Abstract
BackgroundSpastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population.MethodsTargeted next-generation sequencing was performed on the patients to identify disease-causing mutations. Variants were analyzed according to their predicted pathogenicity and their relevance to the clinical phenotypes. The segregation in the family members was validated by Sanger sequencing.ResultsA total of 12 mutations in SPG11 gene from 9 index cases were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation. In 6 of these patients, the mutations were homozygous, and the other 3 patients carried two compound heterozygous mutations. Six mutations were novel; 2 were classified as pathogenic, 1 were considered as likely pathogenic, and the other 3 were variants of unknown significance. Additionally, 1 missense heterozygous variant we found was also carried by amyotrophic lateral sclerosis (ALS) patient. Clinically and electrophysiologically, some of our ARHSP patients partially shared various features of autosomal-recessive juvenile amyotrophic lateral sclerosis (ARJALS), including combination of both UMN and LMN degeneration.ConclusionsThe results contribute to extending of the SPG11 gene mutation spectrum and emphasizing a putative link between ARHSP and ARJALS.
Highlights
Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP)
Genetic findings A total of 9 index cases with SPG11 gene mutations were identified out of unrelated Hereditary spastic paraplegia (HSP) patients, and 12 mutations were identified, including 6 frameshift mutations, 3 missense mutations, 1 nonsense mutation, 1 splicing mutation, and 1 intron deletion mutation
Sanger sequencing showed the correct segregation of this missense mutation in family members and it is predicted to have a great impact on mRNA splicing, its importance in combination with the frameshift mutation is uncertain and remains to be elucidated
Summary
Spastic paraplegia type 11 (SPG11) mutations are the most frequent cause of autosomal recessive hereditary spastic paraplegia (ARHSP). We are aiming to identify the causative mutations in SPG11 among families referred to our center with ARHSP in a Chinese population. Hereditary spastic paraplegia (HSP), characterized by progressive weakness the lower limbs and spastic paraplegia, is a rare group of neurodegenerative diseases with high clinical and genetic heterogeneity [1]. Spastic paraplegia type 11 (SPG11) mutations are the most frequent form of autosomal recessive hereditary spastic paraplegia (ARHSP). The mutations of SPG11 primarily cause progressive degeneration of the upper motor neurons (UMNs), but lower-limb muscle atrophy and fasciculations are observed in patients carrying SPG11 mutation, indicating the involvement of lower motor neuron (LMN). A characteristic manifestation of SPG11 is the presence of a thin corpus callosum (TCC) in the MRI scanning [6],
Published Version (Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have