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DNA single-strand breaks (SSBs) are non-overlapping discontinuities in strands ofa DNA duplex. Significant attention has been given on the DNA SSB repair (SSBR) system in neurons, because the impairment of the SSBR causes human neurodegenerative disorders, including early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), also known as ataxia-oculomotor apraxia Type 1 (AOA1). EAOH/AOA1 is characterized by early-onset slowly progressive ataxia, ocular motor apraxia, peripheral neuropathy and hypoalbuminemia. Neuropathological examination reveals severe loss of Purkinje cells and moderate neuronal loss in the anterior horn and dorsal root ganglia. EAOH/AOA1 is caused by the mutation in the APTX gene encoding the aprataxin (APTX) protein. APTX interacts with X-ray repair cross-complementing group 1 protein, which is a scaffold protein in SSBR. In addition, APTX-defective cells show increased sensitivity to genotoxic agents, which result in SSBs. These results indicate an important role ofAPTX in SSBR. SSBs are usually accompanied by modified or damaged 5'- and 3'-ends at the break site. Because these modified or damaged ends are not suitable for DNA ligation, they need to be restored to conventional ends prior to subsequent repair processes. APTX restores the 5'-adenylate monophosphate, 3'-phosphates and 3'-phosphoglycolate ends. The loss of function of APTX results in the accumulation of SSBs, consequently leading to neuronal cell dysfunction and death.

We genetically screened patients with ataxia with ocular motor apraxia type 1 (AOA1)/early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), with a Japanese variant form of Friedreich's ataxia. Three patients were found to have a homozygous insertion mutation of the aprataxin gene (689insT). An elder sister of a patient in this series died of cerebral hemorrhage at the age of 45, and underwent autopsy. In her cerebellar cortex, the mean density of Purkinje cells in the flocculus had predominantly decreased to 6.7% of normal controls, whereas the Purkinje cells in the other areas of the cerebellar hemisphere had decreased to 78.2%. This suggests that the cerebellar flocculus is the primary affected lesion in AOA1/EAOH, which should be associated with ocular motor apraxia., ((c) 2007 S. Karger AG, Basel)

At least four disorders, ataxia telangiectasia (AT), an ataxia-telangiectasia-like disorder, early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH)/ ataxia with oculomotor apraxia type 1 (AOA1), and ataxia with oculomotor apraxia type 2, are accompanied by ocular motor apraxia (OMA), which is an impairment of saccadic eye movement initiation. The characteristic pathological findings of EAOH/AOA1 and AT are a severe loss of Purkinje cells, severe myelin pallor of the posterior columns, and moderate neuronal loss in the dorsal root ganglia and anterior horn. Purkinje cells stimulate the fastigial nucleus and suppress omnipause neurons to initiate saccadic eye movement. The selective loss of Purkinje cells might cause OMA and disturb the cancellation of the vestibulo-ocular reflex. These disorders have the following common clinical features: ataxia, involuntary movements, and peripheral neuronopathy. In addition, the causative genes for these disorders are associated with the DNA/RNA quality control system. The impairment of DNA/ RNA integrity results in selective neuronal loss in these recessive-inherited ataxias.