SYNE1 ataxia is a common recessive ataxia with major non-cerebellar features: a large multi-centre study

Abstract

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause a relatively pure, slowly progressive cerebellar recessive ataxia mostly identified in Quebec, Canada. Combining next-generation sequencing techniques and deep-phenotyping (clinics, magnetic resonance imaging, positron emission tomography, muscle histology), we here established the frequency, phenotypic spectrum and genetic spectrum of SYNE1 in a screening of 434 non-Canadian index patients from seven centres across Europe. Patients were screened by whole-exome sequencing or targeted panel sequencing, yielding 23 unrelated families with recessive truncating SYNE1 mutations (23/434 = 5.3%). In these families, 35 different mutations were identified, 34 of them not previously linked to human disease. While only 5/26 patients (19%) showed the classical SYNE1 phenotype of mildly progressive pure cerebellar ataxia, 21/26 (81%) exhibited additional complicating features, including motor neuron features in 15/26 (58%). In three patients, respiratory dysfunction was part of an early-onset multisystemic neuromuscular phenotype with mental retardation, leading to premature death at age 36 years in one of them. Positron emission tomography imaging confirmed hypometabolism in extra-cerebellar regions such as the brainstem. Muscle biopsy reliably showed severely reduced or absent SYNE1 staining, indicating its potential use as a non-genetic indicator for underlying SYNE1 mutations. Our findings, which present the largest systematic series of SYNE1 patients and mutations outside Canada, revise the view that SYNE1 ataxia causes mainly a relatively pure cerebellar recessive ataxia and that it is largely limited to Quebec. Instead, complex phenotypes with a wide range of extra-cerebellar neurological and non-neurological dysfunctions are frequent, including in particular motor neuron and brainstem dysfunction. The disease course in this multisystemic neurodegenerative disease can be fatal, including premature death due to respiratory dysfunction. With a relative frequency of ∼5%, SYNE1 is one of the more common recessive ataxias worldwide.

Targeted sequencing with expanded gene profile enables high diagnostic yield in non-5q-spinal muscular atrophies

“…Recently, ataxia has been described as a main phenotypical manifestation of recessive LoF SYNE1 mutations. However, ataxia may develop at later stages, whereas motor neuron signs are the initial features of this disease (Synofzik et al., ).…”

Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets

“…Indeed, biallelic truncations of SYNE1 underlie autosomal recessive cerebellar ataxia Type I (ARCA1), a progressive form of pure cerebellar ataxia that consists of limb and gait ataxia, dysarthria and severe cerebellar atrophy [13, 36, 37]. More recent studies have emphasized that these cerebellar pathologies are most often accompanied by variable combinations of multisystemic pathologies that include upper and lower motor neuron disease, muscle atrophy and spasticity, kyphoscoliosis, respiratory distress and neurocognitive disorders [14, 15, 38–40]. The molecular pathogenesis of these mutations is currently unknown but our results suggest that at least a subset of these pathologies may be linked to a loss of function of ciliary Nesprin1.…”

“…The molecular pathogenesis of these mutations is currently unknown but our results suggest that at least a subset of these pathologies may be linked to a loss of function of ciliary Nesprin1. To that respect, several pathologies associated with SYNE1 mutations include respiratory distress, kyphoscoliosis or mental retardation [14, 15], a set of phenotypes commonly associated with human ciliopathies [41]. The docking of rootletin filaments by SUN2/Nesprin1 LINC complexes has many biological implications.…”

Overcoming the divide between ataxias and spastic paraplegias: Shared phenotypes, genes, and pathways

“…For almost a decade mutations in SYNE1 were thought to cause a slowly progressive, largely pure cerebellar ataxia, 21,22 before it was realized in 2016 that they are in fact causative for a broad pleiotropic phenotypic spectrum, with corticospinal tract damage and even predominant complicated HSP presentations among the most frequent features. 23,24 Recessive mutations in PLA2G6 were found in 2006 to cause, among others, a childhood-onset ataxia cluster (termed infantile neuroaxonal dystrophy). 25 Although concomitant corticospinal tract features have already been described in several reports in recent years, it was not until recently that complicated HSP has been acknowledged as one of the main phenotypic presentations of PLA2G6 (Ozes et al, submitted).…”