Neurodegeneration in hereditary nucleotide repair disorders

Both xeroderma pigmentosum group A (XPA) and Cockayne syndrome (CS) are rare autosomal disorders, have a genetic defect in the step of nucleotide repair, and involve various neurological abnormalities caused by progressive neurodegeneration. We performed comprehensive neuropathological analysis of five cases of XPA and four cases of CS. The XPA cases showed widespread neuronal loss throughout the central nervous system, in sharp contrast to the comparative preservation of neurons in the CS cases, who rather exhibited patchy demyelination in the cerebral and cerebellar white matter, and multifocal calcium deposition in the basal ganglia and cerebral white matter, respectively. Exceptionally in the cerebellar cortex, neuronal loss was more severe in CS than in XPA. Grumose or foamy spheroid bodies occurred in the globus pallidus and substantia nigra, and axonal torpedoes were increased in the cerebellar cortex in both disorders. Neither silver impregnation nor immunohistochemistry for ubiquitin or tau succeeded in visualizing neurofibrillary tangles, senile plaques or augmented ubiquitination in either disorder, and these findings did not support the involvement of facilitated aging in the neurodegeneration in XPA or CS.