A DRPLA-Affected Family: Clinical Course and Autopsy Findings in a Long-Surviving Case

A long-surviving older sister and her younger brother, both with a juvenile type of DRPLA, were autopsied. They had 69 and 77 CAG repeats in the atrophin-1 gene (ATN1), respectively. The older sister developed intellectual disability at the age of 10 years, followed by epilepsy, and survived for 40 years supported by tube feeding and tracheostomy with laryngeal closure without signs of anoxia and malnutrition. As the disease progressed, brain CT revealed a progressive skull thickening alongside brain atrophy. The younger brother, who had developmental delay at the age of 3 years, died of status epilepticus aged 24 years. Their father developed cerebellar ataxia at 56 years old when his daughter was 27 years old, and the expanded allele had 63 CAG repeats in ATN1. His clinical course was characterized by the sudden onset of severe psychiatric symptoms and choreatic movement. He died of aspiration pneumonia and suffered from malignant lymphoma aged 72 years. Neuropathological examination of this older sister with extended survival of DRPLA revealed a thickened skull, atrophic brainstem and cerebellum, and a thin spinal cord. We found neuronal loss and gliosis across a wide range of brain regions in addition to severe degeneration of the dentatorubral and pallidoluysian systems along with regions previously reported to exhibit polyglutamine pathology. In contrast, some regions previously reported to exhibit polyglutamine pathology remained preserved. The cerebellar cortex showed three-layer degeneration, and changes in the cerebral white matter appeared to correspond to lesions in the cerebral cortex.