Overview
A hereditary myopathy caused by a pathogenic mutation in the anti-myotrophic protein gene, often characterized by progressively increasing muscle weakness and atrophy in male children. This is a hereditary disease caused by a mutation in the anti-myotrophic protein gene and is treated with symptomatic supportive therapy, but gene therapy has already been achieved in some patients.
Definition
Duchenne muscular dystrophy (DMD) is an X-linked recessive myopathy and is the most common and typical type of muscular dystrophy.
Mutations in the antimyotrophic protein gene lead to a lack of antimyotrophic protein (AMP), a protein required to maintain cellular stability, causing destruction of cells in skeletal muscle, brain, cardiac muscle, retina, kidneys, peripheral nerves and other tissues, and leading to a wide range of manifestations such as persistently worsening limb muscle weakness and atrophy, cardiomyopathy, mental retardation and other symptoms.
There is no cure for this disease, which begins in childhood and affects the vast majority of boys, and most patients die before the age of 30 due to respiratory failure or heart failure.
Even so, aggressive treatment is extremely valuable and can help control symptoms, slow disease progression, and improve quality of life and longevity.
Morbidity
Duchenne muscular dystrophy (DMD) is a rare disease, with a prevalence of about 1 in 4560 surviving male infants in China.
It is an X-chromosome-linked recessive disease, with male patients predominantly and females as carriers of the causative gene. In the rare case of biased inactivation of the X-chromosome, females can also develop the disease and become patients, known as female symptomatic carriers of the causative mutation of the DMD gene.
Causes
Causes
Mutations in the antimyotrophic protein (DYS) gene on chromosome Xp21 cause two types of muscular dystrophies, Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), with Duchenne muscular dystrophy (DMD) being the most common and typical.
This gene mutation causes a deficiency of anti-myasthenic protein in the patient’s body. This protein has the function of maintaining cellular morphology, and when deficient, it causes cell membrane instability, leading to cell necrosis and loss of function.
There are several isoforms of antimyotrophic protein. One of the muscle isoforms is located primarily in skeletal muscle and determines symptoms of muscle weakness and atrophy.
Other isoforms are distributed in brain, cardiac muscle, retina, kidney, peripheral nerves and other tissues, causing mental retardation, behavioral abnormalities, cardiomyopathy and many other manifestations.
The disease is an X-linked recessive disorder. Since the X chromosome is inherited from the mother to her offspring and males have only one X chromosome, male fetuses develop the disease after inheriting the disease-causing mutation of the DMD gene; whereas females, who have 2 X chromosomes, mostly do not develop the disease, and are carriers of the disease-causing mutation of the DMD gene.
Symptoms
Main Symptoms
Muscle weakness
This type of patient has an early and severe onset of the disease, often manifesting abnormally in infants during the toddler stage.
It manifests as difficulty in toddling, slow walking after learning to walk, easy to fall, and difficulty in getting up on their own after a fall.
Because the lesions first start in the gluteal muscle groups, the patient walks with the pelvis swaying from side to side, the lumbar spine protruding too far forward, the stomach sticking out, and the head and chest tilted back like a duck walking (duck walk).
If the patient lies on his back and tries to get up, he must roll over, kneel on both knees, support himself with both hands, and leave the ground with his calves and thighs in turn before he can stand up (Gowers’ sign).
As the condition worsens, the muscle weakness spreads to the trunk and upper limbs, and there will be an inability to raise both arms, and the shoulder blades shrug up like wings (winged scapula).
Some patients may be unable to raise their head while lying on their back because of weakness in the neck muscles.
Pseudohypertrophy of muscles
In 90% of children, the muscles of multiple limbs may be abnormally thick and tough to the touch, but with reduced strength instead.
It is most obvious in the gastrocnemius muscle (calf belly), and can also occur in the deltoid, gluteus, quadriceps (anterior thigh) and other parts of the body.
Bone and joint abnormalities
Contracture, atrophy and deformity of the limbs may occur with the development of the disease.
Achilles tendon contracture may occur, and the heels of both feet cannot land, turn inward, and resemble a horseshoe (horseshoe foot).
The elbow, knee and hip joints are contracted and cannot be straightened normally.
Subluxation or dislocation of the hip joint.
Scoliosis.
Systemic manifestations
The child gradually becomes unable to walk, wheelchair bound, bedridden, shallow breathing and weak cough.
Most patients also develop heart damage, which is characterized by panic, shortness of breath, and weakness.
Children may have varying degrees of intellectual, behavioral, and emotional abnormalities, such as attention disorders, learning difficulties, communication difficulties, and depression.
Gastrointestinal symptoms such as swallowing disorders, acid reflux, heartburn, dyspepsia and constipation may occur.
Growth and development are slow since childhood, height is lower than that of peers, and puberty appears later.
Complications
Patients may develop complications such as aspiration, coughing weakness, respiratory weakness, scoliosis, lung infection, respiratory failure, heart failure, etc. due to systemic skeletal muscle and cardiac muscle involvement, which ultimately leads to death.
Characteristics of disease development
The above symptoms of the patient will appear at different time stages and gradually aggravate. The progression of the disease can be divided into five stages, which are pre-symptomatic stage, early solo stage, late solo stage, early inability to walk alone stage and late inability to walk alone stage. Typical time points are as follows:
Pre-symptomatic stage – infancy and early childhood; Early solitary stage – 3 to 7 years of age; Late solitary stage – 7 to 9 to 10 years of age; Early inability to walk alone stage — 9 to 10 to 14 to 15 years of age; late inability to walk alone — 14 to 15 years of age to before 30 years of age; most deaths before 30 years of age are due to respiratory or heart failure.
Consultation
Department of Medicine
Neurology
If a child has difficulty in walking, limb weakness, abnormal gait, or abnormally thick calves, it is recommended that he or she seek prompt medical attention from the Department of Neurology. Pediatrics, especially pediatric neurology, may also be consulted.
Preparation for medical treatment
Preparing for your visit: registering, preparing your documents, and frequently asked questions.
Tips for seeking medical treatment
When visiting the doctor, try to describe the medical history, symptoms, family history, growth and development in detail and accurately, and provide the doctor with information such as videos and photos of the patient.
Preparation List
Symptom list
Pay special attention to the time of onset of symptoms, special manifestations, etc.
Is there any slow walking, landing on toes, easy to fall, hobbling?
Are there symptoms of difficulty in walking up stairs and standing in a squatting position?
Are there any symptoms such as inability to raise both arms, inability to abduct over the head, difficulty in combing hair, washing face, dressing, etc.?
Are there any symptoms of scoliosis or inward turning of the feet?
Are there any symptoms such as panic, chest tightness, shortness of breath, etc.?
Is there any attention deficit, learning difficulty, communication difficulty, emotional depression?
List of medical history
At what age did the above symptoms start to appear? Did they get worse gradually?
Is there any family member who has been diagnosed with the disease, is a carrier of the disease-causing gene, or has similar symptoms?
Checklist
Test results from the last 6 months, which can be brought to the doctor’s office
Serum enzyme tests: creatine kinase, lactate dehydrogenase, and creatine kinase isoenzymes, etc.
Other laboratory tests: total protein, creatinine, calcium, phosphorus, vitamin D3 and hormone levels, etc.
Imaging tests: muscle magnetic resonance, cranial magnetic resonance, echocardiography, etc.
Other tests: electromyography, electrocardiogram, histology of muscle pathology, genetic testing, etc.
Medication List
Medication used in the last 3 months, if available in boxes or packages, bring with you to the doctor’s office
Prednisone, coenzyme Q10, vitamin E, etc.
Diagnosis
Diagnosis based on
medical history
Patient has a family history of the disease, similar symptoms, or carriers of the causative gene.
Clinical manifestations
Symptoms
Typically, male patients present with limb weakness, difficulty in walking up stairs and standing in a squatting position, abnormal gait, abnormally thick calves, scoliosis, and inversion of the feet from childhood onwards.
Physical signs
Doctors use physical examination to find out if there are any abnormalities in muscle strength, muscle volume, muscle tone, nerve reflexes and bone and joints.
Muscle strength check: Judge the muscle strength by the patient’s movements such as lifting arms and legs, walking and squatting.
Muscle Volume Examination: Visual and tactile examination of changes in muscle volume to see if there is muscle atrophy or abnormal hypertrophy.
Muscle tone: To understand which parts of the muscle tone have changed by feeling the resistance when passively flexing and extending the patient’s joints by hand.
Tendon reflexes and pathological reflexes: use the percussion hammer to strike the periosteum and tendons; use a blunt bamboo stick to gently stroke the soles and dorsum of the feet to determine the location of lesions.
Bones and joints: palpate and move the joints to find out whether there is joint contracture, especially Achilles tendon contracture, and scoliosis.
Serum enzyme test
Purpose: To determine the presence of myocyte damage, which is the preferred test for this disease.
Commonly used items: creatine kinase (CK), lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB).
Significance: Significant elevation of CK can be detected in the neonatal period, usually tens of times above the normal value, and CK levels gradually decrease after entering the early inability to walk alone period.
Cautions: Fasting is not required, but test results are related to gender, age, race, physiological status, medication and exercise.
Genetic Testing
Purpose: To discover disease-causing genes, confirm the type of disease, and determine the prognosis.
Significance: It can detect large deletions, duplications and small mutations of disease-causing genes.
Precautions: Family members of diagnosed patients (those who fulfill the x-linked recessive inheritance pattern) should be screened for mutations in high-risk groups.
Muscle Magnetic Resonance Imaging (MRI)
It is useful for early diagnosis and follow-up of the disease.
It reveals edema, fatty infiltration, and mesenchymal hyperplasia in the affected muscles in a “cannibalization” pattern. In patients with this disease, the muscle lesions begin with the gluteus maximus and progress to the thigh muscles, although some of the thigh muscles are relatively preserved.
Precautions: Prior to the MRI examination, if you have any metal, stents, pacemakers or stimulators in your body, you should inform your doctor in advance, and the doctor will decide whether or not the examination can be performed.
Pathohistology
Purpose: To detect myofibrillar lesions that cannot be diagnosed by genetic testing and to differentiate Becker muscular dystrophy (BMD) from other types of muscle disease.
Significance: The muscle fibers are often atrophic, necrotic, regenerative, hypertrophic, with a large amount of adipose tissue and fibrous connective tissue hyperplasia; under immunohistochemical staining with anti-dystrophin antibodies, the membrane of the diseased muscle fibers is partially or completely unstained (under normal conditions, the membrane of the muscle fibers is uniformly stained).
Precautions:
Muscle biopsies are painful and need to be performed under local anesthesia when removing the biopsy specimen.
Keep the area clean and dry after the biopsy to avoid wound infection.
Other Tests
Electromyography can be used to assess the severity and progression of muscle damage, and patients with this disease often have typical manifestations of myogenic damage.
Echocardiography is used to detect structural abnormalities of the heart, assess cardiac function and prognosis. Patients with this disease often have enlarged left ventricle, abnormal function and valvular insufficiency.
Cardiopulmonary function tests are used to understand respiratory function and cardiopulmonary endurance.
Intelligence Scale, Attention Deficit-Hyperactivity Disorder Assessment, Griffiths Mental Development Scale, etc. help to determine the cognitive and psychological status of patients.
Bone and joint examinations, including blood and urine calcium and phosphorus tests, bone age, bone density, and spinal X-ray, help to detect growth and developmental abnormalities, deformities, and other problems.
Gastrointestinal function assessment, including nutritional status assessment, video fluoroscopy, 24-hour pH monitoring of the esophagus, gastroscopy, enteroscopy, etc., which helps to find out the nutritional status, swallowing function, the presence of gastroesophageal reflux, and the function of the gastrointestinal tract.
Differential Diagnosis
The disease is often differentiated from Becker-type muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LGMD).
Table 1.Differentiation of several common types of muscular dystrophies
Main types DMDBMDLGMD
Patient sex male predominantly male predominantly both sexes
Patient gender
Male predominant
Male predominant
Both sexes
Age of onset before 5 years old5-15 years old during adolescence, with high variability
Age of onset
Before 5 years old
5 to 15 years old
Adolescence, high variability
Rate of progression Progression is rapid, often failing to go before 12 years of age Relatively slow Individual patient variability is high
Rate of progression
Progresses rapidly, often unable to walk by age 12 years
Relatively slow
Large individual patient variability
Primary site Pelvic girdle muscles, proximal limb Pelvic girdle muscles, proximal limb Pelvic girdle muscles, proximal limb Pelvic girdle muscles, proximal limb
Primary site
Pelvic girdle muscle, proximal limb
Pelvic girdle muscle, proximal limb
Pelvic girdle muscle, proximal limb
Muscle pseudohypertrophy is evident and may be mild or absent.
Pseudohypertrophy
Pseudohypertrophy
May be present
Mild or absent
Late myocardial damage is often present, often some types may be present.
Myocardial damage
Late stage often
Often
Some types may occur
Hypokinesia partially present rarely absent
Hypomelanosis
Partially present
Rare
None
Serum creatine kinase very high very high variously elevated
Serum creatine kinase
Very high
very high
Varying degrees of elevation
Treatment
Aim of treatment: There is no cure for this disease, and the main purpose is to improve symptoms, improve quality of life and prolong life.
Treatment principle: Multidisciplinary management is the main focus, in addition to drug treatment, nutrition, respiration, spine bone and joint, growth and development, and other aspects of rehabilitation and management are given at the same time.
Drug therapy
Gene therapy
Gene therapy can partially repair the expression of anti-myasthenia gravis proteins, but it does not achieve a cure, and most of them are currently in the research stage. However, it remains the hope for the causal treatment of the disease in the long run.
These include stop codon read-through therapy, exon skipping therapy, exogenous tiny DMD gene replacement therapy, and gene repair therapy.
Among them, the big breakthroughs are the stop codon read-through therapy PTC124/Ataluren (Ataluren) and the exon 51-specific jump therapy Eteplirsen (Eteplirsen), both of which have been approved for conditional marketing by the European Medicines Agency (EMA) in 2014 and the U.S. Food and Drug Administration (FDA) in 2016, respectively.
From the results of current studies, both are efficacious but not significant and are only indicated for patients with specific types of mutations.
Glucocorticoids
Commonly used drugs: prednisone, difcort.
Continuous use can prolong the time of independent walking, life expectancy and improve cardiorespiratory function.
The mechanism of drug action is unclear and may be related to reducing the inflammatory response and contributing to muscle cell membrane stabilization.
Precautions:
The use of such drugs for this disease is a supra-indication for the use of drugs, the doctor will fully communicate with the patient and his family and sign an informed consent form before treatment.
Adverse reactions include obesity, hirsutism, acne, delayed growth and development, behavioral abnormalities, immunosuppression, blood pressure, blood sugar abnormalities, abdominal pain, vomiting, cataracts, osteoporosis.
Supplementation with calcium, potassium, and vitamin D is required and should not be discontinued abruptly.
Other drugs
Coenzyme Q10 and vitamin E may be useful in improving muscle strength in patients.
Idebenone may improve and delay the patient’s decreased respiratory function and reduce the occurrence of pneumonia.
To improve heart function, drugs such as captopril, enalapril, irbesartan, propranolol, and digoxin may be used to improve heart rhythm and increase ejection function.
To treat osteoporosis, drugs such as alendronate, vitamin D3, and calcium carbonate are often used.
Gastroesophageal reflux is found to be treated with pantoprazole, ranitidine, and aluminum thioglycollate; constipation or fecal intestinal obstruction can be treated with medications such as cecrops and polyethylene glycol.
Surgical treatment
When there is a problem that seriously affects the patient’s ability to exercise and quality of life, surgical methods can be considered to improve symptoms.
Achilles tendon release can be performed in cases of Achilles tendon contracture to relieve the symptoms of walking on the toes and not landing on the heel.
Posterior spinal fusion may be considered for severe scoliosis that affects cardiopulmonary function.
Those with severe atrioventricular block require pacemaker therapy, and those with dilated cardiomyopathy with heart failure may undergo heart transplantation.
Rehabilitation
Rehabilitation focuses on protecting weak muscles, slowing the progression of muscle weakness, preventing and minimizing progressive joint contractures and spinal deformities, and maintaining ideal cardiopulmonary function.
Aerobic training
For children with fair muscle strength, low-intensity aerobic exercise training such as swimming and bicycling can be performed to maintain a certain amount of exercise.
It is not advisable to do up and down stairs, repeated squatting and standing up, and to avoid over-training and exertion.
Posture and stretching training
For patients who have difficulty walking, joint contractures and kyphosis can be controlled by using a standing bed.
Drafting and stretching exercises 4 to 6 times a week can help maintain joint range of motion in the ankles, knees and hips.
Use of assistive devices
Supports and orthotics can be used to prevent and slow down the development of joint contractures, scoliosis and other bone and joint problems.