|Ahead of print
Fast channel congenital myesthenic syndrome: Reporting two cases with mutation of CHRNE gene and short review
Md Mizanur Rahman, Kanij Fatema
Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
|Date of Submission||01-Jun-2021|
|Date of Decision||03-Aug-2021|
|Date of Acceptance||05-Aug-2021|
|Date of Web Publication||07-Jan-2022|
Department of Pediatric Neurology, Bangabandhu Sheikh Mujib Medical University, Dhaka.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Congenital myasthenic syndromes (CMSs) are hereditary neuromuscular disorders. Fast channel CMSs are a rare entity characterized by onset at birth or early infancy, easy fatigability, ptosis, proximal muscle weakness, ophthalmoplegia, etc. A positive family history may be present. Genetic mutation related to fast channel CMSs is diverse; there is variability of phenotype with genotype. CHRNE is the most common gene associated with this disorder in which post-synaptic acetylcholine receptor (AChR) is affected. Diagnosis is done by repetitive nerve stimulation (RNS) test and genetic test by excluding autoimmune cause. Most of the cases are responsive to pyridostigmine. Here we report two cases—siblings and male—with early onset of disease with typical clinical feature. The RNS test was positive, and AChR autoantibody was negative. The final diagnosis was made by next generation sequencing in which both the cases had pathogenic mutation of the CHRNE gene.
Keywords: CHRNE, congenital myasthenia syndrome, fast channel
| Introduction|| |
Congenital myasthenic syndromes (CMSs) are heterogeneous groups of disorders which have a genetic basis. This condition is caused by the impairment in the transmission of neuromuscular junction resulting in clinical syndromes, which appear usually in early childhood., Patients usually present with fluctuating fatigable muscle weakness. The muscles of limbs, trunk, bulbar muscles, respiratory system, and extra-ocular muscles are involved. Weak cry, stridor, less fetal movement, feeding difficulty, choking episodes, and skeletal deformities are observed in the perinatal period.
It is an autosomal recessive disorder. About 35 genetic mutations have been identified in relation to CMS, and phenotypes vary according to these genotypes. Genetic mutation affects the molecular mechanism of neuromuscular transmission. The site may vary such as presynaptic, synaptic, and postsynaptic proteins.,, The commonest protein which is affected is postsynaptic acetylcholine receptor (AChR), whereas the most frequently occurring mutation is in the e-subunit gene CHRNE (Cholinergic Receptor, Nicotinic, Epsilon Polypeptide). This CHRNE gene mutation causes a deficiency of AChR at the endplate.
Patients with fast channel CMS with CHRNE mutation usually present at birth or before 2 years of life. The predominant clinical features are respiratory difficulty, bulbar disorder, and ophthalmoplegia. The muscles typically involved are limb-girdle, cervical (axial), respiratory, eye, facial, and bulbar muscles. Abnormal fatigability is observed. Smooth muscles and heart muscles are generally spared. A positive family history may be present.
Fast channel CMSs are a rare entity. Here we report two cases with clinical, neurophysiological profile and genetic mutation pattern and a short review.
| Case Description|| |
This is a 6-year-old male child, first issue of nonconsanguineous parents, presented with delay in motor milestones of development. He also had weakness to perform task and easy fatigability since his early childhood. Mother also noticed that he had occasional difficulty in swallowing. He developed ptosis at the age of 2 years in both eyes which was more prominent in the evening hours. The child was born by lower uterine cesarian section (LUCS), term, with normal birth weight. There was no history of perinatal insult. His younger brother is affected with similar type of illness. He had no history of difficulty in respiration or apneic spells. Regarding developmental history, he learned to sit at 1 year of age and started to walk at 2 years. Other domains including vision, hearing, and cognition were normal. On examination, he had bilateral ptosis, anthropometrically well thriving and vitals were stable. On neurological examination, bilateral symmetrical ptosis was present with limitation of movement of third, fourth, and sixth cranial nerves. On motor system examination, tone was normal, power was diminished in both upper and lower limbs (MRC scale 4/5), more prominent in the proximal parts of the limbs. Deep tendon reflexes were normal. Gait was waddling gait.
Routine tests such as complete blood count, liver function test, renal function test, and creatine phosphokinase (CPK) were normal. The thyroid function test showed TSH 6.5 mIU/L and FT4 1.3 ng/dl suggestive of hypothyroidism. The AChR antibody test showed the level as 0.10 nmol/L (negative).
The repetitive nerve stimulation (RNS) study at 3 Hz showed decremental response in abductor pollicis brevis.
Next generation sequencing showed as follows.
The patient was treated with pyridostigmine (5 mg/kg/day in divided doses). For hypothyroidism, thyroxine was added. With the above treatment, he showed significant clinical improvement. At 5-month follow-up, the patient was stable.
This was the younger brother of case 1, and age was 1 year 5 months. This child, a male, presented with delay in motor development and drooping of both eyelids since 1 year of age. He also had difficulty in swallowing with choking episodes. On examination, weakness and fatigability were more prominent in the later part of the day. He was delivered by LUCS with no definite perinatal insult. Developmental history revealed that he started to sit at 10 months of age and still unable to stand or walk. On examination, he had ptosis with normal eye movement. He was vitally stable and anthropometry was within normal range. Neurological examination showed tone slightly decreased, power 4/5 in all four limbs, and deep tendon reflexes were intact. Gait could not be evaluated.
The RNS test at 3 Hz showed decremental response in abductor pollicis brevis. Other baseline tests including complete blood count, thyroid test, liver function test, renal function test, serum electrolytes, and CPK were normal. The AChR antibody test was negative.
Next generation sequencing showed a similar mutation of CHRNE gene in chromosome 17 as his sibling [Table 1].
The patient was treated with pyridostigmine (5 mg/kg/day in divided doses). There was some improvement of weakness and ptosis after 1 month. Physiotherapy and occupational therapy were offered for the motor delay. This patient was followed up for 6 months, no deterioration of motor features was observed, and ptosis was improved.
| Discussion|| |
CMS is a rare clinical entity, characteristically different from autoimmune myasthenia by the early onset of disorder, positive family history, absence of autoantibody, and positive genetic mutation. CMS is classified according to the pattern of inheritance, site of involvement in the neuromuscular junction (presynaptic, synaptic, or postsynaptic), or type of the protein involved at the motor end plate. Fast channel CMS falls in the early onset phenotypes. This syndrome arises from autosomal recessive mutation in different domains of acetylcholine subunits. Moreover, they clinically mimic a typical autoimmune acquired myasthenia gravis. Therapeutic response to pyridostigmine and amifampridine is also a clue to diagnosis.,,
The patients of fast channel CMS usually present at birth or in early infancy. The clinical features are variable. Some patients have severe respiratory failure, swallowing difficulty, ophthalmoplegia, whereas some patients have very mild clinical features initially. The patients may have ptosis, fatigable weakness, low pitched crying, skeletal deformity, etc. Other features are diurnal variation of weakness, deterioration with stress or exercise, frequent recurrent respiratory infections, etc. The course of the disease may be static or progressive., Both the patients of this article had early onset of disease, motor delay, ptosis, easy fatigability, and worsening of symptoms in the later part of the day. Case 1 had ophthalmoplegia. Proximal muscle weakness evidenced by decreased power was noted in both the cases. Motor developmental delay was noted here with intact cognition, vision, and hearing.
Early onset of disease even at birth is an important feature of fast channel CMS. Less fetal movement is observed in the antenatal period. After birth, newborns may need respiratory support or neonatal intensive care unit admission. They may present with neonatal hypotonia, ptosis, weak cry, feeding difficulty, stridor, apneic attacks, arthrogryposis, etc., In a study by Palace et al., out of 12 patients, respiratory problems were noted at birth in 6 cases and respiratory support was needed in 2 cases. Seven patients were admitted to special care baby unit. Both the cases reported in this paper were born by cesarian section with no perinatal insult.
Family history of similar illness or sibling death is very important for fast channel CMS. In a related study, sibling death due to respiratory illness, early infancy death in siblings, and siblings affected with similar type were observed. Consanguinity of marriage of the parents may be noted. Family history was obvious in our cases. Parents were not consanguineous but both the cases were siblings and had similar pattern of disorder.
For confirmation of clinical diagnosis, neurophysiology and genetic test play an important role whereas the AChR antibody test helps to exclude autoimmune MG. RNS is performed at rest with low frequency stimulation (3 Hz). A decremental response in amplitude at the fourth potential that was higher than 10% when compared with the first potential is considered abnormal. Jitter measurement is also a useful tool for CMS. The sensitivity of RNS in CMS patients ranges from 65% to 88%, whereas sensitivity of jitter measurement varies from 85% to 93%.,, In the first case reported here, RNS was positive whereas in the second case it was not done.
Till date, there are limited number of reported cases of CMS with genetic profile. The genes related to CMS are as follows: CHAT, COLQ, CHRNE, DOK7, RAPSN, MUSK, slow channel, fast channel, etc. In their study, Finlayson et al. reported that fast channel syndrome comprises around 5% of genetically confirmed CMS in the UK and is autosomal recessive in inheritance. In these cases, mutation of AChR subunits leads to a kinetic abnormality of the AChR ion channel pore whereby channel opening is abnormally brief (or fast). In both the cases reported here, a heterozygous nonsense variation in exon 10 of the CHRNE gene (chr17:g.4802520G>A; Depth: 21x) was noted, which resulted in a stop codon and premature truncation of the protein at codon 398 (p.Gln398Ter; ENST00000293780.4). Notably, mutations in the CHRNE gene have been associated with both fast and slow channel kinetic abnormalities.,
Thus, early onset of disorder, positive family history, typical phenotype, absence of autoantibody in blood, and positive genetic test excluded the possibility of autoimmune MG and made the diagnosis of CMS.
Treatment of CMS is challenging due to the rarity of the disorder as well as phenotypic and genotypic heterogeneity. Acetylcholinesterase inhibitors (AChEIs) (e.g., pyridostigmine) are the most commonly used drugs here. Other drugs used are 3,4-diaminopyridine (3 4-DAP), albuterol, ephedrine, fluoxetine, quinidine, etc. These drugs are used either alone or in combination. In CHRNE mutation, the AChEIs are effective; however, in some subtypes, AChEIs are ineffective and may worsen symptoms, like CMS with mutation of the following genes: COLQ, COL13A1, LAMB2, DOK7, LRP4, and MUSK. That is why, genetic study is very important here to determine the treatment., In both the cases of this paper, pyridostigmine has been administered with significant improvement. Nonpharmacological management including physical therapy, speech therapy, occupational therapy, orthoses, walkers, and wheelchairs is also offered.
The prognosis of CMS is variable and depends on the subtypes. In fast channel CMS, the long-time features observed are progressive muscular weakness, ophthalmoplegia, shortening of walking distance, scoliosis, bulbar symptoms, respiratory insufficiency, joint contracture, etc.
| Conclusion|| |
CMS is a rare entity, and there is heterogeneity of the phenotype and genotype. As a potentially treatable group of neuromuscular diseases, clinicians should be aware of the syndrome. Here, two cases of fast channel CMS with CHRNE gene mutation have been reported, which may attribute in early diagnosis and appropriate management of this rare disorder.
Informed written consent has been taken from the parents of the both patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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