Progressive Duchenne/Becker muscular dystrophy

Differential diagnosis

• Limb-gridle muscular dystrophy — FKRP gene
• Emery-Dreifuss muscular dystrophy — EMD, FHL1, LMNA genes
• Spinal muscular atrophy — SMN1
• Barth syndrome — TAZ gene

Dystrophin

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.

Peculiarities of clinical manifestations are associated with the type of mutation in the dystrophin gene:

Progressive Becker muscular dystrophy

Generally characterized by later manifestation and milder clinical signs. Clinical signs begin to manifest around the age of 10 to 20 years. The disease progresses quite slowly, in most cases, the patient loses the ability to move without a wheelchair no earlier than the age of 40.

Despite the milder neuromuscular phenotype, heart failure is the most frequent cause of death in PBMD (the average age of death is 40-50 years).

DMD gene-associated dilated cardiomyopathy

According to sources, mutations in the DMD gene can cause not only DMD/BMD but also dilated cardiomyopathy 3B [2,6], which is a disease of the heart muscle that leads to ventricular dysfunction and, consequently, heart failure. Women heterozygous for the pathogenic variant are at high risk of developing this pathology.

Xp21.2–p21.1The 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 (over 2Mb, containing 79 exons).

Dystrophinopathies are X-linked recessive diseases by type of inheritance. The penetrance of dystrophinopathies is complete in hemizygous boys; it varies in heterozygous girls carrying the pathogenic variant.

If a woman is a carrier of a heterozygous pathogenic mutation in the DMD gene, the probability of transmission of the mutation:

At the same time, identification of heterozygous female carriers is important for clinical monitoring of cardiac pathologies in such patients.

Male PDMD patients usually do not manage to leave offspring because of early death; patients with PBMD and DMD gene-associated dilated cardiomyopathy can have offspring: all their daughters will be heterozygous carriers of the pathogenic variant and none of their sons will inherit the pathogenic variant.

Detection of carriage of the DMD gene 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 Becker muscular dystrophy:

• Debuts between the ages of 10 and 20 with the appearance of weakness and fatigue in the pelvic girdle and leg muscles.
• Muscle spasms become the early symptoms.
• The clinical manifestations are similar to PDMD, but milder.
• Progressive symmetrical muscle weakness in the proximal parts; weakness of the quadriceps femoris muscle is sometimes the only sign of the developing disease.
• Wheelchair dependence develops after age 16, although some patients retain independent motor activity in their 30s and rarely in their 40s.
• Hypogenitalism and testicular atrophy are detected in some cases [9].

DMD gene-associated dilated cardiomyopathy

• Dilated cardiomyopathy with congestive heart failure, with men usually manifesting between the ages of 20 and 40 years, and women at a later age.
• Typically, clinical signs of skeletal muscle damage are absent.
• Rapid progression of the disease, leading to death within a few years in men and slower progression (decades or more) in women.

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:

• Peripheral blood (EDTA tube)
• Amniotic fluid from 16 weeks of pregnancy 
• Chorionic villi
• Umbilical cord blood (EDTA tube)

Literature Cited:

1. Marina Basta, Ashish M. Pandya. Genetics, X-Linked Inheritance. Treasure Island. 2021 Jan; PMID: 32491315

2. https://www.omim.org/entry/302045

3. Hum Mutat. The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations. Human Mutation. 2015 Apr; 36(4): 395–402.

4. Eppie M Yiu, Andrew J Kornberg. Duchenne muscular dystrophy. J Paediatr Child Health 2015 Aug; 51(8):759-64

5. "A method for molecular genetic testing for carriage of deletions and duplications of exons of the DMD gene. Authors: Vilchuk K.U., Gusina N.B., Gusina A.A., Myasnikov S.O., 2016.

6. Nakamura A. X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy. Pharmaceuticals (Basel) 2015; 8:303–320.

7. Maria Sofia Falzarano, Chiara Scotton, Chiara Passarelli, Alessandra Ferlini. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. 2015 Oct 7; 20(10):18168-84.

8. Van Westering T.L.E., Betts C.A., Wood M.J.A. Current understanding of molecular pathology and treatment of cardiomyopathy in Duchenne Muscular Dystrophy. Molecules. 2015

9. Ivanov V.I., Baryshnikova N.V., Bileva D.S., Dadali E.L., Genetics. 2006