
Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous group of disorders characterized by impaired neuromuscular transmission [1-3]. It is a very rare hereditary muscle disease with the prevalence of individual diseases reported as 0.1-1/100,000 [4-7]. Clinically, it shows various symptoms such as motor weakness, ptosis, respiratory failure, dysphagia, scoliosis, and joint contractures. It shows a broad spectrum of severity from the case of floppy infant syndrome that develops in the neonatal stage to the case with only mild ptosis in adulthood. Often, it is difficult to distinguish CMS from other neuromuscular disorders including congenital myopathy, congenital muscular dystrophy, limbs girdle muscular dystrophy, and seronegative myasthenia gravis [8,9].
The causative genes for congenital myasthenia syndrome are very diverse. More than 30 causative genes of CMS have been reported to date and new genes are constantly being discovered [10,11]. Commonly identified causative genes of CMS include
Here, we describe the clinical and genetic characteristics of CMS patients diagnosed and treated in a single tertiary center. Through this, we aim to provide the clue for early diagnosis and improved therapeutic strategies in CMS.
This study was approved by Seoul National University Hospital Institutional Review Board (IRB No. H-2009-070-1157). All cases were ascertained from the neuromuscular disorders database in the Seoul National University Children’s Hospital. We performed next generation sequencing (NGS) in total 230 patients with genetically unclassified neuromuscular disorders (onset age ≤10 years). Before the NGS testing, genetic tests including spinal muscular atrophy, Duchenne muscular dystrophy, and myotonic dystrophy were performed in some patients, based on the clinical and pathologic findings, but were negative. Eleven patients from nine unrelated Korean families and one Emirati family were included in this study. All cases were genetically confirmed as CMS. A retrospective medical record review was carried out for the clinical data analysis.Diurnal variation and ptosis were subjectively classified to mild, moderate, and severe symptoms. The severity of scoliosis was scaled by Cobb angles (mild: 10-30 degree, moderate: 30-45 degree, and severe: >45 degree). Respiratory dysfunction was described as severe when the patient was dependent on permanent ventilator care or underwent therapeutic tracheostomy. Laboratory data including serum creatine kinase, electrophygiologic studies, and muscle pathology were also reviewed.
DNA was extracted from peripheral blood leukocytes. Informed consent was obtained from all families for the extraction of DNA to perform mutation analysis. We performed targeted panel sequencing of 432 selected genes known to cause monogenic neuromuscular disorders including 20 CMS causative genes (
We found eleven CMS patients from ten unrelated families (Table 1). The age of patients ranged from 5 to 23 years, with the median age of 16 years. The peak age at onset of symptoms was the neonatal period. Seven out of the eleven patients were symptomatic at birth. The most commonly reported initial finding was generalized hypotonia with poor suck and cry. Diurnal variation in seven cases and mild ptosis in six cases were observed. Respiratory distress at birth was noticed in seven patients, four of them suffered transiently and recovered after the neonatal period. Eight patients showed variable degrees of scoliosis. Mean time to accurate diagnosis was 9.3±5.0 years. Total fifteen different variants in seven genes associated with CMS (DOK7, AGRN, RAPSN, CHRNE, COLQ, SLC5A7, and GFPT1) were identified.
The homozygous c.1185C>G mutations and compound heterozygous c.467C>A and c.1502c>T mutations of
Case 5 harbored a heterozygous c.850A>C mutation of
Case 6 carried compound heterozygous c.107-2A>G and c.1354C>T mutations of
The homozygous c.886G>A mutations of SLC5A7 were identified from an Emirati boy (case 7). He had a history of respiratory distress during neonatal period and showed persistent ptosis since birth. He was clinically diagnosed with CMS but previous sequencing result of
Three different compound heterozygous variants of
We report detailed clinical and genetic features of eleven cases with CMS. All patients shared the clinical features of muscle weakness, but the age of onset, distribution and severity of weakness, and response to treatment were very diverse according to the genes harboring the mutations. Typical clinical features were generalized muscle weakness presenting in the neonatal period or early infancy. Diurnal variation of weakness was not so much distinct during infantile and early childhood period and often appeared after childhood as an important clinical clue. Presence of diurnal fluctuations should raise clinical suspicion of CMS even in patients diagnosed with myopathy previously [8]. Ptosis was recognized in five patients but often combined with facial weakness, leading to difficulty in differentiating it from other hereditary myopathy faces. Seven patients had respiratory distress at birth and three patients underwent tracheostomy for managing the persistent respiratory insufficiency. Eight patients had scoliosis and three of them were treated surgically. Paying attention to the posture of patients and continued assessment of spine throughout lifespan is essential.
Laboratory findings were not very helpful in the differential diagnosis of CMS in our cohort. Two cases showed Jolly test negative and case 6 showed once negative and once positive result on repeated tests. All seven patients who underwent electrodiagnostic tests showed myopathic findings with short-duration and low-amplitude motor unit potentials. This is thought to result from functional loss of myofibers caused by chronic neuromuscular transmission failure [9]. Muscle biopsy was performed in nine patients and showed nonspecific myopathic findings with myofiber size variations and minimal degenerating changes in five cases. However, one patient (case 2) was pathologically diagnosed as a congenital myopathy with type 1 fiber predominance and three patients (case 3-2, case 9, and case 10) were diagnosed as muscular dystrophies before molecular diagnosis of CMS. Even serum creatine kinase were mildly elevated in two cases with
The response to treatment depends on the subtype of CMS [2,3,10,15,18]. Traditionally, pyridostigmine, a competitive acetylcholinesterase inhibitor, was the mainstay of treatment for the neuromuscular junction disorders. Oral pyridostigmine can be given at an initial dose of 0.5 to 1 mg/kg every 4 to 6 hours and the maximum recommended total daily dose is 7 mg/kg. Consistent with previous reports, our patients with defects of acetylcholine receptor, presynaptic choline transporter, and protein glycosylation had much benefited from pyridostigmine. But some subtypes such as endplate acetylcholinesterase deficiency due to
Our study suggested the importance of molecular diagnosis of CMS to warrant appropriate treatment. Due to the wide heterogeneity of clinical and genetic features, the diagnosis of CMS remains challenging even for experienced clinicians. The number of causative genes continues to grow and the clinical differentiation of subtypes is usually very difficult. The advent of NGS technologies opened a new era of molecular genetic diagnosis in various neuromuscular disorders. Since molecular diagnosis is crucial for the therapeutic decision making in CMS, it is important for clinicians to recognize clinical clues and confirm the genetic analysis earlier.
This research was funded by Research program of Korea Centers for Disease Control and Prevention (2018-ER6901-02).
The authors declare that they do not have any conflicts of interest.
Clinical and genetic characteristics of the eleven patients with congenital myasthenic syndromes
Case 1 | Case 2 | Case 3-1 | Case 3-2 | Case 4 | Case 5 | Case 6 | Case 7 | Case 8 | Case 9 | Case 10 | |
---|---|---|---|---|---|---|---|---|---|---|---|
F/16 | M/5 | M/10 | M/8 | M/14 | M/19 | M/19 | M/10 | M/21 | M/19 | M/23 | |
Classifications | Postsynaptic (endplate development and maintenance defects) | AChR def | AChE def | Presynaptic | Protein glycosylation defects | ||||||
Genotypes | DOK7 | DOK7 | AGRN | AGRN | RAPSN | CHRNE | COLQ | SLC5A7 | GFPT1 | GFPT1 | GFPT1 |
c.1185C>G | c.476C>A | c.5023G>A | c.5023G>A | c.133G>A | c.850A>C | c.107-2A>G | c.886G>A | c.520G>A | c.706A>T | c.128A>T | |
homo | c.1502C>T | homo | homo | c.690G>A | hetero | c.1354C>T | homo | c.766G>C | c.1549A>C | c.706A>T | |
Clinical findings | |||||||||||
Onset | At birth | At birth | At birth | At birth | At birth | At birth | 3 mon | At birth | 6 yr | 7 yr | 6 mon |
Presentations | FIS | FIS | FIS | FIS | Ptosis | FIS | Motor DD | FIS | Weakness | Weakness | Weakness |
Clinical diagnosis | CMP | CMP | CMP | CMP | MG | MG | CMS | CMS | LGMD | LGMD | CMD |
Diurnal variation | + | – | – | – | ++ | + | + | – | + | ++ | ++ |
Ptosis | + | – | – | – | + | + | – | + | – | – | + |
Scoliosis | +++ | ++ | ++ | ++ | – | + | +++ | + | – | – | +++ |
Respiratory dysfunction | Transient | +++ | +++ | +++ | – | Transient | – | Transient | – | Transient | – |
NICU 2w | NICU 1w | NICU 2m | NICU 3w | ||||||||
Laboratory findings | |||||||||||
Serum CK (IU/L) | 46 | 106 | 26 | 36 | 102 | 123 | 55 | NA | 162 | 257 | 376 |
Jolly test | NA | Negative | NA | NA | NA | Positive | Positive | NA | Negative | Positive | NA |
EMG/NCV | MP | MP | NA | NA | NA | MP | MP | NA | MP | MP | MP |
Muscle pathology | NS | CFTD | NA | MD | NA | NS | NS | NS | NS | MD | MD |
Treatment response | |||||||||||
Pyridostigmine | NE | NE | E | E | E | NE | E | E | E | E | |
Salbutamol | E | E | E | E | E | E | E | E | E | ||
3,4 Diaminopyridine | E | E | E | NE | E | E |
Case 3-1 and 3-2 are siblings.
F, female; M, male; Def, deficiency; FIS, floppy infant syndrome; DD, developmental delay; CMP, congenital myopathy; MG, myasthenia gravis; CMS, congenital myasthenic syndrome; LGMD, limb girdle muscular dystrophy; CMD, congenital muscular dystrophy; MP, myopathy; MD, muscular dystrophy; CFTD, congenital fiber type disproportion; CK, creatine-kinase; EMG, electromyography; NCV, nerve conduction velocity; –, negative; +, mild; ++, moderate; +++, severe; NA, not available; NS, nonspecific; E, effective; NE, not effective.
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