Clinical, genetic, and instrumental features of congenital myasthenic syndrome type 11

Background. Congenital myasthenic syndrome (CMS) type 11, caused by pathogenic biallelic variants in the RAPSN gene, is one of the most common forms of CMS in patients of European origin. The disease is characterized by significant clinical heterogeneity, which, combined with the variability of electrophysiological findings, leads to diagnostic challenges. Accurate diagnosis determines the management strategy, enabling symptomatic treatment and improvement of functional outcomes.

Aim. To characterize the phenotypic spectrum of CMS type 11 and evaluate genotype–phenotype features based on clinical and instrumental examination of a cohort of patients with biallelic variants in the RAPSN gene.

Materials and methods. The study included 6 patients (4 female) from 5 families with a verified diagnosis of CMS type 11. All patients underwent molecular genetic testing: whole exome sequencing in all cases; in one case, whole genome sequencing using a targeted gene panel for myopathies and myasthenic syndromes was additionally performed, followed by Sanger sequencing validation of identified variants. Variant pathogenicity was assessed according to ACMG/APM (2015) criteria. All patients underwent clinical and genealogical analysis and laboratory testing (creatine phosphokinase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, myoglobin). Electrodiagnostic evaluation in 5 patients included neuromuscular transmission testing at 3 Hz repetitive nerve stimulation and needle electromyography of skeletal muscles; in two cases the protocol was extended – one patient underwent stimulation at 10 Hz and another at 50 Hz. Muscle magnetic resonance imaging was performed in 3 patients.

Results. Molecular genetic analysis identified the recurrent variant in RAPSN (NM_005055.5): c.264C>A, p.(Asn88Lys) in all patients: in homozygous state in 4 patients, and in compound heterozygous state in 2 patients – in combination with c.61C>T, p.(Gln21Ter) and c.149_153delins24, p.(Val50GlufrTer114). In patients with the homozygous c.264C>A variant, the disease manifested in childhood or adolescence and followed a relatively mild course, presenting with blepharoptosis, oculomotor disturbances, and predominantly limb-girdle distribution of pathological muscle fatigability and weakness, without bulbar or respiratory involvement. In patients with compound heterozygous variants, the disease manifested in the neonatal period with respiratory failure requiring mechanical ventilation, diffuse muscular hypotonia, and bulbar dysfunction, and was accompanied by delayed motor development, recurrent episodes of respiratory failure, and early orthopedic complications. Repetitive nerve stimulation at 3 Hz revealed a decremental response exceeding 30 % in 1 of 5 examined patients; preconditioning with physical exercise allowed verification of a decrement of 10–16 % in 2 additional patients. Needle electromyography in all 5 patients demonstrated a myopathic pattern of motor unit potential remodeling. Muscle magnetic resonance imaging in 3 patients revealed minimal fatty infiltration predominantly in the posterior muscle groups of the thighs and legs, combined with diffuse edematous changes in the posterior leg muscles. All patients with the homozygous recurrent variant and one patient with compound heterozygous variants received pyridostigmine bromide therapy with a positive clinical response.

Conclusion. CMS type 11 is characterized by a wide phenotypic spectrum – from a mild limb-girdle phenotype with extraocular involvement and childhood onset to severe forms with neonatal manifestation and respiratory failure. Disease severity is determined by the zygosity of the c.264C>A variant: in homozygous state it is associated with a mild late-onset phenotype, whereas in compound heterozygous combination with another pathogenic allele it is associated with neonatal manifestation and severe course. A myopathic pattern of motor unit potential remodeling on needle electromyography, combined with absent decrement on 3 Hz repetitive stimulation and minimal muscle magnetic resonance imaging changes, should not exclude CMS from the differential diagnosis with congenital myopathies. Timely molecular genetic verification of CMS determines the feasibility of symptomatic treatment and is of critical importance for prognosis and patient management.