Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Nemaline Myopathy: A Case Report

Generalized weakness in the pediatric and adolescent population is caused by many disorders that affect the neuromuscular axis. As next-generation sequencing (NGS) is becoming of high yield in replacing more invasive procedures, that is, muscle and nerve biopsy, more previously undiagnosed diseases of the muscles are now labeled with specific pathogenicity. A 16-year-old-girl diagnosed with nemaline myopathy but previously was misdiagnosed with congenital myasthenia and put-on unnecessary medications. Clinicians should be aware of congenital diseases that affect the muscles and know the importance of the NGS in reaching the correct diagnosis more so when there is a history of consanguinity.

Mechanism of disease and therapeutic rescue of Dok7 congenital myasthenia

Congenital myasthenia (CM) is a devastating neuromuscular disease, and mutations in DOK7, an adaptor protein that is crucial for forming and maintaining neuromuscular synapses, are a major cause of CM1,2. The most common disease-causing mutation (DOK71124_1127 dup) truncates DOK7 and leads to the loss of two tyrosine residues that are phosphorylated and recruit CRK proteins, which are important for anchoring acetylcholine receptors at synapses. Here we describe a mouse model of this common form of CM (Dok7CM mice) and a mouse with point mutations in the two tyrosine residues (Dok72YF). We show that Dok7CM mice had severe deficits in neuromuscular synapse formation that caused neonatal lethality. Unexpectedly, these deficits were due to a severe deficiency in phosphorylation and activation of muscle-specific kinase (MUSK) rather than a deficiency in DOK7 tyrosine phosphorylation. We developed agonist antibodies against MUSK and show that these antibodies restored neuromuscular synapse formation and prevented neonatal lethality and late-onset disease in Dok7CM mice. These findings identify an unexpected cause for disease and a potential therapy for both DOK7 CM and other forms of CM caused by mutations in AGRIN, LRP4 or MUSK, and illustrate the potential of targeted therapy to rescue congenital lethality.

Anaesthetic Management of a Patient with Myasthenia Gravis Posted for Tonsillectomy- A Case Report

Myasthenia gravis is a chronic autoimmune disease of neuromuscular junction which causes skeletal muscle weakness and fatigability, characterised by decrement in postsynaptic acetylcholine receptor at neuromuscular junction caused by auto-antibodies destruction. There are three types of myasthenia gravis in children- transient neonatal, congenital and juvenile. Juvenile Myasthenia Gravis (JMG) is an autoimmune disorder that can affect the all skeletal muscles including extraocular muscles, which may lead to fatigability and generalised weakness. This report is about a case of seven-year-old patient weighing 25 kg presented with throat pain since one and half month. Patient was a known case of congenital myasthenia gravis and diagnosis was confirmed by Edrophonium test. He underwent tonsillectomy and was successfully managed under general anaesthesia with no muscle relaxant technique. Tonsillectomy in paediatric patients is not an uncommon surgical procedure. In spite of being a common surgery, it is still challenging to the surgeon as well as the anaesthesiologist as there is a shared airway between the two. Also, in the postoperative period there are chances of post-tonsillectomy bleeding causing airway obstruction, if not diagnosed and treated early could risk the life of the patient. Therefore, this surgery poses an increased risk of mortality and morbidity.

A case study on various disorders and defects present in congenital myasthenia syndrome

The Congenital Myasthenia Syndromes (CMS) are a different gathering of problems that have a hidden deformity in the transmission of signs from nerve cells to muscles. These problems are described by muscle shortcoming, which is declined upon effort. The time of beginning, seriousness of introducing indications and dissemination of muscle shortcoming can shift starting with one patient then onto the next. The synapse, acetylcholine, or ACh for short that goes about as a compound 'courier' with guidelines for the muscles to contract. A three years old child female patient was brought to our department with the complaints of drooping of the left eyelid after one week she developed drooping of right eye. With scientific and laboratory discoveries, she is identified by congenital myasthenia and treatment was started. Evidence from case notes, history, review and accept. Muscle fatigue habits included limb, trunk, bulbar, respiratory, nasal, extraocular muscles and patients reacted with anticholinesterase and 3,4-diaminopyridine. Quick channel syndrome compared with AChR in serious respiratory emergencies in infancy or early childhood. Two children's fatalities, also in care and family history of sibling deaths, highlight the need for effective genetic diagnosis.

Fluctuating Weakness in an 18-Month-Boy: Congenital Myasthenia

We report a case of an 18-month-old child who presented with motor predominant delay in attaining developmental milestones and early onset fatiguable weakness with ptosis and ophthalmoparesis. This ptosis and ophthalmoparesis typically worsened with progression of the day. Examination showed proximal weakness with preserved muscle stretch reflexes. Electrophysiology showed characteristic decrement on repetitive nerve stimulation test that localized to disorders of the neuromuscular junction. Next-generation sequencing showed a pathogenic variant of CHRNE that was responsible for congenital myasthenic syndrome. Such variants show increased improvement with salbutamol in addition to anticholinesterase inhibitors. Hence, the child was started on pyridostigmine, and the plan was to add on salbutamol on follow-up if optimal improvement does not occur.