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A rare case of myasthenia gravis due to CHRNE mutation
*Corresponding author: Venkata Vijayalakshmi Vantaku, Department of Pediatrics, Rangaraya Medical College, Kakinada, India. vijayalakshmivantaku@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Duggirala M, Sailaja ES, Murupudi SJ, Vantaku VV. A rare case of myasthenia gravis due to CHRNE mutation. RMC Glob J. 2025;1:101–104. doi: 10.25259/RMCGJ_23_2025
Abstract
Congenital myasthenia syndromes (CMS) are a group of heterogeneous inherited disorders of the neuromuscular junction characterized by easy fatiguability of muscles after sustained activity, followed by improvement in muscle weakness after rest. It is a very rare disorder with only a few cases reported in India. A 20-month-old male child presented with bilateral ptosis, a poor cry, and feeding difficulties associated with choking episodes. The symptoms gradually progressed. Based on history, congenital myasthenia gravis was suspected in this child. A series of tests was conducted to confirm the diagnosis, including repetitive nerve conduction tests and whole-genome sequencing. This case illustrates the challenges in diagnosing congenital myasthenia gravis and highlights the benefits of early treatment in improving quality of life.
Keywords
Anti AChR antibodies
AchE inhibitors
Congenital myasthenia syndromes
Muscle weakness
Neostigmine
INTRODUCTION
Congenital myasthenia syndromes (CMS) are a group of heterogeneous inherited disorders that result from a general mutation affecting the structure and function of the neuromuscular junction.1 Most patients present in the first 2 years of life, with many becoming symptomatic in the neonatal period or early infancy. Congenital myasthenia syndromes are rare, and few cases are reported from the Indian subcontinent; hence, we intend to present a case of congenital myasthenia gravis reported at our institution. Early diagnosis and initiation of effective treatment are necessary to improve the quality of life and prevent complications.
CASE REPORT
A 20-month-old male child presented with bilateral ptosis noticed since birth; ptosis was less severe in the morning and worsened by evening. The child had poor cry and feeding difficulties and choking episodes. A first-order child is born out of a third-degree consanguineous marriage. There was no history suggestive of myasthenia in family members, and the mother did not notice any delay in quickening or sluggish fetal movements. There is a mild delay in motor and language milestones, and on examination, the child was found to have bilateral ptosis, with power of 4/5 in all limbs and depressed deep tendon reflexes. The neostigmine provocative test was performed with an intramuscular injection of 0.04 mg/kg, and a response was observed (improvement of ptosis) after 15 minutes [Figure 1a and 1b].
- (a) Photo before the administration of neostigmine injection; (b) Photo after administration of neostigmine injection.
EMG (electromyography) was suggestive of a decremental response. The MRI (magnetic resonance imaging) scan of the brain was normal. The whole genome sequencing report was suggestive of a CHRNE (cholinergic receptor, nicotinic, epsilon polypeptide) mutation with AR (autosomal recessive inheritance) inheritance [Figure 2].
- Whole genome sequencing report.
The child was started on oral pyridostigmine at a dose of 1 mg/kg/day, gradually increased to 4 mg/kg/day in divided doses, which resulted in a partial response, characterized by improvement in ptosis, cry, and gait. As there was little improvement, the child was also started on oral salbutamol at a dose of 1 mg/kg/day. The child is now on regular follow-up.
DISCUSSION
Congenital myasthenia syndromes are a group of inherited disorders characterized by gene defects that affect proteins present at the neuromuscular junction, which may be presynaptic, synaptic, or postsynaptic.They are nearly always permanent, static disorders without spontaneous remission and are typically inherited in an autosomal recessive manner, and less commonly in an autosomal dominant manner.2 De novo mutations can occur.
Mutations responsible for congenital myasthenia syndromes have been identified in 24 different genes. The most common genes include CHAT (choline acetyltransferase), CHRNE, DOK7, COLQ, GFPT, and RAPSN. A CHRNE gene mutation is the most common and is responsible for 50% of cases of CMS. The CHRNE gene is responsible for producing a protein that is part of the acetylcholine receptor, which is necessary for transmitting signals between muscles and nerves. Common clinical features include ptosis, difficulty in feeding, and hypotonia. Some may present with episodes of apnea, cyanosis, and respiratory distress precipitated by intercurrent illness.
Diagnosis is primarily achieved through a thorough history, clinical examination, genetic testing, electromyography (EMG), and serum acetylcholine receptor (AchR) antibodies.3
The child should have a specific fatigable weakness that can be measured, like ptosis, dysphagia, or neck drop.
Laboratory findings
CMS is characterized by the absence of anti-AchR and anti-Musk antibodies.
EMG in the majority of CMS subtypes shows a decremental response of the compound action potential (CMAP). Some presynaptic subtypes may exhibit an increase in CMAP amplitude with repetitive stimuli.
Nerve conduction studies are typically normal.
Role of genetic testing
Identifying specific gene defects helps in selecting treatment options. Some patients with CMS, like slow-channel CMS or DOK7 related CMS, don’t respond or even deteriorate with AChE (Acetylcholinesterase) inhibitors like pyridostigmine, which is the drug of choice in adult myasthenia gravis.
Gene testing aids in prognostication, as the severity and prognosis of a condition depend on the underlying genetic defect. Once a specific pathogenic variant is identified, prenatal/preimplantation testing can be offered for the next pregnancy.
Diagnostic testing with cholinesterase inhibitors
Intramuscular administration of neostigmine in a dose of 0.04 mg/kg is recommended. If the result is negative, a second dose may be given after 4 hours. The peak effect is seen in 20–40 minutes. Edrophonium is not recommended for use in infants, as its effect is too brief for objective assessment, and an increased incidence of acute cardiac arrhythmias is reported in infants.4
Treatment
Treatment options vary with genetic defects.
AchE inhibitors
Although the majority of patients respond to AchE inhibitors, some symptoms may remain refractory to treatment. Some subtypes may even deteriorate with the use of AchE inhibitors.
3,4-diaminopyridine, a potassium channel blocker that increases acetylcholine release and prolongs the presynaptic action potential, can be used as an alternative or add-on drug to acetylcholinesterase inhibitors.
Adrenergic agonist drugs like ephedrine and salbutamol can be used as add-on drugs to AChE inhibitors in some variants of CMS.
Open-channel blockers of the acetylcholine receptor (AchR), such as fluoxetine, are useful in some forms of CMS.
Drugs that affect neuromuscular transmission, like aminoglycosides, ciprofloxacin, chloroquine, quinidine, lithium, etc., should be avoided or used with caution.
Complications like frequent respiratory infections can occur following aspiration due to choking. Respiratory failure and apnea are also common in these children, requiring hospitalization and mechanical ventilation.
CONCLUSION
Congenital myasthenia syndrome should be considered in patients with fatigable weakness, especially of facial muscles, who have a family history of consanguinity in the absence of anti-AChR and anti-MuSK antibodies. Next-generation sequencing reveals that myasthenia is only one component of CMS, which are multisystem disorder. The treating physician must be aware of the possibility of respiratory insufficiency or apnea precipitated by any infection, as well as drugs that can increase neuromuscular blockade.
Ethical approval
Institutional Review Board approval is not required.
Declaration of patients consent
The authors certify that they have obtained all appropriate patient consent.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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