An Autopsy Case With Fragile X‐Associated Tremor/Ataxia Syndrome Presenting Intranuclear Inclusion Bodies Mainly in the Limbic System

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder characterized by a late onset and slow progression caused by a premutation (55-200 CGG repeat) in the fragile X mental retardation (FMR1) gene. Here, we report the case of a Japanese patient with FXTAS which is the first case autopsied in Japan. The patient was a 74-year-old man with a family history of fragile X syndrome at the time of death. The clinical features included postural tremors, mild cognitive decline, and ataxia. Magnetic resonance imaging (MRI) showed a high-intensity lesion in the bilateral middle cerebellar peduncles and deep white matter around the ventricle on T2-weighted images. A gene analysis revealed that the patient had a pre-mutation of the CGG expansion (83 CGG repeats) in the FMR1 gene. Neuropathologically, ubiquitin- and p62-positive intranuclear inclusions were widely present, especially in the hippocampus. The middle cerebellar peduncle (MCP), where the "MCP sign" was seen on MRI, showed marked spongiosis with accompanied demyelination and axon loss, and a similar pathology was seen in the cerebral and cerebellar white matter. In an electron microscopy study, intranuclear inclusions were found to consist of a non-membrane-bound filamentous material. The clinical, MRI, and neuropathological findings were similar to those of neuronal intranuclear inclusion disease. Awareness of the disease is gradually increasing, and the number of autopsy cases is likely to increase, contributing to the elucidation of the pathology and development of treatments.