| Disease Name | X-linked recessive (XR) | | NMD Category | Muscular Dystrophy | | Clinical Onset | Almost always between 18 months and 4 years. Mean age at onset is 3 ± 2 years. | | Clinical Findings | DMD is the most common neuromuscular disease of childhood with prevalence rates ranging from19 to 95 per million and an overall prevalence of 63 per million individuals.
Rate of progression (without prednisone treatment):
Relentlessly progressive weakness leading to inability to walk within 7 to 13 years. Mean age of wheelchair use is 10 ± 3 years. Death is in the second or third decade from cardiac or respiratory failure. Mean age of death is 20 ± 5 years. With current long-term use of corticosteroids upright ambulation and length of life are increased by several years.
Distribution of Weakness:
Early and selective involvement, during preschool years, of the neck muscles that bend the head forward with normal strength of those that bend the neck back. Weakness is generalized and symmetrical, but predominantly proximal (near center of body) early in disease course. Pelvic girdle weakness predates shoulder girdle weakness by several years. Muscles that turn the ankle outward and back are weaker than those that turn the ankles up and inward. Those that straighten the knee are weaker than those that bend the knee downward. In the upper extremities the muscles of the chest and back are involved first and later the muscles that bend the elbow.
Other Clinical Characteristics:
Unless there is mental retardation, developmental landmarks are normal followed by clumsiness in walking and especially in running or climbing stairs . Child then usually walks with a waddle, protrudes the abdomen with lordosis, and rises on the toes resulting in a Gower sign. At ages 4 or 5 years, growth may outstrip the progress of the disease, leading to a false impression of improvement. There is focal enlargement of muscles(pseudohypertrophy) secondary to increase in fat and connective tissue in calf and shoulder muscles; selective enlargement and wasting in muscles of same region; in late-stage difficulty with speech and swallowing; increased fatigue and decreased endurance.
Secondary Conditions:
Increase in body fat and obesity followed by loss of weight and muscle in later stage; joint contractures and scoliosis after end of upright ambulation; osteoporosis and fractures, musculoskeletal pain, restrictive lung disease, decreased pulmonary function and decreased cardiopulmonary capacity; cardiopulmonary (later onset with corticosteroids) and conduction defects; mild mental retardation in about one third of the cases.
Helpful links:
Medical Dictionary.
| | Diagnostic Work-up | In addition to a positive family history compatible with X-linked recessive inheritance, the clinical findings that support the diagnosis of Duchenne muscular dystrophy in males are progressive symmetrical muscular weakness, proximal greater than distal, often with calf hypertrophy.
EMG is rarely necessary for the diagnostic workup. Serum creatine kinase (CK) is markedly elevated. Muscle biopsy reveals dystrophic myopathic features such as absence of dystrophin on immunofluorescent staining and/or 0-3% dystrophin using Western blot. Such testing is available in clinical laboratories.
Precise methods for diagnosis and carrier detection are available. GeneClinics provides a state-of-the-science review of the dystrophinopathies and a list of diagnostic labs that offer genetic testing.
Differential Diagnosis: Severe childhood autosomal recessive limb-girdle muscular dystrophy (SCARMD), some types of congenital muscular dystrophy and some of the congenital myopathies. | | Treatment Notes | Treatment is palliative. Appropriate management can prolong survival and improve quality of life. Medical rehabilitation, through weight management and physical therapy, can improve quality of life by promoting mobility, as well as preventing obesity, contractures and scoliosis. Monitoring and surgical intervention address orthopedic complications, especially scoliosis. Routine monitoring should also be practiced for evidence of cardiomyopathy as well as aggressive medical management with anti-congestive medications.
Treatment with prednisone in DMD has been shown to improve strength and function in patients who are given a single dose of 0.75 mg/kg/day. Improvement begins within ten days and plateaus after three months. Improvements have been shown in ability to lift weights, nine meter walking time, pulmonary function, four-stair climbing time and time taken to rise from floor. Side effects, such as excessive weight gain, behavioral abnormalities, chushingoid appearance and excessive hair growth should be monitored and a reduction in dose may be required to reduce side effects. A dose as low as 0.3 mg/kg/day reduces side effects and gives functional improvement, but there is less improvement than with the higher dose. Deflazacort at a dose of 0.9 mg/kg/day can also be used in countries where it is available.
Other approaches to treatment are being studied, some in animals and a few that are currently in clinical trials on patients. Animal studies of various gene transfer techniques are being conducted. Clinical trials, ongoing and just getting underway, include studies to examine compounds to affect the stop codon (produces short dystrophin) and others studying exon skipping (errors in dystrophin formation). See Clinical Trials page on this web site for further information on ongoing studies. Clinical Trials
Boys with DMD can and do reproduce, although it is rare due to severity of disease symptoms during the teen years. All daughters will be carriers of the DMD mutation. They (like the proband's mother, if she is a carrier) would have a 50% chance of passing along the mutation in each pregnancy. Sons who inherit the DMD mutation will develop the disease; daughters who inherit will be carriers. A complete cardiac evaluation is recommended for females carriers, who are at greater risk for dilated cardiomyopathy (DCM). If left ventricular dilatation or DCM is present, close follow-up is warranted.
Progression: Disease progresses slowly and ultimately will affect all voluntary muscles. With disease progression, muscle weakness and atrophy affect trunk and forearms, gradually progressing and involving most major muscles of the body. Loss of ambulation typically occurs at age 10-12 years old. Death usually results from respiratory complications (18-25 years old). Survival is rare beyond the late twenties. | | Protein ID | 41 | | Gene Location | Xp21.2 | | Abstract | The dystrophinopathies comprise a spectrum of muscle diseases that ranges from mild to severe. Approximately 30% of individuals with any type of muscular dystrophy have no familial history. The mild end of the spectrum includes the phenotypes of an increase in serum concentration of creatine kinase (CK) with no other apparent symptoms, muscle cramps with hemoglobinuria, and isolated quadriceps myopathy. The severe end of the spectrum includes progressive, x-linked recessive muscle diseases that are classified as Duchenne/Becker muscular dystrophy, when skeletal muscle is primarily affected, and as X-linked dilated cardiomyopathy, when the heart is primarily affected.
Duchenne muscular dystrophy (DMD), a degenerative disease of the skeletal (voluntary) muscles, is considered the most prevalent form of childhood muscular dystrophy. DMD is caused by changes (mutations) of a gene on the short arm (p) of chromosome X (Xp21.2). This can happen sporadically for unknown reasons (a boy is affected, but his mother is not a carrier), or a boy can inherit the mutation from his mother. The gene regulates the production of the protein dystrophin, which is found in skeletal and cardiac muscle. Dystrophin is thought to play an important role in maintaining the structure of these muscle cells.
The first symptoms of DMD, as identified by parents, include general motor delays (42%), gait problems, including persistent toe-walking and flat-footedness (30%), delay in walking (20%), learning difficulties (5%), and speech problems (3%). Another major characteristic of DMD is the apparent enlargement of the calf and sometimes other muscles, which is due to an accumulation of fat and connective tissue in the muscle. A blood sample of the area would show a very high level of creatine kinase (CK), an enzyme that leaks out of damaged muscle. Duchenne muscular dystrophy is also typically characterized by additional abnormalities, including varying degrees of intellectual impairment. Among children with DMD, the incidence of cardiomyopathy increases steadily in the teenage years, with approximately 33% of patients being affected by age 14 years, 50% by age 18, and all patients after age 18. Few survive beyond the third decade, when respiratory complications and cardiomyopathy are the main causes of death.
X-linked inheritance is a genetic trait or mutation that is carried on the X chromosome. The basis for X-linked inheritance is that females have two X chromosomes and males have only one X chromosome. Affected individuals generally are males, since their one X chromosome has the mutant gene. Mothers of the affected males are carriers, and the sisters of affected males may be either carriers or not carry the gene at all. Affected females are usually homozygous (that is, both X chromosomes, one each from the mother and father, have the mutant gene). Affected males transmit the gene to all daughters, but not to any of their sons. The daughters of an affected male will usually be a carrier (heterozygote, i.e., one copy of the mutant gene) and thus not show the trait. Sons of heterozygous females have a 50% (1 in 2) chance of receiving the gene and thus expressing the trait or condition. br>
In rare instances, females who carry a copy of the mutated gene (heterozygous carriers) may develop certain, typically milder symptoms associated with the disorder. However, there is no family history of the disease for some affected individuals.
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