Intractable & Rare Diseases Research | A Multidisciplinary Management Cohort Study of Chinese Children with Fabry Disease

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Based on the Chinese Children Genetic Kidney Disease Database, this study systematically characterizes the clinical features and management status of pediatric Fabry disease in China for the first time, revealing significant diagnostic delays and multisystem involvement, and emphasizing the importance of multidisciplinary collaboration and family cascade screening.

 

Literature Overview

The article titled 'Multidisciplinary approach to the assessment and management of children with Fabry disease: Insights from the Chinese Children Genetic Kidney Disease Database,' published in the journal Intractable & Rare Diseases Research, reviews and summarizes clinical, genetic, and biochemical data from 64 pediatric patients with Fabry disease (FD) collected through multicenter collaboration following the establishment of China's first nationwide pediatric multidisciplinary team (MDT). The study systematically analyzes diagnostic patterns, clinical manifestations, multisystem involvement, and current use of enzyme replacement therapy (ERT), revealing significant diagnostic delays among Chinese pediatric FD patients. It also highlights the critical roles of family cascade screening, early recognition, and MDT collaboration in improving outcomes. This research provides key real-world evidence for optimizing the diagnostic and treatment pathways for pediatric FD in China.

Background Knowledge

Fabry disease is an X-linked recessive lysosomal storage disorder caused by mutations in the GLA gene, leading to reduced or absent α-galactosidase A (α-Gal A) enzyme activity, which results in the accumulation of globotriaosylceramide (GL-3) and its deacylated form, lyso-GL-3, in cells across multiple organs. The disease exhibits highly heterogeneous clinical manifestations, with early symptoms such as neuropathic pain, hypohidrosis or anhidrosis, and angiokeratomas commonly appearing in childhood or adolescence. Without timely intervention, it may progress to severe complications including renal failure, heart failure, and stroke. Due to nonspecific early symptoms, diagnostic delays are common worldwide, averaging over 10 years. Enzyme replacement therapy (ERT) was approved in China in 2019, making FD one of the few treatable inherited metabolic diseases. Early diagnosis and treatment can significantly delay organ damage. However, nationwide pediatric cohort data are lacking in China, and the clinical phenotype spectrum and current diagnostic and treatment practices remain unclear. This study leverages the Chinese Children Genetic Kidney Disease Database (CCGKDD) and a national MDT network to fill this gap, providing critical evidence for developing screening and management strategies suited to China’s context.

 

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Methods and Experiments

This study is a multicenter, retrospective cohort study that included 64 patients with Fabry disease aged ≤18 years from the Chinese Children Genetic Kidney Disease Database (CCGKDD), with data collected up to March 2025. Diagnostic criteria included: carrying GLA gene variants classified as pathogenic or likely pathogenic by ACMG; males carrying VUS variants with α-Gal A enzyme activity <2.4 μmol/L/h; and females carrying VUS variants with lyso-GL-3 ≥1.11 ng/mL or reduced enzyme activity. Demographic data, initial symptoms, multisystem involvement, genetic and biochemical data, and treatment information were collected using a standardized electronic case report form (e-CRF). Descriptive statistics were used for data analysis, with continuous variables presented as mean ± SD or median (range), and categorical variables as frequencies and percentages.

Key Findings and Insights

• A total of 64 patients were included (46 males, 18 females), with a median age at diagnosis of 11.4 years for males and 9.4 years for females, indicating significant diagnostic delays (4.4 years for males, 4.0 years for females)
• Family cascade screening was the primary route for female diagnosis (72.2%), while 6.5% of male patients were incidentally identified through genetic testing for other conditions, suggesting gender disparities in current diagnostic strategies
• Missense variants were the most common mutation type (65.2% in males, 66.7% in females); male patients showed significantly reduced α-Gal A activity (0.6±0.4 μmol/L/h), while female enzyme activity was mostly within the normal range (2.3±0.9 μmol/L/h)
• Elevated lyso-GL-3 levels were observed in most patients (87.0% of males, 83.3% of females), highlighting its value as a biomarker for diagnosing female patients
• Neuropathic pain was the most common presenting symptom, more prevalent in males (52.2%) than females (27.8%), primarily manifesting as acroparesthesia, with males reporting burning pain and females pricking sensations
• Multisystem involvement was common: frequent symptoms in males included hypohidrosis/anhidrosis (58.7%), arrhythmia (27.5%), and obstructive lung disease (24.2%); arrhythmia was the main issue in females (44.4%); corneal whorls were highly prevalent in both genders (>48%)
• Skeletal system involvement was underestimated: 57.1% of tested males had low bone mineral density; additionally, 10.8% of males exhibited sensorineural hearing loss, suggesting these should be included in routine assessments
• Thirty-seven patients (31 males, 6 females) received enzyme replacement therapy (ERT), with a median treatment initiation age of 12.9 years for males and 11.7 years for females; most received agalsidase beta, with good tolerability and only two males experiencing grade 3 adverse reactions
• Severe clinical events were rare during the study period—only one male required kidney transplantation, with no deaths or cardiovascular/cerebrovascular events, suggesting early intervention may improve prognosis

Implications and Future Directions

This study provides the first systematic clinical atlas of pediatric Fabry disease patients in China, confirming multisystem involvement from an early age and persistent diagnostic delays, especially among male patients. It highlights the decisive role of family cascade screening in early identification of female patients and underscores the critical importance of lyso-GL-3 in diagnosis, even when enzyme activity is normal.

The study reveals higher-than-previously-recognized involvement of the skeletal, respiratory, and auditory systems, indicating that bone density, pulmonary function, and hearing assessments should be incorporated into routine follow-ups for more comprehensive disease management. Although ERT initiation is slightly later than international recommendations, the overall good tolerability supports the safety of early treatment.

This study provides real-world evidence for establishing an MDT-based FD diagnosis and management network in China. Future efforts should further integrate newborn screening, testing of high-risk populations, and family cascade screening to shift from symptom-driven diagnosis to early detection, enabling true early intervention and improved long-term outcomes.

 

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Conclusion

Basing on the Chinese Children Genetic Kidney Disease Database, this study systematically analyzed the clinical characteristics and management status of 64 pediatric patients with Fabry disease, revealing significant diagnostic delays and early multisystem involvement among Chinese children. Neuropathic pain was the most common initial symptom, and family cascade screening significantly improved female diagnosis rates, while lyso-GL-3 proved to be a key biomarker for identifying female patients. The study found that involvement of the skeletal, respiratory, and auditory systems has long been overlooked, indicating a need to expand monitoring. Although enzyme replacement therapy is widely used and well-tolerated, treatment initiation remains later than ideal. This study emphasizes the importance of multidisciplinary collaboration, family screening, and early recognition, providing key evidence to optimize the diagnostic and treatment pathways for pediatric Fabry disease in China, supporting the establishment of a more proactive screening and intervention system to improve long-term outcomes. Prospective studies are needed to evaluate the actual impact of early treatment on disease progression.

 

Jing Wang, Jialu Liu, Jing Chen, Qian Shen, and Hong Xu. Multidisciplinary approach to the assessment and management of children with Fabry disease: Insights from the Chinese Children Genetic Kidney Disease Database. Intractable & Rare Diseases Research.