Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness

Abstract

Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS.

Congenital myasthenic syndrome due to mutations in MUSK suggests that the level of MuSK phosphorylation is crucial for governing synaptic structure

“…The underlying reason explaining this phenomenon is unknown but could be related to the fact that severe MUSK mutations are incompatible with life due to the crucial role of MuSK as the key organizer at the postsynaptic membrane. The clinical phenotype reported in individuals with MUSK mutations is variable and differs in both severity and time of onset (Chevessier et al, ; Gallenmüller et al, ; Giarrana et al, ; Luan et al, ; Maselli et al, ; Mihaylova et al, ; Murali et al, ; Owen et al, ). The current case lies on the severe side of the clinical spectrum with the neonatal onset and life‐threatening complications.…”

Pregnancy‐associated respiratory failure in muscle specific kinase congenital myasthenic syndrome

“…A wide variety of mutations are associated with worsening of myasthenia in pregnancy, but the cases are too few to infer a relationship with a specific genetic mutation. In MuSK ‐CMS, 2 earlier studies had briefly reported worsening of weakness in pregnancy (Table ). In both instances, there was no respiratory compromise.…”

“…A clinical indicator of the diagnosis in our case was the central tongue wasting. This was described as a marker for downstream of kinase 7 ( DOK7 ) mutation but has since been reported in MuSK mutations . Other similarities between the 2 are a predominant limb‐girdle pattern and poor response to pyridostigmine.…”

“…Results of next‐generation sequencing showed a homozygous missense mutation of exon 3 of the MuSK gene (c.308A > G, p.Asn103Ser in chromosome 9). The identified variant has previously been reported as disease causing in compound heterozygous and homozygous states …”

“…Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders of neuromuscular transmission. Congenital myasthenic syndrome related to mutations of the gene coding for muscle‐specific tyrosine kinase (MuSK) is extremely rare, with fewer than 20 cases reported worldwide . Muscle‐specific tyrosine kinase CMS can cause generalized fatigable weakness and has a variable age of presentation .…”