Abstract
BackgroundHereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs. SPG4, SPG3A and SPG31 are the three leading causes of autosomal dominant (AD) HSPs.MethodsA total of 20 unrelated AD-HSP families were recruited for clinical and genetic assessment. Detection of mutations in SPG4, SPG3A and SPG31 genes was conducted according to a standard protocol. Genotype-phenotype correlations and determinants for disease severity and progression were analyzed.ResultsMutations in the SPG4 gene (SPAST) were detected in 18 (90%) of the AD-HSP families. Mutations in SPG4, SPG3A and SPG31 genes were not detected in the remaining two families. Considerable variations in clinical features were noted, even for mutation carriers from the same family. Mutations causing complete loss of the spastin AAA cassette were associated with earlier onset of disease (20 ± 18 years) compared with those with preservation of partial or total AAA cassette (32 ± 19 years, p = 0.041). For those with SPG4 mutations, disease severity was related to the patients’ current age, and the progression rate of disease was positively correlated with age at onset.ConclusionsSPG4 accounts for most of the AD-HSP cases in Taiwanese, with a frequency significantly higher than in other populations. SPAST mutations which predict complete loss of the spastin AAA cassette were associated with an earlier onset of disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-014-0216-x) contains supplementary material, which is available to authorized users.
Highlights
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs
The protein encoded by the SPG4 gene, is a member of the family of AAA proteins (ATPase associated with diverse cellular activities) which share a common functional domain called the AAA cassette [6]
SPG4 accounted for 90% of the autosomal dominant (AD)-HSP families
Summary
Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative diseases characterized by progressive spasticity and weakness of the lower limbs. SPG4, SPG3A and SPG31 are the three leading causes of autosomal dominant (AD) HSPs. Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive spasticity and weakness of the lower limbs [1]. Hereditary spastic paraplegias (HSPs) are a heterogeneous group of neurodegenerative disorders clinically characterized by progressive spasticity and weakness of the lower limbs [1] They can be classified according to the mode of inheritance, or by the absence (“pure form”) or presence (“complicated form”) of additional neurological or systemic manifestations such as dementia, epilepsy, mental retardation, thin corpus callosum, cerebellar ataxia, peripheral neuropathy, deafness, retinopathy, and optic atrophy [1,2]. The SPG3A gene encodes the protein atlastin-1 which is structurally
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