I. Overview /strong>
Congenital myasthenic syndrome (CMS) is a group of genetic disorders characterized by fatigue-induced muscle weakness. Impaired neuromuscular junction information transmission at the motor endplate is due to genetic defects in the presynaptic, synaptic basement membrane, and postsynaptic portions of the neuromuscular junction. CMS is more common in adolescents, children, and infants. The main clinical features include proximal extremity weakness, bulbar palsy, and respiratory failure. According to the location of CMS lesions, it is divided into presynaptic membrane, synaptic cleft, postsynaptic membrane lesions, glycosylation defects and myopathy overlap syndrome.
II. Etiology and Epidemiology< /p>The pathogenesis of CMS is the abnormal function of proteins responsible for neuromuscular signaling. According to the type and location of protein abnormalities caused by gene mutations, they are divided into 4 types (the following table), and their pathological mechanisms are also different: for example, ChAT syndrome, which is caused by ChAT gene mutation. Production is reduced, resulting in muscle weakness. For example, ColQ syndrome, which is the denaturation of the ColQ protein in the synaptic cleft cholinesterase complex, leads to the mis-anchoring of cholinesterase, the relative lack of cholinesterase in the synaptic cleft, and in addition to muscle weakness, synaptic cholinesterase The posterior membrane is continuously excited, and after a current stimulation, repetitive compound action potentials (R-CMAPs) can appear. The average incidence of CMS reported abroad is about 9.2 per 1 million adolescents and children. There are no epidemiological data on the disease in my country. The vast majority of CMS is autosomal recessive inheritance, and it is rare to have a family history. Some autosomal dominant CMS syndromes may have a family history.
Table: Inheritance of commonCMS syndromes Mode and Pathology
modes of inheritance< /span>
1. Presynaptic membrane
often hidden< /span>
Insufficient catalytic synthesis of acetylcholine
2． Synaptic Cleft
usually hidden span>
AChEanchoring error span>
3< /span>. Postsynaptic membrane
Receptor structural defects
< span>AChRNumber dropped
Receptor motility defects
Slow Channel Syndrome
Fast Track Syndrome
AChRreduced opening hours
Receptor complexes and endplate maintenance
EPDevelopmental and maintenance abnormalities
< /t d>
Same as above
|< p>Same as above|
Voltage Gated sodium channel
4. Abnormal Glycosylation or Myopathy Overlap
often hidden span>
Abnormal acetylcholine receptor glycosylation
Centronuclear myopathy withCMS(BIN1< span>Isogene related)
normally hidden span>
Centronuclear myopathy with neuromuscular junction dysfunction< /p>
Normally recessive: autosomal recessive; often dominant: autosomal dominant; AChR: Acetyl Choline receptor; AChE: acetylcholinesterase; EP: end plate; RNS: repetitive frequency electrical stimulation; Nav1.4: voltage-gated sodium channel
III. Clinical manifestations
CMS can appear after birth Symptoms can also begin in infancy to early adulthood. The main manifestations are fluctuating muscle weakness, intolerance to fatigue, and are mostly distributed in the extraocular muscles, facial muscles, medulla oblongata, limbs and respiratory muscles, and even life-threatening apnea episodes may occur in infancy. Simple CMS syndrome is mainly characterized by skeletal muscle weakness without congenital deformities. Glycosylation defects and myopathic overlap syndromes in CMS are often associated with congenital developmental abnormalities. Different types of clinical manifestations are also different, such as ChAT syndrome, which is generally proximal muscle weakness after birth. Cholinesterase inhibitors are effective. In severe cases, sudden respiratory distress and apnea caused by bulbar palsy may occur, which can be caused by stress. , cold, infection, etc. ColQ syndrome, with onset after birth or in infancy, may present with severe, axially distributed muscle weakness, but the extraocular muscles may not be involved. LAMB2 syndrome, Pierson syndrome caused by missense and frameshift mutations in LAMB2 has been reported in a patient with concomitant ocular and renal dysplasia and CMS.
IV. Auxiliary examination
1. Electrophysiological examination Repeated electrical stimulation of nerves in congenital myasthenic syndrome is characterized by a decrease in amplitude after repeated stimulation of low-frequency current, and Jitter block and widening can be seen on single-fiber electromyography (SFEMG). In the ChAT mutation, low-frequency repetitive electrical stimulation (3 Hz) may lack a decreasing response. At this time, prolonged stimulation at 10 Hz or exercise induction before stimulation can elicit a decreasing response. In ColQ syndrome and slow channel syndrome, a repeating CMAP wave (R-CAMP) appears after the first CMAP wave after the first CMAP wave because the postsynaptic membrane is continuously excited (below).
Figure ColQ syndrome visible R-CMAPWave
A. After stimulation of the ulnar nerve, CMAP waves appeared; B.After stimulation of the facial nerve, The main peak is double peak and CMAP wave appears; C.normal control, after stimulation of ulnar nerve, no span>CMAP waves appear. Quoted from: Dai Yi et al..Clinical study of a family with endplate cholinesterase-deficient congenital myasthenic syndrome , Electrophysiology, Muscle Pathology and Genetic Research. Chinese Journal of Neurology,2016,49(8):604-609.
2. Genetic testing When a specific In clinical syndromes, Sanger sequencing can rapidly and precisely pinpoint the mutation of the causative gene. Meanwhile, when targeting a specific causative gene, Sanger sequencing is recommended for pedigree verification. When the clinical manifestations are not typical, high-throughput sequencing methods can be selected to detect and screen a variety of potentially related genes. It is possible to find unknown genetic mutations using whole-exome sequencing, but their pathogenicity needs to be verified, emphasizing the importance of clinical and electrophysiological data for diagnosis.
< span>The clinical diagnosis of congenital myasthenic syndrome can be based on the following points:1. Onset after birth or in infants, craniofacial, limb, trunk muscle weakness, often similar to myasthenia gravis Symptoms, such as easy fatigue, exercise intolerance, heaviness in the morning and evening, effective cholinesterase inhibitors; with or without congenital myopathy-like manifestations; with or without apnea episodes. 2. Repetitive electrical stimulation suggests that the amplitude of low-frequency stimulation decreases, or electrical stimulation after exercise shows a decreasing amplitude, SFEMG see Jitter widening or block; some CMS have repetitive CMAP after single electrical stimulation, but not all CMS appeared; some cases showed myogenic damage on needle electromyography. 3. Serum acetylcholine receptor antibody and skeletal muscle-specific tyrosine receptor kinase antibody were negative. 4. Immunotherapy is ineffective. Gene-specific testing has diagnostic value when phenotypic features suggest that myasthenic syndrome is caused by a specific gene mutation. In difficult-to-diagnose cases, high-throughput sequencing of multiple related genes may be helpful for diagnosis, and whole-exome sequencing may identify novel pathogenic gene mutations.
Six. Differential Diagnosis
The differential diagnosis of CMS mainly needs to be differentiated from congenital myopathy, muscular dystrophy, myasthenia gravis (MG), and Lambert-Eaton syndrome (LES). The main distinguishing points are as follows: 1. Age of onset Most of the onset of CMS occurs after birth or in infants and young children, and there are also a few patients with late onset. Congenital myopathy and muscular dystrophy are more common in infants and young children, and MG and LES are more common in adulthood. 2. Symptoms and signs CMS is characterized by fluctuating muscle weakness and fatigue intolerance, while congenital myopathy and muscular dystrophy are mostly persistent muscle weakness. The onset of CMS is more than that of craniofacial muscle weakness. Congenital myopathy affects the proximal extremities in the early stage. Myasthenia gravis and Lambert-Eaton syndrome are early manifestations of external ophthalmoplegia and fatigue of the proximal limbs. 3. Electrophysiological R-CAMP phenomenon and decrease in repetition frequency after exercise suggest that CMS is possible, but not a necessary condition. CMS, MG, and LES can show low-frequency decrement of repetitive electrical stimulation, Jitter block, and widening performance, which are generally not seen in congenital myopathy and muscular dystrophy. 4. Systemic manifestations Joint contractures and scoliosis may appear in a small number of CMS [Lisa2], similar to some congenital myopathy and muscular dystrophy, but not in MG and LES. 5. Antibody CThe peripheral blood of MS was negative for acetylcholine receptor antibodies and MuSK antibodies, and most of the MGs were positive for these antibodies.
< p>There is currently no treatment for the cause. Some drugs can improve the symptoms of myasthenia. See the table below for details.
table different types span>CMStherapeutic principles
Type of syndrome
|< p>Treatment recommendations|
Cholinesterase inhibitor contraindications
Cholinesterase inhibitor, 3, 4-DAP
slow channel< /p>
cholinesterase inhibitor contraindications
cholinesterase Inhibitor, 3, 4-DAP
Cholinesterase inhibitors are contraindicated
|< p>Ephedrine or albuterol may be effective|
cholinesterase inhibition agent, 3, 4-DAP
Cholinesterase Inhibitor, Salbutamol
VIII. Other treatments span>
(1) Respiratory monitoring: Monitor for apnea in patients with ChAT, avoid cold, stress, etc., and avoid triggering apnea.
(2) Respiratory support: Respiratory management is an important aspect of treatment. Because hypoventilation can occur in all subtypes of congenital myasthenic syndrome, those with severe ChAT may benefit from noninvasive ventilation at home.
IX. Diagnosis and treatment processFigure:Congenital myasthenic syndrome ( CMS) diagnosis and treatment process
Abbreviation:RCMAP. Repetitive compound action potential; Jitter.Single-fiber EMG “jitter”;MG.myasthenia gravis; LES.Lambert Eatonsyndrome;CMS-panel.CMSgene< span>Spectrum
Source: Zhengzhou Pulilai Test
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