Myasthenic Syndrome, Congenital, 19

A number sign (#) is used with this entry because of evidence that congenital myasthenic syndrome-19 (CMS19) is caused by homozygous mutation in the COL13A1 gene (120350) on chromosome 10q22.

Description

Congenital myasthenic syndrome-19 is an autosomal recessive disorder resulting from a defect in the neuromuscular junction, causing generalized muscle weakness, exercise intolerance, and respiratory insufficiency. Patients present with hypotonia, feeding difficulties, and respiratory problems soon after birth, but the severity of the weakness and disease course is variable (summary by Logan et al., 2015).

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

Clinical Features

Logan et al. (2015) reported 3 patients from 2 unrelated families with onset of congenital myasthenic syndrome soon after birth. Two unrelated patients were aged 2 years and 27 years at the time of the report; the younger sib of the older patient had died of respiratory insufficiency at age 8 years. All patients presented with respiratory insufficiency, hypotonia, and feeding difficulties, including gastroesophageal reflux in 2 patients. Features of muscle weakness included ptosis, poor head control, and proximal and distal limb hypotonia. The 2-year-old girl had delayed cognitive development, and the young man had mild learning difficulties. The muscle disorder in the 2 sibs varied in severity: the older sib had normal motor development, but showed ptosis, dyspnea on exertion, recurrent chest infections, and mild weakness of hip extensors as a young adult. He had distal weakness of the upper limbs and mild axial weakness, but the disease course was not progressive. His younger sister had delayed motor milestones, facial and bulbar weakness, distal joint laxity, limited walking and exercise tolerance, and reduced muscle bulk. She was dependent on oxygen for the first 2 years of life and was fed mainly via gastrostomy tube. She had recurrent chest infections resulting in chronic lung disease and early death. All patients had similar dysmorphic features, including low-set ears, micrognathia, retrognathia, high-arched palate, and pectus carinatum. The young man also had pes cavus, and both sibs had spinal rigidity. None of the patients had joint contractures. Muscle biopsy of 1 patient showed abnormal variation in fiber size, few central nuclei, and occasional vacant peripheral vacuole-like areas. Repetitive nerve stimulation performed in 2 unrelated patients showed a significant decremental response, consistent with a congenital myasthenic syndrome.

Clinical Management

One of the patients with CMS19 reported by Logan et al. (2015) had motor and respiratory improvement with 3,4-diaminopyridine and salbutamol treatment. Pyridostigmine was ineffective in the 2 patients treated.

Inheritance

The transmission pattern of CMS19 in the family reported by Logan et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 3 patients from 2 unrelated families with CMS19, Logan et al. (2015) identified 2 different homozygous truncating mutations in the COL13A1 gene (120350.0001 and 120350.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. Patient muscle showed absence of COL13A1 at the motor endplate, consistent with a complete loss of function. Expression of the mutation in mouse muscle cells resulted in a significant decrease in acetylcholine receptor (AChR) clustering at the postsynaptic membrane during myotube differentiation.

Animal Model

Kvist et al. (2001) found that homozygous transgenic mice with an altered Col13a1 gene lacking the short cytosolic and transmembrane domains were not phenotypically different from their normal littermates. However, skeletal muscle biopsy showed some abnormalities, including smaller muscle fibers, focal regions of abnormal myofibers with fuzzy plasma and basement membranes along the muscle fiber and at the myotendinous junctions, disorganized myofilaments, and streaming Z-discs. Immunohistochemical studies showed that the mutant protein was not located properly at the plasma membrane of skeletal muscle, but was located in the adjacent extracellular matrix. These histologic abnormalities were more pronounced in older mice, suggesting a progressive condition, and exercise induced more significant muscle fiber degeneration and inflammation in mutant mice compared to controls. Cultured fibroblasts from the mutant mice showed decreased adhesion to collagen type IV.

Latvanlehto et al. (2010) found the Col13a1-null mice grew more slowly compared to wildtype mice and showed tremors and generally worse general condition with age. Skeletal muscle fibers showed abnormal AChR cluster at the postsynaptic region of the neuromuscular junction and abnormal Schwann cells that enwrapped nerve terminals and invaginated into the synaptic cleft, resulting in a decreased contact surface for neurotransmission. Many postsynaptic membranes were not apposed by nerved terminals. Some presynaptic defects were also noted, including degenerative changes at the active zone and failure of synaptic vesicles to properly cluster at nerve terminals. Electrophysiologic studies showed decreased amplitude of postsynaptic potentials, diminished probabilities of spontaneous release, and reduction in the readily releasable neurotransmitter pool. There was a slight decrement in the response to repetitive stimulation.