Background Acid sphingomyelinase deficiency (ASMD), historically termed Niemann-Pick disease types A and B, and Niemann-Pick disease type C (NPC) represent distinct lysosomal storage disorders with different molecular etiologies. ASMD results from SMPD1 mutations causing sphingomyelinase deficiency, whereas NPC arises from NPC1 or NPC2 mutations disrupting intracellular cholesterol trafficking. Despite their historical grouping under “Niemann-Pick disease,” these conditions are genetically, biochemically, and clinically distinct. Methods This study investigated 11 unrelated Iranian individuals referred for genetic testing with suspected NPD (Niemann-Pick disease). Whole exome sequencing (WES) was performed, and variants were classified according to ACMG guidelines. Results Pathogenic or likely pathogenic variants were identified in 10 of 11 cases. SMPD1 variants (ASMD) were detected in six cases, with truncating variants associated with severe neuronopathic presentations (type A) and missense variants associated with predominantly visceral involvement (type B). NPC1 variants were identified in three cases, and NPC2 variants in two cases. Homozygosity was observed in 10 of 11 cases, consistent with autosomal recessive inheritance and the high rate of consanguinity (63.6%) in this cohort. Conclusion This study provides a comparative genetic analysis of ASMD and NPC in the Iranian population, highlighting the variant spectrum and genotype-phenotype correlations within each distinct disorder. The findings underscore the importance of molecular diagnosis for accurate classification and genetic counseling, particularly in populations with high consanguinity.
Gaucher disease (GD) is a rare, autosomal recessive disease with reduced β-glucocerebrosidase activity, leading to symptoms including hepatosplenomegaly, anemia, thrombocytopenia, and bone disease. Velaglucerase alfa is a native human β-glucocerebrosidase preparation approved as enzyme replacement therapy for Type 1 GD in many countries and for all GD types, including neuronopathic Type 2 and Type 3, in Japan. In this report, we provide the final (up to 8 years) safety and somatic effectiveness results of an all-case, open-label, post-marketing surveillance study in Japan. Among all patients, the incidence of adverse drug reactions (ADRs) was 23.3% (14/60 patients) and serious ADRs was 8.3% (5/60 patients). In the safety analysis population (excluding patients who did not provide consent for publication), ADR incidence was 19.5% (8/41 patients), most commonly vomiting and positive antibody test (4.9% [2/41 patients] each); one patient experienced vomiting as a serious ADR. ADRs were more common in Type 2 (7/14 patients) compared with Type 1 (1/12 patients) and Type 3 (0/15 patients). Three patients (7.3%), all Type 2, had five infusion-related reactions of pyrexia, vomiting (serious), swelling of eyelid, and hypersensitivity; all resolved or recovered. In the effectiveness analysis population (patients with any effectiveness data; n = 39), hemoglobin concentration, platelet count, and plasma angiotensin-converting enzyme concentration improved by Week 48 in patients with no prior GD treatment and were maintained in patients with prior GD treatment. These results support long-term use of velaglucerase alfa in Japanese patients with all GD types, with safety and somatic effectiveness consistent with previous findings.
Background Plasma globotriaosylsphingosine (lyso-Gb3) concentrations decrease after enzyme replacement therapy (ERT) in patients with Fabry disease (FD). However, it remains unclear whether absolute or relative changes in lyso-Gb3 concentrations better reflect treatment response. We evaluated the clinical relevance of absolute and relative changes in lyso-Gb3 concentrations after ERT. Methods This retrospective observational study included 16 patients with FD (8 males and 8 females) with elevated baseline lyso-Gb3 concentrations and paired measurements at baseline and one year after ERT. Absolute and relative changes in lyso-Gb3 concentrations were assessed, and their relationships with baseline lyso-Gb3 concentrations were examined. Kidney outcomes, including the estimated glomerular filtration rate (eGFR) slope and percent change in urinary albumin-to-creatinine ratio (UACR), were analyzed using linear mixed-effects models. Results ERT significantly reduced plasma lyso-Gb3 concentrations in both sexes. Absolute changes in lyso-Gb3 concentrations were strongly correlated with baseline lyso-Gb3 concentrations, particularly in males, whereas relative changes showed weaker dependence on baseline concentrations. In males, larger relative reductions in lyso-Gb3 concentrations were associated with a slower decline in eGFR. Smaller relative reductions were associated with greater increases in UACR in the overall cohort, but in males this was only a nonsignificant trend. Conclusion Relative changes in lyso-Gb3 concentrations after ERT appeared to be less influenced by baseline lyso-Gb3 concentrations than absolute changes. Associations with kidney outcomes were observed in males but were not demonstrated in females. Relative changes in lyso-Gb3 concentrations may provide additional information for assessing treatment response in FD.
Aims: To assess the diseasecourse in paediatric patients with mucopolysaccharidosis (MPS) type VI and efficacy of enzyme replacement therapy, to guide precision-based medicine in the Irish context.Methods: This was an ethically approved retrospective case series conducted at Children's Health Ireland (CHI) at Temple Street in Dublin, reviewing our paediatric MPS type VI cohort. Informed consent was obtained. Data sources included hospital patient charts, laboratory results and radiological images.Results: Four patients were included in the study (age 3 years 9 months to 16 years at data cut-off). Age at diagnosis ranged from 2 months to 3 years in our cohort. Presenting features included coarse features, broad ribs, upper airway issues, corneal clouding, hernias, hearing loss and motor delay. All patients were treated with enzyme replacement therapy (ERT) with galsulfase. GAG/creatinine ratio at time of diagnosis ranged between 29.2 - 159 mg/mmol creatinine compared to 12.8–26 mg/mmol creatinine following one year of ERT. Two of the patients had hyperintensities noted on MRI brain but, interestingly, these resolved after one year of ERT. All patients had significant disease burden requiring multidisciplinary team input and follow up by multiple medical specialists.Conclusion: Among the main findings in our study are the resolutions of hyperintensities on MRI brain images in 50% of cases on ERT during childhood. However, disease burden remained high during childhood. Precision-based medicine for MPS type VI requires a multidisciplinary approach, including proactive surveillance.Short abstract: A hospital-based retrospective study was conducted to assess the course of mucopolysaccharidosis (MPS) type VI in four young people, to guide precision-based medicine in the Irish paediatric context. All patients were treated with enzyme replacement therapy (ERT) with galsulfase, essentially leading to normalisation of GAG/creatinine ratios. Two patients had hyperintensities on MRI brain, but, interestingly, these resolved after one year of ERT. All patients had significant disease burden, requiring tailored multidisciplinary treatment including proactive surveillance.
Objective To characterize the epidemiological profile, variant spectrum, and clinical phenotypes of abnormal hemoglobins in the northern Guangxi region of China, and to establish and validate a tiered diagnostic strategy combining capillary electrophoresis with multi-platform molecular techniques, thereby providing evidence for regional prevention and control of hemoglobinopathies. Methods A retrospective study was conducted. A total of 3890 individuals of reproductive age who visited Guilin People's Hospital between March 2022 and March 2025 underwent initial screening by capillary electrophoresis. Samples confirmed to carry true hemoglobin variants were subjected to genotyping using reverse dot blot hybridization, Sanger sequencing, and third-generation sequencing (TGS). The electrophoretic characteristics, hematological parameters, and genotype–phenotype correlations of different globin variants were analyzed. Results The overall detection rate of abnormal hemoglobins was 1.13% (44/3890), encompassing three α-globin and six β-globin variants. HbE was the predominant variant (0.46%), followed by Hb New York. Rare variants, including HbO-Arab and Hb Barcelona, were also identified. The compound variant -α4.2αQ-Thailand/--SEA manifested as a typical HbH disease phenotype. Double heterozygotes for HbE and β-thalassemia frequently presented with moderate or severe thalassemia requiring long-term clinical intervention. Most simple heterozygotes of β-globin variants exhibited essentially normal hematological parameters. Due to their unaltered net molecular charge, electrophoretically silent variants such as Hb Hekinan II were challenging to detect by conventional capillary electrophoresis, posing a risk of missed diagnosis. Conclusion Abnormal hemoglobins in the northern Guangxi region of China display a distinct variant spectrum dominated by HbE. Capillary electrophoresis is suitable for large-scale population screening, and its integration with multi-tiered molecular testing compensates for the limitations of electrophoretic methods, enabling precise identification of rare and silent variants. Implementing genetic counseling and prenatal diagnosis for high-risk populations is a crucial measure to reduce the incidence of severe hemoglobinopathies.
