg)	Deficiencies impair gut motility and neuromuscular coordination	Tailored dietary interventions, vitamin supplementation
Mobility status	Reduced physical activity due to progressive muscle weakness	Slows intestinal transit, leading to severe constipation and GERD	Early physiotherapy and bowel training programs
Medications	Corticosteroids (e.g., used in Duchenne muscular dystrophy), opioids, anticonvulsants	GERD, delayed gastric emptying, constipation	Medication adjustments and use of gut motility agents
Environmental and psychosocial factors	Stress, anxiety, healthcare access disparities	Can worsen functional gut disorders (e.g., IBS-like symptoms in myopathies)	Psychological support and patient education

GERD: Gastroesophageal reflux disease; GI: Gastrointestinal; MtDNA: Mitochondrial DNA.

Genetic modifiers and their role in GI dysfunction

Several genetic factors beyond the primary causative mutation influence the severity and progression of GI symptoms in genetic myopathies: Some patients with DMD exhibit severe esophageal dysmotility and gastroparesis, while others have milder symptoms. This variation may be attributed to modifier genes influencing smooth muscle integrity and neuromuscular transmission in the gut[15]. For example, variations in the laminin alpha 2-chain gene (which encodes laminin alpha 2, a component of the extracellular matrix) have been implicated in modifying the progression of gut dysmotility in muscular dystrophies[128]. Mitochondrial myopathies are often associated with GI dysmotility, pseudo-obstruction, and malabsorption. The severity of these symptoms is influenced by mtDNA mutations and nuclear-encoded mitochondrial proteins. Patients with heteroplasmic mtDNA mutations may have variable mitochondrial dysfunction, impacting energy-dependent processes such as intestinal peristalsis, secretion, and nutrient absorption[129]. Epigenetic changes, such as DNA methylation and histone modifications, may alter gene expression related to gut motility and inflammation. For instance, maternal diet and early-life exposures can modify the expression of neuromuscular genes regulating gut function, potentially exacerbating symptoms in genetically predisposed individuals[130].

Environmental and lifestyle modifiers

Beyond genetic factors, environmental influences, diet, microbiome composition, and lifestyle factors significantly impact the GI manifestations of genetic myopathies.

The gut microbiota plays a critical role in regulating intestinal motility, immune responses, and metabolism[131]. Patients with genetic myopathies often exhibit gut dysbiosis, characterized by an imbalance in protective vs. pathogenic bacteria, which can exacerbate GI symptoms such as constipation, diarrhea, and bloating. Alterations in the microbiota composition in mitochondrial disorders may further impact energy metabolism, leading to intestinal inflammation and motility disturbances[132].

Protein intake influences muscle function, including smooth muscles in the GI tract. A deficient or imbalanced diet can worsen esophageal dysmotility and delayed gastric emptying. High-fat diets have been associated with increased GI symptoms in patients with metabolic myopathies, whereas fiber-rich diets may enhance motility and reduce constipation. Vitamin deficiencies, particularly B₁₂, D, and magnesium, can contribute to neuromuscular dysfunction, exacerbating gut dysmotility[133]. Reduced mobility due to progressive muscle weakness in genetic myopathies can slow intestinal transit, increasing the risk of severe constipation, pseudo-obstruction, and reflux disease. Patients with DMD or BMD who remain ambulatory for longer durations tend to have less severe GI dysfunction compared to those who become non-ambulatory earlier[134].

Many medications used to manage genetic myopathies, such as steroids, anticonvulsants, and muscle relaxants, can significantly impact gut function. Chronic corticosteroid use in patients with DMD may predispose them to gastroesophageal reflux, delayed gastric emptying, and dysbiosis. Pain medications such as opioids, often prescribed for neuromuscular pain management, can further worsen constipation and reduce gut motility[135]. Emotional stress and anxiety have been linked to worsening gut symptoms in myopathies, particularly in conditions such as DM, where autonomic dysfunction contributes to bowel dysmotility. Access to healthcare and nutritional support varies across populations, affecting early intervention and symptom management and leading to disparities in disease progression[136].

Recognizing the role of genetic and environmental modifiers in GI manifestations of genetic myopathies has important implications for personalized treatment approaches. Identifying genetic modifiers may allow for the development of targeted therapies to modulate gut function in specific patient populations. Probiotics and fecal microbiota transplantation may potentially correct gut dysbiosis and alleviate GI symptoms[137]. Personalized nutritional interventions can improve gut motility and reduce disease burden in genetically predisposed individuals. Understanding how genetic variations influence medication response may help optimize drug therapy for GI symptoms, minimizing side effects while improving motility and digestion.

GI manifestations in genetic myopathies

While the hallmark features of genetic myopathies primarily involve skeletal muscle impairment, it's increasingly recognized that the GI tract can also be affected by these conditions. GI manifestations in genetic myopathies encompass a spectrum of symptoms affecting the digestive system, often accompanying primary muscle weakness and dysfunction. Histological studies of the smooth muscles showed edema, atrophy, and fibrosis of smooth muscles involving the distal esophagus, stomach, and small and large intestines[118]. The specific GI symptoms can differ greatly depending on the type of genetic myopathy and can also vary from person to person, even if they have the same condition.

DMD

GI manifestations are increasingly recognized in DMD. While the primary symptoms of DMD involve skeletal muscle dysfunction, GI involvement can occur and significantly impact patients' quality of life. The GI manifestations usually occur in the second decade of life due to atrophy and degeneration of the smooth muscle layers with connective tissue infiltration[25]. Various GI manifestations can impact digestion, absorption, and ‎waste elimination.‎ Chewing difficulties could be observed in patients with DMD, making it difficult to properly break down food properly, hindering ‎digestion, and potentially leading to malnutrition[134].

Dysphagia is the most frequently reported GI symptom observed in patients with DMD due to impaired pharyngeal and oesophageal functions caused by dystrophin deficiency and weakness in the muscles responsible for chewing and swallowing. This can lead to problems with oral intake, including choking, coughing, and aspiration of food or liquids into the airway[34]. GERD, with difficulty emptying the ‎stomach, is prevalent in patients with DMD due to weak smooth muscle tone in the lower esophageal ‎sphincter.‎ The flow of gastric acid back into the esophagus causes symptoms like heartburn, regurgitation, and difficulty swallowing. Barohn et al[26] found a significant delay in gastric-emptying times in patients with DMD using radionuclide scintigraphy studies. Gastroparesis with delayed stomach emptying may occur due to impaired smooth ‎muscle ‎function in the gastric wall‎. This can lead to symptoms such as early satiety, bloating, nausea, vomiting, and abdominal discomfort. Acute gastric dilatation was also reported in patients with DMD[137]. Elevated hepatic transaminases were observed in some children with DMD. Therefore, many authors suggest that unexplained elevated liver transaminases could help early diagnosis of muscular dystrophies[138,139]. Liver steatosis and non-alcoholic fatty liver disease are observed in some patients[140]. Weakening abdominal muscles can hinder ‎the effectiveness of pushing stool during defecation, contributing to ‎constipation.‎ Constipation, fecal impaction, and intestinal pseudo-obstruction may also occur due to dysregulated smooth muscle contractions in the intestines. Kraus et al[19] showed that functional constipation is present in 46.7% of patients with DMD, regardless of age or functional status. Weakness in the muscles responsible for maintaining bowel control, such as the external anal sphincter, can result in fecal incontinence. This can lead to involuntary leakage of stool and difficulties in controlling bowel movements[140]. GI manifestations in DMD, such as dysphagia, can lead to inadequate oral intake and difficulties in maintaining a balanced diet. This can result in malnutrition and growth failure, affecting overall health and development. Additionally, dietary factors, reduced physical activity, and medication side effects can exacerbate GI symptoms in individuals with DMD.

However, Lo Cascio ‎et al[18] found a markedly disturbed GI motor function even without GI manifestations. They recommended testing GI motility functions to ensure adequate intestinal transport to prevent potentially life-threatening constipation, especially in older patients with DMD[18]. In addition, Nart et al[20] described a series of patients with DMD who presented with severe colonic pseudo-obstruction or volvulus affecting sigmoid that needed urgent intervention. The presence of GI manifestations can also predict impairment of respiratory functions in patients with DMD. Lee et al[23] found that constipation is correlated with maximal expiratory pressure; swallowing difficulty is correlated with maximal insufflation capacity, assisted peak cough flow, maximal inspiratory pressure, and maximal expiratory pressure; and mastication difficulty was correlated with forced vital capacity, peak cough flow, assisted peak cough flow, maximal inspiratory pressure, and maximal expiratory pressure. In one study of the cause of Death in the Swedish Registry in patients with DMD, by Wahlgren et al[141] showed that GI complications are the cause of death in 1.0/1000 person/year in patients with DMD to be the 3^rd cause of death in these patients after cardiopulmonary complications and injury-related pulmonary embolism[141].

BMD

As BMD is a less severe related condition to DMD, characterized by less progressive muscle weakness and degeneration than observed in DMD, the patients usually developed milder and later onset GI manifestations than that observed with DMD. Common GI manifestations include dysphagia, GEED, gastroparesis, abdominal pain, constipation, and fecal Incontinence. Bianchi et al[142] described two brothers with BMD who developed heart failure and various GI symptoms, including dysphagia, post-prandial abdominal pain, constipation, nausea and vomiting, and intestinal pseudo-obstruction. The abdominal pain arises initially after ingesting large amounts of food, progresses to be frequent, and occurs after normal meals[142]. However, Borrelli et al[24] studied gastric emptying time in children with DMD and BMD. They found markedly delayed gastric emptying time in these children than in the controls, and children with DMD had longer gastric emptying time than children with BMD[24].

Boys and young men affected with BMD may present with an asymptomatic increase in liver enzyme levels assayed for other reasons, sometimes accurately diagnosed only after extensive GI workouts[21]. Some patients with BMD may also present with non-alcoholic fatty liver disease due to a combination of factors. These include reduced mobility and physical activity resulting from muscle weakness and degeneration, which can lead to weight gain and metabolic disturbances. Metabolic abnormalities inherent to these conditions, such as insulin resistance and dyslipidemia, further contribute to NAFLD development. Additionally, long-term use of glucocorticoid medications, commonly prescribed to improve muscle function, may exacerbate metabolic complications[140,143]. Malnutrition and weight loss could also be observed in BMD, like that observed in DMD, but with later onset and when severely complicated with respiratory failure[144].

LGMD

There is very scarce data about GI manifestations associated with LGMD. Although GI manifestations are not typically a primary feature of LGMD, they can significantly impact affected individuals. These include swallowing difficulties (dysphagia), GERD, nutritional challenges, constipation, and medication-related side effects. These issues stem from muscle weakness and immobility associated with LGMD. The LGMD-associated GI manifestations are not universal and may vary depending on the specific subtype. In LGMD2B, GI symptoms such as dysphagia (difficulty swallowing), gastroesophageal reflux, and elevated liver enzymes have been reported in some patients[27,145,146]. Dysphagia can occur due to weakness in the muscles involved in swallowing, including those in the throat and esophagus[12]. While GI symptoms are less commonly reported in LGMD2C compared to LGMD2B, some patients may experience dysphagia or other GI issues due to muscle weakness[43,147].

Congenital myopathies

Congenital myopathy is a condition characterized by early-onset muscle weakness accompanied by low muscle bulk and tone. Although these symptoms usually appear in neonates and infants, they can also be present in children or adults with milder forms of the condition[51]. Patients suffering from congenital myopathies often face challenges in managing their oral secretions during their neonatal and childhood stages due to excessive salivation and/or poor oral motor control. This excessive salivation can lead to pulmonary complications like aspiration and can have significant negative social impacts[148]. Infants and children who have congenital myopathies often experience difficulties with feeding and swallowing[149]. These difficulties can significantly impact their overall health, including their growth, pulmonary function, oral health, energy levels, and activity levels. Children with nemaline myopathy commonly experience feeding issues during their first year of life, but these tend to improve as they age. Additionally, children with congenital myopathies may experience lower facial weakness, poor oral hygiene, dental care, malocclusion, high-arched palate, jaw contractures, gastroesophageal reflux problems, such as chest or upper abdominal pain, vomiting, aspiration, and recurrent respiratory infections. Constipation and failure to thrive are also common issues they may face[150]. Other less common GI manifestations include diarrhea, incontinence, pyloric stenosis, cholestatis/cholelithiasis, and GI bleeding[151]. Yoo et al[28] showed that even in the presence of severe dysphagia and oral motor dysfunction which requires tube feeding for months in neonates with nemaline myopathy, it is possible to obtain sufficient nutrition with an oral diet through a series of dysphagia rehabilitation therapy.

Metabolic myopathies

Metabolic myopathies occur due to missing or deficient enzymes in the energy production process. Some people may not experience any symptoms, while others may have fatigue, exercise intolerance, muscle cramping, and heart or respiratory problems[55]. In severe cases, rhabdomyolysis can develop, leading to kidney damage and failure. This condition can be triggered by various factors such as strenuous exercise, illness, stress, exposure to cold temperatures, or prolonged fasting. While these conditions primarily affect skeletal muscle function, GI manifestations are increasingly recognized as important clinical features[53,152]. GI manifestations in metabolic myopathies are diverse, depending on the specific disorder and underlying metabolic abnormalities. Common symptoms include recurrent abdominal pain, often associated with metabolic disturbances or rhabdomyolysis episodes[54]. Metabolic disruptions can affect gastric motility and emptying, leading to nausea and vomiting. Dysregulation of intestinal motility may result in diarrhea or constipation, causing GI discomfort[142]. Certain metabolic myopathies may increase the risk of GERD due to impaired esophageal or gastric motility. Additionally, weakness or dysfunction of oropharyngeal and esophageal muscles can lead to dysphagia, posing a risk of aspiration[12].

In Glycogen storage disease type I, patients may experience intermittent diarrhea, which appears to worsen with age. The exact cause is unclear, possibly due to inflammation related to disturbed neutrophil function commonly observed in Glycogenosis type IB (GSD IB), as evidenced by high fecal calprotectin[153,154]. GSD IB can also cause a Crohn's disease-like inflammatory bowel disease (IBD) that can significantly impair a patient's quality of life[155]. Medium-chain acyl-CoA dehydrogenase deficiency deficiency usually occurs in infants or young children and may result in vomiting, lethargy, and hypoglycemia which may progress to coma[156]. Carnitine deficiency may be a cause of GI dysmotility, with recurrent episodes of abdominal pain and diarrhea. It also may present with fulminant liver failure and presentation like that in Reye syndrome[157]. Hepatomegaly may also be one of the manifestations of GSDs and neutral lipid storage disease[158]. Patients with neutral lipid storage disease may also present with liver steatosis, hepatosplenomegaly, and even liver cirrhosis[159]. Wolman disease is a rare autosomal-recessive disease caused by a lysosomal acid lipase deficiency. Infants suffering from this disease may present with GI symptoms such as diarrhea, vomiting, feeding difficulties, hepatosplenomegaly, failure to thrive, stunted growth, and calcifications in the adrenal glands[160].

Danon disease is a rare genetic X-linked lysosomal storage disorder that affects males and is caused by mutations in the LAMP2 gene. This disorder causes a build-up of glycogen and autophagic debris in the tissues, particularly in the cardiac and skeletal muscles[161]. Individuals affected by Danon disease may experience a variety of symptoms, including GI problems, breathing difficulties, and visual abnormalities. Some of the GI symptoms that may occur include difficulty swallowing, GERD, abdominal pain, diarrhea, and constipation. Many affected males may also experience liver enlargement and elevated liver enzymes, which may be due to skeletal muscle damage rather than liver dysfunction[162].

Mitochondrial myopathies

Mitochondrial myopathies are a group of disorders characterized by dysfunctional mitochondria, the energy-producing organelles in cells. While these disorders primarily affect skeletal muscles, they can also involve various other organs, including the GI system[63]. GI manifestations are common in mitochondrial myopathies, reflecting the systemic nature of these disorders. Patients with mitochondrial myopathies often experience dysphagia, GERD, and gastroparesis due to impaired muscle function in the esophagus and stomach. Additionally, dysregulation of intestinal motility can lead to diarrhea, constipation, abdominal pain, GI pseudo-obstruction, pancreatitis with/without diabetes and with/without exocrine pancreas insufficiency, and hepatopathy. Malabsorption of nutrients, pancreatic dysfunction, and liver involvement may further exacerbate GI symptoms[163-165].

Mitochondrial neuro-GI encephalopathy (MNGIE) is the most well-known mitochondrial disorder involving the GI tract. It causes dysphagia, achalasia, GERD, vomiting, especially at night, Pancreatitis, hepatopathy, steatosis, Pseudo-obstruction, megacolon, and diarrhea[166]. MELAS is a mitochondrial disorder that causes recurrent stroke-like episodes, seizures, and muscle weakness. One of the main symptoms of MELAS is cyclic or episodic vomiting, which can sometimes be mistaken for bulimia due to its intensity[167]. Migraine is also common in patients with MELAS and can cause vomiting as well. However, administering phenytoin to MELAS patients may trigger intestinal pseudo-obstruction[168]. Additionally, diarrhea may occur due to GI dysmotility or pancreatic insufficiency. Occasionally, patients with MELAS may present in the acute surgical abdomen[169]. Patients with MNGIE may be easily satiated and nauseated and may have an increased bowel frequency or intermittent diarrhea[32].

Leigh syndrome, also known as subacute necrotizing encephalomyelopathy, is a severe neurological disorder caused by mitochondria dysfunction. It typically appears in infancy and can cause muscle weakness and movement disorders. Patients may also experience GI issues such as dysphagia, vomiting, and diarrhea, which are likely due to damage in the brainstem's swallowing center. These issues can further decrease the patient's nutrition intake, leading to malnutrition or failure to thrive[170]. In cases of Kearns-Sayre syndrome, around 15% of patients may experience dysphagia due to primary esophageal dysmotility, neurogenic causes, or a combination of factors[33]. Patients with this syndrome may also have a near absence of pharyngeal peristalsis, abnormally low upper esophageal sphincter resting pressure, and an absence of proximal esophageal peristalsis[171].

MD

DM, particularly DM1 and DM2, presents with a variety of GI manifestations due to the multisystem nature of the disease. GI manifestations occur in about 50% of patients, especially in DM1, and may occur at any level and affect various parts of the GI tract. The onset of GI manifestation may even precede the musculoskeletal features and may be the first sign of dystrophic disease. However, these manifestations could develop gradually, so the patient is unaware of the exact onset and has little awareness of symptoms[118]. Common GI symptoms include asymmetric pharyngeal contraction, dysphagia, dyspepsia, heartburn, regurgitation, GERD, and gastroparesis, which can lead to symptoms like early satiety, bloating, nausea, vomiting, and abdominal discomfort[172]. These manifestations are due to pathological atrophic abnormalities of striated pharyngeal, esophageal, and gastric muscles[11,31]. Radiological, manometric, and ultrasonographic evidence reveal reduced peristaltic activity, delayed gastric emptying, and visceral dilatation, contributing to symptoms like gastroparesis[173,174]. Moreover, studies highlight abnormalities in small intestine motility, with reports of low-amplitude contractions and myotonic phenomena[175].

Diarrhea, often accompanied by malabsorption, steatorrhea, and abdominal cramps, is a common complaint among MD patients. Additionally, paralytic ileus has been documented. The abdominal pain associated with MD can occur in any part of the abdomen without specific characteristics or triggers. Episodic diarrhea, present in up to 33% of cases, is particularly debilitating and can significantly impact a patient's social life, especially when compounded with anal incontinence. Diarrhea is a common complaint among patients with DM, often accompanied by malabsorption, steatorrhea, and abdominal cramps. In addition, paralytic ileus has been documented[176]. The abdominal pain associated with DM can occur in any part of the abdomen without specific characteristics or triggers. Episodic diarrhea, present in about one-third of cases, is particularly debilitating and can significantly impact a patient's social life, especially when compounded with anal incontinence[177]. Constipation, often associated with dyschezia and fecal incontinence, are other common features frequently attributed to weakened abdominal muscles and dysregulated intestinal motility, which makes it difficult to pass stool and alterations in resting and squeezing pressures[29]. It could also occur secondary to hypothyroidism, which is also common in DM[178]. Megacolon, sigmoid volvulus, and segmental narrowing indicate significant motility disturbances[30]. Histologic studies suggest muscular abnormalities, with findings of atrophy, fibrosis, and cellular changes in the anal sphincter. Dystrophy and fatty infiltration of the smooth fibers of the stomach, small bowel, and colon have been described[31]. Peristaltic abnormalities can be documented radiologically.

Hilbert et al[16] conducted a study revealing GI manifestations in both DM1 and DM2. They observed that individuals with DM1 and DM2 had a higher likelihood of getting cholecystectomy at a younger age compared to the control group. The study also found that higher body mass index and longer disease duration were associated with a greater risk of GI manifestations in DM1. At the same time, female sex was a risk factor in DM2[16].

Diagnostic approaches of GI manifestations in genetic myopathies

Diagnostic approaches for evaluating GI manifestations in genetic myopathies aim to identify the underlying causes of symptoms, evaluate their severities, and guide appropriate management strategies (Figure 2)[179]. These approaches typically involve a combination of clinical evaluation, imaging studies, physiological tests, histological analysis, and genetic testing. Clinical evaluation is the initial step in this approach. A detailed patient history should involve inquiry about different GI symptoms such as dysphagia, reflux, abdominal pain, constipation, diarrhea, and fecal incontinence, together with documenting the onset, duration, severity, and progression of symptoms[177]. Then, a thorough physical examination, including assessment of muscle strength, tone, and bulk, should be performed, paying attention to signs of muscle weakness, atrophy, or contractures, as well as abdominal tenderness or distention and peri-anal area[180].

Figure 2 Diagnostic approaches for gastrointestinal manifestations in genetic myopathies. CT: Computed tomography; BMD: Becker muscular dystrophy; DMD: Duchenne muscular dystrophy; GERD: Gastroesophageal reflux disease; GI: Gastrointestinal; LGMD: Limb-girdle muscular dystrophy; MRI: Magnetic resonance imaging; MtDNA: Mitochondrial DNA; NGS: Next-generation sequencing.

Imaging studies are frequently needed to evaluate the degree of GI involvement in various types of myopathies. Abdominal X-rays can help detect signs of intestinal obstruction, megacolon, volvulus, or other structural abnormalities[181]. Abdominal ultrasound is useful for assessing liver size, detecting hepatomegaly or fatty liver changes, and evaluating gallbladder abnormalities. Upper GI series with barium swallow and small bowel follow-through can assess for esophageal dysmotility, gastroesophageal reflux, gastric emptying abnormalities, and small bowel transit time[121]. Radiological evaluation of colon transit time can help assess patients with constipation and other colonic or rectal impairments[182].

While CT and MRI are both used to evaluate GI anatomy and complications such as volvulus or intussusception, MRI offers distinct advantages over CT in several key areas. MRI provides superior soft tissue contrast, allowing for detailed visualization of muscle atrophy, fibrosis, and inflammation in the GI tract[183]. It is particularly beneficial for assessing intestinal pseudo-obstruction, gastroparesis, and dysphagia, which are common in DMD, DM, and mitochondrial myopathies[184]. Additionally, MRI enables cine imaging, which allows for real-time assessment of gastric and intestinal motility, helping distinguish true mechanical obstruction from functional dysmotility—a crucial factor in surgical vs medical management decisions[185]. Another major advantage of MRI is its ability to detect hepatic and pancreatic involvement, particularly in metabolic myopathies, where MRI can quantify hepatic steatosis in conditions such as mitochondrial myopathies and GSDs, guiding early dietary and hepatoprotective interventions. Furthermore, MRI does not expose patients to ionizing radiation, making it a safer option for pediatric patients and those requiring serial imaging[186].

On the other hand, CT remains valuable in acute settings, particularly for detecting intestinal obstruction, perforation, ischemia, and GI bleeding, conditions that may necessitate urgent surgical intervention. CT’s rapid acquisition time and widespread availability make it the preferred first-line imaging modality in emergencies[187]. Additionally, CT angiography can be used to evaluate vascular complications, which may be present in mitochondrial disorders. However, CT’s reliance on ionizing radiation makes it less suitable for repeated imaging, particularly in children. While MRI is superior for functional and soft tissue assessments, CT is often preferred for evaluating acute structural abnormalities and life-threatening GI emergencies[188]. In clinical practice, these two imaging techniques are complementary, with MRI being the preferred choice for chronic, functional, and metabolic evaluations. In contrast, CT is more suited for acute, structural, and emergency assessments. By integrating both modalities, clinicians can comprehensively understand GI involvement in genetic myopathies, optimizing diagnostic accuracy and guiding appropriate management strategies (Table 7)[17].

Table 7 Comparison between magnetic resonance imaging and computed tomography in gastrointestinal myopathies.

Feature	MRI	Computed tomography
Tissue contrast	Superior soft tissue contrast; excellent for detecting muscle atrophy, fibrosis, and inflammation	Moderate contrast; better for bony structures and acute bleeding
Radiation exposure	No ionizing radiation—safer for children and repeated follow-ups	Uses ionizing radiation, which may be concerning for pediatric patients and those needing serial imaging
Visualization of smooth muscle	More detailed assessment of intestinal wall abnormalities, fibrosis, and motility issues	Less sensitive in detecting smooth muscle pathology
Gastric and intestinal motility	MRI can provide cine imaging for real-time assessment of gastric emptying and intestinal movement	Lacks dynamic imaging capability for motility disorders
Bowel obstruction and pseudo-obstruction	Can differentiate between true obstruction vs pseudo-obstruction based on bowel wall motion	Effective for detecting acute bowel obstructions but lacks functional assessment
Detection of liver and pancreatic involvement	Better visualization of hepatic and pancreatic steatosis, common in metabolic myopathies	Good for detecting structural abnormalities, such as tumors or calcifications
Practical limitations	Longer scan time, requires patient cooperation, contraindicated in patients with metal implants	Quick scan time, widely available, useful for emergency settings

MRI: Magnetic resonance imaging.

Various physiological tests may also be needed. Esophageal manometry can measure esophageal motility and pressure dynamics, helping diagnose disorders such as achalasia, esophageal spasm, or ineffective oesophageal peristalsis[189]. Ambulatory pH monitoring evaluates esophageal acid exposure over time, helping diagnose GERD and assess treatment efficacy[190]. GI motility studies, such as esophageal transit studies or colonic transit studies, can assess the coordination and function of the GI tract, aiding in the diagnosis of dysmotility disorders[172]. Gastric Emptying evaluation is needed to evaluate gastroparesis. Radionuclide or scintigraphy studies assess gastric emptying times, aiding in diagnosing gastroparesis or delayed gastric emptying[191]. Anorectal manometry evaluates anal sphincter function, rectal sensation, and recto-anal reflexes, assisting in the diagnosis of fecal incontinence, constipation, or pelvic floor dysfunction[192].

Histological analysis could occasionally be helpful. Endoscopic evaluation with mucosal biopsy may be performed to assess for histological changes in the GI tract, such as inflammation, fibrosis, or smooth muscle abnormalities[193]. This can be particularly useful in diagnosing conditions like eosinophilic esophagitis or IBD. In cases where GI smooth muscle involvement is suspected, such as in certain genetic myopathies, a muscle biopsy may be indicated to evaluate for histological abnormalities, including muscle atrophy, fibrosis, or lipid accumulation[194].

Genetic testing can evaluate the exact type of myopathy and the presence of any syndromic myopathies. Genetic testing using NGS panels can identify pathogenic mutations associated with various genetic myopathies, including DMD, BMD, LGMD, congenital myopathies, metabolic myopathies, mitochondrial myopathies, and DM[195]. Targeted sequencing may be performed for specific genes implicated in GI motility disorders or metabolic myopathies, depending on the clinical presentation and suspected underlying condition[54]. Given the multisystem nature of many genetic myopathies, a multidisciplinary approach involving gastroenterologists, neurologists, geneticists, and other specialists may be necessary to evaluate and manage GI manifestations comprehensively.

Impact of GI symptoms on quality of life and daily functioning

GI symptoms are a significant yet often overlooked component of genetic myopathies, profoundly affecting nutrition, daily activities, social interactions, and mental well-being. While much of the clinical focus in genetic myopathies is on muscle weakness and mobility impairment, dysphagia, GERD, constipation, gastroparesis, and intestinal pseudo-obstruction impose additional burdens, leading to malnutrition, dehydration, chronic pain, and reduced independence[196]. The cumulative effects of these GI complications significantly impact the quality of life, necessitating a multidisciplinary approach to management.

One of the most critical consequences of GI dysfunction in genetic myopathies is malnutrition, which results from poor oral intake, impaired digestion, and inefficient nutrient absorption. Dysphagia (swallowing difficulties) and esophageal dysmotility, common in conditions like DMD, DM1, and mitochondrial myopathies, lead to reduced calorie and protein intake, exacerbating muscle atrophy, fatigue, and immune dysfunction[197]. Additionally, gastroparesis (delayed gastric emptying) results in early satiety, nausea, and bloating, making it difficult for patients to consume adequate nutrition. Over time, malnutrition worsens disease progression, delays wound healing, and weakens the immune system, increasing susceptibility to infections[173]. The resulting malnutrition impacts the child's daily functioning as reduced energy levels due to muscle wasting impair mobility and functional independence. In addition, nutritional deficiencies often lead to frequent hospital admissions for hydration and feeding support. Furthermore, severe dysphagia may necessitate gastrostomy tube (G-tube) placement, impacting eating habits and social participation[198,199].

GERD and esophageal dysmotility are prevalent in BMD, LGMD, and mitochondrial myopathies, leading to chronic acid reflux, heartburn, and regurgitation. Frequent aspiration events can result in recurrent pneumonia and worsening respiratory function, particularly in non-ambulatory patients. Chronic epigastric pain and discomfort further reduce appetite, disrupt sleep, and impair overall well-being[200]. Nocturnal reflux causes sleep disturbances, leading to daytime fatigue and cognitive difficulties. Patients may avoid eating in public due to reflux-related discomfort and coughing. Chronic GERD often necessitates long-term PPIs and dietary restrictions, adding to the treatment burden[201].

Chronic constipation, slow colonic transit, and intestinal pseudo-obstruction are significant issues in DMD, mitochondrial myopathies, and DM, resulting from weakened smooth muscle contraction and autonomic dysfunction. Patients experience severe abdominal pain, bloating, nausea, and incomplete bowel movements, leading to emotional distress and decreased daily productivity[178]. Additionally, some patients suffer from fecal incontinence, which significantly affects self-esteem and social participation. Frequent episodes of abdominal pain and unpredictable bowel movements make it difficult for patients to maintain school attendance or employment. Fear of accidents in public settings can lead to social isolation and anxiety. Patients often require assistance with toileting and bowel management programs, impacting both their autonomy and caregiver burden[202].

GI symptoms in genetic myopathies not only affect physical health but also lead to significant emotional and social burdens. Anxiety, depression, and reduced self-esteem are common among patients experiencing chronic pain, dietary restrictions, and unpredictable bowel habits. The need for feeding tubes, dietary modifications, and bowel programs can make patients feel different from their peers, leading to withdrawal from social activities[203]. Chronic illness and social embarrassment from GI symptoms contribute to mental health issues. Patients may avoid eating in restaurants or attending events due to dietary restrictions or bathroom concerns. The need for specialized diets, feeding assistance, and frequent medical visits places financial strain on families and increases caregiver fatigue[204]. GI symptoms in genetic myopathies lead to a vicious cycle of malnutrition, chronic pain, emotional distress, and reduced independence. The cumulative effects significantly diminish patients' overall quality of life and daily functioning[205]. To address these challenges, multidisciplinary management involving gastroenterologists, dietitians, neurologists, physiotherapists, and mental health professionals is essential.

Management of GI manifestations in genetic myopathies

Managing GI manifestations in genetic myopathies involves a multidisciplinary approach to alleviate symptoms, improve nutritional status, and optimize GI function (Figure 3). Treatment strategies may vary depending on the specific symptoms, underlying genetic disorders, and individual patient needs. Nutritional Support is a cornerstone of managing patients with genetic myopathies, as malnutrition is usually a frequent complication. Implementing dietary adjustments tailored to address specific GI symptoms helps manage many GI disorders[205]. For example, in cases of dysphagia or swallowing difficulties, modify food consistency or texture to facilitate safer swallowing and reduce the risk of aspiration. Oral or enteral nutritional supplements are provided to address malnutrition, weight loss, or deficiencies in essential nutrients. These supplements may include high-calorie formulas, protein supplements, vitamins, and minerals[206].

Figure 3 Management strategies for gastrointestinal manifestations in genetic myopathies. GERD: Gastroesophageal reflux disease; PPIs: Proton pump inhibitors.

Management of myopathy-associated GI symptoms aims to improve the patient's quality of life and general well-being. If the patient suffers from dysphagia, implementing swallowing rehabilitation exercises, dietary modifications, and positioning techniques improves swallowing function and reduces the risk of aspiration[207]. Speech-language pathology evaluation and therapy may also be beneficial. In symptomatic GERD, using pharmacological agents such as PPIs, histamine-2 receptor antagonists, or prokinetic agents helps to manage symptoms of GERD and reduce gastric acid secretion. To manage gastroparesis, we need to employ dietary modifications (e.g., small, frequent meals; low-fat diet), prokinetic medications (e.g., metoclopramide, domperidone), antiemetics, and gastric electrical stimulation for refractory cases to improve gastric emptying and alleviate symptoms[208]. As constipation and fecal incontinence are common problems in patients with genetic myopathies, we may need to implement dietary fiber supplementation, osmotic laxatives, stool softeners, bowel management programs, biofeedback therapy, or sacral nerve stimulation to manage constipation and fecal incontinence[209]. To manage abdominal pain, patients can utilize analgesic medications and antispasmodics, modify their diet, practice relaxation techniques, and may need psychological interventions to address these manifestations. At the same time, diarrhea can be controlled by properly identifying and treating underlying causes, such as bacterial overgrowth, malabsorption, or medication side effects. Antidiarrheal agents, dietary modifications, and probiotics may be beneficial[210]. We may need surgical intervention to relieve the myopathy-associated GI manifestations in certain conditions. Fundoplication can be performed in severe GERD, pyloroplasty, gastric bypass for refractory gastroparesis, or fecal diversion procedures can be performed in intractable fecal incontinence. Gastrostomy or jejunostomy feeding tubes may be considered in patients with severe dysphagia, swallowing difficulties, or inadequate oral intake to ensure adequate nutrition and hydration[211].

General rehabilitation and supportive care are other vital cornerstones in managing patients with genetic myopathies. Physical therapy interventions improve or maintain muscle strength, mobility, and functional independence, which may indirectly benefit GI function by enhancing overall physical health[14]. Occupational therapy can address activities of daily living, adaptive equipment needs, and meal preparation and feeding strategies in patients with upper extremity weakness or coordination deficits[212]. Speech-language pathologists can be engaged to assess and manage swallowing disorders, dysphagia, and communication difficulties, providing exercises and strategies to improve swallowing safety and efficiency[213].

Another cornerstone in the management is patient and caregiver education. Patients need to be educated about the nature of their genetic myopathy, associated GI manifestations, and available treatment options. Patients should be empowered to actively participate in their care and advocate for their needs[214]. They also may need psychological support, counseling, and coping strategies to address emotional distress, anxiety, depression, or social isolation associated with chronic GI symptoms and genetic myopathies. Given the genetic nature of genetic myopathies, we must provide genetic counseling to patients and families to discuss inheritance patterns, genetic testing options, recurrence risks, and family planning decisions[215]. We also need to facilitate access to support groups, online communities, or peer networks for individuals and families affected by genetic myopathies, allowing them to share experiences, seek advice, and receive emotional support[216]. By employing a comprehensive and individualized approach to management, healthcare providers can effectively address GI manifestations in genetic myopathies, improve patients' quality of life, and promote optimal GI health. Regular monitoring and multidisciplinary collaboration are essential for ongoing assessment and adjustment of treatment plans based on patients' evolving needs and responses.

Patients perspectives

Understanding patient perspectives in genetic myopathies is essential for delivering patient-centered care, addressing unique challenges, and improving overall well-being. There are various impacts of GI disorders on patients with genetic myopathies, impacting their daily life, social, and psychological life, expose them to many communication challenges[14]. The impact of GI disorders affects different life aspects of patients with myopathies. Patients with genetic myopathies often experience progressive muscle weakness, fatigue, and mobility limitations, impacting their ability to perform activities of daily living independently. Muscle weakness and motor difficulties can affect tasks such as walking, climbing stairs, lifting objects, and maintaining balance, leading to increased dependency on caregivers and assistive devices[217]. Patients may also face challenges with mobility both indoors and outdoors, affecting their ability to navigate their environment, participate in social activities, and access community resources[218].

Living with a genetic myopathy can cause emotional distress, anxiety, depression, frustration, and feelings of isolation due to physical limitations, unpredictable disease progression, and uncertainty about the future. Patients may experience social isolation or withdrawal from social activities due to mobility limitations, communication difficulties, stigma, and barriers to accessibility[219]. Genetic myopathies can strain relationships with family members, friends, and peers, as patients may require increased support, understanding, and accommodations to participate in social interactions and maintain meaningful connections[220]. Some genetic myopathies affect the muscles involved in speech and swallowing, leading to dysarthria, dysphonia, and dysphagia, which can affect communication clarity, fluency, and effectiveness. Therefore, Patients may require assistive communication devices, such as speech-generating devices, communication boards, or alternative augmentative communication systems, to facilitate effective communication and expression of needs and preferences[221].

Maintaining independence and autonomy is a significant concern for patients with genetic myopathies, as they strive to preserve their ability to engage in meaningful activities, make decisions, and manage daily tasks[222]. Patients prioritize factors that enhance their quality of life, such as access to supportive care services, assistive technologies, physical rehabilitation, social support networks, and opportunities for participation and inclusion. Patients value collaborative decision-making processes that involve open communication, mutual respect, and consideration of their preferences, goals, values, and priorities in treatment planning. Patients appreciate personalized and holistic approaches to care that address their unique needs, preferences, and goals, recognizing that one-size-fits-all interventions may not be suitable for everyone[223].

Patients may encounter barriers to accessing healthcare services, including financial constraints, transportation limitations, geographical distance to specialized centers, and insurance coverage issues, impacting their ability to receive timely and comprehensive care[224]. Patients benefit from access to multidisciplinary healthcare teams comprised of specialists in neurology, rehabilitation, genetics, nutrition, psychology, and social work, who collaborate to provide coordinated and integrated care. Patients and their caregivers advocate for their needs, rights, and interests by raising awareness, participating in advocacy initiatives, engaging with patient advocacy organizations, and promoting policy changes to improve access to care, research funding, and social support services[225]. Patients develop self-advocacy skills to communicate their needs effectively, navigate healthcare systems, access resources, and assert their rights as active participants in their care and decision-making processes[226].

Patients can contribute to research efforts by participating in clinical trials, observational studies, patient registries, and patient-reported outcome measures, providing valuable insights into disease progression, treatment outcomes, and quality of life. Patients embrace technological advancements, assistive devices, adaptive technologies, and telehealth solutions that enhance their independence, communication, mobility, and access to healthcare services, fostering innovation and empowerment within the community[227]. By considering patient perspectives in genetic myopathies, healthcare providers can deliver compassionate, patient-centered care that addresses the holistic needs, preferences, and priorities of individuals and their families, ultimately improving their quality of life and well-being. Collaboration between patients, caregivers, healthcare professionals, researchers, and advocacy organizations is essential for promoting positive outcomes and fostering a supportive and inclusive community for individuals living with genetic myopathies.

Future directions and research recommendation

Future directions and research in GI manifestations of genetic myopathies are essential for advancing understanding, improving diagnosis, developing targeted therapies, and enhancing patient care. Further genetic studies, including whole-exome sequencing, genome-wide association studies, and functional genomics approaches, are needed to identify novel genes and variants associated with GI manifestations in genetic myopathies. Research efforts should focus on elucidating GI involvement's molecular mechanisms, including the role of genetic mutations, aberrant signaling pathways, cellular dysfunction, and tissue-specific pathophysiological changes[228].

Research should continue to identify biomarkers, such as circulating biomarkers, genetic markers, imaging biomarkers, and molecular signatures, for early detection, risk stratification, disease monitoring, and treatment response assessment in GI manifestations of genetic myopathies. We also need to develop non-invasive diagnostic tools, including imaging modalities, functional tests, and molecular assays, for assessing GI motility, smooth muscle function, neuromuscular integrity, and tissue pathology in patients with genetic myopathies. We also need to explore targeted therapeutic approaches, including pharmacological interventions, gene therapies, and molecular interventions, aiming to correct underlying molecular defects, modulate signaling pathways, restore muscle function, and improve GI motility and function. Investigating novel treatment modalities, such as gene editing technologies, RNA-based therapies, stem cell therapies, and tissue engineering strategies, could help to address GI manifestations and associated complications in genetic myopathies[229].

Research also could extend to the pathophysiology of enteric neuropathy, neurodegeneration, and dysregulation of the enteric nervous system in genetic myopathies, including the role of neurotransmitters, neural circuits, and neuromodulator pathways in GI motility and function. We also need to explore neuroprotective strategies, neuromodulating interventions, and neural stimulation techniques to preserve enteric nervous system integrity, restore neuronal function, and enhance GI peristalsis and coordination. In addition, there is a need to develop and characterize preclinical models, including animal models, cellular models, organoid cultures, and patient-derived induced pluripotent stem cells, for studying GI manifestations of genetic myopathies, testing therapeutic interventions, and predicting clinical outcomes[230]. It is also important to translate these preclinical findings into clinical applications, including the validation of therapeutic targets, preclinical efficacy studies, early-phase clinical trials, and the implementation of personalized medicine approaches for patients with genetic myopathies affecting the GI tract[231]. We also need to conduct clinical trials to evaluate the safety, efficacy, and tolerability of novel therapeutic interventions, disease-modifying agents, symptomatic treatments, and multidisciplinary care approaches for managing GI manifestations and improving patient outcomes in genetic myopathies. Long-term observational and natural history studies are also required to characterize the progression of GI involvement, identify prognostic factors, assess treatment responses, and evaluate the impact of interventions on disease course, quality of life, and survival[232].

Integrating patient-reported outcomes, patient-centered measures, and quality-of-life assessments into clinical research studies and therapeutic trials helps capture GI manifestations' impact on patient's symptoms, functional status, psychosocial well-being, and overall quality of life[233]. We also should engage patients, caregivers, advocacy organizations, and community stakeholders in research prioritization, study design, recruitment strategies, and dissemination of research findings to ensure that research efforts are patient-centered, relevant, and impactful. It is also vital to establish collaborative research networks, consortia, and multidisciplinary teams comprising clinicians, researchers, industry partners, patient advocates, and regulatory agencies to facilitate data sharing, resource sharing, collaborative research projects, and knowledge exchange in the GI manifestations of genetic myopathies[234]. We should also promote data-sharing initiatives, biobanks, registries, and open-access databases for sharing clinical, genomic, imaging, histopathological, and experimental data to accelerate research progress, foster collaborations, and enhance reproducibility and transparency in research efforts.

Limitations of the study

The review has several limitations that warrant consideration. Firstly, although the review included a substantial number of studies, the overall sample size may still limit the generalizability of findings to broader populations. Additionally, the potential for publication bias exists, as the review may have favored studies reporting positive results, potentially skewing the overall understanding of GI manifestations in genetic myopathies. Moreover, the presence of heterogeneity across included studies, stemming from variations in study designs, patient populations, and methodologies, may affect the synthesis of results and the formation of conclusive interpretations. Furthermore, the quality of evidence across studies varied, which could impact the reliability and validity of the conclusions drawn from the review. The limited availability of data on certain aspects of GI manifestations in genetic myopathies may also restrict the comprehensiveness of the review. Language bias may be present, as only studies published in English were included, potentially excluding relevant research published in other languages. Finally, bias in reporting within the included studies could influence the accuracy of the synthesized findings, affecting the overall robustness of the review's conclusions.

CONCLUSION

In conclusion, GI manifestations in genetic myopathies pose significant diagnostic and management challenges, necessitating a comprehensive and multidisciplinary approach for optimal care. Clinical evaluation, imaging studies, physiological tests, histological analysis, and genetic testing play pivotal roles in identifying underlying causes, assessing severity, and guiding management strategies. Nutritional support, symptomatic management, rehabilitative interventions, and patient education are essential components of managing GI symptoms in genetic myopathies, aiming to improve quality of life and overall well-being. Future research directions should focus on elucidating molecular mechanisms, identifying biomarkers, developing targeted therapies, and enhancing patient-centered care to address the complex interplay of GI manifestations in genetic myopathies effectively. By integrating patient perspectives, advancing scientific knowledge, and fostering collaborative efforts, healthcare providers and researchers can strive towards improving outcomes and enhancing the lives of individuals living with genetic myopathies and associated GI complications.