Congenital Myasthenic Syndromes

CMSs are caused by defects affecting the presynaptic, synaptic basal lamina–associated, and postsynaptic regions of the neuromuscular junction. Inheritance is autosomal recessive, except in the dominantly inherited slow-channel CMS. While clinical profile alone cannot distinguish among different forms of CMS, elegant morphologic and in vitro electrophysiologic studies have made it possible to distinguish among most of the CMSs and identify their associated genetic defects. In a small number of cases, however, a specific genetic diagnosis remains elusive.

Most mutations underlying the CMSs are in genes coding for proteins localized to the postsynaptic portion of the neuromuscular junction. When the abnormality involves the acetylcholine receptors (AChRs), mutations are concentrated in the gene encoding the epsilon subunit of the AChR (CHRNE). The most frequent CMS, caused by AChR deficiency due to CHRNE mutations, is usually benign, with prominent ophthalmoparesis and mild or no diplopia. Onset is usually at birth or infancy, with poor cry/suck and fluctuating ptosis. Bulbar symptoms regress with time, but fatigue and ptosis persist. There is partial response to AChEi and 3,4-diaminopyridine (3,4-DAP). Fast-channel CMS is similar regarding phenotype and treatment, but unlike AChR deficiency, acute respiratory crises occur frequently in childhood.

Almost all the proteins in the muscle-specific kinase (MuSK)/rapsyn signaling pathways have been associated with CMSs. Among them, postsynaptic rapsyn and DOK-7 deficiencies are major causes of CMS. In both, extraocular muscle involvement is mild or absent, while ptosis is common. Rapsyn deficiency causes a form of CMS characterized by mild arthrogryposis, strabismus, and frequent respiratory crises. Symptoms usually start at birth and rarely in adulthood. Patients improve with age and respond well to AChEi and 3,4-DAP.

DOK-7 mutations are responsible for some cases of limb girdle myasthenia. Proximal weakness, generally accompanied by ptosis and facial weakness, usually begins in early childhood. The severity of weakness may fluctuate over weeks. Respiratory problems may occur. AChEi are harmful, but the response to ephedrine or albuterol/salbutamol is generally favorable. Another subset of CMS patients with a limb girdle pattern of weakness and normal eye movements has a molecular defect mapped to the glutamine-fructose-6-phosphate transaminase 1 gene (GFPT1). These patients have tubular aggregates on muscle biopsy. They respond well to AChEi.

Two CMS syndromes with phenotypic similarities are postsynaptic slow-channel CMS and synaptic AChE deficiency. In both, the postsynaptic membrane is exposed to excessive acetylcholine, explaining the presence of repetitive compound muscle action potentials and the lack of response to AChEi. The clinical findings include variable ophthalmoparesis, neck muscle and upper extremity muscle weakness/atrophy, and respiratory insufficiency. The structural abnormalities of the end plate lead to clinical features resembling a myopathy. In slow-channel CMS, onset is in childhood or adult life and open channel blockers, such as quinidine and fluoxetine, are helpful. In synaptic AChE deficiency, onset is at birth or infancy, slow pupillary responses may be present, and strength and functional capacity are improved markedly by ephedrine or albuterol/salbutamol, their effect increasing over months.

A very rare presynaptic CMS syndrome, choline acetyltransferase (ChAT) deficiency, causes episodic apnea, presenting with sudden respiratory insufficiency in infancy or childhood, particularly during the course of infections. Some patients have mild myasthenic symptoms in the interim, others become severely disabled. RNS may be normal at rest, with a decrement appearing after prolonged high-frequency stimulation or activity. Prophylactic AChEi may have a salutary effect.

The diagnosis of the CMSs is challenging, in part because patients with congenital disorders of the neuromuscular junction often have clinical features traditionally associated with congenital myopathies, such as a high arched palate, joint contractures, kyphoscoliosis, mild creatine kinase (CK) elevation, myopathic electromyography (EMG), and mild myopathic histopathologic changes. Once the clinical diagnosis is established, molecular genetic studies are important because therapeutic options will depend upon which specific mutation is identified. Although a small subset of patients with CMS experience pronounced weakness (requiring a wheelchair) and respiratory insufficiency (requiring noninvasive ventilatory support), with appropriate treatment, many individuals have a good prognosis and fare well through adolescence and adulthood.

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