Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers

Abstract

A neurological syndrome involving progressive action tremor with ataxia, cognitive decline and generalized brain atrophy has been described recently in some adult males with pre-mutation alleles of the fragile X syndrome (FXS) fragile X mental retardation gene (FMR1). Neurohistological studies have now been performed on the brains of four elderly premutation carriers, not reported previously, who displayed the neurological phenotype. Eosinophilic, intranuclear inclusions were present in both neuronal and astrocytic nuclei of the cortex in all four individuals. Systematic analysis of the brains of two of these carriers demonstrated the presence of the intranuclear inclusions throughout the cerebrum and brainstem, being most numerous in the hippocampal formation. The cerebellum displayed marked dropout of Purkinje cells, Purkinje axonal torpedoes and Bergmann gliosis. Intranuclear inclusions were absent from Purkinje cells, although they were present in a small number of neurones in the dentate nucleus and diffusely in cerebellar astrocytes. The presence of inclusions in the brains of all four FXS carriers with the neurological findings provides further support for a unique clinical entity associated with pre-mutation FMR1 alleles. The origin of the inclusions is unknown, although elevated FMR1 mRNA levels in these pre-mutation carriers may lead to the neuropathological changes.