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Mucopolysaccharidosis Type II (Hunter Syndrome): A Brief Review of Pathophysiology, Clinical Spectrum, and Current Therapeutic Strategies - Inherited Metabolic Disorders and Nutrition

Neutrophil dysfunction and neutropenia are burdensome findings in glycogen storage disease type Ib (GSDIb). Treatment with granulocyte‐colony stimulating factor (G‐CSF) often corrects neutropenia but fails to improve clinical symptoms like inflammatory bowel disease (IBD). Recently, empagliflozin (EMPA) was shown to correct the neutrophil dysfunction and its clinical consequences. It is increasingly used as first‐line monotherapy, but long‐term, real‐world data are lacking. This nation‐wide retrospective study investigated 42 GSD1b patients (36 children) treated with EMPA as first‐line monotherapy and compared them with those receiving combination therapy with G‐CSF and treatment‐naïve patients (I:EMPA first‐line monotherapy [ n = 9]; II:G‐CSF monotherapy [ n = 7]; III:EMPA plus G‐CSF [ n = 16]; and IV: neither EMPA nor GCSF [ n = 10]). Pediatric (P) patients were evaluated separately. In pediatric patients receiving EMPA as first‐line monotherapy (P‐I) and those with EMPA plus G‐CSF (P‐III), the frequency of infections, hospital admissions, and IBD was significantly lower than in patients receiving GCSF‐monotherapy (P‐II) or no treatment (P‐IV). Additionally, significantly improved weight gain was observed in P‐I. While clinical improvement related to correction of neutrophil dysfunction was seen with EMPA first‐line monotherapy (P‐I), significant improvement in absolute neutrophil count (ANC) and hemoglobin levels was only seen in P‐III with additional G‐CSF treatment. In three cases, EMPA was safely paused and subsequently resumed, for example, during pregnancy or liver transplantation. First‐line EMPA monotherapy effectively corrects clinical symptoms of neutrophil dysfunction in GSD Ib patients, even in the absence of a statistically significant increase in ANC.

Background: X-linked immunodeficiency with magnesium defect, Epstein–Barr virus (EBV) infection, and neoplasia (XMEN) disease is a rare inborn error of immunity caused by loss-of-function mutations in MAGT1, leading to impaired N-linked glycosylation. Although chronic EBV viremia is a hallmark of XMEN disease, the mechanisms underlying its marked clinical heterogeneity remain poorly understood. Methods: We performed an in-depth clinical, immunological, and genetic characterization of two siblings carrying a pathogenic MAGT1 variant (c.369_370insCC; p.Gly124fs), validated and deposited in ClinVar (SCV007293792). Assessments included whole-exome sequencing, multiparametric flow cytometry focusing on NKG2D expression, and longitudinal clinical follow-up. Results: Despite shared absence of NKG2D expression, the siblings exhibited strikingly divergent phenotypes. One sibling developed progressive neurodegeneration with central nervous system atrophy. The other presented with a complex immuno-hematologic phenotype, including EBV-positive Hodgkin lymphoma, recurrent autoimmune cytopenias, and lymphoma-associated thrombotic microangiopathy, representing a novel clinical association in XMEN disease. Comparative immunophenotyping revealed shared defects in B-cell maturation but distinct T-cell differentiation patterns. To contextualize neurological variability, we propose a descriptive, hypothesis-generating three-category conceptual classification comprising early-onset neurodevelopmental forms, adult-onset neurodegenerative manifestations, and secondary immune-mediated or vascular involvement of the nervous system. Conclusions: These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect.

Pompe disease is a rare lysosomal storage disorder with a wide clinical spectrum ranging from infantile-onset Pompe disease (IOPD) with early severe cardiomyopathy to late-onset Pompe disease (LOPD) with progressive muscle weakness. This study aimed to evaluate clinical features, genotype–phenotype correlations, treatment outcomes, and significant events in a real-life pediatric cohort of Pompe patients. We retrospectively analyzed 30 pediatric patients diagnosed with Pompe disease (27 IOPD, 3 LOPD). Demographic, clinical, biochemical, genetic, and radiologic data were collected. Recurrent clinical events were assessed using the Andersen-Gill extension of the Cox model to evaluate the effect of enzyme replacement therapy (ERT). The median age at diagnosis was 5 (range 20 days to 80 months) months, and consanguinity was present in 83% of cases. IOPD cases predominantly showed hypotonia and cardiac involvement, whereas LOPD cases were asymptomatic or mildly symptomatic, with delayed motor development and increased CK levels. Novel GAA mutations were identified in seven patients. ERT was administered to 24 IOPD patients, leading to improved cardiac function and prolonged survival. Event incidence was significantly lower in the ERT group (HR = 0.06, p < 0.005), despite a longer follow-up. However, 56% of patients—all with IOPD—died during follow-up. Non-muscular findings such as neurogenic bladder in 6.6% (2/30), sensorineural hearing loss in 13.3% (4/30), and white matter abnormalities in 40.9% (9/21) were also documented. This real-life evidence reinforces the central role of early, individualized ERT and comprehensive multidisciplinary care in altering the natural course of Pompe disease.

Introduction: Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood‐onset dyslipidemia and explore genotype–phenotype correlations. Methods: We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next‐generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis. Results: Pathogenic or likely pathogenic variants were identified in 17% of patients ( n = 23). The most frequently affected gene was LDLR (74%), followed by significant variants in APOB , APOA5 , LDLRAP1 , and ALMS1 . Three novel pathogenic variants were identified in this cohort: a splice‐site variant in LDLRAP1 (c.231+2T>C) and two truncating variants in APOB (p.Tyr992Ter and p.Lys576Ter). Genotype–phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, APOB variants were associated with both hypercholesterolemia and hypocholesterolemia. Conclusion: Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions.

Objectives: Mucolipidosis (ML) type II α/β (I-cell disease) and type III (Pseudo-Hurler polydystrophy) are rare autosomal recessive lysosomal storage disorders caused by mutations in the GNPTAB (ML III α/β) and GNPTG (ML III γ) genes, leading to impaired lysosomal enzyme trafficking. These disorders manifest as progressive multisystem diseases with skeletal, neurological, cardiovascular, and respiratory involvement. This study aims to characterise pediatric patients’ clinical, biochemical, genetic, and radiological findings with ML II α/β and IIIα/β or γ to enhance understanding of disease diagnosis and progression. Methods: This retrospective cohort study included 19 pediatric patients (15 ML II α/β, 3 ML III γ, 1 ML III α/β) diagnosed at a tertiary referral center. Clinical data, including facial dysmorphism, skeletal abnormalities, organomegaly, cardiovascular involvement, and neurological findings, were recorded at baseline and follow-up. Biochemical analysis included urinary glycosaminoglycan (GAG) levels and lysosomal enzyme activities. For molecular diagnostics, next-generation sequencing (NGS) was utilized using a targeted gene panel that contained GNPTG and GNPTAB leukocytes from peripheral blood were used to harvest genomic DNA. Following the 2015 ACMG/AMP standards, variant interpretation was carried out by evaluating pathogenicity using in silico prediction methods, population frequency data, and segregation analysis. Radiological findings were evaluated via skeletal X-rays and brain MRI. Results: The median age at diagnosis was 8 months (range: 1 day–252 months), with a consanguinity rate of 63.1 %. ML II α/β patients presented earlier and had more severe findings, including coarse facies, respiratory tract involvement, cardiac abnormalities, and joint contractures. Cardiac valve disease, kyphosis, and progressive hearing loss were frequent. The most common mutation in GNPTAB was c.3503_3504delTC in ML II α/β, while GNPTG variants were linked to ML III γ. Radiologic findings often included hip dysplasia; brain MRIs showed callosal and subarachnoid abnormalities in a few cases. Median survival in ML II α/β was 28 months, mainly due to respiratory failure. Enzyme assays revealed elevated β-hexosaminidase A and A+B, α-D-mannosidase, and α-L-fucosidase activities in both leukocyte and DBS samples, consistent with molecular diagnoses. Conclusions: In addition to reporting six novel GNPTAB/GNPTG mutations, this study highlights the diagnostic potential of dried blood spot (DBS) samples, where elevated lysosomal enzyme activity may offer a valuable, minimally invasive screening method for ML II/III.

Objective: Cardiac involvement is a common but often underrecognized feature of inherited metabolic disorders (IMDs), particularly in pediatric populations. Early detection is crucial, since many IMDs have disease-specific treatments that can improve outcomes. This study aimed to evaluate the frequency and spectrum of inherited metabolic disorders among pediatric patients presenting with cardiomyopathy, and to emphasize the importance of early recognition for targeted management. Material and Methods: We retrospectively analyzed the records of 71 pediatric patients referred to a tertiary metabolic center between 2004 and 2020 due to cardiomyopathy or other cardiac findings. Demographic, clinical, and diagnostic data were reviewed, with a focus on final diagnoses and metabolic etiology. Results: The median age at presentation was 17 months (range, 15 days-17 years). Dilated cardiomyopathy was the most common phenotype (57.7%), followed by hypertrophic (21.1%) and non-compaction cardiomyopathy (15.4%). An inherited metabolic disorder was diagnosed in 12 patients (16.9%), most commonly Pompe disease, carnitine transporter deficiency, and very long-chain acyl-CoA dehydrogenase deficiency. Parental consanguinity was present in 50% of diagnosed cases. Despite therapy, four patients died due to cardiac failure. Conclusion: Inherited metabolic disorders account for a substantial proportion of pediatric cardiomyopathy cases. Early metabolic screening should be considered in all children with cardiomyopathy, especially when suggestive features are present. Prompt diagnosis may allow for timely intervention, genetic counselling, and improved outcomes.

Aim: Mucopolysaccharidoses (MPS) are a heterogeneous group of diseases characterised by systemic manifestations due to impaired glucosaminoglycans (GAG) degradation within lysosomes. Mucopolysaccharidosis type II (MPS II, Hunter) is a lysosomal disease caused by mutations in the iduronate-sulfatase (IDS) gene. MPS II is inherited in an X-linked recessive manner. Mucopolysaccharidosis type III (MPS III, Sanfilippo) is an autosomal recessive lysosomal disease. It has four subtypes (A, B, C, and D). MPS II and III particularly exhibit significant central nervous system involvement. Early clinical manifestations may include cognitive delay, behavioural disturbances, progressive behaviour-sleep problems, delayed speech, autism-like features, and unexplained intellectual disability. Materials and Methods: In this retrospective study, we recorded the clinical findings of patients who were diagnosed with mucopolysaccharidosis type II and III and presented with neuropsychiatric symptoms such as seizures, developmental delay, speech impairment, and loss of neurological milestones. Results: The study included eleven cases, comprising 6 (54.5%) males and 5 (45.5%) females. Among them, 4 (50%) were diagnosed with MPS IIIA, 3 (37.5%) with MPS IIIB, and 1 (12.5%) with MPS IIIC. Six patients (54.5%) had speech delay, while two (18.1%) had cognitive delay, and three (27.2%) had hyperactivity, with nine (81.8%) experiencing motor delay. The mean age at presentation was 8.4 (±5.2 SD) years, with six patients (54.5%) receiving physical therapy and special training. Conclusion: In patients presenting with neuropsychiatric symptoms, consideration of mucopolysaccharidoses along with urine GAG, enzymatic assays and, when indicated, genetic testing is crucial for early diagnosis and intervention.