Charcot-Marie-Tooth Disease (CMT), also known as hereditary motor and sensory neuropathy (HMSN), is the most common group of peripheral neurological monogenic disorders with a high degree of clinical and genetic heterogeneity. Charcot, Marie, and Tooth were first reported in 1886. The clinical features are progressive symmetric distal muscle weakness and atrophy, mild to moderate distal hyperalgesia, diminished or absent tendon reflexes, and high arched feet with onset in childhood or adolescence.
The prevalence of CMT is approximately 40/100,000 and the mode of inheritance can be autosomal dominant (AD-CMT), autosomal recessive (AR-CMT) and X-linked (CMTX). According to the clinical and electrophysiological features, CMT is divided into two types: CMT type 1 (demyelinating type), with slowed NCV (median nerve motor conduction velocity <38m>38m/s) and nerve biopsy showing axonal degeneration and rarely demyelinating changes.
[Admission assessment].
(A) Key points of medical history inquiry
1. The time of myasthenia and myasthenia gravis, the extent, sequence and rate of progression of involvement, the impact on life, work and sports.
2. The location and degree of sensory impairment.
3.The presence of high arched feet, scoliosis and other skeletal deformities.
4.Whether there are other symptoms such as diplopia, vision loss, nystagmus, deafness, hoarseness, unstable walking, etc.
5.Whether there are similar patients or high arched feet in the family members.
(B) Key points of physical examination
1. Muscle weakness and atrophy Weakness and atrophy of the foot, calf muscles and lower 1/3 of the thigh muscles, forming “crane legs” or inverted bottle-like deformity. At the later stage, the interosseous muscles and the small and large interphalangeal muscles are weak and atrophied, resulting in claw-shaped hand or ape hand deformity, and the atrophy usually does not exceed the elbow joint.
2, tendon reflex changes The tendon reflexes of the affected limbs are weakened or disappeared, the Achilles reflex usually disappears, and the tendon reflexes of all four limbs disappear in half of the patients.
4.Sensory impairment There may be hyperalgesia, warmth and vibration sensation in the glove-sock type distribution area.
5.With or without autonomic dysfunction and signs of dystrophy, in some cases, thick nerve trunks can be touched under the skin.
6.Whether there are high arched feet, scoliosis and other skeletal deformities.
7.Other Some patients may show signs such as decreased visual acuity, extraocular muscle paralysis, nystagmus, ataxia, and limb tremor.
(C) Analysis of outpatient data
1. Routine blood, biochemical and immunological examinations are generally free of abnormal findings. Serum myoenzymology is mostly normal, and a few may be mildly increased.
Neurophysiological examination is particularly important for the diagnosis of CMT, not only for the typological diagnosis of CMT type 1 and CMT type 2, but also for the differential diagnosis of CMT and other diseases such as distal spinal muscular dystrophy and myotonic dystrophy. CMT2 NCV is near normal. In most patients, sensory nerve action potentials are absent. The EMG shows neurogenic damage, with increased motor unit potential amplitude, prolonged motor terminal latencies, and fibrillation or fasciculation potentials.
(D) Continuing examination items
1.Cerebrospinal fluid examination Mostly normal, a few cases may show mildly increased protein content
2. Evoked potentials Patients with CMTX due to connexin32 mutation often have abnormal brainstem auditory evoked potentials and slowed central and peripheral nerve conduction velocities in somatosensory evoked potentials, suggesting involvement of both central and peripheral nerve conduction pathways. In a few cases, abnormal visual evoked potentials can be seen.
3, neuromuscular biopsy muscle biopsy for neurogenic muscle atrophy features, visible bundles of atrophied type II muscle fibers, type I muscle fibers interspersed with angular fibers, usually without inflammatory reaction. The nerve biopsy of CMT type 1 shows segmental demyelination and Schwann cell hyperplasia with “onion head”-like changes, while CMT type 2 shows axonal degeneration and reduction of myelinated fibers without demyelination and fiber hyperplasia.
The genotype of CMT can be further determined by genetic analysis. 70% of CMT1 patients and 90% of disseminated cases are CMT1A, for autosomal dominant CMT1 patients and disseminated cases, we can first test for repeat mutations in large segments of the 17p11.2 region, and then perform point mutation testing for PMP22, MPZ, CX32, HSPB8, HSPB1 and other genes if they are negative. The mutation test was done first for the large repeat mutation in the 17p11.2 region.
Analysis of the disease
(I) Diagnosis
The clinical diagnosis of CMT can be made based on the insidious onset in childhood or adolescence, slowly progressive symmetrical muscle weakness and atrophy of both lower limbs, “crane legs” or inverted bottle-like deformities, high arched feet, drooping feet, claw-shaped hands, scoliosis and other deformities, decreased or absent tendon reflexes of the affected limbs, sensory disorders and skin dystrophy, and positive family history. The clinical typing of CMT is mainly based on neurophysiological testing and neuromuscular biopsy when necessary.
(B) Clinical types
1. CMT1 (demyelinating) type
(1) Most of the disease develops before the age of 20, with insidious onset and gradual progression; symmetrical progressive degeneration of peripheral nerves leads to muscle weakness and muscle atrophy in the distal limbs, starting from the foot and lower limbs, and in severe cases, horseshoe foot deformity, spreading to the hand and forearm muscles in a few months to a few years, but not more than the middle and lower 1/3 of the forearm, with or without sensory loss; often accompanied by scoliosis, drooping feet, and a cross-threshold gait; some patients have Some patients have genetic mutations, but do not have muscle weakness and atrophy, only bowed feet or slowed nerve conduction, or even no clinical symptoms;
(2) examination can be seen in the lower 1/3 of the calf and thigh muscle atrophy, resembling “crane legs” or inverted champagne bottle, hand muscle atrophy into claw-shaped hands, can spread to forearm muscles, knee tendon reflexes are reduced or disappeared, Achilles tendon reflexes usually disappeared, half of the patients tendon reflexes of all four limbs are disappeared; deep and superficial sensory hypoesthesia is glove, sock-like distribution, with autonomic nerve In some cases, thick nerve trunks, such as the common peroneal nerve, can be palpated under the skin, but the cerebral nerves are usually not involved;
(3) Motor and sensory NCV is slowed down, and the motor conduction velocity of median nerve is below 38m/s (normal 50m/s); cerebrospinal fluid protein is normal or mildly increased; muscle biopsy shows neurogenic muscle atrophy, and nerve biopsy shows peripheral nerve demyelination and proliferation of Schwann cells to form “onion ball”-like structures.
2, CMT2 (axonal) type, late onset, adult onset of myasthenia gravis, symptoms and site similar to CMT1, less severe; some familial CMT2 can be combined with vocal cord paralysis, deafness and intellectual disability; motor and sensory NCV normal or near normal, median nerve motor conduction velocity greater than 38m/s, cerebrospinal fluid protein normal or mildly increased, nerve biopsy is mainly axonal degeneration .
(C) Etiological analysis
CMT is a monogenic genetic disease, and with the progress of molecular genetics, at least 36 types have been localized, among which 24 types of causative genes have been cloned.CMT type 1 is the most common type, accounting for about 70% of the total CMT, and the causative genes of CMT1A, CMT1B and CMTX1 are PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero) and CX32 (gap junction protein 32) gene, and approximately 50% of CMT patients are caused by mutations in one of these three genes. The vast majority of CMT1A are caused by repetitive mutations in a 1.5 Mb large segment of DNA containing the PMP22 gene in the 17p11.2 region, with a small proportion caused by point mutations in the PMP22 gene; the mechanism by which repetitive mutations in the PMP22 gene cause disease is related to the dosage effect of the gene, and point mutations may be caused by a gain-of-function mechanism or a dominant-negative mechanism. The point mutation may be caused by a gain-of-function mechanism or a dominant-negative effect.
The MPZ gene encodes the transmembrane adhesion protein MPZ, which accounts for 50% to 60% of the total peripheral nerve myelin protein, and mutations in the MPZ gene may reduce the overall amount of normal protein through a loss of function mechanism, resulting in the CMT1B phenotype. The CX32 gene mutation does not form a functional channel, or results in smaller channel pores and reduced channel opening probability, affecting the propagation of second messengers such as cAMP and thus leading to altered expression of genes required to maintain myelin.
Other less common genotypes are the EGR2 (early growth response protein 2) gene causing CMT1D, the NEFL (neurofilament light chain) gene causing CMT2E, the HSP27 (small molecule heat shock protein 27) gene causing CMT2F, the HSP22 (small molecule heat shock protein 22) gene causing CMT2L, the GDAP1 (ganglioside-induced differentiation-associated protein 1) gene causes CMT4A, etc. Among them, the CMT2L type was localized and cloned by Professor Beisha Tang in the Department of Neurology, Xiangya Hospital, Central South University. With the application of molecular genetic techniques, PMP22 large segment repeat mutations and point mutations, MPZ, CX32 gene mutations can now be analyzed, and 50% of CMT patients can make genetic diagnosis.
(D) Differential diagnosis
1, distal-type myotonic dystrophy: progressive upward development of muscle weakness and myasthenia gravis in the distal extremities, which can be differentiated by adult onset, myogenic damage electromyography, and normal motor NCV.
2, distal spinal muscular atrophy: the distribution and course of myasthenia are quite similar to CMT2, but this disease has no sensory impairment, EMG can be found in the anterior horn damage.
3, hereditary ataxia with muscular atrophy (hereditary ataxia with muscular atrophy): also known as Roussy-Levy syndrome, childhood onset, slow progression, performance of peroneal muscle atrophy, bowed feet, scoliosis, extremity tendon reflexes are reduced or disappeared, motor NCV is slowed, but there is standing instability, gait staggering, hand tremor Ataxia, etc.
4, chronic inflammatory desynovial polypoidal peripheral neuropathy: relatively rapid progression, increased cerebrospinal fluid protein content, prednisone treatment is effective.
5, hereditary compression susceptibility neuropathy: recurrent limb numbness and weakness after minor trauma, with diffuse nerve conduction slowing, peripheral neuropathology characterized by stage demyelinating peripheral neuropathy with salami-like structure formation, some cases are easily misdiagnosed as CMT, genetic testing found PMP22 gene deletion can confirm the diagnosis.
Treatment plan
There is no effective treatment to restore or slow down the disease process. Vitamin B, vitamin C, energy combination, herbal medicine and physical therapy can be tried. The application of braces to correct foot drop or orthopedic surgery to stabilize the foot may be helpful. In younger patients, it may be useful to educate the patient about the progression of the disease and to initiate vocational counseling. Continued in-depth molecular biology research and gene therapy may offer hope for a cure.
Prognostic evaluation]
The course of the disease is slow and the prognosis is good. Most patients are able to maintain basic self-care without wheelchair dependence and can live a normal life span. Vocational education, orthopedic treatment and symptomatic management can improve the quality of life of patients.
[Discharge medical advice].
Pay attention to the functional position placement of the limb, avoid overexertion and trauma, and long-term supportive allopathic treatment. Genetic diagnosis, genetic counseling and prenatal diagnosis are recommended for those with preexisting evidence to avoid delivery of diseased fetuses.