BACKGROUND/ PURPOSE: Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Defects in the SPG4 and SPG3A genes are the two leading causes of HSPs with autosomal dominant inheritance (AD-HSPs). The purpose of this study was to investigate the clinical features and associated genetic mutations in Taiwanese families with AD-HSP. METHODS: Four kindreds with AD-HSP were recruited, and clinical data were collected from the affected individuals. Genetic studies were conducted in the following order: sequence analysis of the SPG4 gene (SPAST) exons, multiplex ligation-dependent probe amplification to detect genetic rearrangements in SPAST, and sequence analysis of the SPG3A gene exons. RESULTS: Four different SPAST mutations were detected, including a novel small deletion, a missense mutation, and two gross deletions involving exon 17. Although all symptomatic cases manifested as uncomplicated phenotypes, considerable intrakindred and interkindred variations in terms of age at onset, rate of progression, and severity of disease were observed. CONCLUSION: Mutation patterns and phenotypic expressivity are heterogeneous in Taiwanese patients with SPG4-related HSP. Genetic rearrangements could be a significant cause of SPG4-related HSP in the Taiwanese population. Assessment of the large deletions that could present in SPAST is warranted when direct sequencing is uninformative.
BACKGROUND/ PURPOSE:Hereditary spastic paraplegias (HSPs) are clinically and genetically heterogeneous neurodegenerative disorders. Defects in the SPG4 and SPG3A genes are the two leading causes of HSPs with autosomal dominant inheritance (AD-HSPs). The purpose of this study was to investigate the clinical features and associated genetic mutations in Taiwanese families with AD-HSP. METHODS: Four kindreds with AD-HSP were recruited, and clinical data were collected from the affected individuals. Genetic studies were conducted in the following order: sequence analysis of the SPG4 gene (SPAST) exons, multiplex ligation-dependent probe amplification to detect genetic rearrangements in SPAST, and sequence analysis of the SPG3A gene exons. RESULTS: Four different SPAST mutations were detected, including a novel small deletion, a missense mutation, and two gross deletions involving exon 17. Although all symptomatic cases manifested as uncomplicated phenotypes, considerable intrakindred and interkindred variations in terms of age at onset, rate of progression, and severity of disease were observed. CONCLUSION: Mutation patterns and phenotypic expressivity are heterogeneous in Taiwanese patients with SPG4-related HSP. Genetic rearrangements could be a significant cause of SPG4-related HSP in the Taiwanese population. Assessment of the large deletions that could present in SPAST is warranted when direct sequencing is uninformative.