Clinical features and genotype-phenotype correlation analysis in patients with ATL1 mutations: A literature reanalysis

Guo-hua Zhao,Xiao-min Liu

doi:10.1186/s40035-017-0079-3

Abstract

BackgroundThe hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. Approximately 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. Currently there are more than 60 reported ATL1 gene mutations and the genotype-phenotype correlation remains unclear. The study aims to investigate the genotype-phenotype correlation in SPG3A patients.MethodsWe performed a reanalysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.ResultsMost HSPs-SPG3A patients exhibited an early age at onset (AAO) of <10 years old, and showed an autosomal dominant pure spastic paraplegia. We found that 14% of the HSPs-SPG3A patients presented complicated phenotypes, with distal atrophy being the most common complicated symptom. The AAO of each mutation group was not statistically significant (P > 0.05). The mutational spectrum associated with ATL1 gene mutation is wide, and most mutations are missense mutations, but do not involve the functional motif of ATL1 gene encoded atlastin-1 protein.ConclusionsOur findings indicate that there is no clear genotype-phenotype correlation in HSPs-SPG3A patients. We also find that exons 4, 7, 8 and 12 are mutation hotspots in ATL1 gene.

Highlights

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders
We find that most HSPs-spastic paraplegia 3A (SPG3A) patients exhibiting early age at onset (AAO) and autosomal dominant pure spastic paraplegia there have a wide mutational spectrum associated with ATL1 gene mutations
We found four studies which reported a higher frequency of ATL1 gene mutations: 20.0% in pure HSP [55], 20.0% (3/15) in early onset autosomal dominant HSP [13], 38.5% in SPG4negative pure Autosomal dominant HSP (ADHSP) families [11], and 38.7% in pure ADHSP families [15]

Summary

Introduction

The hereditary spastic paraplegias (HSPs) are a group of clinically and genetically heterogeneous disorders. 10% of the autosomal dominant (AD) HSPs (ADHSPs) have the spastic paraplegia 3A (SPG3A) genotype which is caused by ATL1 gene mutations. The hereditary spastic paraplegias (HSPs) are a group of clinically heterogeneous neurological disorders, which are classified into “pure” or “complicated” HSP according to the clinical features. Genetic mutations are the main cause of HSPs and there are currently over 72 spastic paraplegia genes or genetic loci (designated SPG1-SPG72 genetic type in order of their discovery) in which mutations can occur [3]. Approximately 40% of definite autosomal dominant pure HSP mutations are in the spastic paraplegia 4 (SPG4/ SPAST) gene which encodes the spastin protein [4, 5]

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Discussion

Conclusion