MUSK – Congenital Myasthenic Syndrome

MUSK encodes muscle-specific receptor tyrosine kinase (MuSK), a postsynaptic protein essential for agrin-LRP4-Dok7 signaling during neuromuscular junction formation and maintenance. Pathogenic biallelic variants in MUSK underlie a rare autosomal recessive congenital myasthenic syndrome (CMS) characterized by impaired neuromuscular transmission and fatigable muscle weakness (PMID:16550915).

Genetic evidence across 14 probands has identified homozygous and compound heterozygous LoF and missense mutations in MUSK, including frameshift (c.220insC) and missense alterations. Segregation in two sibling pairs supports recessive inheritance (PMID:24183479; PMID:30719842). The variant spectrum encompasses at least 4 LoF, 9 missense, and splice-site mutations without recurrent founder alleles reported to date.

Functional studies demonstrate that frameshift mutations abolish MuSK expression, while kinase-domain missense variants (p.Met605Ile, p.Ala727Val) impair agrin-dependent MuSK phosphorylation, AChR clustering, and Dok7 interaction in vitro (PMID:15496425; PMID:20371544). In vivo electroporation of mutants recapitulates synaptic structural abnormalities observed in patient biopsies, confirming pathogenicity.

Clinically, MUSK-CMS presents with neonatal or early-onset ptosis (HP:0000508), fluctuating ophthalmoplegia, limb-girdle muscle weakness (HP:0007340), antenatal onset in severe cases (HP:0030674), feeding difficulties (HP:0011968), sleep-disordered breathing including obstructive sleep apnea (HP:0002870), and respiratory failure. β2-adrenergic agonists (salbutamol) improve strength in several patients more effectively than acetylcholinesterase inhibitors (PMID:24183479).

No studies dispute the association. The consistency of recessive inheritance, multiple affected families, and concordant functional data support a Strong clinical validity.

Key take-home: Genetic testing for biallelic MUSK variants is critical for precision diagnosis of CMS and informs therapeutic choice, particularly β2-adrenergic agonist responsiveness.

References

• Acta myologica : myopathies and cardiomyopathies | 2005 | Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK. PMID:16550915
• PLoS One | 2013 | A mutation causes MuSK reduced sensitivity to agrin and congenital myasthenia. PMID:23326516
• Neuromuscular Disorders : NMD | 2014 | Salbutamol-responsive limb-girdle congenital myasthenic syndrome due to a novel missense mutation and heteroallelic deletion in MUSK. PMID:24183479
• Muscle & Nerve | 2015 | A severe congenital myasthenic syndrome with “dropped head” caused by novel MUSK mutations. PMID:25900532
• American Journal of Medical Genetics Part A | 2019 | Isolated vocal cord paralysis in two siblings with compound heterozygous variants in MUSK: Expanding the phenotypic spectrum. PMID:30719842
• Human Molecular Genetics | 2004 | MUSK, a new target for mutations causing congenital myasthenic syndrome. PMID:15496425
• Human Molecular Genetics | 2010 | Mutations in MUSK causing congenital myasthenic syndrome impair MuSK-Dok-7 interaction. PMID:20371544
• Journal of Personalized Medicine | 2023 | Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature. PMID:37240968

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