Progressive muscular dystrophy

Introduction to progressive muscular dystrophy Progressive myodystrophy is a group of primary skeletal muscle diseases caused by genetic factors. The main clinical manifestations are slow muscle atrophy, muscle weakness and varying degrees of dyskinesia. The disease can be caused by a variety of genetic methods, and its clinical manifestations have different characteristics, thus forming many types. The disease can be caused by a variety of genetic methods, mostly in children and adolescents. basic knowledge Sickness ratio: 0.05% Susceptible people: no specific population Mode of transmission: mother-to-child transmission Complications: Acne Multiple lung infections

Causes of progressive muscular dystrophy

(1) Causes of the disease

The pathogenesis of this disease has been noticed by the world. For decades, there have been vascular, neurological, muscle fiber regeneration disorders and cell membrane defects, but a large amount of research evidence indicates that cell membrane defects play an important role in the occurrence of this disease. One third of newborn boys are caused by genetic mutations.

With the deepening of molecular biology research, the etiology and pathogenesis of this disease have been further clarified. It has been clarified that this disease is a kind of single-gene genetic disease, and its genetic methods are diverse. Many pathogenic genes have been located and cloned. The gene products have been elucidated, and some of the causative genes are still unknown. The related gene locus mutations can cause defects and abnormalities of the sarcolemmal structural proteins of the expressed products.

The molecular mechanisms of different types and different subtypes have also been newly recognized. Among them, Duchenne type and Becker type muscular dystrophy (DMD, BMD) are the most in-depth research. DMD is an X-linked recessive genetic disease, and the causative gene has been Located in the short arm 2 region 1 band 2 to 3 subband of X chromosome (Xp21.221.3), the cDNA of its gene has been cloned, the full length is 14kb, there are 60-65 exons, and the gene expression product is resistant. Dystrophin (Dys), when large deletions, repeats or other forms of variation, such as point mutations, cause Dys deficiency or structural dysfunction is the root cause of DMD pathogenesis. BMD gene is in the same region as DMD. Mutual is an allele, Dys is located in the inner layer of the muscle fiber membrane. It is a cytoskeletal protein that has the function of stabilizing the muscle fiber membrane. In DMD patients, due to the lack of Dys in the muscle fibers, the integrity of the sarcolemma structure is destroyed, and it is rich in The extracellular components of calcium ions flow into the muscle cells, eventually leading to muscle fiber degeneration and necrosis. The pathogenic gene of Emery-Dreifuss muscular dystrophy is located at xq28, and its encoded protein is emerin. In recent years, limb muscles have been found. The occurrence of malnutrition (LGMD) is associated with genetic defects in the dystrophin-glycoprotein complex (DGC) attached to the muscle fiber membrane. DGC plays a role in maintaining the stability of the muscle fiber membrane and preventing membrane damage and necrosis. A very important role, facial scapular muscular dystrophy (FSHD) is the most common common body infection in adults. Its gene location is 4q35, the gene has not been cloned, and the encoded protein has not been isolated, but FSHD has been proved. The deletion of the copy number of the 3.3 kb tandem repeat at the end of the long arm of chromosome 4 is also associated with other molecular mechanisms such as different subtypes of distal muscular dystrophy.

(two) pathogenesis

Membrane structural proteins involved in the pathogenesis of muscular dystrophy are a large complex composed of a variety of proteins, called dystrophin-glucoprotein complex (DGC), including dystrophin. Muscular dystrophy glycan complex (consisting of ,-dystroglycan), sarcoglycan complex (,,,-sarcoglycan) and syntrophin complex, one end of dystrophin and muscle movement The protein is linked to the other end, which is linked to -dystroglycan, and then linked to the extracellular matrix protein 2-Laminin on the basement membrane by -dystroglycan, which is structurally linked to actin and extracellular matrix in muscle cells. Bridge function, the components of DGC are closely combined, and the correlation can maintain the stability and integrity of the sarcolemma. When the corresponding gene locus is mutated, a defect in a certain component of DGC, such as dystrophin or any type of sarcoglycan The lack of it will affect the stability of the entire membrane structure, causing damage to the sarcolemma, which in turn leads to a series of reactions and leads to muscle fiber necrosis.

The pathological changes in the early stage of the disease only showed that the size of the muscle fibers was different, the inner core increased, and the muscle fibers were disordered in the advanced stage of the lesion. The size of the muscle fibers was disproportionate. The atrophic fibers in the same muscle bundle, the tear fibers and the hypertrophic fibers showed an irregular mixed distribution under the light microscope. See muscle fiber thickness, muscle fiber degeneration, necrosis, such as hyaline degeneration, granular degeneration, flocculation and phagocytosis, sarcolemma nucleus, arranged in a chain, early visible regenerated fiber, late muscle fiber disappeared, Replaced by fat and connective tissue.

The above lesions were the heaviest with DMD, and other types were lighter. In addition, the myocardium also had similar changes. Muscle histochemical staining showed that both I and II fibers were involved, and there was no homogenized muscle grouping. DMD often showed loss of IIA fibers. The IIC fiber increased significantly, and the latter suggested that the regeneration process was active. This is certainly a response to the compensatory repair of necrotic fiber, but the regenerative capacity and its speed are far less than the development of necrosis, so its condition is still progressively aggravated.

Electron microscopy showed muscle-dissolved lesions, sarcoplasmic membrane rupture, defects or complete disappearance, Z-line blurred, sarcoplasmic reticulum expansion and hyperplasia with vacuolization, increased glycogen granules, mitochondrial degeneration, interstitial connective tissue hyperplasia, frozen etching electron microscopy scan The number of muscle fiber membrane protein particles was significantly reduced, and there was a similar change in the erythrocyte membrane. Immunohistochemical staining of muscle samples from patients with DMD and BMD using dystrophin monoclonal antibody showed partial or complete loss of sarcoplasmic dystrophin.

Progressive muscular dystrophy prevention

The only effective means of preventing this disease is genetic counseling, prenatal diagnosis and selective abortion, especially for DMD/BMD. Biochemical methods such as serum CPK and Mb detection can be used to help identify pathogenic gene carriers, molecular biology. The application of technology, such as cDNA probe detection, PCR amplification, Dys imprinting and immunofluorescence, greatly improves the detection rate of DMD/BMD pathogenic gene carriers, and can be used for prenatal genetic diagnosis. The occurrence of the disease is of great significance.

Progressive muscular dystrophy complications Complications multiple lung infections of acne

In the advanced stage, the limbs are contracted and the activity is completely impossible. Often due to a pulmonary infection, hemorrhoids are equal to death before the age of 20. IQ often has different degrees of decline, more than half can be associated with heart damage, abnormal ECG. Early manifestation of cardiac hypertrophy, generally asymptomatic except palpitations.

Symptoms of progressive muscular dystrophy Common symptoms Eyelid sag expression is indifferent and easy to fall "Duck step" gait joints tough esophageal dilatation dysphagia progressive thinning upper body weight loss, next...

Tradition is divided into the following types:

1. pseudohypertrophic muscular dystrophy (pseudohypertrophic muscular dystrophy)

X-linked recessive inheritance, the gene locus is in Xp21, the defect of the gene can lead to the deficiency of its encoded protein dystrophin in skeletal muscle, which is divided into Duchenne and Becker. The former is early onset, the disease is heavy, the progress is fast, dystrophin is almost Absence; the latter is younger onset, the condition is relatively benign, and the amount of dystrophin is reduced or qualitatively altered.

(1) Duchenne muscular dystrophy (DMD): It is the most common type of muscular dystrophy, the most serious type of disease, often disabling and causing death in early years, so it is called "severe type", almost all patients are Boys and girls are extremely rare. Most of them develop after 3 years of age. It is obvious that children are awkward, running, jumping, etc. are not as good as their peers. Because of the weakness of the pelvic girdle and quadriceps, they are slow to walk, easy to fall, and climb upstairs. Difficult to slope, squat or fall after standing up; when standing, the lumbar vertebrae are excessively lordotic, and when walking, the abdomen and pelvis swing are "duck step"-like gait. When standing upright, you must first turn over and prone, and then support with both hands. Supported on both knees, and then slowly stand up, called Gower sign, as the disease develops and affects the shoulder strap and upper arm muscles, then the arms are lifted weakly, winged shoulders, the muscles of atrophy and weakness are progressively aggravated, and can affect the ribs Intermuscular, etc., pseudo-muscle hypertrophy is most common in the bilateral gastrocnemius muscle, because the muscle fibers are replaced by connective tissue and fat, become hypertrophic and hard, pseudo-hypertrophy can also be seen in the deltoid muscle, quadriceps and other parts of the muscle The tendon reflex is weakened or disappeared. With the aggravation of muscle atrophy and the decrease of joint activity, muscle contracture and joint stiffness can occur. It can not stand and walk around 12 years old. Many children have myocardial lesions and electrocardiogram Abnormalities, such as high R waves, deepening of Q waves, etc., some children with mental retardation, about 20 years old, patients died of respiratory failure, lung infection and heart failure.

(2) Beker muscular dystrophy (BMD): similar to DMD, the main difference is that the disease course is long, the development is relatively slow, and there is a normal life period, so it is called "benign type", this type is generally 5~ 20 years old, about 20 years after the onset of symptoms can not walk, limbs proximal muscle atrophy, especially lower limbs, gastrocnemius hypertrophy is often an early sign, myocardial damage and joint contracture deformity is less common, intelligence is normal, mostly Can survive to 40 to 50 years old.

2.Emery-Dreifuss muscular dystrophy

It is a rare benign X-linked recessive genetic disease, which occurs more than 2 to 10 years old. It often shows weakness of the upper extremity and scapular muscles in the early stage. After several years, it gradually affects the pelvic girdle and the distal extremity muscles. The weakness and atrophy of the anterior and tibialis muscles are most obvious, and a few may be associated with mild weakness of the facial muscles. This type often presents with neck, elbow, knee, and ankle contracture at an early stage. Almost all patients are accompanied by varying degrees of heart damage. Heart block and sudden death.

3. Facioscapulohumeral muscular dystrophy (FSHD)

For autosomal dominant genetic diseases, both men and women can suffer from the disease, and the age of onset varies widely, usually 5 to 20 years old.

The lesion mainly invades the facial muscles, the scapula and the upper arm muscles. When the facial muscles are involved, the facial expression is indifferent, the eyes are closed, the tooth strength is weak, the eyebrows cannot be frowned, the wrinkles, the air, the whistle, etc. The pseudo-hypertrophy of the muscles causes the upper and lower lips to thicken and become slightly paralyzed. At the same time, the lesions extend to the bilateral scapula and arm muscles, which are often asymmetrical, so that the patient's arms cannot be lifted, the abduction cannot be over-headed, and the comb is present. , wash your face, dressing and other difficulties, due to the weakness of the scapula muscles, the obvious wing-like shoulders, some performance free shoulders or "hanger-like shoulder blades", visible deltoid muscle, gastrocnemius pseudohypertrophy, myocardial involvement is rare, late only involved pelvis With muscle groups, the disease progresses slowly, and the general prognosis is good.

4. Limb girdle muscular dystrophy (LGMD)

In the past, because of the little understanding of this type of lesion, it was only classified according to clinical symptoms and hereditary methods. With the deepening of molecular biology research, Bushby and Beckmann (1995) proposed a new score for LGMD based on the results of genetic analysis. Type naming, they divide LGMD into two types according to heredity: LGMD1 stands for autosomal dominant inheritance, LGMD2 stands for autosomal recessive inheritance; and LGMD1 or LGMD2 adds letters to indicate the corresponding subtypes caused by different pathogenic genes. Up to now, LGMD1 is divided into LGMD1A, 1B and 1C types; LGMD2 is divided into LGMD2A, 2B, 2C, 2D, 2E, 2F, 2G and 2H, a total of 8 types, in LGMD, more than 90% is LGMD2.

The more common types are briefly described below:

(1) LGMD1A type: the gene is located at 5q22.3-q31.3, and its encoded protein is myotilin, which occurs mostly during the young and middle-aged period. The initial manifestation is weakness of the proximal extremities, gradually involving the distal part of the limb, and later there is ankle contracture. The disease progresses slowly, eventually losing walking ability, serum CPK level is elevated, and EMG is myogenic damage.

(2) LGMD2A: The gene is located at 15q15.1-p121.1, and its encoded protein is calpain-3. The clinical severity is different, most of them are mild. The age of onset is 4 to 15 years old, mainly manifested as the proximal end of both lower limbs. Inability, symmetry, after the scapular muscle group, more than 30 years old to lose walking ability, some patients may have gastrocnemius pseudo-hypertrophy, but to a lesser extent, later may have calf muscle contracture, spinal rigidity, serum CPK levels are obvious Raise.

(3) LGMD2C (heavy childhood autosomal recessive muscular dystrophy, SCARMD): The gene is located at 13q12, the encoded protein is r-sarcoglycan, the condition is serious, some cases have a similar DMD course, and others are mostly between DMD and BMD. Between the age of onset, 3 to 12 years old, first invade the pelvic girdle muscle, and later spread to the chest, neck muscles, but also with myocardial involvement, generally does not affect intelligence, and more gastrocnemius pseudohypertrophy, often lost in 10 to 13 years old Walking ability, respiratory failure occurred in 30 to 40 years old, and serum CPK level was significantly increased.

5. Oculopharyngeal muscular dystrophy

It is an autosomal dominant myopathy. It usually starts in about 40 years old. First, there is symmetry of extraocular muscle weakness and/or drooping of the eyelids. After that, it gradually shows swallowing, difficulty in articulation, and progress is very slow. A small number of patients swallow. As a first symptom, some patients have mild weakness and atrophy of the facial muscles, masseter muscles, diaphragm muscles and limb muscles.

6. Distal muscular dystrophy

At present, this type of muscular dystrophy has been divided into at least four subtypes, namely autosomal dominant type I, type II and autosomal recessive type I, type II, the former mostly appearing in Europe, and the cases reported in Japan. Mostly autosomal recessive type I and type II, the common feature of this type of myopathy is that muscle weakness is mainly manifested in the distal end of the extremities, with the most obvious weakness and atrophy of the extensor muscle; no sensory disturbance and autonomic nerve damage Performance; EMG is myogenic damage, and some types of pathology are similar to hereditary inclusion body myopathy.

7. myotonic dystrophy (myotonic dystrophy)

The disease is autosomal recessive, the disease-causing gene is located at 19q13.3, and the encoded protein is myotonic dystrophy protein kinase (MDRK) or DM-kinase (DMK), DMK of normal healthy people. There are 5 to 37 CAG nucleotide repeats, and in patients with myotonic dystrophy, the CAG repeat of this gene can reach 50-300. Such diseases caused by trinucleotide repeats are collectively called trinucleotide repeat disease. (triplet repeat diseases), the pathological features of this disease are different from other types of muscular dystrophy, muscle fiber necrosis and regeneration are rare, and the main change is the formation of a large number of sarcoplasmic mass around the muscle fibers, the core muscle fibers are significantly increased, and the longitudinal section shows nuclear chain formation. In addition, there may be selective type I fiber atrophy, so there is now a view that tonic muscular dystrophy is not classified as muscular dystrophy in classification, but belongs to the category of myotonic myopathy.

This disease is also known as dystrophia myotonica. It is divided into three types: adult type, congenital type and mild type. The age of onset is related to the severity of the disease. The earlier the onset, the more severe the clinical symptoms, the heads and the heads. The muscles of the muscles, the neck muscles and the distal extremities are heavier, showing a drooping sag, a massaging of the masseter and buccal muscles to form a unique "axe face"; the sternocleidomastoid muscle atrophy causes the neck to bend, excessively forward, Forming a "swan neck", early can have tibialis anterior muscle weakness, atrophy and foot drop, throat muscle involvement can lead to nasal sounds, monotonous voice, low voice blunt, upper skeletal muscle involvement of the esophagus can cause esophageal dilation, as the disease progresses, proximal Muscles and skeletal muscles are also affected, sputum reflexes are low or disappear, muscle rigidity is characterized by spontaneous slamming or electrical stimulation, muscle spontaneous spontaneous contraction, large intermuscular muscles, tongue muscles and orbicularis muscles are easily induced. Tonic symptoms can occur before muscle weakness for many years, and some patients may be misdiagnosed as congenital myotonia in the early stage, congenital and infancy-induced tonic muscular dystrophy, early period of time Within muscle rigidity can be no symptoms, some only appear after 20 to 30 years old even in this disease mostly in the 15 to 20-year-old lost the ability to walk, most patients do not survive to normal life.

Tonic muscular dystrophy is a multi-systemic dystrophic disease, in addition to muscle atrophy, muscle weakness and muscle rigidity, as well as endocrine system damage such as impotence, hair loss, testicular atrophy, breast enlargement and ovarian function decline; cardiac damage such as arrhythmia, atrioventricular Conduction block; neuropsychiatric damage such as mental retardation, forgetting, suspicious; eye damage such as crystal opacity and cataract (see 90% of patients), some patients may also be associated with motor-sensing peripheral neuropathy.

Progressive muscular dystrophy

Blood biochemical examination

The increase of serum creatine phosphokinase (CPK) is an important and sensitive indicator, with the most obvious increase of pseudo-fertilizer, the second is the limb-belt type, and the facial scapular type is slightly elevated or normal, in the early stage of pseudo-hypertrophic large CPK increased most significantly, and late activity decreased. In addition, serum myoglobin (Mb), pyruvate kinase (PK) and lactate dehydrogenase (LDH) were also sensitive indicators, alanine aminotransferase (ALT) and Tianmen. Aspartate aminotransferase (AST) is also frequently elevated, and the combined determination of various enzyme indicators is more conducive to cross-referencing.

2. Determination of urinary creatine

The 24-hour urine creatine output increased.

3. Electromyography

When it is slack, the self-generating position can occur. When the light contraction, the average time limit of the motor unit potential is shortened, the average amplitude is reduced, and the short-wave multi-phase potential appears. When the strong contraction occurs, the pathological interference phase is present, and the peak voltage is generally less than 1000 V.

4. Skeletal muscle CT or MRI examination

CT or MRI imaging of multiple skeletal muscles can be used to understand the extent and severity of skeletal muscle damage, helping early diagnosis and providing a preferred site for muscle biopsy.

5. Muscle biopsy

(1) Morphology: The pathological changes of skeletal muscle are shown under light and electron microscopy as described above.

(2) Determination of skeletal muscle gene product-protein: The specific protein of the corresponding protein, immunohistochemistry and immunoblotting were used to detect the distribution of the corresponding proteins in skeletal muscle and the changes in their quality and quantity, such as Duchenne muscle. The dystrophic skeletal muscle membrane dystrophin is almost absent.

6. Heart function check

90% of patients with DMD are associated with heart damage. In general, electrocardiogram can cause sinus tachycardia, abnormal R wave, shallow S wave of V1 lead, deep Q wave, shortening of PR interval and abnormal branch bundle block. Emery-Dreifuss muscular dystrophy often has abnormal manifestations of cardiac damage, arrhythmia and cardiac conduction disorders in cardiac function tests, but is less common in other types of cardiac involvement.

7. Genetic testing

Take peripheral blood from patients and use molecular biology techniques to directly or indirectly analyze the causative genes, and to diagnose them at the DNA level, such as detecting exon deletions or other types of genetic defects in Duchenne muscular dystrophy. .

(1) DMD/BMD gene detection: Among the DMD gene defects, 65% are deletion mutations, 5% are repeated mutations, and the rest are point mutations and other mutant forms. Currently, different methods can be adopted for different mutation forms. Make a diagnosis:

1 For gene deletions and repeats, multiple pairs of primers can be used in combination for multiplex PCR amplification.

2 For the non-deletion type, PCR-STR linkage analysis is often used.

3 For point mutations, PCR-SSCP and DNA sequencing techniques can be used.

(2) FSHD gene detection: In recent years, it has been found that more than 95% of FSHD cases and 3.3 kb repeat units of 4q35 region are deleted, resulting in a shortening of an EcoRI fragment in this region. This fragment can be Southern hybridized by P13E-11 probe. The method is to detect that the normal segment of the fragment is 35-300 kb, and the patient is less than 35 kb due to the above-mentioned deletion. Therefore, direct detection of the size of the fragment can be used for genetic diagnosis of the disease.

Diagnosis and identification of progressive muscular dystrophy

According to clinical symptoms and signs, reference family genetic history, plus serum enzymes, EMG and muscle biopsy positive findings, often can be diagnosed.

Diagnostic points

1. There is often a family history.

2. The diseased muscle first affects the proximal muscles of the extremities. Symmetrical hypertrophy on both sides, weakness of the lower limbs, gait swing, positive Gower's sign; difficulty in lifting the upper limbs.

3. Skin perception is normal, sputum reflex and shallow reflexes are hyperthyroidism, no muscle fibrillation.

4. Significant increase in blood CPK is the most sensitive indicator, which is helpful for early diagnosis; ALT, AST, LDH may be elevated.

5. Electromyography conforms to muscle thickness damage; muscle biopsy shows fibrosis; dystrophin content determination and PCR technology are helpful for diagnosis.

Differential diagnosis

Mainly need to identify with spinal muscular atrophy, chronic polymyositis and mitochondrial myopathy, in addition to clinical history and performance, serum enzyme assay, electromyography and muscle biopsy results in the diagnosis and diagnosis of valuable value.

1. Juvenile spinal muscular atrophy (Kugelberg-Welander disease)

Generally from the onset of childhood to puberty, manifested as progressive limb proximal muscle weakness and atrophy, so it is easy to be confused with DMD / BMD, but the disease can be affected by men and women, mostly accompanied by fasciculation, according to serum enzyme determination, The characteristics of electromyography and muscle pathology are generally not difficult to identify.

2. Polymyositis

Must be different from limb-type muscular dystrophy, polymyositis generally progresses faster, muscle weakness is more obvious than muscle atrophy, often have muscle pain, no family history, and corticosteroid treatment often works better, through muscle Biopsy can be clearly identified.

3. Myasthenia gravis

Generally, it is characterized by weakness and fatigue of muscle strength, application of anti-cholinesterase drug effect, and diminishing phenomenon of low-frequency repeated stimulation of electromyogram, and is distinguished from eye-pharyngeal muscular dystrophy.

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