Glycogen storage disease type XIV in the Middle East and North Africa region: A case report

Abstract

BACKGROUND

This case report expands the limited literature on phosphoglucomutase-1 deficiency (GSD XIV), a rare disorder that combines features of glycogen storage disease and congenital disorders of glycosylation. Given its wide clinical spectrum and often subtle early signs, under-recognition remains common. We report this case to highlight its multisystem involvement, emphasize diagnostic challenges, and reinforce the need for early consideration of GSD XIV in patients with unexplained hepatic, metabolic, and neuromuscular abnormalities.

CASE SUMMARY

We describe a case of a three-year-old girl born to consanguineous parents who presented with a constellation of atypical features, including cleft palate with bifid uvula, transient ventricular septal defect, hepatomegaly, persistent transaminitis, recurrent ketotic hypoglycemia, coagulopathy, febrile seizures, and emerging proximal muscle weakness. Despite an extensive workup, including metabolic, infectious, and immunologic testing, no clear diagnosis was identified in early infancy. Whole-exome sequencing revealed a homozygous pathogenic variant in PGM1 (c.1294G>T), confirming the diagnosis of GSD XIV.

CONCLUSION

This case highlights that genetic analysis is highly useful for diagnosing and specifying the subtype of GSD in patients with suspected multiorgan involvement, particularly those presenting with persistent transaminitis and neurological abnormalities.

Key Words: Glycogen storage disease; Genetic testing; Whole exome sequencing; Phosphoglucomutase-1 deficiency; Case report

Core Tip: Phosphoglucomutase-1 deficiency is a rare, under-recognized disorder with a broad and often subtle multisystem presentation. The condition was first recognized in 1963 through paternity testing and later classified as glycogen storage disease type XIV after reports of glycogen accumulation, severe enzyme deficiency, and rhabdomyolysis. This case underscores the importance of considering phosphoglucomutase-1 deficiency in children with unexplained hepatic dysfunction, hypoglycemia, neuromuscular symptoms, and congenital anomalies, and highlights the diagnostic value of early genomic testing.

INTRODUCTION

Glycogen storage diseases (GSDs) are inherited metabolic disorders of carbohydrate processing that lead to excessive or abnormal glycogen accumulation in tissues. Their onset varies from the neonatal period to adulthood, with clinical manifestations arising either from impaired glycogen mobilization for energy production or from the deleterious buildup of glycogen[1]. The overall incidence of GSDs is estimated at approximately 1 in 20000 to 43000 live births. There is a broad spectrum of clinical presentations[2]. In hepatic GSDs, hypoglycemia is the primary feature, and hepatomegaly is typically present in all liver-involved subtypes except GSD-0. In contrast, muscle GSDs often manifest with exercise intolerance, muscle pain, rhabdomyolysis, and progressive muscle weakness[3]. Phosphoglucomutase-1 deficiency (GSD XIV) has been identified as both a glycogen storage disorder and a mixed congenital disorder of glycosylation. In one cohort, most developed multisystem disease, though a bifid uvula was often the only sign at birth. The condition was first recognized in 1963 through paternity testing and later classified as GSD type XIV after reports of glycogen accumulation, severe enzyme deficiency, and rhabdomyolysis[4]. Here, we present a case of GSD XIV with multisystem involvement.

CASE PRESENTATION

Chief complaints

A three-year-old female child had multisystem involvement, including recurrent hypoglycemia, hepatomegaly, coagulopathy, cleft palate with repeated surgical dehiscence, and emerging neuromuscular signs.

History of present illness

This child was born from a consanguineous marriage at 38 weeks of gestation via cesarean section due to transverse lie with a birth weight of 2.35 kg. Despite term delivery, intrauterine growth restriction was suspected antenatally and estimated at around 35 weeks of gestation. The neonate was admitted to the neonatal intensive care unit for feeding. At birth, an isolated cleft palate with a bifid uvula was identified with no other dysmorphic features. On the second day of life, a systolic murmur was noted and echocardiography revealed a small apical ventricular septal defect (VSD) (4 mm) with a left-to-right shunt and mild pulmonary stenosis. Follow-up imaging at 8 months of age confirmed spontaneous closure of the VSD, with persistent mild pulmonary stenosis and at 13 months of age, preoperative cardiac evaluation for cleft palate repair revealed no abnormalities. At 11 months of age, the infant experienced febrile convulsions following an upper respiratory infection and was hospitalized four times in the following months due to wheezing episodes, where she was diagnosed with asthma and managed with inhaled albuterol and beclomethasone.

Three attempts for surgical cleft palate repair were performed at 15, 18, and 30 months of age, respectively, yet all were unsuccessful. During preoperative assessment for the second operation, the patient was incidentally found to have elevated liver enzymes through the first liver function test performed since her initial presentation (Table 1) and hepatomegaly without jaundice. The patient had also experienced two prior episodes of ketotic hypoglycemia at 12 months of age and 18 months of age, respectively, which prompted further investigations for possible underlying metabolic, hematological, or hepatic disease. After a month of follow-up, further laboratory testing was performed upon suspected underlying metabolic, hematological, or hepatic disease (Table 2). Two months later, the patient then presented with febrile convulsions, epistaxis, and metabolic acidosis (Table 3).

Table 1 Initial liver function and coagulation profile.

Parameter	Value
ALT (U/L)	237.2
AST (U/L)	323.5
Albumin (g/L)	45.2
PT (seconds)	17.0
PTT (seconds)	34.6
INR	1.33

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; PT: Prothrombin time; PTT: Partial thromboplastin time; INR: International normalized ratio.

Table 2 Comprehensive coagulation factor and liver enzyme evaluation suggestive of chronic hepatic dysfunction.

Parameter	Value
ALT (U/L)	94.3
AST (U/L)	224.3
PT (seconds)	16.7
PTT (seconds)	33.0
INR	1.25
Factor V (%)	64
Factor VII (%)	36
Factor VIII (%)	98
Factor IX (%)	59
Factor X (%)	47
Protein C (%)	23
vWF antigen (%)	87
Factor V leiden (seconds)	180.9

ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; PT: Prothrombin time; PTT: Partial thromboplastin time; INR: International normalized ratio; vWF: Von Willebrand factor.

Table 3 Arterial blood gas analysis during acute metabolic acidosis.

Parameter	Value
pH	7.293
PaCO2 (mmHg)	31.4
HCO3- (mmol/L)	14.9

PaCO₂: Partial pressure of carbon dioxide; HCO₃^-: Bicarbonate.

History of past illness

The patient’s family stated that there is no relevance to past medical history.

Personal and family history

The pregnancy was complicated by oligohydramnios, and the mother had a history of acute lymphoblastic leukemia previously treated with chemotherapy in 2017 and her sister has type 1 neurofibromatosis. The patient has two younger siblings without similar symptoms or significant medical history. Notably, two maternal cousins became wheelchair-dependent at the ages of 10 and 12, respectively, due to an undiagnosed neuromuscular condition, raising suspicion for a hereditary condition.

Physical examination

Physical examination revealed delayed and nasal speech and positive Gower’s sign, suggestive of proximal muscle weakness. No evidence of skin abnormalities or skeletal deformities was noted.

Laboratory examinations

Further laboratory investigations following the third cleft palate repair at around 2.5 years of age demonstrated transaminitis, prolonged prothrombin time, partial thromboplastin time, and elevated international normalized ratio, along with mildly decreased levels of several coagulation factors and low protein C activity (Table 2). A comprehensive infectious workup, including testing for cytomegalovirus, Epstein-Barr virus, and hepatitis B and C, was negative. Metabolic and immunologic screening, comprising serum alpha-1 antitrypsin, ceruloplasmin, autoimmune markers (anti-nuclear antibody, anti-neutrophil cytoplasmic antibody, anti-cardiolipin, anti-LKM-1, antiphospholipid antibodies, anti-beta-2-glycoprotein I), tissue transglutaminase antibodies (immunoglobulin A and immunoglobulin G), thyroid function, and sweat chloride levels, were all within normal limits. Whole exome sequencing was then performed upon the suspicion of GSD.

Imaging examinations

Brain computed tomography revealed no evidence of structural abnormalities or periventricular calcifications. Electroencephalography did not show epileptiform activity. Ophthalmologic evaluation was negative for uveitis or retinal involvement.

FINAL DIAGNOSIS

Considering the patient’s multisystem involvement, including recurrent hypoglycemia, hepatomegaly, coagulopathy, cleft palate with repeated surgical dehiscence, and emerging neuromuscular signs, genetic evaluation was pursued. Whole exome sequencing revealed a homozygous pathogenic variant in the PGM1 gene (NM-002633.3: C.1294G>T), confirming a diagnosis of type XIV GSD.

TREATMENT

Following the confirmation of type XIV GSD, the patient was initiated on oral D-galactose supplementation, the recommended therapeutic approach for this condition. Galactose dosing was carefully titrated according to weight and tolerance, with ongoing monitoring of liver enzymes, coagulation parameters, and biochemical markers of glycosylation. Given the chronic and multisystemic nature of the condition, she will require regular, long-term follow-up to assess future outcomes. Ongoing adjustments to galactose therapy and supportive management will be guided by her evolving clinical course and repeat laboratory evaluations.

OUTCOME AND FOLLOW-UP

The patient is being followed up.

DISCUSSION

GSD type XIV primarily affects skeletal muscles[1], and its features usually vary amongst patients, as with other GSDs, leading to difficulty in determining their true incidence, as symptoms may overlap with other conditions and since no standardized testing has been established across most areas globally[1]. In this patient, type XIV GSD was confirmed via whole exome sequencing, highlighting the potential of genetic screening in patients with a background of consanguineous families. Notably, the patient experienced multiple episodes of ketotic hypoglycemia, which is often more associated with liver GSDs yet also with GSD XIV[5,6]. This supports maintaining a high index of suspicion for phosphoglucomutase mutations in patients presenting with ketotic hypoglycemia[7]. Additionally, this patient is uniquely presented with recurrent episodes of febrile seizures rather than recurrent unprovoked seizures suggestive of epilepsy. In patients with GSDs, brief neonatal hyperinsulinemic hypoglycemic seizures may occur, while other patients may develop epilepsy. Gataullina et al[8] suggest that recurrent status epilepticus was often associated with fever in type I GSD patients, warranting further investigation and care for these patients. This makes it essential to distinguish between patients who require long-term administration of antiseizure medications. Further studies must explore this specifically in type XIV GSD to better understand the association between febrile seizures, controlling the disease, and neurological manifestations.

Regarding diagnosis, a comprehensive assessment of patients is necessary, as seen in this case, necessary in mitigating the risk of delayed or misdiagnosis, which could potentially result in adverse sequelae of GSDs generally[8]. A muscle biopsy could be performed when there is a suspicion of GSD XIV. Negative findings do not exclude diagnosis since only 1 of 24 patients exhibited abnormal glycogen accumulation in periodic acid-schiff staining, highlighting pathological heterogeneity that seems to be related to different impacts of various mutations on the enzyme[6]. While a muscle biopsy was not conducted, our patient has shown signs of myopathy, which suggests the importance of further investigation, whether through genetic testing or muscle biopsy, to rule out GSDs.

The treatment of GSDs mainly involves supplementation, specifically galactose, which aims to improve growth, decrease hypoglycemic episodes, and restore hypogonadotropic hypogonadism[9]. Voerman et al[9] have demonstrated that galactose supplementation also improves walking distance, normalizing the use of skeletal muscle substrate from fat to carbohydrates during exercise. However, further research is needed to investigate the potential of AAV9-PGM1 gene therapy expressing PGM1 in mice, showing promise in preventing and halting dilated cardiomyopathy, which galactose supplementation does not alleviate[10].

To the best of our knowledge, this is the first confirmed case of type XIV GSD reported in the Middle East and North Africa (MENA) region, adding valuable geographic and genetic diversity to the limited global literature on this condition, particularly in a region where consanguinity is relatively more common. Uniquely, this patient presented with early hepatic manifestations preceding the onset of classical myopathy, including ketotic hypoglycemia, persistent transaminitis, and coagulopathy characterized by reduced protein C and multiple clotting factors, in the absence of structural liver disease. The case is further distinguished by the presence of a VSD that resolves spontaneously and recurrent febrile seizures occurring independently of hypoglycemic episodes or progression to epilepsy. These findings raise important questions about potential genotype-phenotype correlations and the broader phenotypic variability within GSDs. If substantiated in larger cohorts in association with certain variants of PGM1 mutations, certain features may serve as early prognostic markers or therapeutic decision points.

Despite our case presenting a unique case of GSD XIV, there are multiple limitations to consider. Firstly, no liver or muscle biopsy was performed, which could have further substantiated the clinical diagnosis and provided histopathological correlation with the identified PGM1 mutation. While previous studies report that muscle biopsies may be inconclusive in many patients with this condition, especially due to variable glycogen accumulation, such data can still contribute to our understanding of the genotype-phenotype relationship. Importantly, while genetic screening of immediate family members was initiated following the index patient’s diagnosis, extended family testing - including in relatives with known neuromuscular disease - remains incomplete. Broader familial analysis could provide valuable insights into the penetrance and expression variability of PGM1 mutations, particularly in consanguineous families, as in this case.

CONCLUSION

This case report highlights the value of a multidisciplinary and genomics-guided approach in managing unexplained multisystem disease in early childhood for timely diagnosis and management of rare GSDs to optimize management strategies and mitigate the risk of adverse sequelae.