Myasthenic Syndrome, Congenital, 6, Presynaptic

A number sign (#) is used with this entry because presynaptic congenital myasthenic syndrome-6 (CMS6) is caused by homozygous or compound heterozygous mutation in the choline acetyltransferase gene (CHAT; 118490) on chromosome 10q11.

Description

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS6 is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (summary by Engel et al., 2015).

For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Clinical Features

Fenichel (1978) and Engel (1980) reported patients with familial infantile or childhood myasthenic syndromes, noting that the syndromes can manifest as severe respiratory and feeding difficulties at birth. They observed that mothers of affected children did not have myasthenia gravis (MG; 254200), and concluded that it was not an autoimmune disorder. Smit and Barth (1980) described arthrogryposis multiplex congenita in patients with congenital myasthenia.

Robertson et al. (1980) reported a boy who had apnea and hypotonia as a neonate and infant. By age 10 months, he had had about 20 episodes of grunting respiration progressing over several minutes to apnea and cyanosis. The spells lasted from several minutes to 5 hours and usually occurred in the late afternoon. During the second year of life, the spells gradually became less frequent, with the last occurring at age 23 months. He subsequently showed easy fatigability following exercise, with generalized weakness most pronounced in the proximal muscles. Acetylcholine receptor antibodies 'were in the normal range.' Neostigmine initiated at age 4 years corrected the muscle weakness. At age 14 years, he continued to have weakness following exercise. One of his 3 sibs, an older brother, had experienced several episodes of respiratory distress during infancy. Although Robertson et al. (1980) suggested that the course of familial infantile myasthenia is benign after infancy, Gieron and Korthals (1985) described a family in which 3 sibs were affected, including 2 sisters, aged 26 and 24 years, who continued to have episodes of respiratory distress, oculobulbar signs, and proximal muscle weakness. Gieron and Korthals (1985) recommended against use of steroids and thymectomy.

Zammarchi et al. (1994) described an affected infant who showed decreased intrauterine fetal movements and had closed fists and polyhydramnios by ultrasonography at 16 weeks' gestation. At birth, she had distal articular rigidity, flexion of the hands, long and tapering fingers, and hypotonia. Episodes of apnea occurred in association with an upper respiratory infection at the age of 13 months. Treatment with pyridostigmine bromide was effective. Palpebral ptosis occurred on one occasion and was controlled by medication. A younger brother, who died at 15 hours of life from respiratory failure, had arthrogryposis and presumably was also affected by congenital myasthenia.

Mullaney et al. (2000) reviewed the natural history and ophthalmic involvement in childhood myasthenia gravis in 34 patients. Among the 7 children with congenital myasthenic syndromes, severity varied. The diagnosis in severe cases was often obscured by apnea attacks, aspiration, and failure to thrive. Ophthalmic signs and symptoms, including strabismus, ophthalmoplegia, and ptosis, were more prominent in mild cases and did not resolve during remissions.

Ohno et al. (2001) reported 5 patients, 4 males and 1 female, with a myasthenic syndrome associated with episodic apnea. The patients ranged in age from 4 to 40 years at the time of the report. All had myasthenic symptoms dating to birth or early infancy, negative tests for antiacetylcholine receptor (AChR) antibodies, and abrupt episodic crises with increased weakness, bulbar paralysis, and apnea precipitated by undue exertion, fever, or excitement. One of the patients had 3 affected sibs and another had 2; 3 of the 5 affected sibs died during febrile episodes, and 1 died suddenly without apparent cause.

Inheritance

The transmission pattern of CMS in the families reported by Ohno et al. (2001) was consistent with autosomal recessive inheritance.

Pathogenesis

On the basis of studies of an affected brother and sister, Hart et al. (1979) proposed a presynaptic defect of acetylcholine resynthesis or mobilization in this syndrome. From in vitro electrophysiologic and morphologic studies in patients with familial infantile myasthenia, Mora et al. (1987) suggested that the phenotype was due to a presynaptic defect of acetylcholine resynthesis or mobilization, or an abnormality of synaptic vesicle metabolism.

Molecular Genetics

In 5 patients with CMS6, Ohno et al. (2001) identified compound heterozygous mutations in the CHAT gene (118490.0001-118490.0010).

In a consanguineous Turkish family in which 2 sibs had CMS6, Kraner et al. (2003) identified homozygosity for a mutation in the CHAT gene (I336T; 118490.0011). Both patients had delayed motor development and increased fatigability, and the index patient had multiple episodes of respiratory distress.

History

Walsh and Hoyt (1959) and Rothbart (1937) each reported a family in which 4 affected brothers had a familial form of childhood congenital myasthenia. Greer and Schotland (1960) reported myasthenia gravis in the newborn. Kott and Bornstein (1969) observed 4 affected sibs. Clinical characteristics included onset in the first year of life, good response to anticholinesterase drugs, good prognosis, and absence of antimuscle antibodies in the serum.