SYNE1-Related motor neuron disease-like phenotype with mild distal contractures and 24-month clinical stability: a case report

Abstract

Background

SYNE1 encodes nesprin-1, a nuclear envelope protein involved in cytoskeletal linkage, nuclear positioning, and neuromuscular integrity. Biallelic SYNE1 variants cause a broad spectrum ranging from cerebellar ataxia to arthrogryposis multiplex congenita and motor neuron disease-like phenotypes. Distinguishing these entities can be difficult when subtle distal contractures coexist with neurogenic electrophysiological findings.

Case presentation

A 22-year-old woman born to consanguineous parents presented with bilateral intrinsic hand muscle wasting, impaired fine motor performance, and mild gait difficulty. Examination showed distal hand atrophy, mild weakness of the abductor pollicis brevis and first dorsal interosseous muscles, brisk deep tendon reflexes, preserved sensation, and mild distal finger contractures. Sensory nerve conduction studies were normal. Motor studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude on the left. Needle electromyography showed widespread chronic neurogenic motor unit changes affecting the upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal. SMN1 deletion testing and selected familial amyotrophic lateral sclerosis gene testing were negative. Whole exome sequencing identified a homozygous truncating SYNE1 variant, NM_182961.4:c.21009G > A; p.(Trp7003Ter). Segregation analysis confirmed heterozygous carrier status in both parents and two unaffected siblings. At 24-month follow-up, weakness, atrophy, contractures, reflex pattern, and functional status remained clinically stable, without bulbar, cerebellar, sensory, or clinically evident respiratory involvement.

Conclusions

This case supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated arthrogryposis multiplex congenita type 3 (AMC3) phenotype. The case also supports including SYNE1 in genetic testing panels for young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.

Background

SYNE1 encodes nesprin-1, a nuclear envelope protein that links the nucleus to the cytoskeleton and contributes to nuclear positioning, cellular mechanical stability, and neuromuscular integrity [1]. Biallelic SYNE1 variants have been associated with autosomal recessive cerebellar ataxia, arthrogryposis multiplex congenita type 3, and other neuromuscular phenotypes [1, 2]. More recent reports have expanded this spectrum to include motor neuron disease-like and juvenile amyotrophic lateral sclerosis-like presentations [1, 3–8].

Arthrogryposis multiplex congenita is a clinically and genetically heterogeneous group of disorders characterised by congenital joint contractures affecting at least two distinct body regions [9–12]. Among the genetic causes of arthrogryposis, biallelic SYNE1 variants are increasingly recognised as a rare but important aetiological factor, particularly in patients with accompanying neuromuscular features [2, 13, 14]. Although arthrogryposis is congenital by definition, distal contractures may be subtle and may not dominate the initial clinical presentation, particularly when neuromuscular features coexist [13].

The overlap between SYNE1-related arthrogryposis, cerebellar ataxia, and motor neuron disease-like phenotypes may complicate diagnosis. Patients may show distal wasting, brisk reflexes, preserved sensory conduction, chronic neurogenic electromyographic changes, and variable contractures. Here, we report a young woman with a homozygous truncating SYNE1 variant, distal hand atrophy, widespread neurogenic electromyographic abnormalities, mild distal finger contractures, and objective clinical stability over 24 months.

Case presentation

A 22-year-old woman presented with a one-year history of bilateral hand muscle wasting, impaired fine motor performance, and mild gait difficulty. She particularly reported difficulty with writing, buttoning, and handling small objects. She had no chronic systemic disease, regular medication use, or toxic exposure. Prenatal and perinatal history was unremarkable, and early motor development was reportedly normal. Her parents were second-degree relatives. There was no family history of similar neuromuscular disease, known motor neuron disease, or unexplained early-onset muscle weakness. Her two younger sisters were clinically healthy.

Neurological examination showed normal cognition and cranial nerve function. There was no tongue atrophy, fasciculation, dysarthria, or dysphagia. Proximal strength was preserved. Distal upper limb examination revealed mild bilateral weakness of the abductor pollicis brevis and first dorsal interosseous muscles, graded as 5-/5 bilaterally. Lower limb strength was preserved on clinical examination. Sensory examination was normal. Deep tendon reflexes were brisk in all extremities, without clear pathological reflexes. Visible bilateral first dorsal interosseous and abductor pollicis brevis atrophy was present (Fig. 1). Mild bilateral distal finger contractures accompanied the distal hand phenotype but did not cause marked fixed functional limitation.

Fig. 1.

Clinical photographs showing bilateral atrophy of the first dorsal interosseous and abductor pollicis brevis muscles, accompanied by mild distal finger contractures

Routine laboratory investigations, including serum creatine kinase, thyroid function tests, vitamin levels, and basic metabolic parameters, were within normal limits. Cranial and cervical magnetic resonance imaging showed no significant abnormality.

Nerve conduction studies and needle electromyography were performed (Fig. 2). Motor nerve conduction studies showed reduced compound muscle action potential amplitude in the right abductor pollicis brevis and borderline-low amplitude in the left abductor pollicis brevis after median nerve stimulation. Sensory nerve conduction studies were normal, supporting a motor-predominant neurogenic process rather than a primary sensory polyneuropathy. Needle electromyography demonstrated chronic neurogenic motor unit potential changes in both upper and lower extremities, including high-amplitude, long-duration motor unit potentials and reduced recruitment in multiple muscles. Active denervation, including fibrillation potentials and positive sharp waves, was most evident in the bilateral abductor pollicis brevis muscles. Genioglossus examination was normal, and the electrophysiological evaluation did not support clinically significant bulbar involvement.

Fig. 2.

Nerve conduction studies and needle electromyography findings demonstrating preserved sensory conduction and widespread chronic neurogenic involvement affecting both upper and lower extremities, with active denervation most evident in the bilateral abductor pollicis brevis muscles

Hereditary motor neuron disease, spinal muscular atrophy, and familial amyotrophic lateral sclerosis-related genetic causes were initially considered. SMN1 deletion analysis was negative. Targeted testing for selected familial amyotrophic lateral sclerosis-associated genes, including SOD1, FUS, and TARDBP, did not identify a pathogenic variant.

Whole exome sequencing identified a homozygous truncating SYNE1 variant: NM_182961.4:c.21009G > A; p.(Trp7003Ter). The variant was interpreted as pathogenic in the context of the clinical phenotype and autosomal recessive segregation. Segregation analysis confirmed that both parents and both clinically unaffected sisters were heterozygous carriers.

The patient received genetic counseling. Physical therapy, range-of-motion exercises, distal strengthening, fine motor training, occupational therapy-based hand support, and orthotic assessment when needed were recommended. At the most recent follow-up, 24 months after the initial evaluation, neurological examination showed no objective progression. Distal hand strength remained 5-/5 bilaterally, proximal strength was preserved, reflexes remained brisk, sensory examination remained normal, and mild distal finger contractures were unchanged. No bulbar, cerebellar, sensory, or clinically evident respiratory involvement developed. She remained independently ambulatory and independent in activities of daily living.

Discussion and conclusions

This case fits within the expanding spectrum of SYNE1-related disorders. Although mild distal finger contractures suggested an arthrogryposis multiplex congenita type 3 (AMC3)-overlapping feature, the complete phenotype is not explained by an isolated AMC3 phenotype. Brisk reflexes, distal hand atrophy, preserved sensory conduction, and widespread chronic neurogenic electromyographic abnormalities support a SYNE1-related motor neuron disease-like phenotype with mild distal contractures.

The distinction is clinically important. Arthrogryposis multiplex congenita is congenital by definition, whereas this patient was recognized in young adulthood. The most cautious interpretation is delayed recognition of subtle distal contractures in a young adult with a motor neuron disease-like SYNE1 phenotype, rather than an isolated AMC3 phenotype. This interpretation also avoids overstating AMC3 as the sole explanation for the presentation.

Published reports have shown that SYNE1-related disease can include motor neuron involvement, sometimes with cerebellar ataxia and sometimes with minimal cerebellar features [3–8]. Selected reports are summarized in Table 1. In contrast to many previously described cases, the present patient had no clinically evident cerebellar or bulbar involvement and remained objectively stable over 24 months. This stability supports a mild or slowly evolving phenotype, although longer follow-up is required before prognosis can be defined.

Table 1.

Selected published SYNE1-associated phenotypes with motor neuron involvement and comparison with the present case

Study	Reported SYNE1 genetic finding(s)	Motor neuron phenotype	Cerebellar / contracture findings	Relevance to present case
Izumi et al. [3]	Patient 1: homozygous c.22456_22457insG, p.R7486fs7488X, together with homozygous c.G553C, p.G185R (source-reported legacy notation; transcript accession not specified in the main article).	Juvenile-onset upper and lower motor neuron involvement preceded cerebellar ataxia by several years and mimicked ALS; respiratory failure developed later.	Cerebellar ataxia and cerebellar/brainstem atrophy appeared later in the disease course; contractures were not reported.	Similar early motor-predominant onset without initial cerebellar involvement; unlike the present case, later cerebellar and severe respiratory involvement occurred.
Synofzik et al. [4]	Twenty-three index patients with biallelic SYNE1 variants (predominantly truncating); motor neuron dysfunction in 15/26 (58%).	Combined upper and lower motor neuron dysfunction in 5/26; isolated upper motor neuron dysfunction in 8/26; isolated lower motor neuron dysfunction in 2/26.	All 26 patients had cerebellar ataxia; 21/26 had ataxia-plus. Scoliosis and pes cavus were reported; Achilles tendon contractures were documented in one patient.	Confirms frequent motor neuron involvement and occasional contractures in biallelic, predominantly truncating SYNE1 disease.
Özoguz et al. [5]	Two Turkish ALS families with autosomal-recessive truncating SYNE1 variants: Q7644X (SYNE#1) and R7842X (SYNE#2); cDNA-level notation was not reported in the source article.	Familial early-onset ALS/MND (onset 20–21 years [SYNE#1] and 17–30 years [SYNE#2]) with spastic-ataxic gait, dysarthria, and dysmetria in both families; oculomotor abnormality additionally reported in Family SYNE#2; fast disease progression noted in Family SYNE#1.	Ataxic/cerebellar features were explicit; cerebellar imaging was not detailed in the source report. Contractures were not reported.	Provides a Turkish comparison with recessive truncating SYNE1-associated MND; the present case adds mild distal finger contractures and 24-month clinical stability.
Nadaf et al. [6]	Homozygous frameshift deletion: chr6:152527389_152527399del; c.22711_22721del; p.(Ala7571ArgfsTer4) (NM_033071).	ALS-like presentation; nerve conduction studies showed preserved sensory responses and upper-limb axonal motor involvement. EMG demonstrated active denervation in the bulbar region and active plus chronic denervation in the cervical, thoracic, and lumbar regions, consistent with clinically definite ALS.	Cerebellar ataxia and severe pancerebellar atrophy were present; contractures were not reported.	Shares motor-predominant neurogenic findings and normal sensory responses, but the present case lacks clinically evident cerebellar involvement.
Naruse et al. [7]	Compound heterozygous SYNE1 variants: c.21,463 C > T, p.(Arg7155Ter), and c.22835_22836delAA, p.(Lys7612SerfsTer28); the transcript accession was not specified in the main article.	Juvenile ALS with upper and lower motor neuron signs, dysarthria, dysphagia, mild limb ataxia, fine hand tremor, pes cavus, cognitive decline, and progressive respiratory impairment; death from respiratory failure at age 39.	Mild limb ataxia and fine hand tremor were present; contractures were not reported.	Represents a complex progressive phenotype; the present case lacks bulbar, cognitive, respiratory, and clinically evident cerebellar involvement and has remained stable over 24 months.
Senghor et al. [8]	Family 1: homozygous NM_182961.4:c.23,131 C > T, p.(Gln7711Ter). Family 2: homozygous splice-site variant NM_182961.4:c.17851-1G > A.	Early-onset MND/juvenile ALS with upper and lower motor neuron signs; progressive weakness, with bulbar and/or respiratory involvement in some affected individuals.	Cerebellar signs were absent or mild; one patient had marked hand contractures and scoliosis, and another developed late mild dysmetria and intention tremor.	Closest MND-predominant/minimal-cerebellar parallel; the reported cases were generally more progressive than the present case.
Present case	Homozygous NM_182961.4:c.21009G > A, p.(Trp7003Ter).	Distal hand atrophy, brisk reflexes, preserved sensory conduction, and widespread chronic neurogenic EMG changes; active denervation most prominent in both abductor pollicis brevis muscles.	No clinically evident cerebellar involvement; mild distal finger contractures; clinically stable over 24 months.	SYNE1-related MND-like phenotype with mild distal contractures. The findings are more consistent with a motor-neuron-predominant SYNE1 phenotype than with an isolated AMC3 phenotype.

ALS amyotrophic lateral sclerosis, AMC3 arthrogryposis multiplex congenita type 3, EMG electromyography, MND motor neuron disease, SYNE1 spectrin repeat containing nuclear envelope protein 1

Motor neuron involvement in SYNE1-related disease is now well documented. Izumi et al. described cerebellar ataxia with motor neuron disease due to a homozygous truncating SYNE1 variant [3]. Synofzik et al. demonstrated in a large multicentre cohort that SYNE1 ataxia frequently includes major non-cerebellar features, with motor neuron dysfunction in 15 of 26 patients (58%) [4]. Subsequently, predominantly motor presentations have been reported: SYNE1 variants in a Turkish amyotrophic lateral sclerosis cohort with accompanying ataxic features [5]; an amyotrophic lateral sclerosis-like presentation from India [6]; juvenile amyotrophic lateral sclerosis with complex phenotypes [7]; and, most recently, SYNE1 deficiency manifesting primarily with motor neuron disease and minimal or virtually absent cerebellar involvement [8]. Against this background (Table 1), the present case is distinguished by mild distal finger contractures, absence of clinically evident cerebellar or bulbar involvement, a homozygous truncating SYNE1 variant on a consanguineous background, and objective clinical stability over 24 months.

The electrophysiological findings were central to phenotypic classification. Normal sensory conduction and widespread chronic neurogenic changes support a motor-predominant process. Active denervation was most evident in the bilateral abductor pollicis brevis muscles, corresponding to the clinically most affected region. Although electromyography alone cannot distinguish all motor neuron disease mimics, it can help characterise neurogenic involvement in atypical neuromuscular presentations and support the selection of appropriate genetic testing in the appropriate clinical context [15].

The relationship between distal contractures and motor neuron involvement remains uncertain. Contractures may represent a subtle SYNE1-related arthrogryposis multiplex congenita type 3-overlapping feature, or they may reflect chronic distal denervation, muscle imbalance, and long-standing hand involvement. These mechanisms are not mutually exclusive, because SYNE1-related disease can affect both neural and muscular tissues.

Genotype–phenotype studies indicate that no consistent correlation has been established between the position of truncating SYNE1 variants and the resulting clinical phenotype. Biallelic loss-of-function variants located in the proximal, middle, or distal regions of the gene have all been associated with either relatively pure cerebellar ataxia or more complex multisystem phenotypes, including motor neuron dysfunction [4, 8]. The distal truncating p.(Trp7003Ter) variant identified in the present case is consistent with this spectrum and is predicted to remove the C-terminal segment of nesprin-1, including the KASH domain, which is essential for nuclear envelope anchorage and cytoskeletal linkage. This localisation is compatible with the presence of subtle distal contractures, while the widespread neurogenic electrophysiological pattern highlights the broader neuromuscular spectrum of SYNE1 dysfunction.

The 24-month follow-up without objective clinical deterioration is relevant for phenotypic interpretation. Classical amyotrophic lateral sclerosis would typically be expected to show a clearly progressive course, whereas SYNE1-related motor neuron disease-like phenotypes may follow variable and sometimes slowly progressive courses [5–8]. Clinical stability over two years therefore supports a mild or slowly evolving SYNE1-related phenotype, although longer follow-up remains necessary to define prognosis. This stability does not exclude the patient from the expanding SYNE1-related motor neuron disease-like spectrum, particularly given the neurogenic electromyographic pattern and upper motor neuron signs reflected by brisk reflexes. Early recognition of SYNE1-related disease supports accurate diagnosis, prognosis assessment, genetic counseling, and family screening, in addition to individualized rehabilitation planning.

This case has practical diagnostic implications. In young patients with distal muscle wasting, brisk reflexes, preserved sensory conduction, neurogenic electromyographic abnormalities, and negative first-line testing for spinal muscular atrophy or selected familial amyotrophic lateral sclerosis genes, SYNE1 should be included in the diagnostic workup. This is particularly relevant when consanguinity or subtle distal contractures suggest autosomal recessive inheritance.

Limitations

This report is limited by its single-case design. Although 24-month clinical follow-up showed no objective progression, longer follow-up is needed to define the lifelong disease course. Repeat electromyography was not performed; therefore, electrophysiological stability cannot be confirmed. Muscle biopsy, functional studies, respiratory function testing, and systematic cardiac evaluation were not performed. These assessments may be useful in future follow-up, given the broad neuromuscular spectrum of SYNE1-related disease.

Conclusions

This case adds to the clinical spectrum of SYNE1-related disease by documenting a young adult presentation with motor neuron disease-like features, mild distal finger contractures, and 24-month clinical stability. The coexistence of brisk reflexes, distal hand atrophy, preserved sensory conduction, and widespread neurogenic electromyographic findings supports classification as a SYNE1-related motor neuron disease-like phenotype with mild distal contractures rather than an isolated AMC3 phenotype. SYNE1 should be considered in young patients with unexplained motor neuron disease-like presentations, particularly when consanguinity, normal sensory conduction, and subtle distal contractures coexist.

Abbreviations

ALS

Amyotrophic lateral sclerosis

AMC

Arthrogryposis multiplex congenita

AMC3

Arthrogryposis multiplex congenita type 3

APB

Abductor pollicis brevis

CMAP

Compound muscle action potential

DTR

Deep tendon reflex

EMG

Electromyography

KASH

Klarsicht/ANC-1/Syne homology

MND

Motor neuron disease

SMA

Spinal muscular atrophy

SYNE1

Spectrin repeat containing nuclear envelope protein 1

WES

Whole exome sequencing

Authors' contributions

Authorship Contributions: Concept – E.S.I; Design – Z.Ö; Fundings – E.S.I; Materials – E.S.I; Data collection &/or processing – Z.Ö; Analysis and/or interpretation – Z.Ö.; Literature search – E.S.I; Writing – Z.Ö; Critical review – E.S.I.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during this study that support the conclusions of this article are included within the published article. Because the data derive from a single patient, no additional datasets were generated; further anonymized information may be made available by the corresponding author upon reasonable request, subject to restrictions necessary to protect patient confidentiality.

Declarations

Ethics approval and consent to participate

Not applicable. Written informed consent was obtained from the patient.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and accompanying clinical images.

Competing interests

The authors declare no competing interests.