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 patients 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 patient 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 patients 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 at a reasonable cost 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.

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:

Treatment of Manifestations

There is no specific treatment for SYNE1 deficiency. The goals of treatment are to maximize function and reduce complications. Each patient 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.