SYNE1-ataxia: Novel genotypic and phenotypic findings

SYNE1 encodes nesprin-1, a scaffold protein which is involved in the binding between cytoskeleton, nuclear envelope and other subcellular compartments. In 2007, recessive truncating SYNE1 mutations have been linked to a genetic form of pure cerebellar ataxia with adult onset and mild phenotype. Subsequent reports described a number of patients with SYNE1-ataxia and widespread neurological involvement including features of motor neuron disease. Recently, heterozygote missense SYNE1 mutations have been associated with muscular disorders, such as Emery-Dreifuss muscular dystrophy, arthrogryposis multiplex congenita and dilated cardiomyopathy.

Herein we describe novel genotypic and phenotypic findings in an independent cohort of 5 patients with SYNE1-ataxia referring to the Department of Neurology of the Innsbruck Medical University and performed a review of the related literature.

We report 3 novel mutations and describe for the first time myocardial involvement in a patient with a complicated spastic-ataxic phenotype and C-terminal mutation. In the literature, mutations associated with additional motor neuron signs spanned over the entire gene, but patients with a particularly severe phenotype and premature death bore C-terminal mutations.

Our findings support a genotype-phenotype correlation in SYNE1-ataxia and suggest the need for a systematic cardiologic evaluation in the setting of complicated spastic-ataxia phenotypes.