Myasthenic Syndrome, Congenital, 14

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-14 (CMS14) is caused by homozygous mutation in the ALG2 gene (607905) on chromosome 9q22.

Description

Congenital myasthenic syndrome-14 is an autosomal recessive neuromuscular disorder characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound. There is no respiratory or cardiac involvement. Treatment with anticholinesterase medication may be beneficial (summary by Cossins et al., 2013).

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

Clinical Features

Cossins et al. (2013) reported 4 sibs, born of consanguineous Saudi Arabian parents, with onset of a slowly progressive muscle disorder within the first 2 years of life. The patients showed delayed motor milestones, hypotonia, and absent reflexes. The 3 older patients had progressive deterioration and became wheelchair-bound in the second decade; the youngest had not achieved ambulation. There was proximal greater than distal muscle weakness and mild facial weakness, but no ophthalmoplegia. All patients had pes planus and high-arched palate, and the 3 older sibs showed knee contractures and distal joint laxity. Mild learning difficulty was also apparent. Electrophysiologic studies of 2 patients showed decremental compound muscle action potentials (CMAP) in response to repetitive nerve stimulation, consistent with myasthenia, and increased jitter. Muscle biopsy of 1 patient showed variation in fiber size with type 1 fiber predominance. An unrelated man, born of consanguineous Italian parents, developed progressive proximal muscle weakness at age 4 years. He was diagnosed with myasthenia in his teens and showed favorable response to pyridostigmine. At age 60 years, he had limited walking ability with a waddling gait, lumbar lordosis, scapular winging, and Gowers sign; facial and neck muscles were strong and there was no ptosis.

Monies et al. (2014) reported 3 young adult patients from an extended consanguineous Saudi Arabian family with a form of congenital limb-girdle myopathy. All had onset of progressive proximal muscle weakness between 2 and 4 years of age after learning how to walk independently, although 1 had delayed motor development and hypotonia. Two patients became wheelchair-bound in their teens, whereas the third was still ambulatory at age 33 years. Both upper and lower limbs were affected, with proximal weakness greater than distal weakness. Other features included lordosis and scoliosis, but there were no bulbar symptoms or respiratory insufficiency. Electrophysiologic studies showed a decrement of the CMAP on repetitive nerve stimulation. Muscle biopsies performed on 2 patients showed myopathic features with type 1 fiber predominance, ragged-red fibers, and subsarcolemmal accumulation of normal mitochondria. These findings supported a mitochondrial myopathy combined with a neuromuscular junction disorder. Laboratory studies showed mildly increased serum creatine kinase in 1 patient and marginally increased carbohydrate-deficient transferrin (190000) in 1 patient.

Inheritance

The transmission pattern of CMS14 in the families reported by Cossins et al. (2013) and Monies et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 sibs, born of consanguineous Saudi Arabian parents, with CMS14, Cossins et al. (2013) identified a homozygous ins/del mutation in the ALG2 gene (607905.0003). The mutation was found by a combination of linkage analysis and whole-exome sequencing. An unrelated patient of Italian descent was homozygous for a different mutation in the ALG2 gene (V68G; 607905.0004). Although ALG2 is involved in glycosylation, transferrin glycosylation was not abnormal in the patients, suggesting that the mutations resulted in only a modest impairment of N-linked glycosylation.

In 3 patients from a large consanguineous Saudi Arabian Bedouin family with limb-girdle myasthenia, Monies et al. (2014) identified the same homozygous ins/del mutation in exon 1 of the ALG2 gene as that found by Cossins et al. (2013). Both families originated from the same small village, suggestive of a founder mutation.