Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.

Letter Mutations in genes involved in singlestrand break repair (SSBR) have been linked to hereditary cerebellar ataxias. Notably, Ataxia-oculomotor apraxia 1 (AOA1 (MIM: 2 08 920)), Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1 (MIM: 6 07 250)) and Ataxia-oculomotor apraxia 4 (AOA4 (MIM: 616267616267616267)) are associated with mutations in APTX (MIM: 606350), TDP1 (MIM: 607198) and PNKP (MIM: 605610), respectively. Recently, compound heterozygous mutations in XRCC1 were identified in one individual with ocular motor apraxia, cerebellar ataxia and axonal neuropathy. However, as this study only identified a single case, the causal role of XRCC1 in Autosomal Recessive Cerebellar Ataxia (ARCA) remained in question and required replication in additional cases. Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related. This confirms the role of XRCC1 in cerebellar ataxia. CLiniCaL features Patient 1 was the eldest of three healthy siblings from a consanguineous relationship (first cousins) (figure 1A). He walked independently at 15 months. Aged 3 years, he had a persistent ataxic gait and recurrent falls. He experienced impaired fine motor skills and upper limb ataxia. In school, he had mild learning disabilities, dysarthria and difficulties playing sports with painful cramps particularly after prolonged exertion. His examination was notable for prominent bilateral calf wasting and pes planus with impaired coordination and dysdiadochokinesis. Aged 15 years, he underwent an MRI brain, which was unremarkable. Nerve conduction studies and electromyogram (EMG) showed a length-dependent Postscript