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COLQ-MUTANT CONGENITAL MYASTHENIC SYNDROME with MICROCEPHALY: a UNIQUE CASE Sulaiman Bazee Al-Mobarak1, with LITERATURE REVIEW Mohammad A

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COLQ-MUTANT CONGENITAL MYASTHENIC SYNDROME with MICROCEPHALY: a UNIQUE CASE Sulaiman Bazee Al-Mobarak1, with LITERATURE REVIEW Mohammad A Case Report • DOI: 10.1515/tnsci-2017-0011 • Translational Neuroscience • 8 • 2017 • 65-69 Translational Neuroscience COLQ-MUTANT CONGENITAL MYASTHENIC SYNDROME WITH MICROCEPHALY: A UNIQUE CASE Sulaiman Bazee Al-Mobarak1, WITH LITERATURE REVIEW Mohammad A. Al-Muhaizea1,2* Abstract 1King Faisal Specialist Hospital & Research Center, Congenital Myasthenic Syndrome (CMS) is a group of inherited neuromuscular junction disorders caused by Riyadh, Saudi Arabia 2Alfaisal University, College of medicine, defects in several genes. Clinical features include delayed motor milestones, recurrent respiratory illnesses Riyadh Saudi Arabia and variable fatigable weakness. The central nervous system involvement is typically not part of the CMS. We report here a Saudi girl with genetically proven Collagen Like Tail Subunit Of Asymmetric Acetylcholinesterase (COLQ) mutation type CMS who has global developmental delay, microcephaly and respiratory failure. We have reviewed the literature regarding COLQ-type CMS and to the best of our knowledge this is the first ever reported association of congenital myasthenia syndrome with microcephaly. Keywords Received 23 January 2017 • COLQ mutant • congenital myasthenic syndrome • microcephaly • Saudi Arabia • pediatrics • Genetics accepted 15 May 2017 Introduction/Literature review decremental EMG response of the compound currents which in turn leads to an overloading muscle action potential (CMAP) on low- of cations at the synaptic space and eventually CMS comprises a heterogeneous group of frequency (2-3 Hz) stimulation, a positive causing endplate myopathy with the loss of rare inherited diseases where neuromuscular response to acetylcholinesterase (AChE) acetylcholine receptors [6]. transmission in the motor plate is compromised inhibitors, an absence of anti-acetylcholine We present here a unique case of COLQ- by one or more of the genetic pathophysiological receptor (AChR) and anti‐muscle specific mutant congenital myasthenic syndrome specific mechanisms [1]. CMS is classified kinase (anti-MuSK) antibodies in the serum, associated with global developmental delay into three groups: postsynaptic, synaptic and and the lack of improvement of clinical and microcephaly. presynaptic, depending on the localization symptoms with immunosuppressive therapy. of the defective molecules [2]. In CMS, the Pathogenic variants found in the genes Case Report safety margin of neuromuscular transmission which encode proteins expressed at the is compromised to an extent by which defines neuromuscular junctions are currently known AQ is an 8-year-old Saudi girl whose parents the severity and progression of the disease to be associated with CMS subtypes. The most are first cousins. She is a product of full and its clinical manifestations. The disease commonly associated genes include: Choline term, uneventful and normal spontaneous manifestations differ according to the time of acetyltransferase (ChAT), Acetylcholine receptor pregnancy with vaginal delivery, no Neonatal its onset and the underlying neuromuscular subunit epsilon (CHRNE), Acetylcholinesterase Intensive Care Unit (NICU) admission and she pathophysiology [3]. The most striking clinical (COLQ), DOK-7, Glucosamine—fructose- was discharged home in stable condition. presentations of CMS in neonates include 6-phosphate aminotransferase (GFPT) Later on, she was found to be suffering from feeding difficulties, poor suckling and crying, and Receptor associated protein of the synapse subglottic stenosis, severe gastroesophageal choking spells, ptosis, facial, bulbar and (RAPSN) [5]. The COLQ gene is located at the reflux, progressive scoliosis, hypotonia, generalized weaknesses. On the other hand, chromosome 3p25 and encodes the collagenic developmental and speech delay, and a history the childhood onset subtypes show abnormal tail of the acetylcholinesterase (AChE) which of recurrent chest infections. During the course muscle fatigability, delayed motor milestones, a allows the molecule to anchor itself to the of evaluation she was found to have COLQ certain degree of ptosis, and fixed or fluctuating basal lamina of the neuromuscular junction mutation. extraocular muscle weakness [4]. endplate. Autosomal recessive missense At the age of 10 months old, she suffered The diagnosis of CMS is based on a mutation of the COLQ gene causes a synaptic from a bronchial asthma with intermittent combination of clinical findings such as a form of CMS. This results in prolonged endplate upper airway stridor at the Security Forces * E-mail: [email protected] © 2017 Sulaiman Bazee Al-Mobarak, Mohammad A. Al-Muhaizea, published by De Gruyter Open. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivs 3.0 License. 65 Translational Neuroscience Hospital. She was then referred to the Pediatric being cachectic with apparent scoliosis, she localization of defective molecules at the Cardiology unit at the King Faisal Specialist also had winging scapulae with poor and neuromuscular junction, CMS is classified into Hospital Research Center for potential vascular thin muscle bulk. The patient had mild ptosis pre-synaptic, synaptic basal lamina associated ring diagnosis. The cardiac Magnetic Resonance with weak upward gaze but there was no and post-synaptic. CMS can have two patterns Imaging (MRI) and Echo ruled out vascular ring ophthalmoplegia. There was weak neck muscle of inheritance. For autosomal recessive CMS and other structural cardiac anomalies. The flexion and extension but normal extraocular (AR-CMS), the parents of an affected child patient was then evaluated by the laryngology movements. During motor examination, she are obligate heterozygotes and therefore service and was found to have subglottic was found to have decreased muscle bulk carry one mutant allele each. Heterozygotes stenosis and underwent tracheostomy. but normal tone, and the power was around (carriers) are asymptomatic. At conception, Subsequently, she was also found to have 4+/5 for the upper and lower limbs. The deep each sibling of an affected individual has a a significant developmental delay. She only tendon reflex was brisk in the upper and lower 25% chance of being affected, a 50% chance started walking at around 3 years of age and limbs, and the limbs elicited extensor plantar of being an asymptomatic carrier, and a 25% her speech is still not fully developed by the age response. In the standing position, there was chance of being unaffected and not a carrier of 8 years old. She uses her hand or shoulder hyperextension with flex knee joint. The head [8]. For autosomal dominant CMS (AD-CMS), as support during walking and falls frequently circumference of the patient was 52 cm which some individuals have an affected parent while during running. She enjoys watching TV and was considered to be microcephalic and ranked others have a de novo mutation. The proportion there has been no diurnal variation in the below the 5th percentile. of cases caused by a de novo mutation is weakness. In addition to the multidisciplinary care unknown. Each child of an individual with AD- Her parents are first-degree cousins. She had provided for various medical conditions, she CMS has a 50% chance of inheriting the mutant one sibling who also suffered from recurrent has been prescribed with albuterol orally 2 mg allele [9]. chest infections and subglottic stenosis with three times a day (TID) with plan to change to The COLQ gene is located at the short arm tracheostomy performed but died at the age intravenous (IV) ephedrine if necessary. Since of chromosome 3 and is responsible for the of 2 years old. Although AQ remains stable starting the albuterol treatment, the patient transcription of triple-stranded collagenic tail of from the respiratory point of view, she is has improved greatly. Even in the absence of the acetylcholinesterase (AChE) which anchors closely monitored by the Pediatric Pulmonary IV ephedrine, there has been no relapse or the itself to the basal lamina of the neuromuscular unit because she is oxygen-dependent mainly need for reintubation. endplates. Autosomal recessive mutation of the during night hours. Additionally, she has COLQ gene causes a synaptic form of CMS. This started to show evidence of scoliosis with Discussion results in prolonged endplate currents which in disease progression and she is being monitored turn leads to an overloading of cations at the by the Pediatric Orthopedic Surgery with plans This case report of congenital myasthenia synaptic space and eventually causes endplate for scoliosis correction. syndrome is unique as no other cases of CMS myopathy with the loss of acetylcholine For developmental delay, she has been have been reported so far to have microcephaly. receptors [6]. An electron microscopy study of evaluated by the Pediatric Neurology and The girl is 8 years old now, however she was the endplate of patients with COLQ mutation Medical Genetics units and her workup is as presented with subglottic stenosis at the has revealed degeneration of the junctional follows: Tandem Mass Spectrometry (TMS), urine age of 10 months. Additionally, she was also folds and the presence of abnormally small Gas Chromatography–Mass Spectrometry suffering from severe gastroesophageal nerve terminals encased by Schwann cells [10]. (GC-MS), Microarray Comparative Genomic reflux, progressive scoliosis, hypotonia, There have only been a few case reports of Hybridization (CGH), carbohydrate-deficient developmental and speech delay, and a history COLQ-mutant CMS.
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