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A test to confirm the diagnosis of progressive muscular dystrophy and clarify the type of the disease. Duration: 21 working days.
An inherited disease characterized by the development of proximal muscle weakness caused by degeneration of muscle fibers. Degeneration occurs as a result of impaired stability and elasticity of muscle fibers during contractions.
As the disease progresses, the muscle fiber is almost completely destroyed and replaced by connective tissue, which leads to pseudohypertrophy of the muscles — an increase in their volume with a loss or significant weakening of functionality..
PDMD is one of the most common X-linked disorders [1].
Progressive muscular dystrophy usually begins with increased fatigue and weakness in the muscles of the lower extremities.
Dystrophin is a membrane protein, and the dystrophin-associated complex is the most important element of the muscle cytoskeleton, which ensures the interaction of internal and external cell structures, participates in the regulation of calcium levels in the muscle and impulse transmission across the muscle fiber membrane.
Dystrophin is mainly found in muscle cells and some neurons. Normally, its function is to provide elasticity and stability of muscle fiber during contraction.
In the absence of dystrophin, the cell membrane is destroyed and, as a consequence, the muscle fiber is destroyed and replaced by connective tissue, which leads to a significant weakening of functionality.
Dystrophinopathies are caused by mutations in the DMD gene gene, which encodes the dystrophin protein.
79%of the total number of mutations are large deletions and duplications.
21%are small changes, including point mutations, small insertions and deletions, as well as splice site mutations [3].
Peculiarities of clinical manifestations are associated with the type of mutation in the dystrophin gene:
In PDMD
Deletions in the gene in most cases result in a frameshift and premature termination of the protein-building information, resulting in dystrophin not being formed.
In PBMD
Structural abnormalities in the gene do not disrupt the reading frame; as a result, a defective, functionally deficient protein is formed.
The dystrophin gene is localized on the short arm of the X chromosome (Xp21.2-p21.1) and is one of the longest in the human genome. Dystrophinopathies are X-linked recessive diseases by type of inheritance.
Most cases are due to heterozygous maternal carriage of the abnormal mutation in the DMD gene.
If pregnant with a boy — 50%The mutation will be passed on to the son and he will have PDMD/PBMD.
All boys who inherit the pathogenic variant from their mother will be sick.
If pregnant with a girl — 50%The daughter will inherit this mutation and will be a carrier of the defective copy of the DMD gene.
Girls who inherit the pathogenic variant may be asymptomatic carriers of the pathogenic mutation in a heterozygous state or may have clinical manifestations of classical dystrophinopathy.
Detection of carriage of the DMD gene mutation and family planning for the risk of having a sick child is the most effective way to prevent dystrophinopathies.
The father of a sick boy usually does not need molecular genetic testing because if he is healthy, he cannot be hemizygous for the pathogenic variant.
The residual risk is the probability of giving birth to a boy with dystrophinopathy even if the maternal DMD gene testing does not show carriage of the pathogenic variant in the leukocyte DNA.
The existence of a residual risk is due to the fact that in 15-20% of cases, the development of muscular dystrophy is due to a de novo mutation (gonadal mosaicism is most likely) [5].
In such a case, all the siblings of a male proband also have an increased risk of inheriting the pathogenic variant and prenatal diagnosis in subsequent pregnancies is advisable.
Progressive Duchenne muscular dystrophy:
Progressive Becker muscular dystrophy:
Methods of molecular genetic diagnosis
The approach to molecular genetic diagnosis of dystrophinopathies consists of the following steps in sequence:
Since most cases of PDMD/PBMD are caused by the loss or doubling of long stretches of DNA, it is advisable to start by searching for mutations by MLPA (chromosomal exon microarray analysis).
If no pathogenic variant is detected, the next step is to sequence the DMD gene.
Mutations of which are characteristic of neuromuscular diseases, including those with similar clinical manifestations.
Including full-exome or full-genome sequencing can be performed in cases of atypical clinical manifestations, in order to clarify the diagnosis and establish possible causal findings in other genes.
The test is usually performed based on information about previously identified pathogenic variants in the DMD gene in family members.
Biological samples suitable for molecular genetic testing:
Give blood (4 mL) in an EDTA tube (with a purple cap)
Be sure to sign each tube!
The courier will pick up the kit with your blood and take it to the lab free of charge . 30 рабочих дней необходимо лаборатории для исследования.
Получить результат на эл. почту через 30 рабочих дней
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Results ready in a short time
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A test confirming or refuting the diagnosis of PDMD/PBMD and clarifying the type of disease.
