Progressive Muscular Dystrophy

OUTLINE

Define

Muscular dystrophy must have the following five characteristics:

• Is a myopathy defined by clinical symptoms, histology, and electromyography (EMG). There are no sensory disturbances and no nerve loss unless there is another comorbidity.
• All symptoms are the result of weakness of the muscles of the head and extremities (heart and internal organs are also damaged).
• The above symptoms are getting worse and worse
• Histological changes showing muscle degeneration and regeneration, but no symptoms of metabolic disease
• It is considered an inherited disease even though the genealogy may not find a person with the disease.

This definition requires a number of conditions such as: some familial myopathies present with symptoms of limb weakness, but are not referred to as dystrophy such as myoglobin Familial recurrent uropathy (metabolic myopathy), or familial cyclic palsy, with episodes of muscle weakness is also not termed progressive myopathy. Congenital hypertonia syndromes are termed hypertonic muscular dystrophy only when limb weakness is present.

Classify

The modern classification of muscular dystrophy, dating back three decades, is a combination of clinical, molecular genetics, and biochemistry. This classification was proposed by John Walton et al based on clinical and genetic features:

• Duchenne muscular dystrophy
• Muscular dystrophy of face - shoulder - arm
• Muscular dystrophy increases muscle tone.

Each of these types differs in age of onset, distribution of muscle weakness, rate of progression, presence or absence of calf muscle hypertrophy or increased or decreased plasma enzyme levels, and genetic pattern.

Table 33.1. The main characteristics of the three bodies

Electromyography and muscle biopsies have become a routine test. Nowadays, one can analyze the DNA in white blood cells. Electrophoresis and the organization of muscular dystrophy in limb-shoulder or limb-hip syndrome can be studied. Electrocardiogram and serum creatinine (CK) tests in all patients with resting myopathy.

CLINICAL

X linked dystrophies

1. Definition

Duchenne muscular dystrophy and limb-band (Becker) types are defined by the above-mentioned features. However, these muscular dystrophies can also be defined in molecular terms. The two diseases above are the result of mutations in the gene for dystrophin (the gene product derived from the DNA sequence called dystrophin) at the Xp21 site. Although diseases associated with the Dp21 site may differ from Duchenne and limbic diseases; It is not possible to diagnose these two diseases without finding abnormalities in genes and gene products. So these diseases are dystrophin diseases. Non-dystrophin diseases involving the same site may be referred to as Xp21 myopathies.

2. Epidemiology

The incidence of Duchene muscular dystrophy is approximately one in 3,500 male children, with no geographic or racial variation in the disease. About one-third of cases are caused by new mutations. The rest are clearly hereditary. Due to the low life expectancy of patients with Duchenne muscular dystrophy, the prevalence is about 1/18,000 men. Becker muscular dystrophy is less common, about 1 in 20,000.

3. Duchenne muscular dystrophy

Duchenne muscular dystrophy is an X-linked recessive genetic disease. Women who carry the disease are referred to as asymptomatic carriers, but some have clinical manifestations such as limb weakness, calf hypertrophy, and muscular dystrophy. elevated CK levels in the blood.

The disease can be detected at birth by measuring serum CK enzymes.

Clinical symptoms in pediatric patients usually appear at 3 to 5 years of age. Children are often slow to walk and cannot run normally, they have a lot of movement but it is difficult to move forward, because they do not raise their knees properly; Waddling gait and tiptoe appear early.

Gradually the patient walked, climbed stairs and stood up while sitting in a chair, all of which were difficult, the spine was too flexed to maintain balance.

Children often fall easily when pushed, jostled, then difficult to get up. In order to sit and get up, children often use the characteristic maneuver (Gowers sign): the child rolls over to kneel, reaches the forearm on the ground to lift the buttocks and straightens the leg, then moves the hand back to the knee and push up (climbing on the torso). This symptom can be seen in other diseases such as trunk and limb weakness (spinal muscular atrophy).

In later stages, the knee reflex may be lost but the heel reflex is still present, as evidenced by weakness of the proximal muscles.

In advanced stages, hands and feet are also affected. Mild facial muscle weakness may be present, but speech, swallowing, and eye movement are normal. Contraction of the pelvic, thigh, and tibial muscles limits flexion hip jointAchilles tendon contractures contribute to the tiptoe gait. At the age of 9-12, the child can no longer walk and has to sit in a stroller, the spine is crooked, and the elbows and knees are stiff, making the child severely disabled. Around the age of 20, the respiratory muscles are weak, so it is easy to get pneumonia and respiratory failure.

Other clinical symptoms such as cardiovascular disorders, on the electrocardiogram showed increased QRS amplitude in VI, deep Q and narrowing in the left prethoracic leads, possibly with symptoms of congestive heart failure. Occasionally, acute gastric dilatation occurs. Some children have mental retardation, children gradually go to disability and death. Pathology showed no specific lesions.

4. Becker . Muscular Dystrophy

This form of disease resembles Duchenne muscular dystrophy in the following main features: X-linked involvement, calf hypertrophy, weakness of the major proximal muscles, and elevated serum CK levels. Electromyography and muscle biopsy are the same. The other two points are that the onset is usually after 12 years of age and the progression is slower, with walking after 20 years of age.

5. Diagnosis

Clinical diagnosis of typical Duchenne muscular dystrophy is usually not difficult, mainly based on the clinical symptoms mentioned above. Atypical forms are often mistaken for spinal muscular atrophy; Spinal muscular atrophy often has local spasticity and loss of nerve control on electromyography; In rare cases, genetic analysis is needed to diagnose muscular dystrophy. Elevated CK in serum more than 20 times, no clinical disease has reached this value. Note that in infected children, routine blood tests should be performed if serum CK levels are elevated, suggesting a myopathy.

From the point of view of molecular genetics: the genes for Duchenne and Becker diseases are the same, this is the process of cloning by location. The gene product derived from DNA stranding is called dystrophin. A cytoskeleton protein located in or near the plasma membrane, these proteins may play an essential role in maintaining muscle fiber integrity. In the absence of dystrophin as in Duchenne muscular dystrophy or abnormal dystrophin in Becker muscular dystrophy, the striated fibromuscular membrane becomes unstable during contraction and extension, resulting in excessive intracellular calcium influx causing caseation muscle cells. These findings have been used in the diagnosis of Duchenne and Becker muscular dystrophy and in providing genetic counseling. DNA analysis revealed deletions or duplications in Xp21 in 60–70% cases with Duchenne or Becker. Point mutations explain the rest but are difficult to identify. Deletions at the Xp21 site together with characteristic clinical symptoms have high diagnostic value. Gene carriers are similarly identified, and this test can be used for early fetal diagnosis.

Immunohistochemistry and electrophoresis studies with immunohistochemical protein determination did not show dystrophin in Duchenne muscular dystrophy, but in Becker muscular dystrophy, cytochemistry showed a intermittent pattern of staining on surface film; Immunoelectrophoresis showed a large reduction in dystrophin and an abnormal protein was found. In gene carriers, biopsies show a mosaic pattern of some fibers containing dystrophin, while others do not. A relationship of deletion in Xp21 and clinical symptoms in Becker muscular dystrophy has been found, the gene contains 79 exons.

Xp21 non-dystrophin myopathy

Typically Meleod syndrome, which was first discovered at blood banks because the donor lacks a red blood cell antigen (Kell antigen), abnormally shaped red blood cells (spiky red blood cells) and Serum CK concentrations above 29 times normal, sometimes with weakness, are associated with Xp21. Therefore, this disease is also considered a dystrophin disease.

Emery-Dreifrus muscular dystrophy

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Differentiate Emery-Dreifurs muscular dystrophy from other diseases such as spondylolisthesis, but without cardiac manifestations and without X-linked inheritance.

Muscular dystrophy of face - shoulder - arm

1. Definition 

The disease is inherited in a dominant fashion, with muscle weakness characteristically distributed in the muscles of the face, shoulders, arms; The progression is slow, the onset usually occurs in adolescence, rarely in children, and serum CK levels are normal. That is the fundamental difference with Duchenne muscular dystrophy.

2. Molecular Genetics

Inherited autosomal dominant disease at position 4q35 - qter, gene product has not been identified.

3. Clinical symptoms

In typical facial-shoulder-brachial dystrophy there are the following clinical features:

• Weakness in facial muscles is not only manifested by limited lip movement, but also found that the lips are slightly delayed and turned outward, and the slits of the eyes are wide open. Patients complain that they are unable to whistle or blow a balloon.
• The protruding shoulder blades look like chicken wings, clinical trials often have patients push the hand against the wall at shoulder level or try to spread the arm, this symptom is more obvious. The patient is unable to raise the arm to shoulder level, although the deltoid is not weak. This limitation of movement is due to improper fixation of the shoulder blades.
• The shoulder belt has a characteristic shape, viewed from the front of the clavicle appears low, the top of the scapula protrudes above the supraclavicular fossa.
• Weakness in the proximal muscles of the legs and arms rather than the peroneal and anterior tibial muscles. Within a family, the disease may be mild or disabling in different members, progress slowly, and reduce life expectancy. Severe patients may require a wheelchair.
• Other symptoms such as deafness, mental retardation, bilateral facial paralysis, and retinal vascular disease such as dilated spots and exudates may be present.

4. Subclinical

Electromyography and muscle biopsies are characteristic of a myopathy, with mild tissue changes, and mild or normal serum CK elevations. Electromyography was normal or slightly altered. Diagnosed when a family member has symptoms of muscular dystrophy.

5. Diagnosis

• Based on the above clinical
• Muscle biopsies and electromyography were variable. It is necessary to make a differential diagnosis with the following diseases:
• Spinal muscular atrophy: has a distribution of muscle weakness similar to facial-shoulder-brachial dystrophy, but the basic difference is based on muscle biopsies and electromyography
• Polymyositis: see inflammatory cells in muscle biopsy specimens
• Shoulder-mandibular atrophy: no facial atrophy.

6. Treatment

Currently only symptomatic treatment, long-term use of corticosteroids has many side effects; vitamins E, A, D and ATP, etc.

Some authors suggest tying the shoulder blades to the chest wall, which would improve the arm performance, but there is little experience with this surgery.

Hypertonic muscular dystrophy

1. Definition

Hypertonic muscular dystrophy is a multisystem, autosomal dominant disease, including: muscular dystrophy with a unique distribution, hypertonia, cardiac lesions, cataracts and disorders endocrine disorders.

2. Epidemiology

Hypertonic muscular dystrophy has a long survival time and the phenotype of the disease gene is 100%, therefore, hypertrophic muscular dystrophy has a high prevalence, estimated at 5/100,000 population, regardless of population. Race and geography are the most common types of muscular dystrophy. The incidence is about 13.5/100,000 live births.

3. Clinical symptoms

As with other autosomal dominant diseases, clinical variables vary widely in terms of age of onset and degree of clinical symptoms. other symptoms of the disease appear.

This muscular dystrophy has a different distribution of muscle weakness than other muscular dystrophies, the muscles of the head and face are atrophied and weak, eyelid drooping, sometimes limited eye movement. Difficulty speaking and swallowing may also occur. The temporal muscles atrophy, so the patient has a very characteristic face: long, thin face and drooping eyelids; In men, frontal baldness gives the face a distinctive shape.

The sternocleidomastoid muscles are small and weak. In the extremities, the distal muscles such as hands and feet are equally damaged, notably weak toe flexors and weak leg muscles, resulting in a "falling foot" or step-by-step gait. loss of tendon reflexes. Respiratory muscles may also be weakened, sometimes preceded by limb weakness. Symptoms may include: lethargy, increased sensitivity to anesthetics. Progression is slow and life expectancy is less affected, but a small number of people may become disabled.

Hypertonia is clinically manifest in the phase of compromised muscle relaxation. Electromyography shows weakness and wax formation, repetitive and repetitive action when muscle relaxation begins, thus prolonging and hindering activity, in this group of diseases, hypertonia is most common in the hand, because Thus, it may impair the patient's delicate movements or upset the patient when he or she tries to shake hands or turn a doorknob, because these movements are difficult to perform. Slow muscle relaxation, which can be detected by gently tapping the fascia muscle or the abdomen of the extensors of the fingers, or having the patient make a tight fist also provokes this symptom, then the finger, hand is extended. out very slowly.

Cataract is the most common symptom, but it takes many years to detect, early clinical manifestations are found: opaque spots under the iris or lens. Using a slit lamp to detect cataracts is the most sensitive; Sometimes cataracts are the only symptom of the disease.

Bệnh nội tiết hay gặp ở nam giới. Hói trán là triệu chứng luôn luôn có và có thể gặp teo tinh hoàn. Tuy nhiên, tính sinh sản chỉ bị hạn chế rất ít, do đó, bệnh tiếp tục được truyền trong gia đình theo dòng họ. Ở phụ nữ, các bất thường về kinh nguyệt và suy buồng trứng ít gặp, tính sinh sản giảm ít. Đái tháo đường gặp tỉ lệ cao hơn so với cộng đồng.

Cardiovascular disorders: manifested mainly on the electrocardiogram, there are conduction abnormalities such as first-degree atrioventricular block or bundle branch block, sometimes arrhythmias are detected but rarely clinically and Pacemaker is rarely required. Recent studies show that the rates of congestive heart failure, syncope, and sudden death in this group of patients are not higher than in the general population of the same age group.

Stomach and bowel disorders are uncommon, but long and semi-obstructed colon can be life-threatening. Patients are often constipated.

Symptoms of brain damage are rare, but some symptoms are observed clinically such as mild personality disorder, unusual temperament, etc.

4. Subclinical

Electromyography shows evidence of myopathy and waxy formation, characteristic muscle fatigue after pulse discharge of hypertonia. Muscle biopsies showed mild but nonspecific changes. CK levels may be normal or slightly elevated, but not to elevated levels such as Duchenne muscular dystrophy or polymyositis. Electrocardiographic disturbances and ophthalmic examination are described above. Computed tomography of the brain showed no specific changes.

5. Molecular genetics and pathophysiology

The disease gene is located at position 19q13.2, but the gene product has not been characterized. The gene product that may be involved in the pathogenesis is proteinkinase, which is reduced in muscle in proportion to the severity of the disease. This gene was one of the first to exhibit amplification or expansion that allows direct DNA diagnosis.

6. Diagnosis

Hypertonic muscular dystrophy has such characteristic clinical symptoms that it can be diagnosed at first glance. The diagnosis is usually confirmed by the presence of small sternocleidomastoid muscles, distal muscle atrophy, and hypertonia on percussion or fisting. Attention should be paid if the male patient is not bald or has atypical facial features as described. The symptom of “falling leg” may be the first symptom of hypertrophic muscular dystrophy (needs differential diagnosis from Charcot-Marie-Tooth neuromuscular atrophy). Electromyography may present with myopathy as hypertonia. Dominance in other family members also helps in the diagnosis of muscular dystrophy.

Congenital hypertonic muscular dystrophy may be mistaken for other causes of intellectual disability (mental retardation).

Another disease is called type 2 dystrophy, which resembles hypertonic muscular dystrophy in terms of heredity, hypertonia, and cataracts, but with the differences of weakness. proximal muscle and calf hypertrophy. Type 2 muscular dystrophy does not have spread to other muscles, it is the result of another mutation (dystrophic dystrophy allele) or the activity of a gene located on a different chromosome (locus heterogeneity).

Increased muscle tone is also seen in some other diseases such as periodic paralysis due to hypokalemia, congenital dystonia, congenital hypertonia. Hypertonic-like changes on electromyography may be seen in acid maltase deficiency, but there is no clinical manifestation of hypertonia.

7. Genetic counseling and treatment

Hypertonicity may be improved with quinine and phenytoin or other anticonvulsants. Hypertonia is just one annoying symptom, while muscle weakness is a potentially disabling symptom that has no cure. Methods Rehabilitation Helps keep muscles functioning at their best and assists patients in daily activities. Eye and cardiovascular symptoms should be treated according to specialist, need to record electrocardiogram and periodically examine the patient's eyes. Health counseling for families with a disease of nature, genetics and diagnosis through fetal DNA is necessary.

Muscular dystrophy - belt

1. History and definition

Muscular dystrophy of the extremities was given as a diagnosis of exclusion, including syndromes that did not meet the criteria for Duchenne muscular dystrophy: face-shoulder-brachial or hypertonia. It has been described as having both autosomal recessive and dominant inheritance, the clinical features of which include weakness of the extremities, distal and proximal muscle weakness, these disorders are considered heterogeneous. Metabolic myopathies have been isolated, particularly enzyme deficiencies, and other limb-band syndromes have been identified such as Becker muscular dystrophy, mitochondrial disease, polymyositis, inclusion body myositis, or other myopathy.

Muscular dystrophy of the extremities can be defined as follows: as a diagnosis of exclusion that includes proximal and often slow-progressing syndromes of proximal myopathy, syndromes that have been genetically mapped by multiplication. line by position.

2. Clinical symptoms

Uncomplicated limb-muscle dystrophy, proximal weakness occurs in adolescents or adults, dominant or recessive inheritance, severity in different families. Legs often atrophy first, so the patient climbs stairs and sits in a chair with difficulty getting up, and then develops a waddling gait. In the late stages, the patient has difficulty raising the hand and may see the shoulder blades raised like chicken wings, the quadriceps tendon reflex is often lost before the heel reflex, the facial muscles are rarely atrophied, the disease progresses slowly.

Electromyography and muscle biopsies show a pattern of myopathy. Serum CK concentrations were slightly increased. Another limb-band syndrome is a recessive hereditary muscular dystrophy in children, the severity of which may resemble Duchenne muscular dystrophy, but without pseudohypertrophy and elevated enzyme levels, and moreover genetically different. The disease is located at the 13q12 gene and the gene product is a glucoprotein, which is part of the dystrophin complex in the cell membrane. This disease is rare and can be seen in inbred populations.

Another limb-strap syndrome that is detected early by cloning by location is scapular-muscular dystrophy, which presents as facial-shoulder-brachial dystrophy but is present without atrophy and has no chromosome involvement. X.

Molecular genetics: cloning by starting position has an influence on the classification and understanding of limb-band syndromes. One is recessive at position 15q and one is dominant at positions 5q22.3 – 31.3. Severe muscular dystrophy in children due to recessive inheritance at position 13q12.

Congenital muscular dystrophies

These are the only diseases known as dystrophies that do not progress clearly. This name is derived from changes in the organization of muscles.

In Fukuyama congenital muscular dystrophy, neuromuscular symptoms appear soon after birth such as dysphagia, limb motor weakness, and congenital brain abnormalities such as microcephaly and hydrocephalus, convulsions epilepsy and mental retardation. The child never learned to walk and was severely disabled and died before the age of 10.

In Walker-Warburg syndrome, there are muscle and brain manifestations such as eyeball malformations, cataracts, dysplasia Retinal. Lissen encephalopathy without gyrus is a prominent brain malformation.

These diseases have not been genetically mapped, but there is a blood relationship in many families with one of the above syndromes, which suggests recessive inheritance.

Distal muscular dystrophies are defined by clinical symptoms such as muscle atrophy in the hands and feet before proximal muscle atrophy. These are hereditary diseases with features of myopathy but with slow progression. Differentiation of hereditary neuropathies is based on electrodiagnostic features and the absence of sensory disturbances of myopathy. There is heterogeneity in clinical symptoms among distal muscular dystrophies. Some families have atrophied hands first, in others more severe heart disease.

ABSTRACT

Progressive muscular dystrophy is a primary, degenerative, and hereditary myopathy; The damage is mainly in the muscle tissue, there is no specific nervous system damage, depending on the disease, there is muscle degeneration in different locations, muscle atrophy or hypertrophy. The life expectancy of the patient depends on the different types of disease. Treatment is still difficult, mainly symptomatic treatment and rehabilitation. Today, with the advancement of science, it is possible to map the genes of the human body, surely in the not too distant future, by genetic engineering, progressive muscular dystrophy can be treated.