ファブリー病

Fabry disease (FD) is the most common lysosomal storage disorder in which a severe, classical phenotype as well as a milder, non-classical phenotype can be distinguished. In this study we investigated the impact of the introduction of broader DNA sequencing techniques and subsequently the addition of the GLA-gene to NGS or WES based panels on the type of FD patient that is diagnosed by analyzing changes in the composition of the Dutch Fabry cohort over time. The current study confirms that Fabry disease is a genetically heterogeneous disorder with 64 different GLA variants established in a cohort of 319 patients. The introduction of broader DNA sequencing techniques, applied to a broader range of individuals with less specific symptoms, results in the identification of a higher proportion of individuals with less deleterious GLA variants and consequently a milder clinical phenotype. For the majority of individuals identified using the broader sequencing techniques cardiomyopathy is the presenting and only symptom of the disorder, in contrast to the multisystem classical Fabry disease phenotype. This phenotypic shift should be taken into account when comparing current to historical clinical and treatment effect data and requires tailored genetic counseling and clinical follow-up to prevent both over- and undertreatment.

Fabry disease is a rare X-linked lysosomal storage disorder caused by pathogenic variants in the GLA gene, resulting in deficient α-galactosidase A activity and progressive accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3). Although lysosomal substrate storage represents the primary molecular defect, accumulating evidence indicates that disease progression is driven by interconnected mechanisms, including chronic inflammation, oxidative stress, endothelial dysfunction, and impaired autophagy, leading to progressive multisystem involvement. The marked clinical heterogeneity of Fabry disease, together with nonspecific early manifestations, frequently delays diagnosis and complicates patient stratification and therapeutic decision-making. While advances in biomarkers, genetic testing, and imaging have improved disease recognition, current diagnostic approaches remain insufficient to fully capture disease complexity. Precision medicine is therefore emerging as a promising strategy through the integration of clinical, molecular, imaging, and multi-omics data. In this context, artificial intelligence (AI) offers novel opportunities for early diagnosis, biomarker discovery, risk stratification, and prediction of therapeutic response. This review provides an integrated overview of the molecular mechanisms, inflammatory pathways, clinical manifestations, and precision diagnostic strategies underlying Fabry disease, highlighting how AI-driven approaches may accelerate the transition toward more accurate, personalized, and predictive disease management.

Objective: To investigate the genetic characteristics and clinical phenotypes across different genotypes in patients with Fabry disease. Methods: Clinical data of 9 confirmed FD patients treated from June 2019 to December 2025 at the Affiliated Huai'an No.1 people's Hospital of Nanjing Medical University were retrospectively analyzed. The diagnostic criteria for FD included α-galactosidase A (α-GalA) activity, GLA gene sequencing, globotriaosylsphingosine levels, and renal biopsy findings, supplemented by clinical symptoms and signs. Genetic testing was performed on both the proband and their family members. Proband underwent next-generation sequencing of the GLA gene using the long-range PCR. Family members were verified by conventional PCR combined with Sanger sequencing. Variants were classified according to the 2015 American College of Medical Genetics and Genomics guidelines for sequence variation interpretation. Results: Of the 9 patients, 4 were males and 5 were females. The mean α-Gal A activity was (0.47±0.13) μmol·L-1·h-1 in males and (2.38±0.91) μmol·L-1·h-1 in females. The mean age at diagnosis was (43.0±16.7) years. The main clinical manifestations included renal impairment in 7 cases (proteinuria, chronic kidney disease, or end-stage renal disease), cardiac involvement in 8 cases (myocardial hypertrophy, arrhythmia, etc.), and autonomic nervous system symptoms in 6 cases (hypohidrosis). Pathogenic or likely pathogenic GLA variants were identified in all 9 patients, of which 8 were classified as pathogenic and 1 as a variant of uncertain significance. Three patients underwent family screening: in one case, the variant was possibly inherited from the maternal grandmother; one case was confirmed as a de novo mutation; and in one case, paternal inheritance could not be excluded. Renal biopsy in one patient revealed characteristic myeloid bodies and zebra bodies. Among the 9 patients, 1 received agalsidase α and 8 received agalsidase β, with one case developing infusion-associated reactions after 12 infusions. During the follow-up period, one patient died due to cardiac complications. Conclusions: FD patients exhibit a broad clinical spectrum and diverse genotypes. Atypical presentations should be closely monitored to enable early diagnosis and treatment, thereby improving prognosis.

OBJECTIVE: To investigate the relationship between routine electrophysiological findings, sympathetic function, and the number and size of functioning motor units in Fabry disease. METHODS: Thirteen patients with Fabry disease and thirteen healthy individuals were evaluated. Nerve conduction studies and sympathetic skin responses were recorded from upper and lower limbs. Motor unit function was analyzed using the Motor Unit Number Index (MUNIX) technique by recording the first dorsal interosseous (FDI) muscle following ulnar nerve stimulation and the tibialis anterior (TA) muscle following peroneal nerve stimulation. RESULTS: The MUNIX protocol demonstrated excellent reproducibility. MUNIX had excellent reproducibility (coefficient of variation: 20.7% in FDI; 14.7% in TA). FDI-MUNIX and MUSIX values were comparable between groups, whereas TA-CMAP amplitude and MUSIX were significantly lower in patients than in healthy controls, with no significant difference in TA-MUNIX. Correlation analysis revealed a positive association between Lyso-Gb3 and MUNIX-FDI (ρ = 0.55, p = 0.049) and inverse correlations between neuropathy scores and MUSIX-TA (ρ = -0.72, p = 0.013; ρ = -0.76, p = 0.004). CONCLUSIONS: The observed reductions in CMAP and MUSIX, particularly in the TA, indicate subtle length-dependent motor unit involvement despite preserved strength and normal MUNIX values. SIGNIFICANCE: This study provides the first evidence that MUNIX can detect early or subclinical motor unit alterations in Fabry disease.