Muscular dystrophy, MD
Autosomal dominant, autosomal recessive, X-linked
Muscular dystrophies are inherited neuromuscular diseases characterized by weakness and wasting due to muscle dysfunction. Age of onset, severity, progression and histopathological findings are variable between different subtypes of muscular dystrophies.
Muscular dystrophies include a heterogeneous group of neuromuscular disorders:
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene located on the X chromosome which encodes protein dystrophin. DMD affects boys in early childhood, causing progression of muscle weakness and resulting gait problems, general motor delay, and speech/learning difficulties. DMD is the most severe form of muscular dystrophy and it is characterized as follows1:
- Rapid progression of muscle weakness, often with calf hypertrophy
- Decreased levels of serum CK concentration
- Onset before age five years
- Wheelchair dependency before age 13 years
- Approximately one third of affected shows DMD-associated dilated cardiomyopathy in teenage years.
DMD has a prevalence from 15.9 to 19.5 per 100,000 live births2, 3. A milder form of disease occurs in very few female carriers, where mild form of muscle weakness develops in 2.5-20% of affected female carriers1.
Becker muscular dystrophy (BMD) is another, milder form of muscular dystrophy caused by mutations in DMD. BMD affects older boys and young men, and it occurs in about 1 in 30,000 male births1.
Becker muscular dystrophy is clinically characterized by the following:
- Progressive symmetric muscle weakness and atrophy with calf hypertrophy
- In some cases quadriceps femoris weakness is the only sign of disease
- Activity-induced cramping in some patients
- Flexion contractures of the elbows
- Wheelchair dependency after age 16 years
- Preservation of neck flexor muscle strength differentiates BMD from DMD
- The most common cause of death in BMD-affected patients is dilated cardiomyopathy and heart failure.
Mutations in the DMD gene cause both DMD and BMD. Deletions of one or more exons of DMD account for approximately 60-70% of pathogenic variants in individuals with DMD and BMD 1, 4. Duplications that lead to in-frame transcripts account for mutations in 5-10% of males with DMD and BMD 4, 5. Single nucleotide variants (single-base changes, small deletions/insertions and splice site changes) account for approximately 25-35% of pathogenic variants in males with DMD and about 10-20% of males with BMD 4, 6.
Emery-Dreifuss muscular dystrophy (EDMD) is another X-linked form of muscular dystrophy that affects young boys, characterized by the following clinical features7:
- Slowly progressive wasting and weakness, typically of the humero-peroneal/scapulo-peroneal muscles in the early stages
- Early contractures of the elbow flexors, achilles tendons and neck extensors resulting in limitation of neck flexion, followed by limitation of extension of the spine
- Cardiac disease with conduction defects and arrhythmias (atrial fibrillation, dilated or hypertrophic cardiomyopathy)
- Serum CK levels are normal or mildly increased, and muscle histopathology shows nonspecific dystrophic changes.
EDMD is caused by mutations in one of the following genes: EMD (encoding emerin), FHL1 (encoding FHL1), and LMNA, encoding lamin A and C. Mutations in EMD are responsible for ~61%8 of XL-EDMD, mutations in FHL1 for ~10%8 of XL-EDMD, and mutations in LMNA account for ~45% of autosomal dominant EDMD9.
Limb-girdle muscular dystrophy (LGMD) is a large group of childhood to early adulthood-onset diseases, mostly characterized by non-syndromic involvement of skeletal muscles. LGMD affects both men and women and has an estimates of prevalence from 1/14,500 to 1/123,000 10. LGMD includes dystrophies caused by mutations in genes encoding sarcoglycans (SGCA, SGCB, SGCG, SGCD), calpain (CAPN3), dysferilin (DYSF), and other muscle-related genes 10.
Facioscapulohumeral muscular dystrophy (FSH), also known as Landouzy-Dejerine disease, is a late childhood to early adulthood-onset muscular dystrophy that affects both men and women, causing weakness in the muscles of the face, shoulders, and upper arms. FSH occurs in about 4-10/100,000 people11.
Approximately 95% of individuals with FSHD have “contraction” mutations of the D4Z4 macrosatellite locus (within subtelomeric region of chromosome 4q35) 11. The pathologic contraction of the D4Z4 repeat region is associated with an opening of the chromatin structure at the D4Z4 locus. The remaining 5% of FSHD patients do not have contraction of the D4Z4 locus, but were shown to have loss of CpG methylation at all D4Z4 repeat arrays on chromosomes 4 and 10, resulting in FSHD type 2 11.
Myotonic dystrophy type 1 (DM1, Steinert's disease) is an inherited form of muscular dystrophy that affects both men and women, characterized by myotonia and cataracts. Estimates of the prevalence of DM1 range from 1:100,000 in some areas of Japan to 1:10,000 in Iceland, with an overall estimated worldwide prevalence of 1:20,000 12, 13.
The disease has three major subtypes:
- Mild DM1, characterized by cataract and mild myotonia and normal life span
- Classic DM1, characterized by myotonia, cataracts, muscle weakness and cardiac conduction abnormalities, and shortened life span
- Congenital DM1, severe form of disease, characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common.
DM1 should be suspected in newborns who present with one or any of the following:
- Facial muscle weakness
- Generalized weakness
- Positional malformations including club foot
- Respiratory insufficiency.
Clinical symptoms and the most common signs of myotonic dystrophy type 1 in adult patients include the following:
- Muscle weakness, starting in distal regions and progressing throughout the body and head
- Myotonia, sustained muscle contraction, most commonly grip myotonia
- Posterior subcapsular cataracts, detectable as red/green opacities on slit lamp examination.
DM1 is caused by expansion of a CTG trinucleotide repeat in the non-coding region of DMPK. It is considered that normal alleles have 5-34 CTG repeats, while fully penetrant alleles have more than 50 CTG repeats12.
Myotonic dystrophy type 2 (DM2) is another inherited muscular dystrophy characterized by myotonia (in~90% of affected DM2 patients) and muscle weakness (~82%), and in some patients by cardiac abnormalities, cataracts, insulin-insensitive type 2 diabetes mellitus, and testicular failure14. The prevalence of DM2 appears to differ in various populations, but a higher prevalence is observed in Germany, Poland and Finland 14, 15. Expansion of the CCTG repeat localized within intron 1 of the CNBP (ZNF9) gene causes DM2. The number of CCTG repeats in expanded alleles ranges from approximately 75 to more than 11,000, with a mean of approximately 5000 repeats14.
Oculopharyngeal muscular dystrophy (OPMD) is a rare inherited muscular dystrophy characterized by swallowing difficulties and ptosis. OPMD has an adult age of onset, affecting both males and females, causing weakness in the eye muscles and throat. The estimated prevalence of OPMD is 1/100,000 in France, 1/1000 in the French-Canadian population of Quebec, and 1/600 among Bukhara Jews in Israel15.
OPMD is caused by an expansion of a “GCN” trinucleotide repeat in the first exon of PABPN1 (N represent any of the 4 nucleotides). Normal alleles contain ten GCN trinucleotide repeats, while pathogenic alleles contain 11-17 repeats.
An overview of those genes most commonly associated with muscular dystrophies is listed in the table.
The differential diagnosis of muscular dystrophy-related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Emery-Dreifuss Muscular Dystrophy
- Metabolic Myopathies
- Spinal Muscular Atrophy
- Congenital Myopathies
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for muscular dystrophy using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Muscular dystrophy panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Muscular dystrophy panel, we further recommend continuing the bioinformatics analysis of the data using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for muscular dystrophy testing:
- Individuals with a family history of muscular dystrophy and presentation of the most common symptoms
- Individuals without a positive family history of muscular dystrophy, but with symptoms resembling the disease
- Individuals with a negative but suspected family history of muscular dystrophy, in order to perform proper genetic counseling.
Sequencing, deletion/duplication of the muscular dystrophy panel genes should be performed in all individuals suspected of having muscular dystrophy and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the muscular dystrophy and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.