Objective: Expanding the phenotype of SYNE1 mutations to include dystonia with ataxia.

Background: In 2007 mutations in the SYNE1 gene were found to cause a recessive pure cerebellar ataxia (1). Typical patients progress slowly with late-onset ataxia, moderate to severe dysarthria, and cerebellar atrophy (1,2). Subsequent genetic research identified multiple mutation sites causing truncation, missense, and frameshift mutations in the SYNE1 gene with a variety of phenotypes including upper and lower motor neuron disease, brainstem dysfunction, mental retardation and musculoskeletal abnormalities (3, 4). Most phenotypes include both cerebellar and non-cerebellar symptoms (4). We report 2 novel heterozygous mutations in a Jamaican man with cerebellar ataxia and generalized dystonia with task-specific jaw dystonia when talking.

Method: All examinations and interviews were performed after obtaining informed consent from the patient. Whole blood was analyzed via Athena labs Ataxia Panel used Next Generation Sequencing, Repeat Expansion Detection by PCR, Dosage analysis, and Southern Blot.

Results: A 74-year-old man presented with difficulty talking since age 60, with initial symptoms of speech stuttering, which progressed to spasmodic adductor dysphonia and talking-specific dystonia consisting of forceful jaw closure with forwarding thrusting. Laryngoscope showed bilateral adductor spasms on phonation only. By age 73 developed dystonic posting of the hands and right foot. Around age 60 he had progressive worsening of balance with a severe decline after age 70. At age 74 he had an ataxic gait with upper and lower limb ataxia. Brain MRI showed cerebral and cerebellar atrophy. Genetic testing revealed 2 heterozygous mutations: c.7494: 1bp duplication of A: codon 2499, resulting in a heterozygous frameshift; and c.336-1G>A heterozygous splice site.  No other affected family members identified.

Conclusion: Until our current report, SYNE1 mutations causing dystonia with ataxia has not been reported. This is also the first report of SYNE1 mutations in a Jamaican person, to our knowledge. This case presents a unique phenotype of spasmodic adductor dysphonia, taking-specific dystonia, and mild generalized dystonia involving the hands and right leg icombined with slowly progressive ataxia with cerebellar atrophy associated with 2 SYNE1 mutations.

References: 1) Gros-Lousi F, Dupre N, Dion P, Fox MA, Laurent S, Verreault S, Sanes JR, Bouchard JP, Rouleau GA. Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia. Nat Genet. 2007: 39(1): 80-5. 2) Noreau A, Bourassa C, Szuto A, Levert A, Dobrzeniecka S, Gauthier J, Forlani S, Durr A, Anheim M, Stevanin G, Brice A, Bouchard J, Dion P, Dupre N, Rouleau GA. SYNE1 Mutations in autosomal recessive cerebellar ataxia. JAMA neuro, 2913 : 70910): 1296-31. 3) Izumi Y, Miyamoto R, Morino H, Yoshizawa A, Nishinaka K, Udaka F, Kameyama M, Maruyama H, Kawakami H. Cerebellar ataxia with SYNE1 mutation accompanying motor neuron disease. Neurology 2013: 5;80(6):600-1. 4) Synofzik M, Smets K, Mallaret M, Di Bella D, Gallenmüller C, Baets J, Schulze M, Magri S, Sarto E, Mustafa M, Deconinck T, Haack T, Züchner S, Gonzalez M, Timmann D, Stendel C, Klopstock T, Durr A, Tranchant C, Sturm M, Hamza W, Nanetti L, Mariotti C, Koenig M, Schöls L, Schüle R, de Jonghe P, Anheim M, Taroni F, Bauer P. SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study. Brain. 2016: 139(Pt 5):1378-93.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/two-heterozygous-snye1-mutations-presenting-as-spasmodic-adductor-dysphonia-task-specific-jaw-dystonia-generalized-dystonia-and-ataxia-in-a-jamaican-man/