Congenital Myasthenic Syndrome Research Articles

Epileptic Channelopathies and Neuromuscular Disorders in Newborns: A Narrative Review.

Neonates can have ion channel abnormalities known as channelopathies, which can impact any organ system. These abnormalities cause seizures, which can result in developmental delays and lead to early death. For a child's long-term neurodevelopment, early identification as a channelopathy is essential to avoid any brain damage. Therefore, this review aims to focus on early diagnostic criteria. Since it might be difficult for doctors to interpret the presenting symptoms of channelopathies, a thorough diagnostic examination that follows a methodical step-by-step procedure is essential. Skeletal muscle fiber and neuron excitability depend on voltage-gated sodium channels. It is now known that mutations in voltage-gated sodium channel genes can cause a growing variety of fatal or debilitating pediatric neurological diseases. Episodic paralysis, myotonia, newborn hypotonia, respiratory impairment, laryngospasm/stridor, congenital myasthenia, and myopathy are examples of muscle phenotypes. There may be a connection between sodium channel malfunction and abrupt infant death, according to recent findings. Numerous epilepsy syndromes and complex encephalopathies are among the manifestations of different channelopathies that are becoming more widely recognized.

Recognizing Symptoms of Congenital Myasthenic Syndromes in Children: A Guide for Paediatricians.

Congenital myasthenic syndromes (CMS) are a rare and diverse group of treatable neuromuscular transmission disorders. Diagnosis is often substantially delayed. This study aimed to identify common symptoms of CMS in children and their manifestation to aid diagnosis and early intervention. We performed a retrospective cohort study, including 18 children (median age 13 years, range 9;5-18;0 years) with CMS. Data on CMS symptoms and their manifestation were extracted from patients' charts and supplemented with parental telephone interviews. Descriptive analyses were used to identify common symptoms. A median diagnostic delay of 4 years and 7 months (interquartile range: 51 months) was observed. Proximal muscle weakness (100%), ptosis (89%), clumsy gait (82%), difficulty eating solid foods (78%), and recurrent respiratory tract infections (72%) were most common in these patients. Symptoms mostly co-occurred and frequently had a fluctuating character, aggravated by infections or fatigue. Early referral to diagnose CMS is crucial to enable timely initiation of treatment. Heightened attention to a combination of symptoms related to muscle weakness, rather than individual symptoms, should support paediatricians in flagging these neuromuscular disorders. Medical history taking should be tailored to parents' perceptions, asking questions about recognizable symptoms of muscle weakness.

NMJ-related diseases beyond the congenital myasthenic syndromes.

Neuromuscular junctions (NMJs) are a special type of chemical synapse that transmits electrical stimuli from motor neurons (MNs) to their innervating skeletal muscle to induce a motor response. They are an ideal model for the study of synapses, given their manageable size and easy accessibility. Alterations in their morphology or function lead to neuromuscular disorders, such as the congenital myasthenic syndromes, which are caused by mutations in proteins located in the NMJ. In this review, we highlight novel potential candidate genes that may cause or modify NMJs-related pathologies in humans by exploring the phenotypes of hundreds of mouse models available in the literature. We also underscore the fact that NMJs may differ between species, muscles or even sexes. Hence the importance of choosing a good model organism for the study of NMJ-related diseases: only taking into account the specific features of the mammalian NMJ, experimental results would be efficiently translated to the clinic.

Long-term muscle-specific overexpression of DOK7 in mice using AAV9-tMCK-DOK7

Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs invivo.

Congenital myasthenic syndrome due to a genetic mutation.

Congenital myasthenic syndrome (CMS) is a group of rare genetic disorders that mimics the symptoms of myasthenia gravis, but it is due to a genetic defect. We present a case of a male CMS patient, and the course of the disease through the years. The patient initially presented with generalized muscle weakness and difficulty swallowing. During the follow-up, he developed difficulty in chewing, bilateral external ophthalmoparesis with an almost full block of eye movements and bulbar syndrome. The case illustrates both the clinical heterogeneity and the progressive worsening of the symptoms of the disease over the years. The optimal treatment for CMS is based on the molecular defect and its localization in the neuromuscular junction. In our case, treatment with pyridostigmine resulted in good long-term control of symptoms. As a result of the patient's good compliance with treatment, he was not admitted to hospital because of respiratory distress. The lack of a unified protocol for the treatment of CMS highlights the need for a more personalized approach when dealing with patients with rare diseases.

Congenital Myasthenia Gravis in Newborn

Congenital myasthenia gravis are very rare, which is an autosomal recessive disease originating from rare genetic disorders. Symptoms of congenital MG usually start at birth and are lifelong. Our case weakness started from birth, need respiratory support and failure of extubation many times, and absent fetal movements with positive family history his cousin was neonatal myasthenia gravis and died.

Rituximab therapy in anti-musk positive juvenile myasthenia gravis; A case report

Juvenile myasthenia gravis is a rare acquired disease of childhood. It is difficult to differentiate it from congenital myasthenic syndrome due to the negativity of the Acetylcholine receptor antibody.

A novel MUSK mutation in a patient with CMS9

Congenital myasthenic syndromes (CMS) are a relatively rare cause of fatigable muscle weakness often with significant ocular, bulbar and respiratory impairment1. Mutations in the gene encoding muscle specific tyrosine kinase (MuSK) can lead to abnormal endplate and acetylcholine receptor functioning and cause an autosomal recessive post-synaptic CMS (CMS9). Only 23 patients with CMS9 have been characterized in the literature since the initial description in 20042. Here, we report a newly diagnosed case of CMS9 in a 23-year-old female who harbored a novel c.296G>T (Cys99Phe) mutation in the MUSK gene, thereby expanding the phenotypic/genotypic characterization of this rare disorder.

1012 Sleep disordered breathing in children with Congenital Myasthenic Syndrome

Abstract Introduction Congenital Myasthenic Syndromes (CMS) include a group of heterogeneous disorders encompassing the neuromuscular junction. These disorders have a wide range of clinical presentations according to the degree and group of muscles involved. While some children can present with modest muscle weakness, others present with significant hypotonia, or even respiratory failure. The natural history of CMS, and in particular, the diagnostic role of polysomnography (PSG) in these children, is not well documented. Report of case(s) Retrospective chart review via EMR in a large tertiary center. Patient 1. 19-month-old male with VAMP-1 gene mutation, treated with pyridostigmine, underwent a PSG to evaluate for sleep disordered breathing (SDB). The PSG demonstrated an AHI of 17.7. Repeat PSG post adenoidectomy showed an obstructive apnea hypopnea index (OAHI) 8.6, and central apnea index (CAI) 1.2. He was started on 0.5 LPM oxygen for sleep. Patient 2. 2-year-old female with GFPT1 gene mutation, chronic respiratory failure, tracheostomy/ventilator dependent had a PSG with tracheostomy uncapped on room air which showed an OAHI 1.7, and CAI 0.3. Four years later, split night PSG was started on room air which showed an OAHI 2.8, and CAI 4.6. The ventilator was added at patient’s home settings which improved sleep quality and resolved respiratory events. She was continued on home ventilator settings for sleep despite pharmacological treatment with pyridostigmine. Patient 3. 3-year-old male with CHRNE gene mutation and treated with pyridostigmine. He was evaluated for SDB due to snoring. The PSG demonstrated an OAHI 3.4, and CAI 1.4. Repeat PSG post adenotonsillectomy showed an OAHI 0.4, and CAI 0.4. A third PSG at age 5 was normal. Conclusion We present 3 children with various mutations leading to CMS. The heterogeneity in the clinical course, response to therapy, and outcome may be related to genetic mutations, severity of the disorder and muscles involved, time of diagnosis and medical response to treatment. Polysomnography is an important modality for diagnosis of SDB as well as to monitor response to treatment over time. We conclude that patients with CMS should have a PSG completed given this increased risk. Support (if any)

COLQ-related congenital myasthenic syndrome: An integrative view.

Congenital myasthenic syndromes are inherited disorders caused by mutation in components of the neuromuscular junction and manifest early in life. Mutations in COLQ gene result in congenital myasthenic syndrome. Here, we present the analysis of data from 209 patients from 195 unrelated families highlighting genotype-phenotype correlation. In addition, we describe a COLQ homozygous variant a new patient and discuss it utilizing the Phyre2 and I-TASSER programs. Clinical, molecular genetics, imaging (MRI), and electrodiagnostic (EEG, EMG/NCS) evaluations were performed. Our data showed 89 pathogenic/likely pathogenic variants including 35 missenses, 21 indels, 14 nonsense, 14 splicing, and 5 large deletions variants. Eight common variants were responsible for 48.46% of those. Weakness in proximal muscles, hypotonia, and generalized weakness were detected in all individuals tested. Apart from the weakness, extensive clinical heterogeneity was noted among patients with COLQ-related patients based on their genotypes-those with variants affecting the splice site exhibited more severe clinical features while those with missense variants displayed milder phenotypes, suggesting the role of differential splice variants in multiple functions within the muscle. Analyses and descriptions of these COLQ variants may be helpful in clinical trial readiness and potential development of novel therapies in the setting of established structure-function relationships.

Discovery and pharmacological characterization of novel positive allosteric modulators acting on skeletal muscle-type nicotinic acetylcholine receptors

Skeletal muscle-type nicotinic acetylcholine receptors (m-nAChRs) are ligand-gated ion channels that open after activation by ACh and whose signals cause muscle contraction. Defects in neurotransmission are reported in disorders such as myasthenia gravis (MG) and congenital myasthenia syndromes (CMS). Although treatments for these disorders exist, therapies which significantly increase muscle strength have yet to be reported. Positive allosteric modulators (PAMs), which promote ACh signaling through AChRs, are expected to be promising therapeutic agents. In this study, we identified an m-nAChR PAM called AS3513678 by high-throughput screening using human myotube cells and modified it to obtain novel compounds (AS3566987 and AS3580239) that showed even stronger PAM activity. AS3580239 caused a leftward shift in the ACh concentration-response curve and was 14.0-fold potent at 10 μM compared with vehicle. Next, we examined the effect of AS3580239 on electrically-induced isometric contraction of the extensor digitorum longus (EDL) muscle in wild-type (WT) and MG model rats. AS3580239 enhanced EDL muscle contraction in both WT and MG model rats at 30 μM. These data suggest that AS3580239 improved neurotransmission and enhanced muscle strength. Thus, m-nAChR PAMs may be a useful treatment for neuromuscular diseases.

Mitochondrial Mutations Can Alter Neuromuscular Transmission in Congenital Myasthenic Syndrome and Mitochondrial Disease.

Congenital myasthenic syndromes (CMS) are a group of rare, neuromuscular disorders that usually present in childhood or infancy. While the phenotypic presentation of these disorders is diverse, the unifying feature is a pathomechanism that disrupts neuromuscular transmission. Recently, two mitochondrial genes-SLC25A1 and TEFM-have been reported in patients with suspected CMS, prompting a discussion about the role of mitochondria at the neuromuscular junction (NMJ). Mitochondrial disease and CMS can present with similar symptoms, and potentially one in four patients with mitochondrial myopathy exhibit NMJ defects. This review highlights research indicating the prominent roles of mitochondria at both the pre- and postsynapse, demonstrating the potential for mitochondrial involvement in neuromuscular transmission defects. We propose the establishment of a novel subcategorization for CMS-mitochondrial CMS, due to unifying clinical features and the potential for mitochondrial defects to impede transmission at the pre- and postsynapse. Finally, we highlight the potential of targeting the neuromuscular transmission in mitochondrial disease to improve patient outcomes.

Vocal Cord Paralysis and Feeding Difficulties as Early Diagnostic Clues of Congenital Myasthenic Syndrome with Neonatal Onset: A Case Report and Review of Literature.

Herein, we present a newborn female with congenital vocal cord paralysis who required a tracheostomy in the neonatal period. She also presented with feeding difficulties. She was later diagnosed with a clinical picture of congenital myasthenia, associated with three variants of the MUSK gene: the 27-month follow-up was described. In particular, the c.565C>T variant is novel and has never been described in the literature; it causes the insertion of a premature stop codon (p.Arg189Ter) likely leading to a consequent formation of a truncated nonfunctioning protein. We also systematically collected and summarized information on patients' characteristics of previous cases of congenital myasthenia with neonatal onset reported in the literature to date, and we compared them to our case. The literature reported 155 neonatal cases before our case, from 1980 to March 2022. Of 156 neonates with CMS, nine (5.8%) had vocal cord paralysis, whereas 111 (71.2%) had feeding difficulties. Ocular features were evident in 99 infants (63.5%), whereas facial-bulbar symptoms were found in 115 infants (73.7%). In one hundred sixteen infants (74.4%), limbs were involved. Respiratory problems were displayed by 97 infants (62.2%). The combination of congenital stridor, particularly in the presence of an apparently idiopathic bilateral vocal cord paralysis, and poor coordination between sucking and swallowing may indicate an underlying congenital myasthenic syndrome (CMS). Therefore, we suggest testing infants with vocal cord paralysis and feeding difficulties for MUSK and related genes to avoid a late diagnosis of CMS and improve outcomes.

Delayed Diagnosis of Congenital Myasthenic Syndromes Erroneously Interpreted as Mitochondrial Myopathies.

Congenital myasthenic syndromes (CMSs) and primary mitochondrial myopathies (PMMs) can present with ptosis, external ophthalmoplegia, and limb weakness. Our method involved the description of three cases of CMS that were initially characterized as probable PMM. All patients were male and presented with ptosis and/or external ophthalmoplegia at birth, with proximal muscle weakness and fatigue on physical exertion. After normal repetitive nerve stimulation (RNS) studies performed on facial muscles, a muscle biopsy (at a median age of 9) was performed to rule out congenital myopathies. In all three cases, the biopsy findings (COX-negative fibers or respiratory chain defects) pointed to PMM. They were referred to our neuromuscular unit in adulthood to establish a genetic diagnosis. However, at this time, fatigability was evident in the physical exams and RNS in the spinal accessory nerve showed a decremental response in all cases. Targeted genetic studies revealed pathogenic variants in the MUSK, DOK7, and RAPSN genes. The median diagnostic delay was 29 years. Treatment resulted in functional improvement in all cases. Early identification of CMS is essential as medical treatment can provide clear benefits. Its diagnosis can be challenging due to phenotypic overlap with other debilitating disorders. Thus, a high index of suspicion is necessary to guide the diagnostic strategy.

Novel DPAGT1 Gene Mutation in Two Twins with Congenital Myasthenic Syndrome and a Review of the Literature.

Congenital myasthenic syndromes (CMS) are rare diseases caused by mutation in genes coding for proteins involved in neuromuscular junction structure and function. DPAGT1 gene mutations are a rare cause of CMS whose clinical evolution and pathophysiological mechanisms have not been clarified completely. We present the case of two twins displaying an infancy-onset predominant limb-girdle phenotype and carrying a novel DPAGT1 mutation associated with unusual histological and clinical findings. CMS can mimic paediatric and adult limb-girdle phenotype, hence neurophysiology plays a fundamental role in the differential diagnosis.

A Novel Homozygous Variant in the CHRNE Gene in 2 Siblings with Congenital Myasthenic Syndrome (P9-9.009)

<h3>Objective:</h3> To report a homozygous variant of uncertain significance in the CHRNE gene in two siblings presenting with symptoms consistent with congenital myasthenic syndrome that is responsive to pyridostigmine. <h3>Background:</h3> A 17-year-old female and a 9-year-old male born to consanguineous parents, with no significant perinatal complications or family history, developed predominantly proximal weakness around 4–5 years of age. The sister additionally developed bilateral fatigable ptosis. Both siblings underwent genetic testing that revealed a homozygous mutation in the CHRNE gene for a variant of uncertain clinical significance, c.322C&gt;T (p.Pro108Ser). Since the mutation was in the CHRNE gene, which codes for the epsilon subunit of the acetylcholine receptor, the brother was initially treated with fluoxetine, which had no response. The sister was previously treated with pseudoephedrine for 2 weeks without response. Both siblings began a trial of pyridostigmine and showed improvement of their symptoms, contrary to slow-channel mutation cases that can worsen with acetylcholinesterase inhibitors. EMG/NCS with RNS on the sister was performed 48 hours after stopping pyridostigmine and showed significant decrements on RNS of the left facial nerve and left spinal accessory nerve. <h3>Design/Methods:</h3> Not applicable <h3>Results:</h3> Not applicable <h3>Conclusions:</h3> Two siblings born to consanguineous parents both shared a homozygous mutation in the CHRNE gene, presenting similarly with symptoms consistent with congenital myasthenic syndrome, responded favorably to pyridostigmine. Given then, we rationalize that the homozygous c.322C&gt;T (p.Pro108Ser) variant in the CHRNE gene causes an acetylcholine receptor deficiency type of congenital myasthenic syndrome. <b>Disclosure:</b> Dr. Chan has nothing to disclose. Ms. Emery has nothing to disclose. Ermal Aliu has nothing to disclose. Dr. Naik has nothing to disclose. Dr. Paul has nothing to disclose. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Audentes Therapeutics. Dr. Kumar has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for PTC therapeutics. Dr. Kumar has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sarepta. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avexis. Dr. Kumar has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for PTC therapeutics. The institution of Dr. Kumar has received research support from PTC therapeutics. The institution of Dr. Kumar has received research support from Sarepta Therapeutics. The institution of Dr. Kumar has received research support from Novartis. The institution of Dr. Kumar has received research support from Fibrogen . Dr. Kumar has received personal compensation in the range of $500-$4,999 for serving as a Draft Report Reviewer with PCORI Health Care Horizon Scanning System.

VAMP-1 associated congenital myasthenic syndrome: a demonstrative case with response to low-dose pyridostigmine (P2-8.003)

<h3>Objective:</h3> To report a case of VAMP1-associated congenital myasthenic syndrome with response to low-dose pyridostigmine, adding to an emerging literature describing this condition. <h3>Background:</h3> Biallelic mutations in VAMP1 are associated with a rare pre-synaptic congenital myasthenic syndrome (CMS). VAMP1 encodes a protein involved in synaptic vesicles formation and fusion. <h3>Design/Methods:</h3> Case report and review of literature <h3>Results:</h3> A 15 month-old boy was referred for evaluation of hypotonia and dysphagia since birth at term. The infant was unable to sit or roll. He was unable to feed orally. Examination revealed myopathic facies, fluctuating ptosis, ophthalmoparesis, hypotonia, and areflexia. Cry was weak. Secretion control was poor. Spontaneous movement was minimal; movements were antigravity in the distal extremities. Results of a prior Whole Exome Sequence identified a homozygous pathogenic variant in VAMP1 [ c.103C&lt;T; p.Q35* (NM_014231.3)]. A proactive airway clearance regimen was instituted. Pyridostigmine (0.25 mg/kg per dose) demonstrated immediate benefit, as indicated by antigravity movement of limbs, louder cry and cough, and improved secretion control despite being admitted for respiratory infection at the time of trial. Dose was increased to 0.5 mg/kg every four hours while awake. Parents observed more robust activity at home. Independent sitting was attained at age 17 months. Dysphagia persisted. A polysomnogram was abnormal (max ETCO2 50torr, AHI 9.8). <h3>Conclusions:</h3> This adds to the literature documenting a recessive VAMP1-related CMS. Recent reports have suggested pyridostigmine responsiveness. This case demonstrated motor benefit from low-dose pyridostigmine. Given risk of mucous plugging and aspiration in patients with neuromuscular weakness, an airway clearance regimen (ex: cough assist device) should be considered prior to a trial of therapy. Assessment of nocturnal ventilation and swallow safety remain crucial, as highlighted by this infant’s still abnormal polysomnogram and persistent dysphagia. <b>Disclosure:</b> Dr. Drakou has nothing to disclose. Dr. Delfiner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Delfiner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis Gene Therapies. Dr. Delfiner has received personal compensation in the range of $500-$4,999 for serving as a MDA Engage Event Chair and speaker with Muscular Dystrophy Association.

The clinical and genetic characteristics of 17 cases with Congenital Myasthenic Syndrome: Data from a single center (P2-8.002)

<h3>Objective:</h3> The aim of this study to investigate the clinical and genetic features of patients with Congenital Myasthenic Syndrome (CMS) in Muscle Disease Center, Koç University Hospital, Turkey. <h3>Background:</h3> CMS is a group of hereditary disorders of impaired neuromuscular transmission characterized by fatigable muscle weakness. <h3>Design/Methods:</h3> Herein, we present the characteristics of 17 patients from 14 unrelated families. <h3>Results:</h3> The mean age (3 male, 14 female) was 18.4+13.6, the onset age ranged between the first day and the first 3 months of life in 11 cases, and 1 and 16 years in 6 patients. The most common complaints at the first 3 months were ptosis (6/11), feeding difficulty (7/11), difficulty in breathing (3/11). After the first age of life, walking late (2/6) and fatigue triggered by movement (6/6) were common. <i>CHRNE</i> (homozygous [c.1219+2T&gt;G]; [c.199 G&gt;T]; and novel [c.452_454delAGG]; heterozygous [c.1220-8+8dup and c.1327–1327delG]; [ c. .1327delG and c803-2A&lt;G]) (5 patients): All showed mildly weakness in ocular, bulbar and limbs muscles and good response to pyridostigmine. <i>DOK7</i> (homozygous [c.93_95delCTGLP+c.1120_1121insGCCTP]) (3 siblings). Mild ocular and bulbar muscle weakness, moderate limbs weakness were found and benefiting from salbutamol. <i>GFPT1</i> (composite heterozygous [c.50G&gt;A and c.408+5G&gt;A]; homozygous [c.686-2A&gt;G]; [c.44C&gt;T, p.]) (3 patients) and <i>CHAT</i> ([c.1669G&gt;A]) (1 patient): All were ambulatory and had good response to pyridostigmine. <i>COLQ</i> (homozygous [14–15 exons] deletion and c.44G&gt;A,) (3 patients ): Two siblings worsened under pyridostigmine, and had a marked response to salbutamol. The other one benefited from 3,4-diaminopyridine. <i>AchR</i> epsilon subunit (combined heterozygous [L240I and C302Y]) (1 patient): , She showed respiratory distress and markedly response to pyridostigmine. <i>AGRN</i> (novel,homozygous [c.5387G&gt;A and C4217 A&gt;C]) (1 Patient). She had fatigue and worsened with pyridostigmine and had a dramatic response from salbutamol. <h3>Conclusions:</h3> In our study, similar to many studies, the most common findings were ocular and bulbar symptoms, and the most common genetic disorder was postsynaptic (65%) conduction defects. <b>Disclosure:</b> Dr. Yunisova has nothing to disclose. Dr. ARDUC AKCAY has nothing to disclose. Dr. Avci has nothing to disclose. The institution of Dr. Eraslan has received research support from THE SCIENTIFIC AND TECHNOLOGICAL RESEARCH COUNCIL OF TURKEY. Prof. Kayserili has received research support from TUBITAK . Prof. Kayserili has received personal compensation in the range of $500-$4,999 for serving as a Projecct PI, advisor, researccher with TUBITAK . Prof. University has nothing to disclose.

A case report of resolving an uncertain variant in CHRN1B as pathogenic leading to Congenital Myasthenic Syndrome type 2C. (P1-8.001)

A case report of resolving an uncertain variant in CHRN1B as pathogenic leading to Congenital Myasthenic Syndrome type 2C. (P1-8.001)

Unique clinical presentations and follow-up outcomes from experience with congenital disorders of glycosylation: PMM2-PGM1-DPAGT1-MPI-POMT2-B3GALNT2-DPM1-SRD5A3-CDG.

Congenital Glycosylation Disorders (CDG) are a large group of inherited metabolic diseases with multi-organ involvement. Herein, we aimed to expand the clinical characteristics of patients with CDG based on our experience with diagnoses and follow-up of CDG patients from different subtypes. The clinical and laboratory findings from the last 15 years were reviewed retrospectively in Ege University Child Metabolism and Nutrition Department. There were 8 (57.2 %) females and 6 (42.8 %) males. Diagnoses of the patients were PMM2-CDG (n=4), PGM1-CDG (n=2), DPAGT1-CDG (n=2), SRD5A3-CDG (n=2), MPI-CDG (n=1), POMT2-CDG (n=1), B3GALNT2-CDG (n=1), DPM1-CDG (n=1). The clinical findings of the patients were dysmorphia (85.7 %), developmental delay (85.7 %), intellectual disability (85.7 %), ocular abnormalities (64.2 %), skeletal malformations (64.2 %), failure to thrive (57.1 %), microcephaly (57.1 %), hepatomegaly (35.7 %), hearing loss (35.7 %), seizures (28.5 %), gastrointestinal symptoms (21.4 %), endocrine abnormalities (21.4 %), and cardiac abnormalities (7.1 %). Laboratory findings were abnormal TIEF (92.8 %), abnormal liver enzymes (64.2 %), decreased protein C (64.2 %), decreased antithrombin III (64.2 %), decreased protein S (42.8 %), hypogammaglobulinemia (35.7 %), cerebellar hypoplasia (28.5 %), CK elevation (7.1 %), and hypoglycemia (7.1 %). This study contributes to the literature by sharing our ultra-rare DPM1-CDG case with less than 20 cases in the literature and expanding the clinical and molecular characteristics of other CDG patients. Hyperinsulinemic hypoglycemia, short stature, hypothyroidism, growth hormone deficiency, hypogammaglobulinemia, pericardial effusion, elevated CK, congenital myasthenia, and anorectal malformation were unique findings that were observed. Cerebello-ocular findings accompanying multi-organ involvement were an essential clue for a possible CDG.