Clinical analysis of PAFAH1B1 gene variants in pediatric patients with epilepsy
Wei-Xing Feng1, Xiao-Fei Wang1, Yun Wu1
1Neurology Department, National Center for Children's Health China, Beijing Children Hospital affiliated to Capital Medical University, 56 Nanlishi Road, Xicheng District, Beijing 100045, China.
Insights
PAFAH1B1 variants cause lissencephaly and epilepsy, with severity linked to genetic changes. Most patients show developmental disorders, highlighting clinical heterogeneity in PAFAH1B1-related conditions.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- PAFAH1B1 (LIS1) gene mutations are linked to type I lissencephaly, a severe brain malformation.
- Lissencephaly results from abnormal neuronal migration during fetal development.
- Epilepsy is a common and often severe comorbidity in lissencephaly.
Purpose of the Study:
- To characterize the genotype-phenotype spectrum of epilepsy associated with PAFAH1B1 variants.
- To investigate the relationship between specific PAFAH1B1 genetic alterations and clinical presentation.
- To understand the range of epilepsy severity and developmental outcomes in PAFAH1B1-related disorders.
Main Methods:
- Retrospective analysis of 11 patients with PAFAH1B1 variants.
- Inclusion of medical histories, MRI findings, and video-EEG recordings.
- Genetic analysis to identify PAFAH1B1 variants and deletions.
Main Results:
- All 11 patients had lissencephaly type 1 and epilepsy, with onset between 2 months and 4 years (median 5 months).
- Generalized tonic-clonic and spasm seizures were predominant; 10/11 patients had severe developmental disorders.
- De novo variants were observed in all patients, including 17p13.3 deletions and previously unreported variants; epilepsy severity correlated with genetic findings.
Conclusions:
- PAFAH1B1 variants present a heterogeneous phenotype, ranging from drug-responsive seizures to epileptic encephalopathy.
- Developmental disorders are a consistent feature in most patients with PAFAH1B1-related epilepsy.
- Genetic variations in PAFAH1B1 significantly influence the severity of both epilepsy and neurodevelopmental outcomes.
Purpose:
PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy.
Methods:
We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022.
Results:
The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant.
Conclusion:
The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.
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