Charcot-Marie-Tooth disease (CMT) is the most common group of inherited peripheral neuropathies with a high degree of clinical variability and genetic heterogeneity. The mode of inheritance can be autosomal dominant and recessive as well as X-linked. The main clinical manifestations are peroneal muscle atrophy, flaccid muscle weakness, bowed feet and mild sensory deficits. It is also classified as a hereditary motor and sensory neuropathy due to the involvement of both motor and sensory neurons. CMT1 is divided into two major groups based on nerve conduction velocity (NCV), CMT1 (demyelinating, NCV <38 cm/s) and CMT2 (neuronal, NCV normal or near normal). is the most common subtype, while other subtypes are rare.
Diagnostic steps
(A) Key points of history taking
CMT1 is the most common type and is the classic form of fibromuscular dystrophy. CMT2 type has a later onset than CMT1 type, mostly at the age of 10-25 years, but also as late as 70 years.
The main clinical manifestations of CMT type 1 are muscle weakness and atrophy of the distal extremities (due to symmetrical progressive degeneration of peripheral nerves), starting from the foot and lower extremities, with clubfoot and claw foot deformity. Difficulty in walking is mainly due to sensory ataxia or myasthenia gravis. Weakness and atrophy of the muscles of the hands and forearms with or without sensory deficits appear after several months or years. Some patients have scoliosis, droopy feet, and a cross-threshold gait. Some patients even have only bowed feet or slowed nerve conduction without muscle weakness and atrophy (which may be related to genetic mutations.) CMT type 2 symptoms and site of appearance are similar to CMT type 1, but to a lesser extent.
3. There is often a family history
(B) Key points of physical examination
1.General condition The patient is wasted, with scoliosis, drooping feet and bowed feet, etc.
2.Neurological examination The lower 1/3 of calf and thigh muscles are atrophied, resembling “crane legs” or upside down champagne bottle. Hand muscle atrophy becomes claw-shaped hand, may spread to forearm muscle, the affected limb tendon reflex is reduced or disappeared. The hyperalgesia is distributed in a glove or garter-like manner, with autonomic dysfunction and nutritional disorders.
(C) Analysis of outpatient data
1. Cardiac enzyme examination CK and LDH were not significantly changed.
2.Electromyography CMT1 type NCV slowed down to 38cm/s or less (normal is 50cm/s), CMT2 type NCV was normal or near normal.
3.From the history and physical examination, it is seen that the patient has mainly muscle atrophy in the distal extremities, which is clinically considered as neurogenic muscular atrophy. And accompanied by sensory changes, consistent with peripheral nerve damage. If it is myogenic, generally weakness and atrophy of proximal extremities are predominant. Cardiac enzymes and electromyography results are also supportive.
(iv) Continuing examination items
1, cerebrospinal fluid Usually normal, a few cerebrospinal fluid protein mildly elevated.
2, muscle biopsy Neurogenic muscle atrophy may be seen.
CMT1 nerve biopsy shows peripheral nerve demyelination and Schwann cell hyperplasia forming “onion head” like structures, CMT2 nerve biopsy mainly shows axonal degeneration. Nerve biopsy can exclude other genetic diseases, as well as lymphocytic infiltration and vasculitis autoimmune neuropathy.
Genetic testing can provide the basis for the diagnosis of each subtype.
(1) CMT1 type is autosomal dominant and is divided into 6 subtypes according to the type of mutation, and the genetic alterations of each type are as follows.
(1) CMT1A type accounts for 70-80% of CMT1 and is a duplication of the short arm of chromosome 17 (17p11, 2-12) 1, 5Mb long fragment (which contains the PMP22 gene) or a point mutation in the PMP22 gene ……PMP22 gene encodes peripheral nerve myelin protein 22.
② CMT1B accounts for approximately 5-10% of CMT1 and is associated with mutations in the MPZ gene, which is localized at 1q22 and encodes myelin protein, the major structural protein of peripheral nerve myelin. Patients with MPZ mutations currently fall into two main categories: juvenile-onset and adult-onset. The pathological changes in the juvenile-onset group are dominated by myelin dysfunction and are classified as CMT1B, whereas the late-onset group is dominated by axonal dysfunction and is classified as CMT2I/2J.
(iii) CMT1C accounts for 1%-2% of CMT1 and is associated with mutations in the LITAF (SIMPLE) gene located at 16p13, 1-p12, 3, which encodes lipopolysaccharide-mediated tumor necrosis factor-α.
④ CMT1D is present in less than 2% of CMT1 and is associated with mutations in the EGR2 gene, which is localized at 10q21, 1-q22, 1 and encodes early growth response protein 2 involved in constitutive signaling channels.
⑤ CMT1E is found in less than 5% of CMT1, with a gene localized at 17p11, 2, and is associated with a point mutation in the PMP22 gene. Deafness and pressure palsy are characteristic symptoms of this type.
(vi) CMT2E/1F is present in less than 5% of CMT1 and is associated with mutations in the NEFL gene. Patients with NEFL mutations result in the CMT2E subtype, which is also recognized as CMT1F because of its slowed nerve conduction velocity.
(2) CMT2 is autosomal dominant and recessive and X-linked, and is divided into 15 subtypes, some of which have not yet been cloned for the causative gene, with the following genetic alterations.
(1) CMT2A1 was first studied in CMT2 and is associated with mutations in the KIF1B gene. This gene is localized at 1p36 and encodes human kinesin 1B.
CMT2A2, which accounts for more than 20% of CMT2, is by far the most common CMT2 subtype and is associated with mutations in the MNF2 gene, which is located at 1p36 and 2 and encodes human mitochondrial fusion protein 2. More than 50 mutations in the MFN2 gene have been identified, and some site-specific mutations are often accompanied by specific clinical features, such as optic nerve atrophy, pyramidal fasciculus, tremor, ataxia, etc. (3) The CMT2B gene is localized to the MFN2 gene.
The CMT2B gene is located at 3q21 and is associated with mutations in the RAB7A gene, which encodes a human Ras-related protein7.
④ The CMT2D gene is located at 7p15 and is associated with mutations in the GARS gene, which encodes a glycine tRNA synthetase.
⑤ The CMT2I/2J gene is located at 1q22 and is associated with mutations in the MPZ gene. It is characterized by late-onset axonal polyneuropathy with significant sensory dysfunction, pupillary abnormalities and hearing loss.
The CMT2F gene is located at 7p11 and 23 and is associated with mutations in the HSP27/HSPB1 gene, which encodes human small heat shock proteins (sHSPs) and plays an important role in maintaining cytoskeletal stability and regulating axonal transport.
(7) The CMT2L gene is located at 12q24 and is associated with mutations in the HSP22/HSPB8 gene, encoding human small heat shock proteins 22, which are mainly involved in the degradation of abnormal proteins.
The AR-CMT2A gene is located at 1q21 and 2 and is associated with mutations in the LMNA gene, which encodes human nuclear fibrillar protein A/C (Lamin A/C), and different splicing of the coding region of this gene can produce two types of nuclear fibrillar proteins, A and C.
The CMT2C gene is located at 12q23-q24; the CMT2G gene is located at 12q12-q13,3; the CMT2H gene is located at 8q21,3; the AR-CMT2B gene is located at 19q13,3; and the CMT2K gene is located at 8p13-q21,1, which may be associated with the GDAP1 mutation. The genetic nature of each of the above phenotypes remains to be determined.
⑩ Two CMT2 types (CMT2XA and CMT2XB) associated with sex chromosome linkage have been reported, but their causative genes have still not been cloned.
[Diagnostic response
(I) Diagnostic points
The diagnosis is based on slowly progressive symmetrical weakness of both lower extremities in childhood or adolescence, as well as “crane legs”, drooping feet, bowed feet and scoliosis, weakened or absent tendon reflexes, often accompanied by sensory deficits, slowed motor nerve conduction, demyelination and Schwann cell proliferation on nerve biopsy to form “onion head”-like structures. Onion head”-like structures on nerve biopsy. There is a family history of the disease, which can be confirmed by genetic testing. (1) CMT type 1 has an age of onset of approximately 12 years, with significant slowing of motor NCV and genetic testing suggesting duplication of the PMP22 gene or a point mutation in the PMP22 gene. (ii) CMT type 2 has an age of onset of approximately 25 years and a normal or near-normal motor NCV. Genetic testing for each subtype showed that the mutations were located at different locations on different chromosomes.
(II) Key points of differential diagnosis
Pay attention to differentiate from some diseases with similar clinical manifestations.
1, distal myotonic dystrophy also manifests as muscle weakness and atrophy that gradually develops upward in the distal extremities.
2, distal spinal muscular atrophy clinical manifestations and CMT similar, muscle bundle tremor is obvious, no sensory changes. Electromyography shows anterior horn cell damage.
3, chronic inflammatory demyelinating polyneuropathy The disease progresses rapidly, with increased cerebrospinal fluid protein content and effective hormonal therapy.
4.Familial amyloid polyneuropathy is clinically difficult to distinguish and must be analyzed with the help of nerve biopsy or DNA analysis.
5, hereditary ataxia with myasthenia gravis, also known as Roussy-Levy syndrome, starts in childhood and progresses slowly, showing atrophy of the peroneal muscles, bowed feet and scoliosis, weakened or absent tendon reflexes in the limbs, and slowed motor nerve conduction. However, there are ataxic manifestations such as unstable standing, staggering gait, and tremor of the hands.
(iii) Clinical types
There are two major groups based on nerve conduction velocity (NCV), CMT type 1 (demyelination, NCV <38 cm/s) and CMT type 2 (neuronal, NCV normal or near normal). Currently, CMT1 type is divided into six subtypes 1A, 1B, 1C, 1D, 1E, and 1F based on genetic localization, and CMT2 type is divided into 15 subtypes, and more subtypes may be available in the future.
【Treatment countermeasures
(I) Treatment principles
1.Early diagnosis and early treatment.
2.Mainly symptomatic and supportive treatment.
3. Due to the slow course of the disease, patients can survive for decades, and symptomatic treatment can improve the quality of life of patients.
(B) Treatment plan
1.Basic treatment
(1) Life precautions Pay attention to rest, do not overwork, do not do excessive physical labor, so as not to increase the load on the affected limbs and aggravate the disease. In case of joint sprain, rest and treatment should be given in time, otherwise it will cause ligament relaxation and aggravate the instability of the joint. Pay attention to keep warm, cold stimulation often aggravates the symptoms. Alcohol should be abstained.
(2) Rehabilitation Ultrashort wave and electrical excitation therapy with acupuncture. Proper passive exercise and massage between muscles and roots can improve blood circulation of the limb and can enhance its stretching ability. For drooping feet, wearing high heels, stockings or orthopedic shoes can improve walking, protect the ankle joint and reduce the risk of ankle injury and prevent falls and fractures.
(3) Surgical treatment Appropriate rehabilitative surgical treatment, such as surgical release or tendon grafting, can also be used for severe cases. Joint deformity and scoliosis can be treated surgically.
2.Specific treatment
(1) Vitamins can help promote nerve fiber regeneration and functional recovery. Including vitamin B, E, C, etc.
(2) neurotrophic drugs ATP, coenzyme Q, inosine, cytidylcholine, inositol injection, etc.
(3) Others Galanthamine and tabazol can also be tried.
Observation and treatment of disease process
1. Observe the change of muscle strength, including the change of proximal and distal muscle strength of the extremities, and encourage patients to adhere to exercise.
2.Measure the circumference of the extremities, observe the muscle atrophy, and encourage the patient to perform massage and rehabilitation exercises.
3.The degree of deformity and sensory impairment. Drugs to improve blood circulation can be tried.
【Prevention】
Firstly, clarify the genetic diagnosis and determine the genotype of the preexisting patient, then analyze the fetal genotype by fetal chorion, amniotic fluid or umbilical cord science, and according to the prenatal diagnosis, the pregnancy can be terminated to prevent the birth of the affected child.
Prognosis assessment
The prognosis is generally good, with a slow progression of the disease, and most patients can still survive for decades with symptomatic management to improve their quality of life.
Discharge follow-up
1. Discharge with medication.
2.Regular follow-up and outpatient medication pickup.
3.Discharge from the hospital should pay attention to the problem, pay attention to keep warm and prevent infection.
4.Continue rehabilitation training.