Muscular Dystrophy, Duchenne Type

Alternative Names

  • DMD
  • Duchenne Muscular Dystrophy
  • Muscular Dystrophy, Pseudohypertrophic Progressive, Duchenne Type

Associated Genes

Dystrophin
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WHO-ICD-10 version:2010

Diseases of the nervous system

Diseases of myoneural junction and muscle

OMIM Number

310200

Mode of Inheritance

X-linked recessive

Gene Map Locus

Xp21.2

Description

Duchenne muscular dystrophy (DMD) is characterized by rapid progression of muscle degeneration in an early age with delayed milestones. At two or three years of age, patients suffer from weakness of the pelvic girdle. Proximal weakness causes a waddling gait and difficulty climbing the stairs, and the size of the calves increases. Serum creatinine kinase (CK) is elevated and myopathic changes appear on electromyography. By the age of ten to 13 years, patients fail to walk. Gradually, the disease becomes worse due to the involvement of smooth and cardiac muscles. All patients have cardiomyopathy after 18 years of age. Also, respiratory complications appear by the beginning of adolescence. Both the cardiomyopathy and respiratory complications are the most common cause of death in patients with DMD. The prevalence of DMD is estimated to be 1 in 3500 boys worldwide.

Molecular Genetics

Mutations in the DMD [dystrophin (muscular dystrophy, Duchenne and Becker types)] gene cause the signs and symptoms of Duchenne muscular dystrophy. The DMD gene is located on the X chromosome and it is the largest known human gene. This gene spans 2.4 Mb of DNA and comprises 79 exons. The DMD gene has at least four promoters. Many intragenic variants have been identified in the DMD gene. The product of DMD gene is a membrane-associated protein (dystrophin) which is found in muscle cells and some neurons. Dystrophin is an important structure that supports and strengthens muscle cells by anchoring elements of the cytoskeleton to the surface membrane. Symptoms of DMD occur due to the absence of dystrophin. Absence of dystrophin results in increasing cell permeability and allowing uncontrolled entrance of the extracellular components. Consequently, the internal pressure of the cells increases till they burst and die.

Disease-causing mutations vary widely and they include deletion of the entire gene, deletion or duplication of one or more exons, and small deletions, insertions, or single-base changes. About 96% of the patients are with frameshift mutations. New mutations are found in 30% of the cases and about 10% to 20% of these new mutations are gonadal mosaic. More than half of the DMD patients were described to have deletion mutations clustered at either the major hot spot of the gene (encompassing exons 45-52), or within the minor hot spot (including exons 3-19).

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
310200.1LebanonMale Muscular Dystrophy; Elevated circulati...NM_004006.2:c.4071+1G>AHemizygousX-linked, RecessiveNair et al. 2018
310200.2LebanonMale Muscular Dystrophy; Elevated circulatin...NM_004006.2:c.1283delAHemizygousX-linked, RecessiveNair et al. 2018

Other Reports

Egypt

Bastaki et al. (1999b) studied 26 patients with DMD or BMD from Egypt to observe any correlation between the size and site of dystrophin gene deletions and the clinical picture of dystrophinopathies. PCR analysis showed that 68% of the Egyptian patients had deletions in the Dystrophin gene. The most common deleted exons among the Egyptian patients were exons 19, 45, 48, and 51. No significant correlation was found between the size or site of the deletion and the clinical severity of the disease in terms of onset of walking, onset of weakness, and average IQ. The average IQ among the Egyptian patients was 90, but involvement of exons 45 and 48 were associated with IQ ranges from 85-86. This association, however, was non-significant. [Bastaki LA, Al-Awadi SA, Moosa A, Shawky RM, Naguib KK. Clinico-genetic study of dystrophinopathies: a comparative study between Kuwait and Egypt. Alex. J Pediatr. 1999b; 13(2):371-77.]

El-Harouni et al. (2001) examined the genotype-phenotype correlation in 10 Duchenne muscular dystrophy (DMD) male patients (from nine families) with double deletion (Ddel) mutations in comparison to 20 unrelated male patients with single deletion (Sdel) mutations. Molecular analysis, immunohistochemical studies, and functional disability grading (FDG) were performed. Each patient from the Ddel group was matched with two patients from the Sdel group who had the same age and disease duration, and harbored Sdel mutations at either hot spot areas. Within each group, there were no significant relationship between the numbers of deleted exons and either CK levels, FDG values, or durations of the disease. However, the range of FDG values was less in the Ddel group than the Sdel group with statistically significant difference. It was found that in both groups the FDG value positively correlated with the disease duration. But only in the Ddel group, the FDG values positively correlated to the CK levels. Muscle biopsies were obtained from four Ddel patients and they showed partial expression of the dystrophin protein which meant that the reading frame was restored. On the other hand, biopsies of seven Sdel patients displayed complete deficiency of the protein. It was suggested that somatic suppression to produce an internally deleted protein in DMD muscle could be caused by secondary deletions which restore the reading frame by extending or removing the original mutation. In an extended study with 250 Duchenne/Becker MD male patients, El-Harouni et al. (2003) proved the previous results. [El-Harouni AA, Amr KS, Effat LK, Eassawi ML, Ismail S, Gad YZ, El-Awady MK. Functional disability is less severe in patients with double deletions in the dystrophin gene. J Arab Child. 2001; 12(4):451-64.]

[See also: Kuwait > Haider et al., 1998; Bastaki et al., 1999b].

Jordan

Al-Qudah et al. (1990) prospectively studied 4 DMD patients by cranial MRI, DNA deletion analysis, clinical evaluation, and intelligence testing. They found no significant correlation between verbal intelligence scores and MRI findings, DNA deletion, or the clinical severity of the disease. These first MRI studies of DMD did not reveal any significant anatomic brain alteration, other than mild atrophy in two patients. Eight years later, Al-Qudah and Tarawneh conducted a study on 28 patients who have been diagnosed as having congenital muscular dystrophy at Jordan University Hospital in the period from January 1990 to February 1997. Of 75 patients diagnosed as having muscle disease, 55 (73.3%) had muscular dystrophy. Of 55 muscular dystrophy patients, 28 (50.9%) had congenital muscular dystrophy, 11 (20%) had Duchenne muscular dystrophy, 9 (16.4%) had Becker muscular dystrophy, 4 (7.3%) had myotonic dystrophy, 2 (3.6%) had limb-girdle dystrophy, and 1 (1.8%) patient had facioscapulohumeral dystrophy. Age of onset of symptoms of congenital muscular dystrophy (hypotonia and weakness) was documented antenatally or in the first few months in the majority (92.9%) of patients. Parental consanguinity was documented in 21 (75%) of congenital muscular dystrophy cases, and family history of possible similar cases in 15 (53.6%).

Kuwait

Haider et al. (1998) used three different sets of multiplex PCRs to study dystrophin gene deletion mutations among 26 Kuwaiti and 16 Egyptian DMD patients. deletions were detected in 86% of the patients, which was the highest deletion detection rate in DMD patients up until that time. Haider et al. (1998) suggested that this pointed towards a population-specific genetic variability among DMD Arab patients.

Bastaki et al. (1999a) studied Dystrophin gene deletions in 26 Kuwaiti patients with DMD and BMD. Among the Kuwait patients, 68% were found to contain deletions in the Dystrophin gene. The most common deleted exons among these patients were exons 81, 45, and 48. No significant correlation was found between the size or site of the deletion and the clinical severity of the disease in terms of onset of walking, onset of weakness, and average IQ. As a continuation of this study, Bastaki et al. (1999b) further studied the clinical characteristics of these patients and compared the observations with those seen in 26 Egyptian patients with dystrophinopathies. Maternal age showed a significant difference between the two populations. A similar result was not observed for paternal age. About 7.7% of the Kuwaiti patients as compared to 19.2% of the Egyptian patients had started walking by the age of two-years. None of the Kuwaiti patients reported weakness after 8-years of age, compared to 7.7% of the Egyptian patients who did. An IQ of over 70 was seen in 82% of both groups, while 26% had an IQ of over 100. ECG abnormalities were observed in 78% of the 45 cases where they were performed. [Bastaki LA, Haider MZ, Shawky RM, Naguib KK. Genotype-phenotype correlation among patients with dystrophinopathies. Alex J Pediatr. 1999a; 13(2):365-70.]

[See also: Egypt > Bastaki et al., 1999b].

Lebanon

El-Khoury et al. 2018 described a male cohort of 52 unrelated Lebanese DMD patients with a late average age of diagnosis (7 years). They described hotspot regions of multi-exon and single-exon deletions in the dystrophin gene in 33 patients, as well as two patients with duplications. Small and point variants were not screened for. 

Saudi Arabia

Bosley et al. (2016) described a 14-year-old Saudi boy with Duchenne Muscular Dystrophy (DMD) and Duane Retraction Syndrome (DRS).  The patient was born to healthy unrelated parents and had two unaffected siblings.  Symptoms of DMD included delayed speech development, mild mental retardation and progressive muscle wastage that resulted in lordosis and Gower’s maneuver while walking.  He also had elevated levels of creatine kinase, alanine aminotransferase and aspartate aminotransferase.  Muscle biopsy of his right thigh showed significant signs of dystrophy including contracted, degenerative and regenerative fibers as well as defective histological stains for dystrophin protein.  Symptoms of bilateral DRS included complete abduction defects, bilateral restriction of adduction with globe retraction and mild left hypertropia in primary gaze.  An attempted left gaze resulted in downshoot of the right eye while an attempted right gaze caused an upshoot of the left eye.  The patient also had a history of seizures in infancy with a single recurrence in childhood that did not require continued treatment.  Multiplex Ligand-dependent Probe Amplification (MLPA) studies revealed the presence of duplications of exons 3 and 4 in the Dystrophin gene.  The authors noted that this was the third reported case worldwide of a patient suffering from both DMD and DRS and the first case involving neurological features.

Syria

Madania et al. (2010) extracted genomic DNA from 51 unrelated Syrian DMD/BMD male patients and analyzed 25 hotspot exons in the Dystrophin gene. Madania et al. (2010) found a deletion in 25 (49%) and a duplication in 5 (10%) out of all 51 patients studied.

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