Spinocerebellar ataxia type 4 is caused by a GGC expansion in theZFHX3gene and is associated with prominent dysautonomia and motor neuron signs

Background Spinocerebellar ataxias (SCAs) are a group of heterogeneous autosomal dominant disorders. Spinocerebellar ataxia 4 (SCA4), one of the rarest SCAs, is characterized by adult-onset ataxia, polyneuropathy and linked to chromosome 16q22.1, the underlying mutation remains to be discovered. Methods Three Swedish families affected by undiagnosed SCA went through detailed examinations, neurophysiological tests, neuroimaging studies and genetic testing. Imaging included MRI of the neuroaxis and brain PET. In 3 cases neuropathological assessments were performed. Genetic testing included SR WGS, STR analysis with Expansion Hunter de novo and long read (LR) WGS. Results Novel features such as dysautonomia, motor neuron affection, and abnormal eye movements, were found. Anticipation was documented as well. Atrophy in the cerebellum, brainstem and spinal cord was found in patients studied with MRI. [18F]FDG-PET demonstrated brain hypometabolism whereas [11C]Flumazenil-PET yielded reduced binding in several brain lobes, insula, thalamus, hypothalamus and cerebellum. Neuropathological assessment revealed moderate to severe loss of Purkinje cells in the cerebellum. In the spinal cord a marked loss of motor neurons in the anterior horns was seen as well as pronounced degeneration of posterior tracts. Intranuclear, mainly neuronal, inclusions positive for p62 and ubiquitin were sparse but widespread in the CNS. This finding prompted assessment for nucleotide expansions. A poly-glycine stretch encoding GGC expansions in the last exon of the zink finger homeobox 3 ( ZFHX3) gene was identified segregating with disease, and not found in 1000 controls. Conclusions SCA4 is a neurodegenerative disease, caused by a novel GGC expansion in ZFHX3, arguably the first polyglycine disorder in humans.