Abstract
Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.
Highlights
The use of generation sequencing (NGS) in clinical diagnosis is allowing the identification of novel disease genes in neuromuscular disorders (Taylor et al, 2015)
Whole exome sequencing identified 13 COL13A1 variants in 16 subjects from 11 different kinships identified by whole exome sequencing (Fig. 1A, B and Table 1)
We describe the clinical spectrum of disease associated with COL13A1 mutations and report a series of novel pathogenic mutations in this recently described congenital myasthenic syndromes (CMS) causative gene
Summary
The use of generation sequencing (NGS) in clinical diagnosis is allowing the identification of novel disease genes in neuromuscular disorders (Taylor et al, 2015). This technology has been crucial to expand the genetic spectrum of the congenital myasthenic syndromes (CMS), which currently exceeds 30 genes (Rodrıguez Cruz et al, 2018). The most common classification of CMS relies on the location of the encoded protein into presynaptic, synaptic or basal lamina-associated and postsynaptic syndromes. Mutations in COL13A1 were recently identified as the cause of autosomal recessive synaptic basal lamina-associated CMS type 19 (Logan et al, 2015). COL13A1 transcripts undergo complex alternative splicing (Pihlajaniemi and Tamminen, 1990)
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