Department of Paediatric Neurology, Hacettepe Children's Hospital, Ankara, 06100, Turkey
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Hatice Bektaşa, Haluk Topaloğlua
Department of Paediatric Neurology, Hacettepe Children's Hospital, Ankara, 06100, Turkey

‘Nuclear envelopathies’ are a group of diseases resulting essentially from mutations of the genes encoding parts of the inner nuclear membrane (Emerin, MAN1, LAP2, LBR), nuclear lamina (Lamins A and C; Lamins B1) and outer nuclear membrane (Nesprins) [1) with mutations affecting Emerin, Lamins A/C and Nesprins being rarer compared with other nuclear envelope components. All three have independent disease causing properties in humans, nesprins being the third in chronology. As a historical note, the first emerin mutation was identified in a small cohort of five patients in 1994, and there was one peculiar family from our own cohort [2]. SUN1 and SUN2 are other inner nuclear membrane proteins that play a major role in nuclear-cytoplasmic connection by formation of a ‘bridge’ across the nuclear envelope known as the LINC complex [3]. Overall formation contributes to nuclear positioning and cellular vitality. All are necessary to establish nuclear-cytoskeletal connections and are required in maintaining cellular architecture [4].

To date, four separate nesprin genes (SYNE1, SYNE2, SYNE3 and SYNE4) have been identified encoding nesprin-1, nesprin-2, nesprin-3 and nesprin-4, respectively. Multiple nesprin protein isoforms are generated through alternative transcription. These tissue specific isoforms localise to multiple compartments of the nuclear membrane [1, 4]. These provide additional functions for nesprins other than nuclear envelope linkage and consequently leading to variable neurological disease phenotypes. They are also required for neuronal nuclear movement and for migration and development [5]. Mutations in SYNE1 and SYNE2 have already been well described in a spectrum of neurological disorders. SYNE4 is one of the causes of autosomal recessive hearing deficit [6]. There is no genetic disorder labelled for SYNE3 yet. 

Clinical abnormalities arising from nesprin-1 and nesprin-2 can be grouped as cerebellar ataxia, Emery-Dreifuss muscular dystrophy, arthrogryposis and isolated cardiomyopathies [7]. These are four varying clinical features quite distinct from each other. This makes nesprinopathies quite interesting for the clinician.

In 2007, recessive mutations in SYNE1 have been identified as a cause of pure cerebellar ataxia in French-Canadian families. The patients had pure cerebellar atrophy, ataxia and dysarthria with late-onset and a slow progression. It was termed autosomal recessive spinocerebellar ataxia type 8 [SCAR8, or autosomal recessive cerebellar ataxia type 1 [ARCA1] or recessive ataxia of Beauce) [SCAR8 or ARCA1, MIM 610743) [8]. Later, mutations in SYNE1 found in Japanese patients resulting in SCAR8 associated with motor neuron disease with upper and lower motor involvement which mimicked juvenile-onset amyotrophic lateral sclerosis (ALS), several years before developing cerebellar ataxia [9]. Similarly, in a study which investigated genetic basis of ALS in Turkey, exome sequencing revealed mutations in SYNE1 gene in 5 patients from 2 families [10]. These patients did not have classical ALS but rather an early-onset lower motor neuron type of disease with slow progression accompanied by ataxia [10]. Following the progress in gene sequencing technologies, other centers across Europe highlighted non-French-Canadian patients with SYNE1 ataxia with variable combinations of cerebellar and extra-cerebellar neurological dysfunctions including in particular motor neuron and brainstem features showing that SCAR8 is not a pure cerebellar degeneration [11, 12].

Dominant mutations in SYNE1 and SYNE2 have been implicated in Emery-Dreifuss Muscular Dystrophy (EDMD) type 4 caused by disruptions in nesprin/lamin/emerin interactions[13, 14]. In a study published in 2007, the analysis of SYNE1 and SYNE2 genes were performed in 190 patients who suffer from EDMD-like phenotype or skeletal and/or heart muscle abnormalities and for whom no mutation in LMNA or EMD were identified [15]. Four heterozygous missense mutations with a segregation pattern of autosomal-dominant inheritance were found. Fibroblasts from these patients exhibited nuclear morphology defects and specific patterns of emerin and SUN2 mislocalization [15].

Mutations in SYNE1 are also responsible for Arthrogryposis Multiplex Congenita (AMC). Recessive SYNE1 mutations that leads to premature stop codons and truncates nesprin-1 isoforms for the C-terminal KASH domain have been described in these patients [16, 17]. The patients show infantile-onset musculoskeletal disease, bilateral club foot, scoliosis and restrictive lung disease. After expansion of the phenotypic spectrum of SYNE1 ataxia patients, it was uncovered that several of the SCAR8 patients, also show scoliosis/kyphosis, restrictive lung disease, foot deformities, and other neuromuscular abnormalities and also carry truncating mutations. In the light of these observations Synofzik et al. suggested that such arthrogryposis syndromes did not represent qualitatively distinct phenotypes, but were part of the continuum of SYNE1 disease [11].

There is a SYNE1 genotype-phenotype correlation under study. Mutations in the C-terminal regions (KASH domain) of the nesprin-1 (SYNE1) and -2 (SYNE2) genes have been identified in patients with muscular disorders. In contrast, mutations in the N-terminus (CHD), are associated with ataxia [18]. Similar pattern was also seen in a study in 2018 from Austria with C-terminal mutations ending with spastic paraplegia and cardiomyopathy [19].
Recently, Kölbel et al. outlined in five cases almost all spectrum of disorders arising from SYNE-1 with a next generation genetic approach [20]. These were: a myopathic type with mainly distal involvement resembling to Emery-Dreifuss muscular dystrophy and with dilated cardiomyopathy; a complicated form of ataxia with mental retardation and peripheral neuropathy being mainly axonal; and an arthrogrypotic form with congenital myopathy, restrictive lung disease, and clubfeet. Interestingly, thumb abnormalities and ultrastructural alterations of nuclear envelope are shared in all patients reported in this study. These alterations of nuclear envelope were also shown in Schwann cell nuclei which predicted possible glial and neuronal involvement.

We think clinical and genetic data along with pathology related to nesprinopathies is escalating. This recently described multi-system disorders with novelty and robust features in the form of ataxia, myopathy and early multiple joint contractures is now a consideration for the clinician.

Authors are grateful to Drs. Gisele Bonne and Rabah Ben Yaou from Institut de Myologie in Paris for critical reading of our manuscript.

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