Duchenne Muscular Dystrophy (DMD)

Muscular dystrophy is a group of genetic diseases characterized by progressive muscle weakness and atrophy.¹ There are different types of muscular dystrophies based on the causative genetic mutation. This also determines the inheritance pattern of each type of disease.

Duchenne and Becker Muscular Dystrophy

Duchenne and Becker muscular dystrophies are both caused by mutations in the DMD gene.² This gene codes for the dystrophin protein, which plays a key role in maintaining muscle cell integrity. The difference between these two types of disease is that in Duchenne muscular dystrophy (DMD) mutations disrupt the reading frame of the DMD gene resulting in no functional dystrophin protein to be synthesized by cells. 

In Becker muscular dystrophy (BMD) on the other hand, the reading frame of the gene is not affected and cells can produce a smaller but still functional dystrophin protein, which maintains some of its function. As a result, the symptoms of BMD are generally milder and usually appear later. Disease progression is also slower compared to DMD.

Both DMD and BMD are inherited in an X-linked manner since the DMD gene is located on the X-chromosome.³ So a female carrier has a 50% chance of passing the mutated gene onto her children. If she has a boy who inherits the mutated gene, he will develop DMD or BMD depending on the type of mutation since he won’t have a second copy of the X-chromosome carrying the healthy gene to compensate. A female carrier also has a 50% chance of having a daughter who is also a carrier, and a 50% chance of having a daughter or son who is neither a carrier nor has the disease.⁴ 

A male DMD or BMD patient cannot pass the disease onto his sons but passes the mutated gene to all his daughters, who will be carriers.

Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the hypomethylation of the D4Z4 region located near the end of chromosome 4.⁵ The D4Z4 region is normally hypermethylated, keeping the DUX4 silenced in most adult cells and tissues. When the D4Z4 region is hypomethylated, the DUX4 gene can no longer be silenced. Although the exact mechanism is not well understood, the overactivity of the DUX4 gene damages and destroys muscle cells.

There is a second type of FSHD called FSHD2 where mutations in the SMCHD1 gene lead to the DUX4 gene being overactive. 

FSHD1 is inherited in an autosomal dominant manner. Most patients inherit the disease from an affected parent. However, in some cases, the disease is the result of a de novo D4Z4 contraction.⁶

FSHD2 is inherited in a digenic pattern. As such, an individual will develop FSHD2 if they inherit a mutated copy of the SMCHD1 gene and a copy of chromosome 4 with a hypomethylated D4Z4 region. 

Limb-Girdle Muscular Dystrophy

Limb-girdle muscular dystrophy (LGMD) can be caused by mutations in many different genes.⁷ Some of these genes code for proteins that are necessary to maintain the physical integrity of the muscle tissue. Others code for proteins that are involved in cell signaling, membrane repair, or waste removal from muscle cells.

LGMD is classified into 2 groups based on the inheritance pattern of the disease. LGMD type 1 is inherited in an autosomal dominant manner, while LGMD type 2 is inherited in an autosomal recessive pattern.

The most common type of recessive LGMD is LGMD type 2A or calpainopathy, which is caused by mutations in the CAPN3 gene; it accounts for 15%-40% of all LGMD cases). LGMD type 2B, also called dysferlinopathy, is caused by mutations in the DYSF gene (this is the second most common type, accounting for 5-35% of LGMD cases). LGMD types 2D, 2E, 2C, and 2F are caused by mutations in the SGCA, SGCB, SGCG, and SGCD genes respectively, and are collectively called sarcoglycanopathies.

The autosomal dominantly inherited LGMD types 1A, 1B, and 1C are caused by mutations in the MYOT, LMNA (most common autosomal dominant type, accounts for 5-10% of all cases), and CAV3 genes respectively.

Other rarer forms of LGMD can be caused by mutations in several other genes including the TTN and ANO5 genes, and other genes that have not yet been identified. 

Emery-Dreifuss Muscular Dystrophy

Emery-Dreifuss muscular dystrophy can be caused by mutations in several genes including the EMD or FHL1 (hemizygous pathogenic variant), and LMNA genes (rare heterozygous pathogenic variant).⁸ These genes encode proteins that are essential for the normal function of skeletal and cardiac muscles. The genetic cause of more than half of Emery-Dreifuss muscular dystrophy cases is not known. 

The disease can be inherited in an X-linked, autosomal dominant, or, rarely, autosomal recessive manner depending on the causative gene. 

Distal Muscular Dystrophy

There are many types of distal muscular dystrophies caused by different genetic defects. These are Welander distal myopathy, Finnish (tibial) distal myopathy, Miyoshi distal myopathy, Nonaka distal myopathy, Gowers-Laing distal myopathy, hereditary inclusion-body myositis type 1 (HIBM1), and distal myopathy with vocal cord and pharyngeal weakness.⁹

This type of muscular dystrophies are classified based on patients’ symptoms and may actually share common genetic causes. Based on the genetic defect, distal muscular dystrophy can be inherited in a dominant or recessive pattern. 

Oculopharyngeal Muscular Dystrophy 

Oculopharyngeal muscular dystrophy (OPMD) is a rare type of muscular dystrophy affecting the muscles of the eyelids and throat.¹⁰ It is caused by mutations in the polyadenylate binding protein nuclear 1 (PABPN1) gene. The PABPN1 protein is important for mRNA processing and transport.¹¹

At least 20 different mutations in the PABPN1 gene that cause OPMD have been identified. The disease can either be inherited in an autosomal dominant or autosomal recessive manner. 

References

1. Overview – Muscular dystrophy. NHS. May 24, 2018. Accessed May 19, 2021.   
2. Wilson K, Faelan C, Patterson-Kane JC, et al. Duchenne and Becker Muscular Dystrophies: a review of animal models, clinical end points, and biomarker quantification. Toxicol Pathol. 2017;45(7):961-976. doi:10.1177/0192623317734823
3. Duchenne and Becker muscular dystrophy. MedlinePlus. August 18, 2020. Accessed May 19, 2021. 
4. X-linked recessive inheritance. National Cancer Institute. Accessed June 24, 2021.
5. Wagner KR. Facioscapulohumeral Muscular Dystrophies. Continuum (Minneap Minn). 2019;25(6):1662-1681. doi:10.1212/CON.0000000000000801
6. Facioscapulohumeral muscular dystrophy. MedlinePlus. September 8, 2020. Accessed May 19, 2021. 
7. Limb-Girdle muscular dystrophy (LGMD). Muscular Dystrophy Association. Accessed May 19, 2021.
8. Bonne G, Yaou RB. Emery-Dreifuss muscular dystrophy. Gene Reviews. August 15, 2019. Accessed May 19. 2021.
9. What causes distal muscular dystrophy (DD)? Muscular Dystrophy Association. Accessed May 19, 2021.
10. Oculopharyngeal muscular dystrophy. National Organization for Rare Disorders. 2012. Accessed May 19, 2021.
11. PABPN1 gene. Medline Plus. August 18,  2020. Accessed May 19, 2021.

Article reviewed by Debjyoti Talukdar, MD, on July 1, 2021.

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Ozge Ozkaya, MSc, PhD

Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.