|Year : 2013 | Volume
| Issue : 3 | Page : 338-341
Congenital myasthenic syndromes: Natural history and long-term prognosis
Sujit Abajirao Jagtap, Kuruvilla Abraham, C Sarada, MD Nair
Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
|Date of Submission||02-Oct-2012|
|Date of Decision||07-Nov-2012|
|Date of Acceptance||30-Dec-2012|
|Date of Web Publication||26-Aug-2013|
Sujit Abajirao Jagtap
Department of Neurology, Sree Chitra Tirunal Institute for Medical sciences and technology, Trivandrum - 695 011, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Congenital myasthenia syndrome (CMS) is a rare, heterogeneous group of genetically determined, disorder of neuromuscular transmission. They have a varied presentation and progression and very few studies have addressed the natural history. Aim of the present study is to describe the clinical profile and natural history of patients with CMS. Materials and Methods: Study includes patients with CMS who attended comprehensive-neuromuscular-clinic (CNMC) during the period January, 2000-2008 with a minimum follow-up of 2 years, with inclusion criteria: (1) Onset in infancy or childhood with fluctuating ocular, bulbar, respiratory or limb muscle weakness (2) Acetylcholine receptor antibody negative (3) normal computed tomography (CT) thymus (4) Abnormal repetitive nerve stimulation (RNS) testing (5) Exclusion of other autoimmune disorders. Results: Out of 314 patients with myasthenia who attended the CNMC during study period, 15 (4.8%) were with CMS (8 boys, 7 girls). Patients were divided as infantile and childhood onset. The mean age of onset and diagnosis in infantile and childhood onset groups were 5.5 months/3.1 years and 3.6 years/6.5 years respectively. Eleven patients had ptosis and 4 had generalized presentation. Most common site of decremental response was over facial nerve in 12 (75%) patients. All patients showed good response to treatment with acetyl cholinesterase inhibitor with stable course on follow-up without exacerbations. Mean dose for neostigmine was 28 mg/day and for pyridostigmine was 153 mg/day. Conclusion: Ptosis is most common symptom at onset in CMS, emphasing importance of RNS of the facial nerve, in the absence of molecular diagnosis of CMS. Our CMS cohort had relatively stable course without intermittent exacerbations with fair response to acetyl cholinesterase inhibitor.
Keywords: Acetylcholine receptor deficiency, congenital myasthenia syndrome, ocular myasthenia
|How to cite this article:|
Jagtap SA, Abraham K, Sarada C, Nair M D. Congenital myasthenic syndromes: Natural history and long-term prognosis. Ann Indian Acad Neurol 2013;16:338-41
|How to cite this URL:|
Jagtap SA, Abraham K, Sarada C, Nair M D. Congenital myasthenic syndromes: Natural history and long-term prognosis. Ann Indian Acad Neurol [serial online] 2013 [cited 2020 Mar 28];16:338-41. Available from: http://www.annalsofian.org/text.asp?2013/16/3/338/116918
| Introduction|| |
Congenital myasthenia syndrome (CMS) is a rare, heterogeneous group of genetically determined, disorders of neuromuscular transmission. There is no reliable information on prevalence and incidence of CMS. The earliest report of CMS was by Rothbart  in 1937 while the term "congenital myasthenia" was coined by Bowman  to describe an infant who had normal parents and whose myasthenic symptoms persisted in childhood. Unlike myasthenia gravis and the Lambert-Eaton myasthenic syndrome, which are autoimmune, CMS is not autoimmune and test negative for known antibodies and have no response to immuno-modulatory therapy. CMS has varied presentation ranging from isolated ocular weakness to life threatening bulbar and respiratory involvement. The common features of CMS are an exercise induced weakness of skeletal muscle. At birth, they may present with hypotonia, respiratory distress or joint contractures. They usually manifest in the first year of life with bilateral ptosis, ophthalmoparesis and facial weakness or in early childhood with walking difficulties and frequent falls. Late onset of muscle weakness in adolescence or early adulthood has been reported as well. Although clinical and electrophysiological data may suggest CMS; specialized microelectrode analysis of neuromuscular transmission, ultra structural studies of neuromuscular junction and molecular analysis are necessary to make precise diagnosis. ,,,, The present study was undertaken with following aims and objectives:
- To analyze the clinical profile of patients with CMS systematically
- To assess the long-term prognosis of this cohort with respect to the treatment given and progression over the study period.
| Materials and Methods|| |
Study included patients with CMS who attended comprehensive-neuromuscular-clinic (CNMC) during the period 2000-2008 with a minimum follow-up of 2 years, with following inclusion criteria; (1) Onset in infancy, childhood with fluctuating ocular, bulbar, respiratory or limb muscle weakness (2) Acetylcholine receptor (AChR) antibody negative (3) normal CT thymus (4) Repetitive nerve stimulation (RNS) study and/or (5) neostigmine test performed. Patients with other autoimmune disorders were excluded. A detailed neurological examination including fatigability test for ocular and limb muscles was done. A detailed family history and whenever possible examination of family members was done. The patients underwent the following tests: Thyroid function tests, serum creatinine phosphokinase, levels, total and differential leukocyte count, erythrocyte sedimentation rate, X-ray chest, computerized tomography of chest and AChR antibody estimation. Anti-Musk antibody which is also essential for exclusion of autoimmune myasthenia, although Musk-positive myasthenia gravis (MG) is very rare in children was not performed due to non-availability as well as economic constraints.
Repetitive nerve stimulation
The electrophysiological tests done were after determining supramaximal stimulation intensity and measurement of amplitude of compound muscle action potential (CMAP) of orbicularis oculi, abductor pollicis brevis and trapezius. We also looked for repetitive CMAP, which is characteristically seen in some forms of CMS. After obtaining a baseline CMAP with supramaximal stimulation, the muscle being studied is exercised with maximal voluntary contraction against resistance for 10 s. Immediately after the 10 s exercise, a single supramaximal stimulus is given and the amplitude of the CMAP is compared to the baseline study. This technique increases presynaptic calcium concentration resulting in facilitation of ACh release. RNS of these muscles at 3 Hz stimulation as per protocol which involves pre- and post- exercise RNS testing at 3 Hz and whenever required high-frequency stimulation as tolerated by the patient was done. If required detailed nerve conduction study and electromyograpghy were also done on individual basis.
| Results|| |
Out of 314 patients with myasthenia who attended the CNMC during study period, 15 (4.8%) were with CMS, 8 boys and 7 girls. Patients were divided into infantile-onset (less than 1 year) and childhood-onset (more than 1 year up to 12 years) In infantile group, mean age of onset was 0.55 years and mean age at diagnosis was 3.1 years, while in childhood-onset group mean age of onset was 3.6 years and mean age at diagnosis was 6.5 years (range 1-6 years) [Table 1]. Mean delay in diagnosis from onset of symptoms in infantile group was 2.6 years and 2.9 years in childhood onset. Eleven patients had ocular and four had generalized presentation. Most common ocular symptom was ptosis and normal extra-occular movements were present in seven patients (46.66%). Four patients (26.6%) had total opthalmoplegia.
|Table 1: Clinical characteristics of patients with congenital myasthenia syndrome|
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Family history of CMS was present in one patient. Developmental milestones were delayed in six patients (40%) with motor delay as the predominant symptom. All patients with infantile onset had delayed milestones. One patient had psychomotor retardation due to prematurity and birth asphyxia. Facial dysmorphism was present in one patient and scoliosis was present in two patients. No patient had any wasting or contracture. All patients had normal tone except one, who had hypotonia. Deep tendon reflexes were normal in all patients. Out of nine patients in whom neostigmine test was performed, seven patients showed positive results. Most common decremental response was seen in the facial nerve (12 patients), followed by spinal accessory nerve (four patients) and ulnar nerve (three patients). None of the patient had repetitive CMAP to single nerve stimulation. Thirteen patients were started on treatment with acetyl cholinesterase inhibitor with fair response and stable course on follow-up without exacerbations. Two patients did not require any treatment as symptoms were non-disabling. Eight patients received only pyridostigmine, four received neostigmine and one patient received both. Mean neostigmine dose was 28 mg/day and pyridostigmine dose was 153 mg/day. Mean duration of follow-up was 4.6 years (range 2-12 years). Only one patient developed myasthenic crisis following severe infection on follow-up at the age of 25 years which was managed with supportive treatment and intravenous immunoglobulin (IVIg) due to sepsis. There are no guidelines for treatment of myasthenic crisis in CMS patient, which are rare and usually managed with supportive treatment. The improvement in our patient could have been spontaneous or due to IVIg. His repeat AChR antibody was negative. One patient had a complex partial seizure and one had ostium secondum atrial septal defect, which was corrected.
| Discussion|| |
CMS has been classified as pre-synaptic, synaptic and post-synaptic depending upon genetic defects in molecules expressed at the neuromuscular junction. Some of the mutations identified are (1) choline acetyltransferase (ChAT) that resynthesizes acetylcholine from recycled choline at the nerve terminal.(2) collagen Q (COLQ) that anchors acetylcholine esterase to the synaptic basal lamina, (3) AChR subunits α, β, δ, ε (AChR deficiency, slow channel syndrome, fast channel syndrome), (4) muscle-specific kinase (MuSK) that transmits the AChR-clustering signal from agrin/LRP4 to rapsyn/AChR, (5) Dok-7 that transmits the AChR-clustering signal from agrin/LRP4/MuSK to rapsyn/AChR, (6) rapsyn that anchors and clusters AChRs at the neuromuscular junction (7) agrin that is released from the nerve terminal and induces AChR clustering by stimulating the downstream LRP4/MuSK/Dok-7/rapsyn/AChR pathway. Most of the CMS have autosomal recessive inheritance except slow channel variety, which is dominant and genetic mutations can be identified in only about 60% of the CMS patients. The age of onset, pattern of weakness, the treatment response and the disease course over time depends upon the molecular mechanisms arising from mutations. ChAT is presynaptic, COLQ is synaptic while rest are post-synaptic genes. ,,,
Patients with mutations of fast channel, ChAT, AChR subunits (predominantly epsilon) and COLQ present at birth or early in infancy. Opthalmoplegia is commonly reported in fast channel, ChAT, AChR sub-units mutations. Contractures are seen in slow channel and rapsyn has mild arthrogryposis multiplex congenita, dysmorphism and/or the presence of a high arched palate. Mutations of the AChR subunits, rapsyn are relatively stable over time, although all the CMS may worsen temporarily with infections. Most of the mutations of the AChR sub-units (predominantly epsilon) derive from an ancient founder mutation in the Indian subcontinent. A double CMAP response to single nerve stimulation is noted in the majority of COLQ CMS but is also reported in the slow channel syndromes. 
Results from this study highlight some important aspects of CMS. All cases except one were sporadic while in most of the studies sporadic cases are rare and familial cases are common. Although dysmorphic features have been commonly described in Iranian and Iraqi Jews, only one of our patient had dysmorphic features.  Our patient had an elongated face, low set ears and high-arched palate [Figure 1]a and b. Facial malformations may be secondary to the neuromuscular defect or may be primary and unrelated. The mean age of onset was 2.7 years (range birth-15 years), which correlates with CMS though few may have late presentation as late as second decade as in one of our patients who had onset of symptoms at the age of 15 years.  Mean delay in diagnosis was 2.6 years in infantile onset and 2.9 years in childhood form. Many a times, the CMS is misdiagnosed as congenital myopathy, central hypotonia or neurometabolic diseases, myasthenia gravis, limb-girdle or congenital muscular dystrophy and spinal muscular atrophy.  Delayed milestones were seen in 40% patients with predominant motor delay in our series while 54% patients had delayed milestones in a study by Kinali et al.  In our study, all patients in infantile onset group had delayed milestones, indicating that a CMS patient should be monitored for developmental delay.
|Figure 1: Patient with elongated face, low set ears and high-arched palate|
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Patients presenting in neonatal age group may present with hypotonia and apnea and may be misdiagnosed as anoxic seizures and may suffer from recurrent apnea with subsequent hypoxic brain damage leading to delayed development. CMS should be suspected in the neonates who present with feeding difficulties, hypotonia with or without limb weakness, ptosis, respiratory insufficiency, contractures and stridor.  Electrophysiology showed most common decremental response in facial nerve (75% patients) suggestive of most common ocular involvement. This emphasizes the need for evaluating decremental response in facial nerve in patients with CMS before documenting that the RNS is negative. Thirteen patients were started on treatment with acetyl cholinesterase inhibitor with fair response and stable course on follow-up. Only one patient developed crisis similar to the study by Schara et al. 
Treatment in CMS depends on underlying defect in neuromuscular transmission. Most patients with Fast-channel or Endplate AChR deficiency respond favorably but incompletely to cholinesterase inhibitors. Most patients treated with 3,4-di-amino pyridine (DAP) combined with pyridostigmine have favourable response.  Patients with Rapsyn Deficiency and Dok-7 respond well to pyridostigmine  with some additional benefit from the use of 3,4-DAP  or ephedrine. The slow-channel syndromes are usually treated with quinidine and fluoxetine, which are long-lived, open-channel blockers of AChR that shorten the duration of channel opening in a concentration dependent manner. , Clinical profile of our patients is suggestive of post-synaptic defect and is likely to be due to mutations of the AChR subunits, rapsyn and fast channel although molecular analysis is not available. The limitation of our study is lack of genetic studies and testing for anti-Musk antibody, although Musk-positive MG is very rare in children.
CMS are usually associated with a favorable prognosis if it occurs beyond neonatal period with early diagnosis and appropriate treatment. It is clear that our series from a specialized tertiary referral center may represent the CMS patients with post-synaptic defect due to selection biases and these observations particularly apply to our cohort.
| Conclusion|| |
Ptosis is most common symptom at onset in CMS. So we emphasize in the absence of molecular diagnosis the importance of performing RNS of the facial nerve. Our CMS cohort had a relatively stable course without intermittent exacerbations and with fair response to acetyl cholinesterase inhibitor.
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