ATP1A3 mutations and genotype-phenotype correlation of alternating hemiplegia of childhood in Chinese patients.

Xiaoling Yang,Xiru Wu,Liping Wei,Xiaoyan Liu,Xiaojing Xu,Hua Gao,Jie Zhang,Yuehua Zhang,Fengfeng Zhou

doi:10.1371/journal.pone.0097274

Abstract

Alternating hemiplegia of childhood (AHC) is a rare and severe neurological disorder. ATP1A3 was recently identified as the causative gene. Here we report the first genetic study in Chinese AHC cohort. We performed whole-exome sequencing on three trios and three unrelated patients, and screened additional 41 typical cases and 100 controls by PCR-Sanger sequencing. ATP1A3 mutations were detected in 95.7% of typical AHC patients. At least 93.3% were de novo. Four late onset, atypical AHC patients were also mutation positive, suggesting the need for testing ATP1A3 mutations in atypical cases. Totally, 13 novel missense mutations (T370N, G706R, L770R, T771N, T771I, S772R, L802P, D805H, M806K, P808L, I810N, L839P and G893R) were identified in our study. By homology modeling of the mutant protein structures and calculation of an extensive list of molecular features, we identified two statistically significant molecular features, solvent accessibility and distance to metal ion, that distinguished disease-associated mutations from neutral variants. A logistic regression classifier achieved 92.9% accuracy by the average of 100 times of five-fold cross validations. Genotype-phenotype correlation analysis showed that patients with epilepsy were more likely to carry E815K mutation. In summary, ATP1A3 is the major pathogenic gene of AHC in Chinese patients; mutations have distinctive molecular features that discriminate them from neutral variants and are correlated with phenotypes.

Highlights

Alternating hemiplegia of childhood (AHC, OMIM 614820) is a rare and severe neurological disorder [1]
The diagnosis of all the patients was made according to clinical diagnostic criteria for typical AHC as follows [4,16]: (1) onset of paroxysmal events before 18 months of age, (2) repeated bouts of hemiplegia involving right and left side of the body in some attacks, (3) episodes of bilateral hemiplegia or quadriplegia starting either as generalization of a hemiplegic episode or bilateral from the start, (4) other paroxysmal disturbances including tonic/ dystonic attacks, nystagmus, strabismus, dyspnoea and other autonomic phenomena occurring during hemiplegic bouts or in isolation, (5) immediate disappearance of all symptoms upon sleep, with probable recurrence of long-lasting bouts 10–20 min after awakening, (6) evidence of developmental delay, mental retardation, neurologic abnormalities, choreoathetosis and dystonia or ataxia, (7) not attributable to other disorders
Together with Sanger sequencing of all ATP1A3 exons in other 41 typical AHC patients, 95.7% (45/47) patients were found to carry ATP1A3 mutations

Summary

Introduction

Alternating hemiplegia of childhood (AHC, OMIM 614820) is a rare and severe neurological disorder [1]. AHC occurs mostly in sporadic cases, though familial cases have been reported [2,3]. It is characterized by episodic hemiplegia or quadriplegia attacks, accompanied by other paroxysmal symptoms, including oculomotor abnormalities, dystonia, seizures and autonomic disturbances. Sodium-potassium (Na+/ K+) ATPase a3 subunit (ATP1A3) has recently been identified as a causal gene for sporadic AHC by three groups [2,9,10], resulting in 82.2% positive rate and at least 78.9% as de novo for European/ American samples. There had been no large genetic study of Chinese cohort Such a study may confirm the main causal gene in Chinese patients, and result in the discovery of novel mutations

Methods

Results

Conclusion