Analyses of up to 20 years of data from the Fabry Outcome Survey (FOS) assessed the long-term effectiveness of agalsidase alfa enzyme replacement therapy.

The impact of agalsidase alfa treatment on renal, cardiac, morbidity, and mortality outcomes in FOS was compared with untreated external Fabry disease (FD) cohorts.

A total of 2171 FOS patients (1014 men, 919 women, 163 boys, 75 girls) received agalsidase alfa (median [range] duration of treatment: 5.38 [0.0-20.8] years). Annual rates of decline in estimated glomerular filtration rate improved in treated patients versus untreated external cohorts regardless of sex or baseline urinary protein levels. Annual left ventricular mass index rates were stable in treated patients regardless of sex or baseline left ventricular hypertrophy status, and better than in untreated external cohorts. The mean age at which 50 % of patients had their first composite morbidity event was later in the agalsidase-alfa-treated population than in the untreated external cohort (51.7 vs 41 years [males]; 60.8 vs 53 years [females]). After 24 months of treatment, the probability of a composite morbidity event was ∼34 % in treated patients and ∼ 45 % in untreated patients. Treated patients were older at death than untreated patients (mean [range]: 61.7 [26.2-87.6] vs 50.3 [34.5-70.1] years). The mean age at which 50 % of male patients were still alive was higher in treated patients than in untreated external cohorts (75.5 vs 60.0 years).

Long-term treatment with agalsidase alfa may provide renal, cardiac, and overall survival protection in FD.

Pompe disease is caused by pathogenic variants in the GAA gene, resulting in lysosomal acid α-glucosidase (GAA) deficiency. The prevalence of Pompe disease is not well-defined, and estimates vary by geographic region. We evaluated the global epidemiology of Pompe disease and the potential reasons for differing prevalence estimates using published data from worldwide newborn screening (NBS) programs and population-based studies.

A comprehensive literature search in PubMed was conducted in July 2023, updated in March 2024, and validated with an Embase search in June 2024. Search terms included Pompe disease, GSDII, prevalence, incidence, epidemiology, survival, mortality, and NBS. Studies were included based on robust epidemiological methods, the presence of disease definition, and publication within the past 5 years. We identified 1210 abstracts, of which 295 met recency criteria, 30 were deemed relevant, and 11 met all inclusion criteria.

Prevalence estimates and GAA enzyme activity cutoff values varied across geographic regions. In NBS studies, the birth prevalence of infantile-onset Pompe disease (IOPD) ranged from 1 in 297,387 in Japan to 1 in 62,186 in Taiwan, and late-onset Pompe disease (LOPD) ranged from 1 in 82,914 in Taiwan to 1 in 17,133 in Pennsylvania. Data from the French National Pompe Registry (N = 246) showed an increase in diagnosis of LOPD from 2.6/year before 2001 to 10.6/year during 2001-2010 and 12.8/year during 2011-2015. Enzyme cutoffs in dried blood spots varied from < 3% of lymphocyte mean to 2.10 μmol/L/h to ≤ 18% of the daily median. Three studies noted higher prevalence in populations of African descent, and two noted a higher frequency of pseudodeficiency alleles in Asian populations.

This scoping review confirmed that prevalence estimates differ for IOPD and LOPD and vary by geographic region, potentially by race and ethnicity. It highlights the need to standardize screening and diagnosis methods, genetic testing protocols, and uniform disease classification between IOPD and LOPD.

Laboratory diagnosis of acid sphingomyelinase (ASM) deficiency (ASMD) was implemented in France in the early 1970s. The aims of this study were (i) to review the combined use of successively developed strategies - enzyme measurement, genetic testing, and biomarkers analysis - and (ii) to describe the mutational spectrum and epidemiological characteristics of a large patient cohort followed in French hospitals.

During the 1974-2023 period, 271 patients with ASMD (238 families) were diagnosed. The chronic visceral form (historical Niemann-Pick type B) constituted 68 % of the cases, the infantile neurovisceral (type A) form 23 %, and the chronic neurovisceral (type AB) form 9 %. Profoundly deficient ASM activities were constantly observed in the neuronopathic forms. Elevated plasma concentrations of LysoSM and LysoSM-509/PPCS proved useful to comfort interpretation of ASM activities near cut-off found in leukocytes or dried blood spots of some patients with ASMD type B. Although not specific, LysoSM-509/PPCS appeared as the most sensitive biomarker. The spectrum of SMPD1 variants was investigated in 183 families. A total of 93 different SMPD1 variants (26 novel ones) was identified (58 % missense, 19 % frameshift, and 12 % nonsense ones). The proportion of null variants was much larger in ASMD type A (63 %) than in type B (24 %). In type AB, c.1177 T > G (p.Trp393Gly) contributed 32 % of the mutant alleles, most patients having Romani or Northwestern-Balkanic roots, while c.880C > A (p.Gln294Lys) only accounted for 9 %. Homoallelic variants in neuronopathic patients allowed genotype/phenotype correlations. In type B, c.1829_1831delGCC (p.Arg610del) represented 57 % of alleles, with a wide diversity of other variants. Among type B families, approximately one-third had a North African origin, and this variant accounted for 91 % alleles in this subgroup, compared to 40 % in non-North-African families. In patients homozygous for p.Arg610del (n = 69), the age at biological diagnosis was significantly higher (34.0 years; IQR 7.4-45.3) than in patients with either one (n = 41) [4.3 years; IQR 2.77-18.30] or no such allele (n = 43) [6.3 years; IQR 2.2-31.7]. A further observation was the proportional increase in the number of type B patients diagnosed after the age of 30 years since 2015. This nearly complete national cohort allowed a tentative evaluation of (minimal) incidences at birth as follows: ASMD (all clinical forms): 0.70/100,000; type B: 0.48/100,000; neuronopathic types (A and AB): 0.22/100,000.

This comprehensive cohort (i) summarizes the real-life experience of laboratory diagnosis of ASMD in two expert centres, (ii) confirms the high frequency of the p.Arg610del allele in France and discloses some characteristics of patients homozygous for this variant; (iii) provides for the first time data on the distribution, mutational spectrum and tentative incidence at birth of the three clinical phenotypes of ASMD in France.

Advanced heart failure (HF) is characterized by changes in the structure, function, and metabolism of cardiac muscle. As the disease progresses, cardiomyocytes shift their ATP production from fatty acid oxidation to glycolysis. This shift results in an accumulation of lipid metabolites, particularly sphingolipids, which can disrupt normal cellular function and contribute to cardiac dysfunction. In animal models of obesity, accumulation of toxic sphingolipid metabolites in the heart has been described as cardiac lipotoxicity. In humans, HF is classified into two groups based on ejection fraction (EF): HF with reduced EF of less than 40% (HFrEF) and HF with preserved EF of greater than 50% (HFpEF). Despite shared risk factors and comorbidities, the structural and cellular differences between HFrEF and HFpEF distinguish them as separate conditions. Ceramides (Cer), a type of sphingolipid, have gained significant attention for their involvement in the development and prognosis of atherosclerotic disease and myocardial infarction, while sphingosine-1-phosphate, a downstream product of Cer, has shown cardioprotective properties. The aim of this review is to describe the role of sphingolipids in HF with reduced and preserved EF. By understanding the role of sphingolipids through animal and human studies, this review aims to pave the way for developing strategies that target abnormal signalling pathways in the failing heart, ultimately bridging the gap between scientific research and clinical applications.

Although α-synuclein pathology is typically associated with Lewy body diseases and multiple systems atrophy, increasing evidence indicates that it also occurs in a group of lysosomal storage disorders termed sphingolipidoses caused by the incomplete degradation, and subsequent accumulation, of a class of lipids termed sphingolipids. Notably, a number of genes that cause sphingolipidoses are also risk genes for Lewy body diseases, suggesting aetiological links between these distinct disorders. In the present review, we discuss the sphingolipidoses in which α-synuclein pathology has been reported: Gaucher disease, Krabbe disease, metachromatic leukodystrophy, Tay-Sachs disease and Anderson-Fabry disease, and describe the characteristic clinical and pathological features of these disorders, in addition to the evidence suggesting α-synuclein pathology occurs in these disorders. Finally, we evaluate the pathological mechanisms that underlie these rare disorders, with particular attention to how the enzymatic deficiency, substrate accumulation, or both, could contribute to the genesis of α-synuclein pathology and the implications of this for Lewy body diseases.

Diagnosing Fabry disease can be challenging due to its broad spectrum of clinical presentations, highlighting the need for a high index of suspicion. A 59-year-old male patient with personal and family history of persistent hematuria was referred to our renal clinic for workup. Genetic workup confirmed a heterozygous inheritance pattern of alpha-4 chain of type IV collagen. A renal biopsy revealed characteristic electron microscopic findings typical of a lipid storage disease within the glomerular podocytes, reminiscent of Fabry disease. This case in an older adult patient underscores the variability of clinical presentation in Fabry disease, together with another inherited type IV collagen disease and the critical role of renal biopsy in diagnosing atypical cases.

Fabry disease (FD) is a rare disorder resulting from a genetic mutation characterized by the accumulation of sphingolipids in various cells throughout the human body, leading to progressive and irreversible organ damage, particularly in males. Genetically-determined deficiency or reduced activity of the enzyme (alpha - Galactosidase; α-Gal) leads to the accumulation of sphingolipids in the lysosomes of various cell types, including the heart, kidneys, skin, eyes, central nervous system, and digestive system, triggering damage, leading to the failure of vital organs, and resulting in progressive disability and premature death. FD diagnostics currently depend on costly and time-intensive genetic tests and enzymatic analysis, often leading to delayed or inaccurate diagnoses, which contribute to rapid disease progression. In this research, mid-infrared Fiber Evanescent Wave Spectroscopy (FEWS) supported by statistical analysis and Machine Learning (ML) algorithms is shown to be an innovative and reliable method to detect globotriaosylsphingosine (Lyso-Gb3) FD biomarker in urine and serum samples by monitoring infrared spectra alone. ML showed a high selectivity for FD in the spectral range of Amide A and Amide I in blood serum, and α-D-galactosyl residues of glycosphingolipids in urine. The developed approach offers a promising, cost-effective express diagnostic tool sensitive enough for early FD detection and monitoring.

Objectives: Mucopolysaccharidoses (MPSs) are a group of a rare inherited lysosomal storage diseases caused by a deficiency or complete lack of lysosomal enzymes participating in glycosaminoglycan (GAG) degradation, which leads to multisystemic impairment and early mortality. This study aimed to determine the birth prevalence of MPS type I, II, III, IVA, VI, and VII in the Republic of Kazakhstan. Methods: Retrospective epidemiological calculations were carried out on all enzymatically and genetically confirmed MPS cases diagnosed between 1984 and 2023 in the Republic of Kazakhstan. Birth prevalence was calculated by dividing the number of patients diagnosed with MPS by the total number of live births in the same period, recalculated for every 100,000 live births. Results: The overall birth prevalence of MPS was 0.77 per 100,000 live births. The highest birth prevalence was MPS II with 0.36 (47% of all diagnosed MPS types), followed by MPS I with 0.16 (21%), MPS VI with 0.12 (16%), MPS IVA with 0.09 (11%), MPS IIIB with 0.03 (4%), and MPS VII (which is the rarest type) with 0.007 (1%). Conclusions: The most common MPS type in the Republic of Kazakhstan is MPS II (Hunter syndrome).

Fabry disease (FD) is the second most common lysosomal storage disorder. It mainly affects young people. FD can be characterized by neurological symptoms that can occur in both the central and peripheral nervous systems. Cerebrovascular involvement is common in FD and is considered an important cause of cryptogenic strokes. This study aimed to describe the neurological symptoms in patients with FD in general and, specifically, to determine the frequency of association between this disease and cerebrovascular manifestations in our environment.

This retrospective, observational, cross-sectional study included all patients in the FD registry of the nephrology and cardiology Departments of our center. A descriptive analysis of demographic, neurological, clinical, and neuroimaging variables was performed, with a particular focus on their association with stroke or other cerebrovascular events prior to diagnosis.

A total of 25 patients were included, with 14 (68%) of them being women. The median age of the patients was 52 years (relative intensity of collaboration [RIC] = 24.5). The patients belonged to five families with specific galactosidase alpha gene (GLA) mutations. Neuroimaging was performed in 13 (52%) patients, most of whom did not have neurological symptoms but had normal imaging results. Only 2 (8%) patients had nonspecific white matter hyperintensities. Among the 11 (44%) patients with neurological involvement, the most common symptom was pain in the extremities (32%). Stroke was identified in only one patient (4%), which occurred prior to the diagnosis of FD and was determined to be of cardioembolic etiology.

FD is found to be associated with several neurological symptoms. In our study, the most common neurological symptom was limb pain, which had varied characteristics. On the other hand, the incidence of stroke was significantly lower than that expected.

Metabolic storage disorders, including lysosomal storage disorders, pose complex challenges in management due to their progressive and life-threatening nature. Although enzyme replacement therapy has substantially improved outcomes for patients with lysosomal storage disorders, limitations of this therapy have become apparent throughout two decades of use. New clinical features of these diseases have emerged as patients live longer, leading to unresolved questions regarding ongoing treatment and long-term care. Innovative therapies are emerging that aim to improve targeting of tissues, particularly for previously inaccessible areas such as the CNS. These next-generation treatments hold promise for enhancing patient outcomes beyond what enzyme replacement therapy can do. Continued exploration of novel therapeutic strategies will be crucial for providing more effective and personalised care for these complex diseases.

Alpha-mannosidosis (AM; OMIM 248500) is a rare autosomal recessive lysosomal storage disorder caused by mutations in MAN2B1, which codes for the lysosomal alpha-mannosidase enzyme (LAMAN; EC:3.2.1.24). Clinical characteristics include developmental delay, hearing impairment, and recurrent infections. A retrospective analysis of nine case series of patients with AM (23 months-42 years) from six consanguineous families in the United Arab Emirates (UAE) was conducted. In two Emirati families, homozygous nonsense mutations were present: c.2368C> T, p.(Gln790*) and c.2119C> T, p.(Gln707*). Further, in the Emirati and Syrian families two splicing variants c.2356-2A>G and c.1929-2A>G were present, respectively. All patients had infantile-onset and common clinical features, including coarse facies, developmental delays, hearing loss, and recurrent infections. Macrocephaly was observed in all patients with documented head circumference, except one microcephalic patient who had a dual genetic diagnosis. Hepatosplenomegaly and autoimmune diseases were reported in one and three patients, respectively. Additionally, psychiatric manifestations were noted in two adult patients. The mean age of diagnosis was 14 years for adults (> 16 years) and 2 years for pediatric patients (< 16 years). Significant diagnostic delay comparing older and younger generations is likely due to the increasing awareness of genetic disorders and the availability of genetic testing. In terms of treatment, enzyme replacement therapy (ERT) was administered to two patients, alleviating recurrent infections. Two patients underwent hematopoietic stem cell transplantation (HSCT), whereas one patient underwent combined ERT and HSCT. This retrospective analysis identified different truncating mutations associated with early-onset AM. The clinical presentations of these mutations range from attenuated to moderate. Our analysis clearly highlights the high birth prevalence of AM in the UAE, indicating the need for awareness and genetic counseling for prevention.

Fabry disease is a rare genetic lysosomal storage disorder, whereby the accumulation of sphingolipids consequently leads to kidney structural damage and dysfunction. We explored the epidemiology of chronic kidney disease (CKD) among patients with Fabry disease at a major UK referral centre in Greater Manchester serving over 7 million people, to inform early predictors of kidney disease and possible treatment planning.

Data were sourced from the electronic records of registered participants from November 2020 to February 2022 of adults diagnosed with Fabry disease, with at least 1 year of follow-up. Four hundred and five participants (female = 223, male = 182) met the initial eligibility criteria. Our study focused on identifying factors linked to incident CKD, with 395 evaluable individuals undergoing outcome analysis over a median of 6.4 years.

Findings concluded that 60.5% of participants received disease-modifying treatments, 29.7% experienced non-fatal cardiovascular events, 3.3% developed end-stage kidney disease (ESKD), and 7.3% died. Men had higher use of disease modifying therapy, progression to ESKD requiring kidney replacement therapy, cardiovascular events, and mortality compared to women. Subgroup analysis over 9 years revealed that older age, cardiovascular history, renin-angiotensin-aldosterone system inhibitor use, and higher urine albumin-to-creatinine ratio (uACR) were predictors of faster estimated glomerular filtration rate (eGFR) decline and increased mortality. At baseline, 47.8% of 249 patients with uACR data had CKD, and 25.4% of the remaining individuals developed CKD during follow-up, associated with higher uACR and lower, albeit normal eGFR levels.

Over 60% of Fabry disease patients are at lifetime risk of developing CKD, with a substantial risk of mortality, even with initially normal uACR and eGFR values.

Background/Objectives: Fabry disease (FD) is a rare X-linked lysosomal storage disorder characterised by progressive glycolipid accumulation affecting multiple organs, including the peripheral nervous system. The dorsal root ganglia (DRG) play a key role in Fabry-related neuropathy, but non-invasive biomarkers of DRG involvement and their association with overall disease severity remain limited. This study evaluated lumbosacral DRG T2 relaxation time (DRG-T2) in FD patients as a potential imaging biomarker of FD severity. Methods: In a prospective, single-centre study, 80 genetically confirmed FD patients underwent 3T MRI with quantitative T2 mapping of the lumbosacral DRG. DRG-T2 was analysed in relation to sex, genetic subtype and Fabry-specific biomarkers. Results: Results showed that DRG-T2 was higher in patients with classical FD mutations than in those with nonclassical mutations (p = 0.03). Furthermore, DRG-T2 showed a negative correlation with body weight (ρ = -0.31, p = 0.005) and BMI (ρ = -0.32, p = 0.004), while no associations were found with lyso-Gb3 levels or alpha-galactosidase A activity. The inter-rater and test-retest reliability of DRG-T2 were good to excellent (ICC = 0.76 and 0.89, respectively). Conclusions: These results demonstrate DRG-T2 as a marker of neuronal involvement, making it a strong and reliable imaging biomarker of disease severity in FD. However, future studies need to correlate its changes with clinical and histological studies.

Prevalence studies of acid sphingomyelinase deficiency (ASMD) are scarce and different in Spain. The objective of the present study was to determine the estimated prevalence of patients diagnosed with ASMD (types A/B and B) in Spain.

PREVASMD was a descriptive, multicenter, and ecological study involving 21 physicians from different specialties (mainly Internal Medicine, Paediatrics and Hematology), of different autonomous communities, with experience in ASMD management.

Between March and April 2022, specialists were attending a total of 34 patients with ASMD diagnosis, 10 paediatric patients under 18 years of age (29.4%) and 24 adult patients (70.6%). The estimated prevalence of patients (paediatric and adult) diagnosed with ASMD was 0.7 per 1,000,000 inhabitants (95% confidence interval, 95% CI: 0.5-1.0), 1.2 per 1,000,000 (95% CI: 0.6-2.3) in the paediatric population and 0.6 per 1,000,000 inhabitants (95% CI: 0.4-0.9) in the adult population. The most frequent symptoms that led to suspicion of ASMD were: splenomegaly (reported by 100.0% of specialists), hepatomegaly (66.7%), interstitial lung disease (57.1%), and thrombocytopenia (57.1%). According to the specialists, laboratory and routine tests, and assistance in Primary Care were the most relevant healthcare resources in the management of ASMD.

This first study carried out in Spain shows an estimated prevalence of patients of 0.7 per 1,000,000 inhabitants: 1.2 per 1,000,000 inhabitants in the paediatric population and 0.6 per 1,000,000 inhabitants in the adult population.

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.

Fabry disease (FD) results from pathogenic GLA variants, leading to a deficiency in lysosomal α-galactosidase A (α-Gal A) and accumulation of the sphingolipid globotriaosylceramide (Gb3). This leads to severe renal and cardiovascular complications, primarily affecting kidney podocytes. As a multisystemic disorder, FD initiates at the cellular level; however, the mechanism(s) underlying Gb3-induced cell dysfunction remain largely unknown. This study aimed to identify potential drivers of FD and explore the underlying cell pathology in induced pluripotent stem cell (iPSC)-derived podocytes from patients with FD.

iPSCs were derived from patients with FD with GLA c.851T>C or GLA c.1193_1196del variants and compared with controls or CRISPR-Cas9-corrected cell lines. iPSCs were differentiated into podocytes; and α-Gal A activity, Gb3 accumulation, and cell morphology were assessed. Label-free mass spectrometry identified the top, differentially expressed proteins which were validated by using western blot.

Podocytes derived from patients with FD exhibited expression of podocyte-specific markers and morphological features of FD. Reduced α-Gal A activity was observed in FD iPSC-derived podocytes along with the accumulation of Gb3. Proteomic profiling revealed distinct proteomic signatures between control and iPSC-derived podocytes from a patient with FD, with apparent variations among FD lines, highlighting GLA variant-specific proteomic alterations. Notably, the ferroptosis-associated protein, arachidonate 15-lipoxygenase (ALOX15), was the most upregulated protein in FD podocytes and ferroptosis was the most enriched pathway. Western blot analysis confirmed the upregulation of ALOX15 in FD podocytes, with validation of other markers implicating ferroptosis in FD pathology.

These findings underscore the heterogeneity of FD and, for the first time, implicate ferroptosis as a potential common pathway driving its pathology.

Sialidosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the NEU1 gene, resulting in deficient neuraminidase-1 activity and the subsequent accumulation of sialylated compounds in lysosomes. This review comprehensively analyzes the genetic and clinical heterogeneity associated with sialidosis, emphasizing the distinction between the milder type I form and the more severe type II form. Over 90 pathogenic NEU1 variants, predominantly missense mutations, have been identified, highlighting significant phenotypic diversity. Advancements in genomic sequencing technologies have facilitated the identification of known and novel mutations, with population-specific insights elucidating ethnic variability in symptomatology and genetic profiles. Recent case studies, including a novel compound heterozygous variant, further illustrate the complexity of the genotype-phenotype correlations. Emerging therapeutic approaches, such as enzyme replacement therapy and adeno-associated virus-mediated gene therapy, demonstrate promising potential for restoring neuraminidase-1 function and improving outcomes in preclinical models. This review emphasizes the critical role of genetic analysis in diagnosis and management while advocating for continued research into the molecular mechanisms underlying sialidosis to enable the development of targeted, personalized treatments.

Preimplantation genetic testing (PGT) is practiced worldwide, allowing the prevention of the transmission and expression of various genetic conditions. Socio-ethical considerations of justified applications for PGT are part of an ongoing debate. Pathogenic variants in the glucocerebrosidase (GBA1) gene, causing Gaucher disease (GD), have emerged as a risk factor for Parkinson's disease (PD) in both patients and carriers. Genotype-phenotype correlations exist between different GBA1 pathogenic variants and the risk to develop PD: mild pathogenic variants increase the risk of developing PD by ~3-fold, while severe pathogenic variants increase this risk by ~15-fold, occurring at a younger age. A woman with GD, a compound heterozygote of N370S (now commonly described as c.1226A>G (N409S)-mild pathogenic variant) and 84insG (severe pathogenic variant), had PGT consulting before planned in vitro-fertilization. Her mother, an 84insG carrier, had early-onset PD. GBA1 sequencing of her spouse was negative. We discussed the selection for N370S carrier embryos to reduce PD risk. This case report demonstrates the expansion of PGT for late-onset conditions. These novel indications will increase the number of subjects who would be candidates for PGT. The medical and bioethical considerations of these cases should be acknowledged by the professional community and discussed with couples during genetic counseling.

Hearing impairment is a prevalent clinical feature in Morquio syndrome (mucopolysaccharidosis IVA or MPS IVA) patients, often presenting in diverse forms: conductive, sensorineural, or a combination known as mixed hearing loss. The mixed form entails a blend of both conductive and sensorineural elements, typically exhibiting a progressive trajectory. This scoping review aimed to comprehensively analyze available evidence pertaining to the pathophysiology, classification, epidemiology, and clinical management of hearing loss in individuals with MPS IVA.

Targeted literature was searched using MEDLINE, Literatura Latino-Americana e do Caribe em Ciências da Saúde, Web of Science, the Cochrane Library, Trip Medical Database, Embase, ScienceDirect, and Google Scholar, with a second search cycle to identify gray literature. A systematic search strategy using Medical Subject Headings keywords was implemented: "Hearing Disorders" OR "Hearing Loss" AND "Mucopolysaccharidosis IV" or "Hearing Disorders" OR "Hearing Loss" AND "Mucopolysaccharidosis IV." The identified bibliography was uploaded to COVIDENCE platform for information management. Articles were screened by 3 independent reviewers following the eligibility criteria.

Twenty-seven articles met the inclusion criteria, spanning information from 568 patients across 16 different countries. None of the studies had complete epidemiological information. Only 2 studies provided sufficient data to address the pathophysiology, while 3 addressed management and treatment. Hearing loss was reported in 210 of 568 patients. A total of 19.2% of patients reported recurrent ear infections. None of the studies reported vertigo, tinnitus, or dizziness in the patients. Pure-tone audiometry was the primary test used to diagnose and monitor auditory impairment in patients with Morquio syndrome.

Five hundred sixty-eight patients with MPS IVA were identified, of whom 210 (37%) developed hearing loss, the most common of which was moderate. Despite the lack of information on the diagnosis and management of hearing loss in Morquio syndrome, this study found that approximately one-third of participants exhibited some form of auditory impairment, with the majority of these cases being sensorineural in nature.

Gaucher disease (GD) is a rare lysosomal disorder characterized by the accumulation of glycosphingolipids in macrophages resulting from glucocerebrosidase (GCase) deficiency. The accumulation of toxic substrates, which causes the hallmark symptoms of GD, is dependent on the extent of enzyme dysfunction. Accordingly, three distinct subtypes have been recognized, with type 1 GD (GD1) as the common and milder form, while types 2 (GD2) and 3 (GD3) are categorized as neuronopathic and severe. Manifestations variably include hepatosplenomegaly, anemia, thrombocytopenia, easy bruising, inflammation, bone pain and other skeletal pathologies, abnormal eye movements and neuropathy. Although the molecular basis of GD is relatively well understood, currently used biomarkers are nonspecific and inadequate for making finer distinctions between subtypes and in evaluating changes in disease status and guiding therapy. Thus, there is continued effort to investigate and identify potential biomarkers to improve GD diagnosis, monitoring and potential identification of novel therapeutic targets. Here, we provide a comprehensive review of emerging biomarkers in GD that can enhance current understanding and improve quality of life through better testing, disease management and treatment.

Background: Mucopolysaccharidosis (MPS) Type III (MPS III) or Sanfilippo syndrome is a rare autosomal recessive inherited metabolic disorder. This disorder is responsible for lysosomal storage disorder at the cellular aspect. Due to lysosomal enzyme perturbance leading to the alteration of macromolecule metabolisms, this cellular perturbance causes multiple severe systemic and mental outcomes. Sanfilippo syndrome is the most frequent lysosomal disorder among the different types of MPS. Case Presentation: A 9-year-9-month-old female was presented at our private clinic accompanied with her parents and referred from a general practitioner, and the preclinical examination revealed atypical craniofacial structure and skeletal features such as abnormal posture and movements adding on atypical behavioral manifestations such as temper tantrums, speech difficulties, dementia, and destructive behavior.

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future.

There are currently at least 70 characterised lysosomal storage diseases (LSD) resultant from inherited single-gene defects. Of these, at least 30 present with central nervous system (CNS) neurodegeneration and overlapping aetiology. Substrate accumulation and dysfunctional neuronal lysosomes are common denominator, but how variants in 30 different genes converge on this central cellular phenotype is unclear. Equally unresolved is how the accumulation of a diverse spectrum of substrates in the neuronal lysosomes results in remarkably similar neurodegenerative outcomes. Conversely, how is it that many other monogenic LSDs cause only visceral disease? Lysosomal substance accumulation in LSDs with CNS neurodegeneration (nLSD) includes lipofuscinoses, mucopolysaccharidoses, sphingolipidoses and glycoproteinoses. Here, we review the latest discoveries in the fundamental biology of four classes of nLSDs, comparing and contrasting new insights into disease mechanism with emerging evidence of unifying convergence.

Pompe disease, also known as Glycogen storage disease type II, is an autosomal recessive disorder caused by defects in alpha-glucosidase, resulting in abnormal glycogen accumulation.

To conduct a systematic review and meta-analysis of birth prevalence of Pompe disease, the MEDLINE and EMBASE databases were searched for original research articles on the epidemiology of Pompe disease from inception until July 01, 2024. Meta-analysis was performed to estimate global birth prevalence of Pompe disease. The funnel plot was used to describe potential publication bias.

Twenty-two studies, screened out of 945 records, were included for data extraction. Studies that fulfilled inclusion criteria involved 15 areas/countries. Global birth prevalence of Pompe disease was 2.0 cases (95% CI: 1.5-2.4) per 100,000 live births. Global birth prevalence of infantile-onset Pompe disease was 1.0 cases (95% CI: 0.5-1.5) per 100,000 live births. Global birth prevalence of late-onset Pompe disease was 2.4 cases (95% CI: 1.8-3.0) per 100,000 live births. The main limitations are that no study was assessed as high-quality and approximately half of the studies were from Europe.

Quantitative data on the global epidemiology of Pompe disease could be the fundamental to evaluate the global efforts on building a better world for Pompe disease patients.

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with a broad clinical spectrum. Early diagnosis and initiation of treatment are crucial for improving outcomes, yet the disease often goes undiagnosed due to its rarity and phenotypic heterogeneity. This study aims to evaluate the feasibility and disease incidence of newborn screening (NBS) for ASMD in Italy. Dried blood spot samples from 275,011 newborns were collected between 2015 and 2024 at the Regional Center for Expanded NBS in Padua. Acid sphingomyelinase activity was assayed using tandem mass spectrometry. Deidentified samples with reduced enzyme activity underwent second-tier testing with LysoSM quantification and SMPD1 gene analysis. Two samples were identified with reduced sphingomyelinase activity and elevated LysoSM levels. Both carried two SMPD1 variants, suggesting a diagnosis of ASMD. Molecular findings included novel and previously reported variants, some of uncertain significance. The overall incidence was 1 in 137,506 newborns and the PPV was 100%. This study demonstrates the feasibility of NBS for ASMD in Italy and provides evidence of a higher disease incidence than clinically reported, suggesting ASMD is an underdiagnosed condition. Optimized screening algorithms and second-tier biomarker testing can enhance the accuracy of NBS for ASMD. The long-term follow-up of identified cases is necessary for genotype-phenotype correlation and improving patient management.

The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke.

A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed.

Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

Fabry disease (FD) is an X-linked rare disorder caused by mutations in the GLA gene. Women with FD have been less enrolled in studies and less treated compared with men. The aim of the present study is to describe the complete phenotype of the women cohort with FD diagnosed and evaluated in Romania and compare it to the male population. This study included all consecutive patients diagnosed with FD referred to the Expert Center for Rare Genetic Cardiovascular Diseases between 2014-2023 which included 73 consecutive Romanian FD patients: 41 women (56.2%) and 32 men (43.8%) from 33 unrelated families. Women with FD were diagnosed later and had a later symptom onset. Comparing with men, women were less often symptomatic, but with similar symptom severity. They had similar ophthalmologic and ENT involvement, but less angiokeratomas. Both women and men had similar heart failure symptoms, which were usually mild to moderate, with no difference between the age of developing of the heart failure symptoms. There were also similar rates of acroparesthesia and stroke between sexes, but women presented less renal involvement, with less requirement for renal transplant. This study demonstrates that women with Fabry disease are not just carriers of the disease, they can present symptoms as severe as men, and they have less or later access to pathogenic therapy. Further studies with more female participations are needed to better understand the burden of Fabry disease in women.

Fabry disease (FD) causes glycosphingolipid accumulation in the vascular endothelium, with predominantly cardiac and renal involvement. Its prevalence in patients with concomitant involvement of these two organs is unknown. The objective of the study was to determine the prevalence of FD in patients with left ventricular hypertrophy and any degree of chronic kidney disease.

Patients with ventricular thickness ≥13mm and kidney disease from 29 Spanish hospitals were included. Sociodemographic variables and target organ involvement of FD were collected. Laboratory determinations of EF were carried out, with an enzymatic activity test±genetic test in men and direct genetic test in women.

Eight hundred ninety-eight patients with left ventricular hypertrophy and chronic kidney disease were included. The presence of heart failure and cardiorenal syndrome was common (46.1% and 40.1%). Three patients (2 men and 1 woman) were diagnosed with FD, based on the presence of a pathogenic variant in the GLA gene and classic signs of FD, resulting in a prevalence of 0.33% (CI 95% 0.06-1%). Six patients (0.66%) presented genetic variants of unknown significance, without showing classic signs of FD, while in 13 patients (3.2%) performing the blood test was impossible.

FD is an important cause of left ventricular hypertrophy and chronic kidney disease. Genetic diagnosis is crucial for avoiding biases and ensuring accurate identification of FD, especially in women. The results support the inclusion of this disease in the differential diagnosis of patients with ventricular hypertrophy ≥13mm and chronic kidney disease.

The clinical diagnosis of Fabry Disease (FD) can be challenging due to the clinical heterogeneity, especially in females. Patients with FD often experience a prolonged interval between the onset of symptoms and receiving a diagnosis. Genetic testing is the gold standard for precise diagnosis of FD, however conventional genetic testing could miss deep intronic variants and large deletions or duplications. Although next-generation sequencing, which analyzes numerous genes, has been successfully used for FD diagnosis and can detect complex variants, an effective and rapid tool for identifying a wide range of variants is imminent, contributing to decrease the diagnostic delay.

The comprehensive Analysis of FD (CAFD) assay was developed for FD genetic diagnosis, employing long-range PCR coupled with long-read sequencing to target the full-length GLA gene and its flanking regions. Its clinical performance was assessed through a comparative analysis with Sanger sequencing.

Genetic testing was performed on 82 individuals, including 48 probands and 34 relatives. The CAFD assay additionally identified variants in two probands: one had a novel and de novo pathogenic variant with a 1715 bp insertion in intron 4, and the other carried two deep intronic VUS variants in cis-configuration also in intron 4. In total, CAFD identified 47 different variants among 48 probands. Of these, 42 (89.36%, 42/47) were pathogenic, while 5 (10.64%, 5/47) were VUS. Sixteen (34.04%, 16/47) of the variants were novel, including 15 SNV/Indels and one large intronic insertion. Pedigree analysis of 21 probands identified four de novo disease-causing variants. Hence, FD exhibits not only variable clinical presentations but also a wide spectrum of variants. Utilizing a comprehensive testing algorithm for diagnosing FD, which includes enzyme activity, clinical features, and genetic testing, the diagnostic yield of CAFD is 97.92% (47/48), which is higher than that of conventional Sanger sequencing, at 95.83% (46/48).

The duration between initial clinical presentation and diagnosis remains long and winding. CAFD provides precise diagnosis for a wide spectrum of GLA variants, promoting timely diagnosis and appropriate treatment for FD patients.

Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme ⍺-galactosidase-A (⍺-Gal A), resulting in widespread accumulation of terminal galactose-containing glycosphingolipids (GSLs) and the impairment of multiple organ systems. Thrombotic events are common in Fabry patients, with strokes and heart attacks being significant contributors to a shortened lifespan in patients of both genders. Previously, we developed an ⍺-Gal A-knockout (KO) murine model that recapitulates most Fabry symptomologies and demonstrated that platelets from KO males become sensitized to agonist-mediated activation. In the current report, we used mass spectrometry, platelet-based assays and histology to define further the mechanisms linking GSL accumulation with thrombotic phenotypes in both sexes. Sera and platelets from ⍺-Gal A-KO females have elevated levels of Fabry-associated GSLs relative to wild-type females, but accumulated less of these GSLs than KO males. Correspondingly, KO females demonstrate a less severe thrombotic phenotypes than KO males. Notably, treatment of platelets from wild-type animals with globotriaosylceramide (Gb3) increased baseline platelet activation and aggregation. In contrast, several control GSLs did not stimulate platelet responses. These data suggest that chronically high concentrations of the Fabry-associated GSL, Gb3, contributes to the prothrombotic phenotypes experienced by Fabry patients by directly stimulating platelet activation.

α-mannosidosis is an inborn error of metabolism caused by the deficiency of the lysosomal enzyme α-mannosidase, which is encoded by the MAN2B1 gene and inherited in an autosomal recessive manner. The impairment of affected individuals is multisystemic and very similar to the observed in some mucopolysaccharidosis (MPS) patients. The aim of this study was to search for α-mannosidosis cases in individuals with clinical suspicion of MPS without a confirmed diagnosis. Biochemical and molecular analysis were standardized by our group for this study. Two hundred and fifty samples from patients with clinical suspicion of MPS, but with inconclusive MPS biochemical and/or molecular analysis, were screened for α-mannosidase activity. Subsequently the MAN2B1 gene was sequenced in samples from 53 patients by the Sanger method.

The measurement of enzymatic activity detected fifty-three samples with abnormal results, suggesting α-mannosidosis. Molecular analysis confirmed three affected families, which presented the nonsense variant p.Ser899Ter. This variant generates a premature stop codon in exon 22, resulting in a truncated protein with no residual enzymatic activity.

In conclusion, this work brings data for the beginning of a genetic characterization of α-mannosidosis in the Brazilian population. It also shows that α-mannosidosis cases may be underdiagnosed due to the clinical similarity to MPS and the lack of information about this ultra-rare disease. Based on our data, we strongly recommend to all screening centers to consider α-mannosidosis testing together with screening for MPS as a tool for diagnosis to MPS-like phenotype individuals, since the phenotype similarity between these diseases poses a significant challenge for clinicians worldwide and often leads to the failure of the correct clinical diagnosis and treatment.

Fabry disease (FD) is a rare X-linked lysosomal storage disorder with a broad spectrum of clinical manifestations, including severe complications, such as end-stage renal disease, hypertrophic cardiomyopathy, and cerebrovascular disease. Enzyme replacement therapy (ERT), when initiated early, has been shown to reduce the incidence of severe events and slow disease progression. In the classic form, characterized by the absence of α-galactosidase A (α-Gal A) enzyme activity, diagnosis is straightforward. However, when residual activity is present, the delayed and less obvious presentation can make diagnosis more challenging. Ophthalmological alterations, which can be detected through non-invasive examinations may play a crucial role in correctly assessing the patient in terms of diagnosis and prognosis, particularly in these atypical cases. Recognizing these ocular signs allows for timely intervention with ERT, leading to improved patient outcomes. This review highlights the importance of ophthalmological findings in FD, emphasizing their role in diagnosis and treatment planning. By raising awareness among ophthalmologists and healthcare specialists, this review aims to improve disease management, offering tools for early detection and better long-term prognosis in patients with FD.

There is growing evidence suggesting that the lysosome or lysosome dysfunction is associated with Alzheimer's disease (AD). Pathway analysis of post mortem brain-derived proteomic data from AD patients shows that the lysosomal system is perturbed relative to similarly aged unaffected controls. However, it is unclear if these changes contributed to the pathogenesis or are a response to the disease. Consistent with the hypothesis that lysosome dysfunction contributes to AD pathogenesis, whole genome sequencing data indicate that heterozygous pathogenic mutations and predicted protein-damaging variants in multiple lysosomal enzyme genes are enriched in AD patients compared to matched controls. Heterozygous loss-of-function mutations in the palmitoyl protein thioesterase-1 (PPT1), α-L-iduronidase (IDUA), β-glucuronidase (GUSB), N-acetylglucosaminidase (NAGLU), and galactocerebrosidase (GALC) genes have a gene-dosage effect on Aβ40 levels in brain interstitial fluid in C57BL/6 mice and significantly increase Aβ plaque formation in the 5xFAD mouse model of AD, thus providing in vivo validation of the human genetic data. A more detailed analysis of PPT1 heterozygosity in 18-month-old mice revealed changes in α-, β-, and γ-secretases that favor an amyloidogenic pathway. Proteomic changes in brain tissue from aged PPT1 heterozygous sheep are consistent with both the mouse data and the potential activation of AD pathways. Finally, CNS-directed, AAV-mediated gene therapy significantly decreased Aβ plaques, increased life span, and improved behavioral performance in 5xFAD/PPT1+/- mice. Collectively, these data strongly suggest that heterozygosity of multiple lysosomal enzyme genes represent risk factors for AD and may identify precise therapeutic targets for a subset of genetically-defined AD patients.

Fabry disease is a multi-organ disease, caused by mutations in the GLA gene and leading to a progressive accumulation of glycosphingolipids due to enzymatic absence or malfunction of the encoded alpha-galactosidase A. Since pathomechanisms are not yet fully understood and available treatments are not efficient for all mutation types and tissues, further research is highly needed. This research involves many different model types, with significant effort towards the establishment of an in vivo model. However, these models did not replicate the variety of symptoms observed in patients. As an alternative strategy, patient-derived somatic cells as well as patient-independent cell lines were used to model specific aspects of the disease in vitro. Fabry disease patients present different phenotypes according to the mutation and the level of residual enzyme activity, pointing to the necessity of personalized disease modeling. With the advent of induced pluripotent stem cells, the derivation of a multitude of disease-affected cell types became possible, even in a patient-specific and mutation-specific manner. Only recently, three-dimensional Fabry disease models were established that even more closely resemble the native tissue of investigated organs and will bring research closer to the in vivo situation. This review provides an overview of human in vitro models and their achievements in unravelling the Fabry disease pathomechanism as well as in elucidating current and future treatment strategies.

Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder where 95% of the cases are caused by mutations in the Niemann-Pick C1 (NPC1) gene. Loss of function in NPC1 mutants trigger the accumulation of cholesterol in late endo-lysosomes and lysosomal dysfunction. The current study examined the potential of polyphenol-rich methanol extracts from Rosa canina L. (RCME) and two of its components, rutin and quercitrin, to enhance protein trafficking of NPC1 and restore cholesterol levels in fibroblasts derived from NPC patients, in comparison with miglustat, a drug approved in Europe for NPC treatment. Interestingly, RCME improved the trafficking of the compound heterozygous mutant NPC1I1061T/P887L, homozygous mutant NPC1R1266Q, and heterozygous mutant NPC1N1156S between the endoplasmic reticulum and the Golgi and significantly reduced the levels of cellular cholesterol in the cell lines examined. Miglustat did not affect the trafficking of the three NPC1 mutants individually nor in combination with RCME. Markedly, rutin and quercitrin exerted their effects on cholesterol, but not in the trafficking pathway of NPC1, indicating that other components in RCME are implicated in regulating the trafficking of NPC1 mutants. By virtue of its dual function in targeting the trafficking of mutants of NPC1 as well as the cholesterol contents, RCME is more beneficial than available drugs that target substrate reduction and should be therefore considered in further studies for its feasibility as a therapeutic agent for NPC patients.

Patients with Fabry disease (FD) consider their quality of life to be significantly affected. The majority of studies evaluate the quality of life using quantitative measures and standardised scales that offer relevant information about experience with the disease in multiple aspects. The main objective of the research was to examine in depth the quality of life and unmet needs of patients diagnosed with FD in relation to their disease and treatment. A qualitative and transversal study was carried out in two stages: (a) nine semi-structured qualitative interviews with patients and one representative of the patient association, conducted individually by phone; (b) a focus group was set up with three patients diagnosed with FD and one relative. A deductive, thematic analysis approach was used for data coding and analysis.

The analysis of the interviews revealed various relevant themes: experience with the disease, impact on daily activities, experience of the family and work environment, experience related to treatment and healthcare professionals, and unmet support needs. Diagnosis has a significant impact on both those suffering from the disease and on the family environment. The symptoms and evolution of the disease are highly variable among the patients interviewed and depend on the years diagnosed as well as the time taken to receive the diagnosis. The families of the interviewees have to go through an adjustment process in light of the significant psychological impact brought about by the disease. Patients show various unmet needs. The need mentioned most is to have more information, support, and understanding from people around them and society, improving empathy and raising awareness about the difficulties faced by people with FD while giving the disease visibility. A lack of social understanding is highlighted as one of the main challenges, as this does not only affect the emotional management of the disease but also has repercussions on working life and social relationships.

It seems necessary to define possible strategies that help to improve the quality of life of patients and their experience with the disease. Some recommendations obtained from the study include: facilitate access to mental health professionals for patients and their families; improve training for specialists and coordination among them; and carry out actions to raise awareness of the disease that are aimed at the general public, the patients themselves, and the people around them.

Scheie syndrome is a mild variant of mucopolysaccharidosis type I (MPS I), a rare group of lysosomal storage diseases that affect multiple organ systems. It is rarely associated with neoplasia. To the best of our knowledge, only a single case of mucopolysaccharidosis associated with a brain tumor has been reported, and it was nearly three decades ago. We present the case of a 10-year-old female with Scheie syndrome associated with a brain tumor. Physical and laboratory findings were suggestive of Scheie syndrome. A skeletal survey also revealed a spectrum of dysostosis multiplex supporting MPS. Children with MPS can have rapidly enlarging head sizes due to hydrocephalus, but our patient had several red flags that demanded further evaluation. A brain MRI revealed a mass in the fourth ventricle and a biopsy of the mass revealed pilocytic astrocytoma grade 1. Intraventricular pilocytic astrocytoma itself is a rare occurrence, accounting for only 4%-15.6 % of all pilocytic astrocytomas. Altered mucopolysaccharide metabolism can be involved in tumor pathogenesis, but the exact mechanism is unknown. Mucopolysaccharidoses, being a group of complicated disorders, are difficult to manage, and many symptoms can be missed in children due to intellectual disability. This case highlights the importance of suspecting brain tumors in children with mucopolysaccharidoses who present with signs and symptoms of increased intracranial pressure. Prompt diagnosis and management can save the child from dire neurological consequences.