23 April 2025: Articles
Neonatal Congenital Myasthenic Syndrome Linked to Gene Variants: A Case Report and Treatment Insights
Challenging differential diagnosis, Management of emergency care, Rare disease
Mohammed Rohi Khalil1ABCDEF*, Lone Walentin Laulund2ABCDEF, Anna Julie Aavild Ploug
DOI: 10.12659/AJCR.946839
Am J Case Rep 2025; 26:e946839
Abstract
BACKGROUND: Congenital myasthenic syndrome (CMS) is a rare inherited neuromuscular disorder characterized by muscle weakness and fatigue, often presenting at birth or early childhood. The condition arises from mutations affecting the neuromuscular junction, with an incidence of 1.5 to 9 per million. CMS is primarily classified into presynaptic, synaptic, and postsynaptic types, with mutations in the choline acetyltransferase (CHAT) gene responsible for 4% to 5% of cases. The CHAT gene encodes an enzyme vital for acetylcholine synthesis, a neurotransmitter essential for neuromuscular communication. Mutations in CHAT disrupt acetylcholine production, impairing signal transmission at the neuromuscular junction. This report aims to present a rare case of CMS and highlight the significance of early genetic diagnosis and treatment.
CASE REPORT: We present a rare case of a newborn girl with autosomal recessive CMS caused by compound heterozygous mutations in the CHAT gene: CHAT c.1679A>G and CHAT c.287-1G>C. Born prematurely at 31 weeks gestation, she presented with severe hypotonia, respiratory failure, and absent spontaneous movements. Genetic testing confirmed CMS. Initial treatment with oral pyridostigmine was ineffective, necessitating a switch to intravenous neostigmine, followed by continuous subcutaneous administration. This resulted in significant clinical improvement, including weaning off mechanical ventilation and achieving developmental milestones, with ongoing physiotherapy.
CONCLUSIONS: This case underscores the importance of early genetic testing in neonates with unexplained muscle weakness and respiratory failure. Early genetic diagnosis and personalized treatment with acetylcholinesterase inhibitors were key to the infant’s recovery, highlighting the potential for positive outcomes even in severe CMS cases due to ChAT mutations.
Keywords: Myasthenic Syndromes, Congenital, Heterozygote, Neuromuscular Diseases
Introduction
Congenital myasthenic syndrome (CMS) is a group of rare inherited neuromuscular disorders characterized by muscle weakness that usually present from birth or early childhood [1]. The cause is usually genetic mutations that affect the neuromuscular junction, where nerve cells communicate with muscle cells to stimulate muscle contraction [1]. The estimated incidence of CMS is 1.5 to 9 per million [2].
The neuromuscular junction can be affected in various ways depending on the location of the mutation [1,2], and CMS is classified into presynaptic, synaptic, and postsynaptic types [3,4]. In presynaptic CMS, the nerve cells initiating the impulse are affected; in synaptic CMS, the space between nerve and muscle cells is affected; and in postsynaptic CMS, the muscle cells receiving the impulse are affected. Most CMS cases are postsynaptic, although presynaptic and synaptic mutations also occur [1,2]. CMS has been linked to 35 genes, each affecting proteins essential for the functioning of the neuromuscular junction, such as ion channels, structural proteins, and signaling molecules [5–7]. For instance, mutations in the
Diagnosing CMS in newborns is challenging, as symptoms can resemble more common conditions, such as prematurity, birth asphyxia, and genetic syndromes affecting muscle tone and respiratory function, which can also cause weak muscles and poor feeding [7]. Symptoms in newborns include hypotonia and respiratory failure at birth, with sudden episodes of apnea and cyanosis [1,2]. In the neonatal period, patients with CMS can show difficulties when eating, with poor suck and choking spells. Infants can exhibit eyelid ptosis and facial, bulbar, and generalized weakness of striated muscles [8]. These symptoms can be triggered or exacerbated by fever, infection, stress, and vigorous physical activity. Arthrogryposis multiplex congenita and dysmorphic features can also be part of the syndrome [8]. However, diagnosing CMS in the neonatal period is challenging because prematurity, birth asphyxia, and other syndromes can exhibit similar symptoms and are much more common [8].
Diagnosing CMS is crucial and typically involves genetic testing to identify the specific mutation, which determines the appropriate treatment and management [7]. Treatment strategies can include medications to improve neuromuscular transmission, physical therapy, and sometimes surgical interventions [5–7]. CMS caused by mutations in the
In this report, we present a rare and severe case of a newborn girl with autosomal recessive CMS caused by compound heterozygosity for 2 pathogenic variants in the CHAT gene, illustrating the importance of early genetic diagnosis and tailored treatment.
Case Report
A 27-year-old pregnant woman at 31 weeks and 1 day gestation presented to the emergency department at 22: 00 with acute epigastric pain, diarrhea, vaginal spotting, and cramping. Over the preceding two hours, she had experienced increasing Braxton Hicks contractions. Blood tests and vital signs were normal, and an ultrasound revealed a live fetus in cephalic presentation with normal activity and amniotic fluid volume. She was admitted that evening for suspected imminent preterm labor. Apart from a prior ultrasound for suspected pes cavus, which she declined to follow up, her pregnancy had been uncomplicated.
To manage the risk of preterm delivery, she was treated with atosiban, betamethasone, and magnesium sulfate. However, cardiotocography revealed abnormal pre-terminal patterns, prompting discontinuation of atosiban and an emergency cesarean delivery at 03: 39 AM. The procedure was uneventful, revealing a heart-shaped uterus and a short umbilical cord, with approximately 100 mL of blood loss.
At birth, the newborn girl had a normal heart rate but no spontaneous movements or respiratory efforts, with an Apgar score of 2 at 1 min. She was edematous, with pitting edema, but had no dysmorphic features. Mask ventilation with the Neo-Puff improved her oxygen saturation and color, but she remained without respiratory effort. Her Apgar score was 4 at 5 min.
At 15 min after birth, she was nasally intubated with a 3.0 Blueline tube. Her oxygen saturation was maintained at 90%, requiring an oxygen fraction of 60% to 70%. Suspecting respiratory distress syndrome, we treated with 200 mg of endotracheal surfactant (Curosurf), which had no apparent effect. Umbilical venous access was established, and she received penicillin V (160 mg) and gentamicin (7.5 mg) empirically.
Umbilical cord blood gas samples were not analyzed, but capillary blood gases at 50 min after birth showed a pH of 7.05, pCO2 of 11.8 kPa, and a base excess of −7.8 mmol/L, which normalized an hour later (pH 7.31, pCO2 6.9, base excess −1.3). She was transferred to the Neonatal Intensive Care Unit for further evaluation. Upon arrival, she remained intubated and mechanically ventilated, with oxygen requirements maintained at 60% to 70%. A chest X-ray confirmed proper endotracheal tube placement and ruled out pneumothorax or other explanations for her oxygen needs. A second dose of surfactant yielded no significant improvement. Her blood pressure (mean 32 mmHg) and rectal temperature (36.3°C) were normal.
Approximately 1 h postpartum, she began to exhibit weak movements and signs of discomfort. She was treated with fentanyl (5+10 μg) and rocuronium (2 mg) to optimize ventilation compliance. At 2 h of age, she was transferred to the University Hospital in Odense, 70 km away.
Differential diagnoses, including asphyxia, intracranial hemorrhage, infection, and rare congenital disorders, were considered. Over the first 2 days, comprehensive investigations were conducted. There were no signs of infection, and metabolic urine analysis results were normal. Imaging studies, including cranial ultrasound and magnetic resonance imaging, were unremarkable. An ophthalmologic examination revealed spontaneously dilated pupils that later normalized. An electroencephalogram showed age-appropriate suppression patterns, with no abnormalities. Chest X-ray and echocardiography were also normal for her gestational age.
Genetic testing was initiated on the first day of life, to investigate the unusual presentation. Trio-genome sequencing and chromosomal microarray analysis were performed, with a 10-day turnaround time. Additional targeted tests for Prader-Willi and Temple syndromes were negative. On day 6, trio-genome sequencing identified 2 variants in the
DNA from peripheral blood was sequenced using the Illumina DNA PCR-Free Library Prep Kit on a NovaSeq 6000 platform, with data mapped to the GRCh38 reference genome. Variants were annotated and filtered using VarSeq software.
The first variant,
The second variant,
Based on the clinical presentation and genetic findings, these 2 variants were determined to cause autosomal recessive CMS. The family was counseled about a 25% recurrence risk, with options for preimplantation genetic testing or prenatal diagnostics.
At 7 days, pyridostigmine was started at 1 mg 6 times daily (0.5 mg/kg). This improved feeding tolerance, allowed spontaneous movements closer to age-appropriate levels, and justified extubation. She was briefly extubated at 10 and 13 days but required re-intubation, due to persistent weakness. Pyridostigmine was increased to 32 mg/day but later reduced to 16 mg due to adverse effects.
At 4 weeks, intravenous neostigmine replaced pyridostigmine at an initial dose of 0.25 mg 8 times daily. She remained mechanically ventilated, experiencing occasional respiratory arrest episodes due to laryngomalacia, which was managed with high-dose caffeine. Neostigmine frequency increased to 12 times daily, and she continued to gain weight and develop comparably to other premature infants.
At 38 weeks +1 day postmenstrual age, she was extubated and required only nasal continuous positive airway pressure briefly. Within a week, high-flow oxygen was limited to nights, and respiratory support ceased entirely. Respiratory arrest episodes resolved, and salbutamol inhalations were discontinued.
Neostigmine transitioned to continuous subcutaneous administration via an Insuflon catheter at 0.09 mg/h (0.7 mg/kg/day). The parents were trained to manage the device. After 2.5 months, she was discharged and was bottle-fed, with no signs of club-foot. Neonatal physiotherapist evaluations were normal.
At corrected age 2 months, her neostigmine dose was adjusted to 0.6 mg/kg/day. At the time of this report, she was thriving, tolerated colds well, and continued physiotherapy twice weekly. Her Achilles tendons appeared short and require treatment.
Discussion
This case report highlights several important aspects of diagnosing and managing CMS, particularly in neonates. From this case, it can be learned that CMS can present with symptoms that overlap with more common neonatal conditions, making early diagnosis challenging. This underscores the importance of genetic testing, especially when symptoms of hypotonia, respiratory failure, and feeding difficulties are present, as they can point to a rare but treatable genetic disorder, like CMS. Moreover, the report emphasizes the significance of understanding the genetic underpinnings of CMS, to guide treatment strategies effectively.
CMS is a diverse group of inherited disorders caused by defects in neuromuscular transmission. Among these, mutations in the
This report describes a rare case of a newborn girl with CMS due to compound heterozygosity for 2 pathogenic variants in the
The identified missense variant
The compound heterozygosity of the 2 variants led to the patient’s diagnosis of CMS, which explains the observed severe phenotype.
The clinical presentation of our patient exhibits a very classical case of CMS, with lack of movement due to weakness of striated muscles, apnea, and poor suck in the neonatal period. The hypotonia, episodic apnea, and difficulties with eating are all very well described in patients with CMS due to CHAT variants [8]. Although very common in patients with CMS [14,15], eyelid ptosis is not described in our patient.
Respiratory failure at birth, with episodes of apnea and cyanosis, is a cardinal symptom of CMS [8]. Although very frequent in patients with CMS due to pathogenic CHAT variants, it is not restricted to this subgroup of CMS [8,14,15]. The significant overlap in symptoms and clinical findings between the different subgroups of CMS and between CMS and other rare congenital diseases makes the clinical presentation inadequate to solely distinguish and diagnose the patients. Trio-genome sequencing is our standard first tier approach when the parents are available for testing. The limitations of trio-genome sequencing have to be considered, which is the reason the analysis for Prader-Willi and Temple syndrome was also initiated in this patient. Capalbo et al [9] previously classified this variant as pathogenic, and Ohno et al [10] performed a functional assay demonstrating that the CHAT enzyme harboring this variant exhibits significantly less enzymatic activity than the wild-type enzyme.
Early genetic analysis to conclude the subtype of CMS, and thereby the possibility to initiate early treatment, is therefore crucial to reduce morbidity and mortality.
The paternally inherited variant
The management of CMS involves improving neuromuscular transmission through the use of acetylcholinesterase inhibitors, such as pyridostigmine and neostigmine. In the present case, the initial treatment with oral pyridostigmine showed some but still insufficient effect, and due to adverse effects, the regimen was adjusted to intravenous neostigmine, followed by continuous subcutaneous administration. This approach effectively managed the girl’s symptoms, allowing for gradual improvement in muscle strength, respiratory function, eating, and general development. The comparison with other CMS mutations, such as those involving acetylcholinesterase (
Despite the severe initial presentation, our patient showed significant improvement with appropriate treatment. She was able to be weaned off mechanical ventilation, and her respiratory support requirements decreased over time. Continuous subcutaneous neostigmine administration was well-tolerated and effective. The girl’s development and thriving are closely monitored, with ongoing physiotherapy to support motor function. This suggests that with early diagnosis and aggressive treatment, patients with severe forms of CMS like this one can experience a significant improvement in outcomes. This emphasizes the importance of early genetic diagnosis to tailor therapy effectively, which is becoming an increasing trend in managing CMS.
The recurrence risk for autosomal recessive CMS in future pregnancies is 25%. Therefore, genetic counseling of the family is crucial before future pregnancies, and options such as preimplantation or prenatal genetic testing has been discussed with the parents. Additionally, understanding the evolution of treatment protocols for CMS, especially with evolving drug formulations (like subcutaneous neostigmine), helps ensure that families are well-informed about the potential for improving outcomes, even in severe cases. Moreover, comparing phenotype and genotype data across CMS mutations can assist clinicians in predicting the likely clinical course and therapeutic response.
Conclusions
This case underscores the critical role of genetic testing in diagnosing CMS, particularly when symptoms overlap with more common conditions. Trio-genome sequencing facilitated early genetic diagnosis, enabling the timely initiation of tailored treatment and significantly improving the patient’s clinical outcome. The use of acetylcholinesterase inhibitors, such as neostigmine, led to substantial improvement in this infant’s respiratory and motor function, even in the presence of severe CMS due to
References:
1.. Lorenzoni PJ, Scola RH, Kay CS, Werneck LC, Congenital myasthenic syndrome: A brief review: Pediatr Neurol, 2012; 46(3); 141-48
2.. parr JR, Andrew MJ, Finnis M, How common is childhood myasthenia? The UK incidence and prevalence of autoimmune and congenital myasthenia: Arch Dis Child, 2014; 99(6); 539-42
3.. Rodríguez Cruz PM, Palace J, Beeson D, The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes: Int J Mol Sci, 2018; 19(6); 1677
4.. Souza PV, Batistella GN, Lino VC, Clinical and genetic basis of congenital myasthenic syndromes: Arq Neuropsiquiatr, 2016; 74(9); 750-60
5.. Ohno K, Ohkawara B, Shen XM, Clinical and pathologic features of congenital myasthenic syndromes caused by 35 genes – a comprehensive review: Int J Mol Sci, 2023; 24(4); 3730
6.. Finsterer J, Congenital myasthenic syndromes: Orphanet J Rare Dis, 2019; 14(1); 57
7.. Abicht A, Müller J S, Lochmüller H: Congenital myasthenic syndromes., 1993–2021, Seattle (WA), University of Washington, Seattle
8.. Mansukhani SA, Bothun ED, Diehl NN, Mohney BG, Incidence and ocular features of pediatric myasthenias: Am J Ophthalmol, 2019; 200; 242-49
9.. Capalbo A, Valero RA, Jimenez-Almazan J, Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes: PLoS Genet, 2019; 15(10); e1008409
10.. Ohno K, Tsujino A, Brengman JM, Harper CM, Choline acetyltransferase mutations cause myasthenic syndrome associated with episodic apnea in humans: Proc Natl Acad Sci USA, 2001; 98(4); 2017-22
11.. Schwartz M, Sternberg D, Whalen S, How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome: Am J Med Genet A, 2018; 176(1); 151-55
12.. Dhasakeerthi T, Aravindhan A, Woodall A: J Clin Neuromuscul Dis, 2021; 23(1); 54-55
13.. Engel AG, Shen XM, Selcen D, Sine SM, Congenital myasthenic syndromes: Pathogenesis, diagnosis, and treatment: Lancet Neurol, 2015; 14(4); 420-34
14.. Arican P, Gencpinar P, Cavusoglu D, Olgac Dundar N: Neuropediatrics, 2018; 49(4); 283-88
15.. Murtazina A, Borovikov A, Marakhonov A, Mild phenotype of CHAT-associated congenital myasthenic syndrome: Case series: Front Pediatr, 2024; 12; 1280394
In Press
Case report
Am J Case Rep In Press; DOI: 10.12659/AJCR.946411
Case report
Am J Case Rep In Press; DOI: 10.12659/AJCR.946041
Case report
Am J Case Rep In Press; DOI: 10.12659/AJCR.947953
Case report
Am J Case Rep In Press; DOI: 10.12659/AJCR.946932
Most Viewed Current Articles
21 Jun 2024 : Case report
96,778
DOI :10.12659/AJCR.944371
Am J Case Rep 2024; 25:e944371
07 Mar 2024 : Case report
52,393
DOI :10.12659/AJCR.943133
Am J Case Rep 2024; 25:e943133
20 Nov 2023 : Case report
31,818
DOI :10.12659/AJCR.941424
Am J Case Rep 2023; 24:e941424
18 Feb 2024 : Case report
23,483
DOI :10.12659/AJCR.943030
Am J Case Rep 2024; 25:e943030