SYNE1 Deficiency

Clinical characteristics.

SYNE1 deficiency comprises a phenotypic spectrum that ranges from autosomal recessive cerebellar ataxia at the mild end to arthrogryposis multiplex congenita (AMC) at the severe end. SYNE1-deficient cerebellar ataxia, the most commonly recognized manifestation of SYNE1 deficiency to date, is a slowly progressive disorder typically beginning in adulthood (age range 6-45 years). While some individuals have a pure cerebellar syndrome (i.e., cerebellar ataxia, dysarthria, dysmetria, abnormalities in ocular saccades and smooth pursuit), many also have upper motor neuron dysfunction (spasticity, hyperreflexia, Babinski sign) and/or lower motor neuron dysfunction (amyotrophy, reduced reflexes, fasciculations). Most individuals develop features of the cerebellar cognitive and affective syndrome (i.e., significant deficits in attention, executive functioning, verbal working memory, and visuospatial/visuoconstructional skills). The two less common phenotypes are SYNE1-deficient childhood-onset multisystem disease (ataxia, upper and lower motor neuron dysfunction, muscle weakness and wasting, intellectual disability) and SYNE1-deficient arthrogryposis multiplex congenita (decreased fetal movements and severe neonatal hypotonia associated with multiple congenital joint contractures including clubfoot).

Diagnosis/testing.

The diagnosis of SYNE1 deficiency is established in a proband with suggestive findings and biallelic SYNE1 pathogenic variants identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications. Each affected individual should be managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists depending on the clinical manifestations.

Surveillance: Annual (or more often as needed) neurologic examination; assessment of mobility and self-help skills (as they relate to ataxia, spasticity, weakness), dysarthria, dysphagia, cognition, and psychiatric manifestations.

Genetic counseling.

SYNE1 deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SYNE1 pathogenic variant). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the SYNE1 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal diagnosis for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

SYNE1 deficiency should be suspected in individuals with a combination of the following clinical features and/or clinical syndrome based on age of onset.

Clinical features

• Cerebellar ataxia
  • Progressive ataxia of gait
  • Clumsiness of hands
  • Dysmetria
  • Dysarthria
  • Abnormalities in ocular saccades and smooth pursuit
• Upper and/or lower motor neuron involvement
  • Spasticity, hyperactive deep tendon reflexes, extensor plantar response
  • Muscle atrophy, diminished deep tendon reflexes, fasciculations
• Cognitive impairment
  • Delayed motor milestones in infancy
  • Intellectual disability
  • Cognitive dysfunction typical of the cerebellar cognitive and affective syndrome (deficits in executive functioning, language, visuospatial/visuoconstructional skills)
• Skeletal involvement
  • Scoliosis or kyphosis
  • Pes cavus
  • Arthrogryposis with distal joint contractures

Clinical syndrome, defined according to age at onset:

• Neonatal onset. Arthrogryposis multiplex congenita (AMC); neonatal hypotonia with decreased fetal movements resulting in distal joint contractures (including bilateral clubfoot, adducted thumbs, flexion contractures of fingers) followed by delayed motor milestones and progressive motor decline after the first decade [Attali et al 2009, Baumann et al 2017]
• Childhood onset. Multisystem phenotype; childhood-onset ataxia with upper and lower motor neuron dysfunction, elevation of serum CK concentration, pes cavus, other skeletal and soft tissue anomalies, intellectual disability, followed by respiratory insufficiency in adolescence [Synofzik & Schüle 2017]
• Adult onset. Cerebellar ataxia (ARCA1); cerebellar ataxia, frequent upper and/or lower motor neuron involvement, and cognitive impairment typical of the cerebellar cognitive and affective syndrome [Dupré et al 2007, Synofzik et al 2016]

Electrophysiologic Studies

Cerebellar ataxia

• Nerve conduction studies. Usually normal; may occasionally show an axonal neuropathy [Synofzik et al 2016, Yucesan et al 2017]
• Electromyography (EMG). Usually normal; may occasionally show acute or chronic neurogenic changes in individuals with clinical evidence of motor neuron dysfunction [Izumi et al 2013, Synofzik et al 2016]

AMC

• Nerve conduction studies and EMG (in newborns). May be normal [Baumann et al 2017]
• EMG (later onset). Includes mild chronic neurogenic findings [Attali et al 2009]

Brain Imaging

Brain MRI in individuals with childhood-onset multisystem disease or adult-onset ataxia usually shows marked diffuse cerebellar atrophy with no other abnormalities (Figure 1).

Figure 1.

MRI of a female age 29 years with SYNE1 adult-onset cerebellar ataxia. Sagittal T₁-weighted imaging shows marked diffuse cerebellar atrophy with no atrophy of the cerebral cortex, midbrain, pons, or medulla.

• Brain stem atrophy has been reported in one individual with childhood-onset multisystem disease [Izumi et al 2013].
• White matter abnormalities in the brain and spinal cord that mimicked findings in multiple sclerosis have been reported in two individuals with adult-onset ataxia [Algahtani et al 2017].

¹⁸F-FDG-PET imaging shows marked homogeneous hypometabolism in the cerebellar hemispheres. Pontine brain stem hypometabolism has been reported in one individual with motor neuron involvement [Synofzik et al 2016].

Establishing the Diagnosis

The diagnosis of SYNE1 deficiency is established in a proband with suggestive findings and biallelic SYNE1 pathogenic variants identified by molecular genetic testing (see Table 1).

Because the phenotype of SYNE1 deficiency is indistinguishable from many other inherited disorders with similar complex neurologic and neuromuscular phenotypes, molecular genetic testing approaches include comprehensive genomic testing or use of a multigene panel [Dupré et al 2007, Baumann et al 2017, Coutelier et al 2018, Sun et al 2019].

Note: Single-gene testing (sequence analysis of SYNE1, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
• A multigene panel that includes SYNE1 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in SYNE1 Deficiency

Clinical Description

The phenotype and severity of SYNE1 deficiency vary widely and span a spectrum ranging from adult-onset cerebellar ataxia at the milder end to childhood-onset multisystem disease and prenatal-onset arthrogryposis multiplex congenita at the more severe end.

Genotype-Phenotype Correlations

Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain. Most – but not all – SYNE1 pathogenic variants associated with motor neuron involvement are located toward the 3' end of the gene [Yoshinaga et al 2017].

SYNE1 pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [Duong et al 2014, Potter et al 2017].

Nomenclature

In this GeneReview, the term "SYNE1 deficiency" refers to the full neurologic and neuromuscular phenotypic spectrum of biallelic SYNE1 pathogenic variants: from autosomal recessive cerebellar ataxia 1 (ARCA1) at the mild end of the continuum to SYNE1-AMC at the most severe end of the continuum.

Note: Autosomal recessive cerebellar ataxia 1 (ARCA1) has also been referred to as "recessive ataxia of Beauce" and "spinocerebellar ataxia recessive 8" (SCAR8).

Most recently, the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders suggested the term "ATX-SYNE1" [Rossi et al 2018].

Prevalence

ARCA1, initially described in the French Canadian population, has now been reported worldwide, notably in Japan, Europe, the Middle East, and Brazil. Although its exact prevalence is not known, it is highly prevalent in the French Canadian population, which is a homogeneous founder population [Dupré et al 2007].

When Friedreich ataxia has been excluded, SYNE1 deficiency represents 5.3%-6% of unexplained early-onset (i.e., age <40 years) autosomal recessive ataxias [Mademan et al 2016, Synofzik et al 2016].

The prevalence of SYNE1-deficient arthrogryposis multiplex congenita cannot be evaluated as it has only been reported in a few families to date.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with SYNE1 deficiency, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Cerebellar Ataxia

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita

Treatment of Manifestations

There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications. Each affected individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists (OT), physical therapists (PT), physiatrists, orthopedists, nutritionists, speech therapists, respiratory therapists, and psychologists depending on the clinical manifestations.

Table 5.

Treatment of Manifestations in Individuals with SYNE1-Deficient Cerebellar Ataxia

Table 6.

Treatment of Manifestations in Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita

Surveillance

There are no published surveillance guidelines for individuals with SYNE1 deficiency or for degenerative ataxias in general.

Table 7.

Recommended Surveillance for Individuals with SYNE1 Deficient Cerebellar Ataxia

Table 8.

Recommended Surveillance for Individuals with SYNE1-Deficient Arthrogryposis Multiplex Congenita

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

SYNE1 deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SYNE1 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with SYNE1 deficiency are obligate heterozygotes (carriers) for a SYNE1 pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SYNE1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the SYNE1 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

Prenatal Testing and Preimplantation Genetic Testing

Once the SYNE1 pathogenic variants have been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Gene structure. SYNE1 is one of the largest genes in the human genome with 0.5 Mb of genomic DNA. Alternatively spliced transcript variants encoding different protein isoforms have been described. The longest transcript NM_182961.3 (27,748 bp; variant 1) has 146 exons, of which exons 1 and 2 are noncoding. A shorter transcript variant NM_033071.3 (27,439 bp; variant 2) has 146 exons with exon 1 noncoding; this variant has multiple differences in the coding region but maintains the same reading frame as transcript variant 1.

See Table A, Gene for a detailed summary of gene, transcripts, and protein isoforms.

Pathogenic variants. Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain [Yoshinaga et al 2017]. Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [Duong et al 2014, Potter et al 2017].

Normal gene product. SYNE1 encodes a multi-isomeric protein called nesprin1, a scaffold protein involved in the binding of the nuclear membrane and the cytoskeleton. Nesprin-1 localizes at the outer nuclear membrane, where it interacts with SUN proteins located at the inner nuclear membrane to form the linker of the nucleoskeleton and cytoskeleton (LINC) complex [Sosa et al 2012]. The longest transcript variant NM_182961.3 encodes a 8,797-amino-acid protein (>1000 kd) known as the nesprin-1 giant isoform (Nes1g or isoform-1 or enaptin) (NP_892006.3) [Gros-Louis et al 2007]. The nesprin-1 giant protein contains two N-terminal paired calponin homology domains that bind cytoskeletal actin, a transmembrane domain, multiple spectrin repeats that mediate anchoring and interaction with other proteins and organelles, and a C-terminal KASH domain that localizes the protein to the nuclear envelope. Transcript variant NM_033071.3 encodes an 8,749-amino-acid protein known as KLNes1g (or nesprin-1 isoform 2) (NP_149062.1) [Razafsky & Hodzic 2015]. The shorter KLNes1g isoform lacks the C-terminal KASH domain.

Two isoforms of the proteins are specifically expressed in the central nervous system when compared with other isoforms and with the related Nesprin2 protein: Nes1g is particularly expressed in CNS tissues along with its KLNes1g, which is abundantly expressed in the cerebellum [Gros-Louis et al 2007, Duong et al 2014, Razafsky & Hodzic 2015].

SYNE1 has multiple alternative start and termination sites that allow for multiple isoforms lacking certain specific domains [Rajgor et al 2012; see also Razafsky & Hodzic 2015, Yoshinaga et al 2017, Potter et al 2018, and references therein]. These isoforms are present in multiple subcellular locations beyond the nuclear envelope and serve to link these structures to the actin skeleton [Zhang et al 2007]. Specific isoforms appear to have a tissue-specific transcription, and this transcription is highly adaptable according to cell needs for maintaining homeostasis [Rajgor et al 2012].

Abnormal gene product. Most pathogenic variants associated with the ARCA1 phenotype are nonsense or frameshift and are localized throughout the gene, excluding the KASH domain [Yoshinaga et al 2017]. Hence, these pathogenic variants are expected to affect the structure of the KLNes1g isoform, whose loss of function is thought to lead to ARCA1 [Razafsky & Hodzic 2015]. Indeed, the KLNes1g isoform is abundantly expressed in the cerebellum, where it localizes to essential synapses between mossy fibers and cerebellar granule neurons within the granule cell layer [Potter et al 2018]. Analyses in murine models suggest that this isoform is involved in vesicular trafficking and dendritic membrane structural organization, which indicates that defective synaptic transmission may underlie ARCA1 pathology; however, this remains to be confirmed [Razafsky & Hodzic 2015]. Pathogenic variants that alter the more C-terminal region of the protein have the potential to also alter the ubiquitously expressed Nesprin1β isoform, which may underlie the more complex multisystem phenotype observed in some individuals [Potter et al 2018].

Pathogenic variants associated with arthrogryposis multiplex congenita (AMC) are distal truncating variants that are expected to lead to a truncated Nesprin1α (or Nesprin1α2) isoform, which is muscle and retina specific [Duong et al 2014, Potter et al 2017]. There is mounting evidence that Nesprin1α is involved in skeletal muscle function: Nesprin1α is upregulated during myogenic differentiation and is required for the recruitment of centrosomal proteins to the nuclear envelope, which ensures proper nuclear positioning [Gimpel et al 2017]. Aberrant nuclear positioning is associated with other muscular diseases, suggesting that proper nuclear localization is essential for skeletal muscle function [Stroud et al 2017]. In murine studies of different Nesprin1 isoforms, loss of Nesprin1α2 led to severe nuclear mispositioning and postnatal lethality, suggesting that this is the isoform essential for skeletal muscle function [Stroud et al 2017]. Hence, loss of the Nesprin1α isoform may underlie muscular involvement in SYNE1 deficiency.

All SYNE1 pathogenic variants would also affect the Nesprin1 giant (Nes1g) isoform, which is predominantly expressed in the central nervous system at the nuclear envelope of Bergmann glia and at ciliary rootlets of ependymal cells [Baumann et al 2017, Potter et al 2018]. Mouse models with loss of Nes1g did not show any cerebellar phenotype but presented ventricular enlargement potentially reflecting cilia dysfunction [Potter et al 2018]. Of interest, scoliosis, respiratory insufficiency, and cognitive impairment are all clinical findings that have been reported in association with other ciliopathies, suggesting that loss of the Nes1g isoform may underlie some non-cerebellar and non-muscular features of the phenotype [Potter et al 2018].

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Author History

Marie Beaudin, MD (2018-present)
Jean-Pierre Bouchard, MD; Laval University (2007-2018)
Nicolas Dupré, MD, MSc (2007-present)
Pierre-Luc Gamache, MD, PhD (2018-present)
François Gros-Louis, PhD (2007-present)
Anne Noreau, MD, PhD; University of Montreal (2011-2018)
Guy A Rouleau, MD, PhD; University of Montreal (2007-2018)

Revision History

• 6 December 2018 (bp) Comprehensive update posted live
• 13 October 2011 (cd) Revision: cognitive changes associated with this disorder as reported by Laforce et al [2010]
• 18 August 2011 (cd) Revision: mutation scanning of select exons and prenatal testing clinically available
• 14 July 2011 (me) Comprehensive update posted live
• 15 September 2009 (cd) Revision: sequence analysis and targeted mutation analysis available clinically
• 23 February 2007 (me) Review posted live
• 6 February 2007 (nd) Original submission