Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky

Abstract

Infantile onset spinocerebellar ataxia (IOSCA) (MIM 271245) is a severe autosomal recessively inherited neurodegenerative disorder characterized by progressive atrophy of the cerebellum, brain stem and spinal cord and sensory axonal neuropathy. We report here the molecular background of this disease based on the positional cloning/candidate approach of the defective gene. Having established the linkage to chromosome 10q24, we restricted the critical DNA region using single nucleotide polymorphism-based haplotypes. After analyzing all positional candidate transcripts, we identified two point mutations in the gene C10orf2 encoding Twinkle, a mitochondrial deoxyribonucleic acid (mtDNA)-specific helicase, and a rarer splice variant Twinky, underlying IOSCA. The founder IOSCA mutation, homozygous in all but one of the patients, leads to a Y508C amino acid change in the polypeptides. One patient, heterozygous for Y508C, carries a silent coding region cytosine to thymine transition mutation in his paternal disease chromosome. This allele is expressed at a reduced level, causing the preponderance of messenger RNAs encoding Y508C polypeptides and thus leads to the IOSCA disease phenotype. Previously, we have shown that different mutations in this same gene cause autosomal dominant progressive external ophthalmoplegia (adPEO) with multiple mtDNA deletions (MIM 606075), a neuromuscular disorder sharing a spectrum of symptoms with IOSCA. IOSCA phenotype is the first recessive one due to Twinkle and Twinky mutations, the dominant PEO mutations affecting mtDNA maintenance, but in IOSCA, mtDNA stays intact. The severe neurological phenotype observed in IOSCA, a result of only a single amino acid substitution in Twinkle and Twinky, suggests that these proteins play a crucial role in the maintenance and/or function of specific affected neuronal subpopulations.

Hereditary ataxias: overview

“…38 Marinesco-Sjögren syndrome is a rare disorder in which ataxia is associated with intellectual disability, cataract, short stature, and hypotonia. 39,40 Polymerase γ-1-associated hereditary ataxias.…”

Abnormal Glycosylation Profile and High Alpha-Fetoprotein in a Patient with Twinkle Variants

“…Twinkle mutations were initially described in patients who exhibited dominant progressive external ophthalmoplegia (adPEO) (Spelbrink et al 2001) and infantile-onset spinocerebellar ataxia (IOSCA) (Nikali et al 2005). The clinical symptoms of IOSCA are progressive; symptoms initially include ataxia, athetosis, and muscle hypotonia with loss of deep tendon reflexes, then ophthalmoplegia and hearing loss, and finally sensory neuropathy and epilepsy.…”

Autosomal recessive ataxias: 20 types, and counting

“…Infantile-onset spinocerebellar ataxia (IOSCA) is currently identified only in Finland and is characterized by acute or subacute cerebellar signs triggered by unspecific infection around the age of 1 year 21,22 . Their clinical features are similar to MIRAS.…”

“…Refractory epilepsy and status epilepticus might contribute to rapid neurological deterioration and death. Further recognized abnormalities are autonomic dysfunction and, in females, primary hypogonadism 21,22 .…”

“…The same founder mutation (p.Y508C) was detected in most Finnish patients with classical IOSCA. Mutations in C10ORF2 might also be associated to different phenotypes, such as Alpers disease (early onset encephalopathy with untreatable epilepsy, mtDNA depletion and liver failure) and autosomal dominant progressive external ophthalmoplegia 22 .…”