Short communicationSYNE1-ataxia: Novel genotypic and phenotypic findings
Introduction
SYNE1 is an exceptionally large human gene encoding the protein nesprin-1 [1]. Nesprins are a family of intracellular scaffold proteins which mediate anchoring between nuclear envelope, other subcellular compartments and the cytoskeleton [1]. Nesprins bind cytoskeletal actin via a calponin-domain at the N-terminus and the nuclear envelope via a KASH domain at the C-terminus. The central part of the protein consists of a variable number of spectrin-domains, which probably mediate anchoring and interaction with other intracellular proteins and organelles [2].
In 2007 truncating recessive SYNE1 mutations were identified in a cluster of French Canadian families with adult onset pure cerebellar ataxia for the first time [3,4]. This newly recognized condition was defined as autosomal recessive cerebellar ataxia type 1 (ARCA1) and subsequently described in other ethnicities [[5], [6], [7], [8], [9], [10]]. ARCA1 was initially believed to result in a relatively mild phenotype, with isolated cerebellar ataxia, but up to now around 30 patients have been reported, who displayed a complex phenotype with more widespread neurologic and non-neurologic dysfunction [5,8,11,12]. In most cases additional neurological features consisted of upper and lower motor neuron involvement in various combinations, ranging from a spastic-ataxic gait to early onset amyotrophy, paresis and respiratory distress [12].
In the present paper, we describe the clinical features in a cohort of newly identified patients with SYNE1-ataxia examined at a third referral center in Austria and provide a review of the related literature.
Six patients from 3 unrelated families were referred to the Department of Neurology of Innsbruck Medical University because of the clinical finding of a cerebellar syndrome with likely recessive inheritance (healthy parents, disease in more than 1 sibling). Five patients agreed to undergo genetic testing and provided written informed consent. In the present manuscript, roman numerals identify families and Arabic numerals individuals.
In patients III-1 and III-2, genetic testing was performed in our Division of Human Genetics by linkage analysis using a DNA-SNP-array (CytoSNP12v2.1 chip Illumina), and subsequent massive parallel sequencing of potential candidate genes by exome analysis. In the other patients genetic testing was performed in a certified external laboratory (Centogene, Rostock) by means of a panel for autosomal recessive ataxias (Pt. II-1), SYNE1 sequencing (Pt. I-2) and mutation carrier testing (Pt. I-1). The nomenclature used for reporting mutations is based on the reference sequence NM_182961.3.
Regular neurological evaluations were performed every 6–12 months on a routine basis. The severity of cerebellar syndrome was rated according to the SARA scale [13].
All procedures were performed in accordance with the ethical standards of the national research committee and with the 1964 Helsinki declaration and its later amendments. We retrospectively described findings from examinations conducted on a routine basis. According with the local regulation, no ethic committee approval was required. Written informed consent was obtained for the genetic testing.
Section snippets
Pure cerebellar ataxia phenotype
Three patients belonging to 2 families showed pure cerebellar ataxia with normal neurophysiological findings and without any signs of cognitive impairment or autonomic dysfunction (I-1, I-2 and II-1 in Table 1). The cerebral MRI showed diffuse cerebellar atrophy with sparing of cerebellar peduncles and brainstem. Disease onset was at the age of 27 (range: 26–27) with gait instability. During follow-up (average 9 years, range: 4–13) only slight, if any, progression of the cerebellar syndrome,
Discussion
In the present paper, we describe novel genetic and clinical features of a new independent SYNE1-ataxia cohort.
To the best of our knowledge, this is the first report of myocardial involvement in a patient with SYNE1-ataxia. Patient III-1 had early signs of structural heart disease, as shown by cardiac MRI. However, the repeated syncopal events clearly presented as typical vasovagal cardioinhibitory syncopes, and neither AV nodal conduction disease nor ventricular tachyarrhythmias were detected
Conclusion
In conclusion, our report confirms previous descriptions of SYNE1-ataxia and adds novel findings concerning genetics and clinical phenotype. The present findings suggest that screening for cardiomyopathy should be performed in patients with an overt motor neuron involvement.
Funding
No funding to report related to this manuscript.
Conflicts of interest
Nothing to declare.
Acknowledgments
Elisabetta Indelicato was supported by a FWF grant I-3352-B28.
References (21)
- et al.
A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I
Neurobiol. Dis.
(2015) Emery-Dreifuss muscular dystrophy - a 40 year retrospective
Neuromuscul. Disord.
(2000)- et al.
Autosomal Recessive Cerebellar Ataxia type 1 mimicking multiple sclerosis: a report of two siblings with a novel mutation in SYNE1 gene in a Saudi family
J. Neurol. Sci.
(2017) - et al.
Nesprins: from the nuclear envelope and beyond
Expert Rev. Mol. Med.
(2013) - et al.
Nesprins: a novel family of spectrin-repeat-containing proteins that localize to the nuclear membrane in multiple tissues
J. Cell Sci.
(2001) - et al.
Mutations in SYNE1 lead to a newly discovered form of autosomal recessive cerebellar ataxia
Nat. Genet.
(2007) - et al.
Clinical and genetic study of autosomal recessive cerebellar ataxia type 1
Ann. Neurol.
(2007) - et al.
SYNE1 mutations cause autosomal-recessive ataxia with retained reflexes in Brazilian patients
Mov. Disord.
(2016) - et al.
SYNE1 mutations in autosomal recessive cerebellar ataxia
JAMA Neurol
(2013) - et al.
Heterogeneity in clinical features and disease severity in ataxia-associated SYNE1 mutations
J. Neurol.
(2016)
Cited by (14)
Autosomal Recessive Cerebellar Ataxias: New Acronyms, Old Eponyms, and the Butterfly Life Cycle
2023, Movement Disorders Clinical PracticeNovel Compound Heterozygous Mutations in the SYNE1 Gene in a Taiwanese Family: A Case Report and Literature Review
2023, Journal of Movement DisordersEtiological analysis of discoid meniscus based on whole exome sequencing
2023, Chinese Journal of Tissue Engineering Research