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[Follow-up and genetic study of 43 Chinese children with type Ⅰ Alexander disease]
1Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
Insights
This study identifies key clinical and genetic features of Alexander disease type I in Chinese children, noting developmental delay, seizures, and macrocephaly as common symptoms. Motor function regression typically begins after age seven.
Area of Science:
- Pediatric Neurology
- Neurogenetics
- Lysosomal Storage Diseases
Background:
- Alexander disease (AxD) is a rare, progressive neurological disorder.
- Type I AxD presents in childhood with distinct clinical and genetic profiles.
- Understanding these profiles is crucial for diagnosis and management.
Purpose of the Study:
- To characterize the clinical and genetic features of 43 Chinese children with type I Alexander disease.
- To analyze long-term follow-up data for disease progression patterns.
- To identify mutation hotspots in the GFAP gene within this cohort.
Main Methods:
- Retrospective analysis of 43 genetically confirmed type I AxD cases (2005-2016).
- Collection of clinical data (history, examination) and MRI findings.
- Longitudinal follow-up data analysis to assess disease progression.
Main Results:
- Common manifestations include developmental delay (79%), seizures (86%), macrocephaly (90%), and paroxysmal deterioration (27%).
- Significant motor function regression observed after age seven; social abilities moderately impaired.
- Seventeen GFAP mutations identified (4 novel); 95% were de novo. Hotspots: p.Arg239, p.Arg79, p.R88.
Conclusions:
- Type I AxD in Chinese children is characterized by developmental delay, seizures, macrocephaly, and paroxysmal deterioration.
- Motor regression after age seven is a significant feature.
- GFAP mutation analysis reveals specific hotspots and a high de novo mutation rate.
Abstract:
Objective: To identify the clinical and genetic characteristics in 43 Chinese children diagnosed with type Ⅰ Alexander disease (AxD). Method: Forty-three type Ⅰ AxD cases identified by glial fibrillary acidic protein (GFAP) gene mutations in Peking University First Hospital from 2005 to 2016 were followed up. The data of medical history, physical examination and magnetic resonance imaging (MRI) were collected. All these patients were followed up in December 2010, Febury 2012, June 2014 and January 2016, respectively. Result: Forty-three patients were genetically confirmed as type I AxD and the median age at the last visit was 11.71 years (10.27, 13.15). The characteristic clinical manifestations of these type Ⅰ AxD patients were developmental delay (79%, 34/43), seizures (86%, 37/43), macrocephaly (the median percentile of head circumference is 90%), and paroxysmal deterioration (27%, 13/43). All the 43 patients' brain MRI satisfied typical MRI features proposed by van der Knaap. According to the analysis of the long-term follow-up, patients with type Ⅰ AxD began to have obvious regression in motor function after 7 years of age, and the social life ability was milally impaired 8(6, 10)scores at the last follow-up. Seventeen heterozygous missense mutations of GFAP were identified in 43 genetically confirmed patients, and 4 mutations were novel. The mutations in 41 patients (95%, 41/43) were de novo. Three hot spots of mutation in Chinese patients were found: p. Arg239(35%, 15/34), p. Arg79 (26%, 11/43) and p. R88 (16%, 7/43). Conclusion: The characteristic clinical manifestations of type Ⅰ AxD patients are developmental delay, seizures, macrocephaly and paroxysmal deterioration. Moreover, a few patients may present with brain stem symptoms, mental abnormalities, scoliosis or kyphosis. Patients with type Ⅰ AxD may show significant regression in motor function after 7 years of age.
