Miao Zhao1, Yi-Jun Chen1, Meng-Wen Wang1, Xiao-Hong Lin1, En-Lin Dong1, Wan-Jin Chen1,2, Ning Wang3,4, Xiang Lin5,6. 1. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. 2. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China. 3. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. ningwang@fjmu.edu.cn. 4. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China. ningwang@fjmu.edu.cn. 5. Department of Neurology and Institute of Neurology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China. linxiang1988@fjmu.edu.cn. 6. Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China. linxiang1988@fjmu.edu.cn.
Abstract
BACKGROUND: Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown. METHODS: A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted. RESULTS: The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity. CONCLUSION: Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.
BACKGROUND:Hereditary spastic paraplegia (HSP) refers to a group of neurodegenerative disorders characterized by bilateral weakness, spasticity, and hyperreflexia in the lower limbs. The autosomal dominant HSP (ADHSP) predominantly presents as the pure form, but the clinical profiles and causal genetic variants underlying ADHSP are complex, and many remain unknown. METHODS: A cohort of 15 Chinese HSP pedigrees (including 35 patients and their 22 relatives) were screened by multiplex ligation-dependent probe amplification (MLPA) or whole-exome sequencing (WES). Neurological assessments were also conducted. RESULTS: The main subtypes of HSP above detected in our cohort were SPG4, SPG3A, and SPG6. Fifteen HSP-inducing mutations were identified, among which six were novel mutations: SPAST c.1277T>C, c.1292G>C, c.1562T>C, and c.1693A>T, NIPA1 c.748A>C, and KIDINS220 c.4448C>G. As expected, the most common presentation of the ADHSP cases was the pure form, manifesting spasticity of lower limbs and hyperreflexia, as well as pyramidal signs. Differing substantially from previous reports for KIDINS220 variants, our study family exhibited autosomal dominant inheritance, and only presented with spastic paraplegia, with no signs of intellectual disability, nystagmus, or obesity. CONCLUSION: Our work reveals a non-classical spastic paraplegia, intellectual disability, nystagmus, and obesity phenotype for a KIDINS220 mutation, which broadens both the clinical and genetic spectrum for ADHSP. Beyond underscoring the utility of using both MLPA and WES in studies of HSP, our work deepens the scientific understanding of phenotypes for ADHSP and defines new genetic variants to facilitate future diagnoses.
Authors: Nikoleta Vavouraki; James E Tomkins; Eleanna Kara; Henry Houlden; John Hardy; Marcus J Tindall; Patrick A Lewis; Claudia Manzoni Journal: iScience Date: 2021-04-28