Congenital Myasthenic Syndrome

Congenital myasthenic syndromes are a group of inherited disorders of neuromuscular transmission, with fatigable weakness from infancy, childhood or sometimes adulthood. Over 30 genes are known. The most frequent are CHRNE (acetylcholine receptor deficiency, about 50%), RAPSN, DOK7, COLQ and CHAT.

Pathophysiology. Variants affect presynaptic, synaptic or postsynaptic proteins, with kinetic or deficiency defects. This determines drug response, so genetic diagnosis guides treatment.

Hypotonia, feeding difficulty, ptosis, ophthalmoparesis, facial and bulbar weakness, respiratory crises (especially with RAPSN, CHAT) and fluctuating limb weakness. DOK7 gives limb girdle weakness. CHAT gives episodic apnoea. COLQ gives slow-channel-like weakness with a slow pupil response. Arthrogryposis may be present at birth.

Red flags.

• Episodic apnoea, cyanosis or respiratory failure triggered by fever or infection.
• Worsening after pyridostigmine (COLQ, DOK7 and slow channel).

Repetitive nerve stimulation shows decrement (3 Hz), and single fibre electromyography shows jitter. Anti-acetylcholine receptor and MuSK antibodies are negative. Multigene panel or exome sequencing identifies the gene. Check creatine kinase, and exclude seronegative myasthenia gravis, spinal muscular atrophy and congenital myopathy.

Differential diagnosis.

• Neonatal myasthenia (transient), seronegative autoimmune myasthenia and botulism.
• Congenital myopathies, spinal muscular atrophy and mitochondrial disease.

Treatment depends on the genetic subtype.

Pyridostigmine (acetylcholinesterase inhibitor): children 0.5 to 1 mg/kg orally every 4 to 6 hours, increased to a maximum of 7 mg/kg daily; adults 30 to 60 mg three or four times daily (maximum 360 mg daily). Effective in CHRNE, RAPSN, CHAT and other deficiency types. Avoid or use cautiously in COLQ and DOK7 disease, and in slow channel syndrome, where it can worsen weakness.

3,4-diaminopyridine. 0.5 mg/kg daily in divided doses, increased to 1 mg/kg daily (adults 5 to 20 mg three or four times daily, maximum 80 mg daily). Monitor for seizures and QT prolongation.

Salbutamol or ephedrine. Used for DOK7 and COLQ disease: salbutamol 2 mg orally two or three times daily (children 0.1 mg/kg two times daily), or ephedrine 15 mg twice daily, increased as tolerated.

Slow channel syndrome. Fluoxetine 80 to 100 mg daily (or quinidine, with monitoring of QT).

Avoid magnesium, aminoglycosides, macrolides and other drugs that worsen neuromuscular transmission.

Crisis care. Respiratory support, infection treatment and an emergency plan.

Monitoring. Respiratory function, swallowing, growth and scoliosis.

Referral and escalation. Refer to paediatric neuromuscular services and clinical genetics.