Genetic And Clinical Features Of Patients With Rare Hereditary Ataxia

Background:Hereditary ataxia is a group of hereditary neurodegenerative disorders and mainly diagnosed by testing genomic DNA mutations currently.However,a few cases of the ataxias cannot be genetically identified by common hereditary ataxia mutations,which may be classified into rare hereditary ataxia category such as mitochondrial ataxia or other rare disorders that prominently or occasionally present with ataxia.Aim:To characterize the rare hereditary ataxia mutations,especially in mitochondrial DNA(mtDNA)and mitochondrion-related nuclear genes(nDNA)of mitochondrial ataxia,and clinical features in Chinese patients with ataxia.Methods:Targeted next-generation sequencing(NGS)technology was performed to screen the whole mtDNA and 149 ataxia-related genes in a cohort of 44 unrelated ataxia patients.Genotype-phenotype correlations was summarized.Results:A total of 5 pedigrees were finally genetically diagnosed as rare hereditary ataxia,with one pathogenic mutation(p.P102L)in PRNP,three pathogenic mutations(m.8344A>G,m.9176T>C and m.9185T>C)in mtDNA,and one pathogenic mutation(p.Ser388Terfs)in PDHA1.The prevalence of mitochondrial ataxia in our patient cohort is 9.09%.In addition,nine likely pathogenic mtDNA variants were detected.all patients with pathogenic mtDNA mutations experienced symptoms of cerebellar ataxia at an early age and developed extrapyramidal symptoms during the disease course.One male patient with pyruvate dehydrogenase deficiency showed an acute intermittent ataxia phenotype.No significant difference of phenotypes was found between mitochondrial ataxia patients and non-mitochondrial ataxia patients.Conclusions:Our results implicate that targeted NGS is an effective and appropriate way to detect the culprit mutations of rare hereditary ataxia.Mitochondrial ataxia may be the main type,which occupied 9.09%in our patient cohort.Our results also highlight the importance of screening PRNP mutations in patients with dominant ataxia and dementia.