Congenital myasthenic syndromes (CMS) in infants and children are rare and at times difficult disorders to diagnose. In evaluation of infants and children with hypotonia and muscle weakness differential diagnosis has to be broadened to include CMS. Molecular genetic analysis should be performed as most of these syndromes are genetically determined.
Consider CMS in differential diagnosis of hypotonia and muscle disease.
Prospective follow up of 3 patients with congenital myasthenic syndromes.
Patient 1 presented at birth with hypotonia and respiratory difficulties requiring neonatal intensive care. Examination was abnormal for micrognatia, flexion contractures at elbows and knees, and hypotonia. Later on, due to dysphagia the patient needed GT placement.
Initial whole exome sequencing (WES) showed a variant of uncertain significance (VUS) in the VAMP1 gene.
Patient 2 and younger sister of patient 1 presented at birth with hypotonia and respiratory distress. On examination found to have weak cry, poor head control, decreased gag reflex (requiring NG feeding), hypotonia, decreased movements of arms and legs, and mild joint contractures.
Repeat WES analysis including samples from patient 1, 2, and their parents, revealed that both patients were homozygous for a newly classified pathogenic variant in VAMP 1 causing autosomal recessive congenital myasthenic syndromes.
Both patients were treated with pyridostigmine and improved, but later added 3,4-diaminopyridine (3,4-DAP) resulted in additional benefits.
Patient 3 presented with slowly progressive muscle weakness in limb girdle distribution since 10 years of age. He has been experiencing fatigue with physical exertion relieved by rest. Examination showed mild weakness in limb girdle distribution, ankle dorsification and fatigue of proximal muscles on repeated muscle contractions. CPK was normal. Repetitive nerve stimulation showed distinct decremental response. A broad gene panel for neuromuscular disorders including a select number of CMS was performed. He was found to have compound heterozygous mutations in GFPT1 gene. The maternal variant, c.331 C>T was classified as pathogenic while the paternal variant c.362 T>C of uncertain significance.
However, we are confident that the variant is pathogenic in our patient given phenotype, electrodiagnostic findings and positive response to pyridostigmine treatment.
We are planning to add 3,4 DAP, but the drug is not readily available.
Phenotype of CMS is broad, ranging from symptoms/signs presenting early at birth or years later as in patient 3. Those cases demonstrate that history, physical examination, and follow ups are very important.
Furthermore, clinicians requesting genetic testing should not be discouraged and ignore VUS but assess these results in context of phenotypes and keep in mind that VUS could be reclassified.