Fluctuating weakness: clue in the eyes!
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A 9-year-old girl presented with a history of increased fatigability and generalized weakness for the past 2 months. Her parents told her that around 8 years of age, she had become very sick with severe respiratory distress requiring hospitalization and ventilation for 7 days after which she improved to her usual state of health. On repeated questioning, the parents only remembered that she was otherwise normal but would tire out easily and not be as physically active as other children of her age group.

She was born out of a consanguineous marriage with an uneventful neonatal period and showed a normal gain of various developmental milestones. On examination, her weight and height were 14 kg and 115 cm, respectively, suggesting acute on chronic malnutrition. She had an elongated expressionless face with bilateral symmetrical ptosis. Motor examination showed the power of grade 4/5 at the shoulder and hip joints suggestive of mild proximal weakness. The deep tendon reflexes were preserved. On careful observation, Doctors found her to be using neck movements more than eye while following objects, with the neck being kept slightly extended. This led us to re-examine her which showed some limitation of eyeball movements towards the extremes in all directions of gaze.

Investigations showed creatine phosphokinase to be 47 U/L and lactate to be 0.8 mmol/L. A repetitive nerve stimulation test at 3 Hz was suggestive of decremental response and improvement with neostigmine. Acetylcholine receptor antibody and anti-Musk antibody were absent. Exome sequencing showed a pathogenic homozygous indel variant in exon 2 of CHRNE gene by insertion of guanine at 130 coding position which is predicted to cause a frameshift and consequent premature truncation of the protein confirming the presence of congenital myasthenic syndrome (CMS) 4B (fast channel) or 4C (acetylcholine receptor deficiency). The child was started on oral pyridostigmine and is showing some signs of improvement.

Congenital myasthenic syndromes comprise phenotypically and genetically heterogeneous diseases caused due to neuromuscular transmission dysfunction. To date, 32 genes causing congenital myasthenic syndrome have been described. Although named congenital, disease onset may be in infancy, childhood, or rarely in adolescence. Phenotypically various subtypes share fatigability and weakness as common features. CHRNE gene mutations and in particular the variant found in our child has been found at a high frequency (around 30%) in patients of CMS in Brazilian and Spanish populations. Opthalmoparesis as seen in our child is a universal finding with

The congenital myasthenic syndrome is one of the rare examples of treatable genetic neuromuscular diseases. Although pyridostigmine is effective for the CHRNE gene mutation subtype of the congenital myasthenic syndrome, in some other subtypes it can make symptoms worse. Hence, genetic testing not only confirms the clinical diagnosis but is also required for the correct treatment approach in congenital myasthenic syndrome.