Hoch et al. (2017) reported a 47-year-old woman of East Indian descent with adult-onset spinocerebellar ataxia. Her early developmental history was completely no...
Hoch et al. (2017) reported a 47-year-old woman of East Indian descent with adult-onset spinocerebellar ataxia. Her early developmental history was completely normal, and she first noted difficulties with balance and gait at age 28. The disorder was progressive and she showed neurologic decline. At age 41, she had gait and limb ataxia, with dysmetria, dysdiadochokinesis, dysarthria, and dysphagia, and she was unable to walk independently. Additional features included oculomotor apraxia with nystagmus and hypermetric saccades and peripheral neuropathy with distal muscle weakness, distal sensory impairment, and loss of reflexes. Nerve conduction studies showed a chronic length-dependent sensorimotor, predominantly axonal peripheral neuropathy. Brain imaging showed progressive cerebellar atrophy.
The transmission pattern of SCAR26 in the family reported by Hoch et al. (2017) was consistent with autosomal recessive inheritance.
▼ Molecular Genetics
In a 47-year-old woman of East Indian descent with SCAR26, Hoch et al. (2017) identified compound heterozygous mutations in the XRCC1 gene (194360.0001 and 194360.0002). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were demonstrated to result in significantly decreased protein levels, consistent with a loss of function. Patient cells and XRCC1-null cells showed elevated levels of protein ADP-ribosylation resulting from increased PARP1 (173870) activity. These cellular changes were similar to those observed in patients with mutations in the XRCC1 partner PNKP (605610) who have ataxia-oculomotor apraxia-4 (AOA4; 616267), which has overlapping clinical features. The findings identified increased ADP-ribose levels as a biomarker of PARP1 hyperactivity and as a cause of cerebellar ataxia induced by unrepaired single-strand DNA breaks resulting from loss of XRCC1. Studies in mice with brain-specific Xrcc1 deletion (see ANIMAL MODEL) showed that deletion of Parp1 ablated the abnormally increased ADP-ribose levels, increased neuronal density in the cerebellum, and improved motor performance even without an effect on single-strand break repair. Hoch et al. (2017) suggested that PARP1 may be a drug target for treating cerebellar ataxias associated with unrepaired single-strand DNA break.
▼ Animal Model
Hoch et al. (2017) noted that germline deletion of Xrcc1 in mice is embryonic lethal. Mice with conditional deletion of the Xrcc1 gene in the brain showed cerebellar ataxia with increased apoptosis of cerebellar granule neurons, reduced numbers of cerebellar interneurons, and decreased electrophysiologic spike activity in Purkinje cells. These changes were associated with increased levels of cerebellar ADP-ribose and hyperactivation of Parp1. Deletion of Parp1 ablated the elevated level of ADP-ribose, increased neuronal density in the cerebellum, and improved motor performance even without an effect on single-strand break repair. The data demonstrated that in the absence of Xrcc1-dependent single-strand break repair, Parp1 is hyperactivated, resulting in the loss and/or dysfunction of cerebellar neurons.