More than 60 mutations exist for SPG3A HSP

Can’t predict symptom profile in this HSP type


A meta-analysis of 51 studies of SPG3A HSP determined that there are more than 60 reported HSP-causing mutations found for this gene, and there is no clear correlation between genotype and phenotype i.e. not able to predict the type of HSP symptom profile and how it will progress for this genetic cause of HSP.



The 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.


We performed a re-analysis of the clinical features and genotype-phenotype correlations in 51 reported studies exhibiting an ATL1 gene mutation.


Most 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 (Pā€‰>ā€‰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.


Our 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.


SOURCE: Transl Neurodegener. 2017 Apr 4;6:9. doi: 10.1186/s40035-017-0079-3. eCollection 2017. PMID: 28396731


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


Zhao GH1,2, Liu XM3.

1 Department of Neurology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009 China.

2 Department of Neurology, Fourth Affiliated Hospital, School of Medicine, Zhejiang University, Yiwu, 322000 China.

3 Department of Neurology, Qianfoshan Hospital, Shandong University, Jinan, 16766 China.

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