Objective: We here report on a novel SYNE1 mutation in an Austrian family extending the classical clinical phenotype in SYNE1 ataxia.

Background: SYNE1 codes for the synaptic envelope protein 1, a cytoskeleton protein of the spectrin family, which is mainly expressed in central nervous system and skeletal muscle tissue. Mutations in SYNE1 are associated with slowly progressive, pure cerebellar ataxia (autosomal recessive cerebellar ataxia type 1/autosomal recessive spinocerebellar ataxia type 8) mainly restricted to French Canadian families. Moreover autosomal dominant inherited mutations cause muscular dystrophy Emery Dreifuss type 4.

Methods: Neurological work-up was extensive in two affected siblings over a follow up period of five years and included regular standardized clinical rating. Cerebral and spinal MR imaging was performed in both subjects. Moreover neurophysiological and neuropsychological assessments, as well as muscle biopsy and cardiac screening were carried out. Genetic testing was done by DNA array linkage analyses, autozygosity mapping and subsequently exome sequencing. Patients gave written informed consent for genetic testing, video recording and presentation.

Results: The 31-year-old male index patient exhibited walking difficulties and impairment in fine motor skills at the age of 25. Clinical examination revealed slowly progressive spasticity of the lower extremities and mild cerebellar ataxia. Recurrent neurocardiogenic syncopes with cardiac arrest required a cardiac pacemaker. Disease onset of his 24-year-old sister was early in her adolescence with more rapid disease progression and need of walking assistance at the age of 20. In addition to upper motor neuron symptoms the patient showed distally accentuated neuropathy with weakness and atrophies. MR imaging revealed extensive cerebellar atrophy with “bat wing configuration” of the fourth ventricle in both patients. Severe cognitive impairment was not obvious. Genetic testing revealed a homozygous truncating mutation (exon 110: c.20263C>T).

Conclusions: Our findings suggest a more variable and wider clinical phenotype in SYNE1 ataxia including predominant upper and lower motor neuron symptoms additionally to cerebellar ataxia. The characteristic MR pattern in this mutation can help to establish diagnosis. Further investigations regarding cardiac involvement in SYNE1 are warranted.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/predominant-motor-neuron-involvement-in-autosomal-recessive-syne1-ataxia/