Adult and adolescent onset muscular dystrophies (MDs) are a group of disorders that cause muscle disease (myopathy) characterized by progressive muscle weakness (myasthenia) and muscle degeneration (atrophy) due to mutations in one or more genes required for normal muscle function.1 These mutations alter the function of proteins responsible for muscle structural support and homeostasis. Other organ systems can be affected in many of these conditions as some of these proteins are not localized to just skeletal muscle. As a general rule, muscle dystrophies present with proximal and symmetric muscle weakness, though some types may present with distal or regional weakness.2,3 They are historically categorized by patterns of weakness (regional MDs, distal MDs) and inheritance (autosomal dominant, autosomal recessive, X-linked). In some cases, a discrete mutation accounts for a specific clinical syndrome. They can also be classified by age of presentation (congenital MDs). It has been increasingly recognized that different mutations can present phenotypically similar, while conversely a specific gene mutation can lead to different phenotypes.
The most common adult and adolescent onset muscular dystrophies that will be briefly reviewed include the following: myotonic dystrophy, Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral dystrophy (FSHD), and limb-girdle muscular dystrophies (LGMDs).
Dystrophinopathies (Duchenne/Becker MD) are discussed as their own subcategory, as are congenital muscular dystrophies such as Merosin-deficient MD, alpha-dystroglycanopathies, and Ullrich congenital MD. These and non-dystrophic myotonic syndromes, metabolic myopathies, and channelopathies are clinically separate syndromes and are discussed elsewhere.
Most MDs are inherited disorders, but spontaneous mutations can occur. These can be X-linked (most EDMD, dystrophinopathies), autosomal dominant (myotonic dystrophies, FSHD and some LGMDs and EDMD) or autosomal recessive (other LGMDs and rare forms of EDMD). Careful history of family members must be a part of medical evaluation.
Epidemiology including risk factors and primary prevention
Myotonic dystrophy type 1 (DM1) is the most common adult-onset muscular dystrophy and is estimated to affect about 1 in 8,000-20,000 in the general population. The prevalence of both DM1 and myotonic dystrophy type 2 (DM2) vary greatly across countries and ethnic groups.4
The overall incidence and prevalence of EDMD is not known.5 FSHD has an estimated prevalence of between 4 and 10 in 100,000 and is the third most common type of MD after the dystrophinopathies and myotonic dystrophy.6 The LGMDs are thought to have a minimum prevalence between 10 and 23 in 100,000.7 Approximately 250,000 people in the United States have some form of MD.8
MDs are genetic disorders obtained by way of inheritance or spontaneous mutation. Identifying risk factors and providing primary prevention for patients is difficult due to variable inheritance patterns, possibility of spontaneous mutations, and irregular phenotypic expression. Regardless, genetic counseling should be made available for parents to understand their genetic characteristics and the risk of their offspring inheriting MD.
Though most of these MDs are inherited disorders, the specific genes and proteins affected in each varies.
Myotonic dystrophy: There are two types of myotonic dystrophy (MD), DM1 and DM2, both caused by an abnormal trinucleotide repeat within two unrelated genes. Though they exhibit a similar phenotype, in DM1 the production of a kinase is affected, whereas DM2 affects a protein abundantly expressed in muscle fibers.9,10
Emery-Dreifuss muscular dystrophy: In EDMD, defects in one of multiple genes can lead to loss of proteins (emerin, lamin A, and lamin C) essential for proper function of a cell’s nuclear membrane. More research is needed to elucidate why malfunction of these specific proteins affect primarily skeletal muscle when emerin and the lamin proteins are found in multiple tissue types.11
Facioscapulohumeral dystrophy: In the majority of patients with FSHD, there is reactivation of a gene (DUX4) used in fetal development but normally silenced thereafter. This gene reactivation in childhood or adulthood leads to aberrant production of a protein that is toxic to muscle cells.12
Limb-girdle muscular dystrophies: LGMDs are phenotypically similar but genotypically diverse, with over 30 identified types. Many of the affected genes code for proteins essential to the sarcolemma, or muscle cell membrane. The LGMDs can be more aptly named depending on the particular protein that is defective or missing. For example, abnormalities in the proteins calpain, dysferlin, or sarcoglycan can lead to clinical syndromes termed calpainopathies, dysferlinopathies, and sarcoglycanopathies, respectively.13
In some cases, many of the aforementioned proteins are important to tissues other than skeletal muscle. This leads to the manifestation of clinical features that involve the cardiac, pulmonary, gastrointestinal and central nervous systems.14
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Although there are several types of adult-onset MDs, they generally begin with loss of strength and endurance. Patients may develop symptoms at different points in their lives. Weakness occurs mostly in the pelvic and scapular region. Patients may experience falls, difficulty ascending stairs, exercise intolerance, muscle cramps, episodic weakness, focal wasting of muscle groups, contractures and/or breathing difficulties.15,16
Specific secondary or associated conditions and complications
Although symptoms tend to be primarily neuromuscular in nature, MDs can have manifestations in additional organ systems. Many of the LGMD subtypes are associated with cardiomyopathy and respiratory involvement. Patients with FSHD commonly have sensorineural hearing loss, cardiac conduction abnormalities, and retinal telangiectasias.17 Individuals with EDMD can have multiple cardiac issues. Finally, those with myotonic dystrophy have learning disabilities, cataracts, cardiac conduction abnormalities, as well as gastrointestinal and pulmonary complications.
Therefore, a multi-specialty approach is essential to properly manage patients with MD and commonly includes cardiologists, pulmonologists, neurologists, orthopedists, physiatrists, audiologists, and ophthalmologists, to name a few.
Essentials of Assessment
A detailed family history is essential, as affected family members can confirm the inherited nature of the disease, and the inheritance pattern will help to refine the differential diagnosis. Most patients present with insidious weakness. Some may complain of fatigue and decreased endurance, though prominent fatigability is more common in neuromuscular junction disorders. Proximal weakness may present as difficulty with overhead activities, hip flexor weakness as difficulty lifting legs in and out of the car, and quadriceps weakness as trouble getting out of chairs or going up or down stairs. Distal weakness can be seen in the LGMDs, which may present with complaints such as dropping objects, wrist drop, or foot drop. Other symptoms may include falls, exercise intolerance, muscle cramps, and breathing difficulties. Some patients may notice atrophy in affected muscles or scapular winging.15,16
Inspection should include assessing for scoliosis, kyphosis, scapular winging, and chest anomalies such as pectus excavatum. Facial muscles may show atrophy or weakness. Of note, ptosis and extraocular involvement may indicate a confounding diagnosis such as a neuromuscular junction disorder or mitochondrial myopathy. Pseudohypertrophy is helpful in diagnosing dystrophinopathies, and significant atrophy can be helpful in recognizing Miyoshi myopathy, for example, one of the LGMDs. The presence of fasciculations can point to other neuromuscular disorders such as motor neuron disease or multifocal motor neuropathy. Abnormal gait pattern can also help localize areas of weakness, for example a trendelenburg gait for gluteus medius and minimus muscles. The presence of contractures in particular joints can help elucidate the type of MD, for example elbow flexor and cervical extensor contractures are almost pathognomonic for EDMD. Examination must include other organ systems such as the cardiovascular, pulmonary and gastrointestinal systems.
Muscle strength evaluation should focus on the pattern of muscle weakness: proximal vs distal, or symmetric vs asymmetric. Some conditions present with asymmetric muscle weakness that can help in the diagnosis, such as FSHD. Percussion or action myotonia can point to other diagnoses that may mimic LGMDs, such as myotonic dystrophies or channelopathies.15,16,18,19,20
Functional assessment should be tailored to the stage of the particular MD in question. A great number of patients diagnosed with MD develop progressive weakness, thus hindering their ability to walk, propel a wheelchair, stand up from a chair, or climb stairs. Cardiopulmonary impairments plus weakness might also affect a patient’s endurance. The aforementioned characteristics usually result in an inability to perform activities of daily living (ADLs) such as dressing, toileting, or grooming, without assistance. Some types of MDs also present with cognitive impairments.21
A number of tools can be used to diagnose muscular dystrophy, including genetic testing, blood tests that identify signs of muscle damage, electrodiagnostic studies (EDX), muscle biopsy, electrocardiogram (ECG), and/or echocardiogram (ECHO).
Laboratory studies can confirm the suspected diagnosis. These can be divided into general and specific laboratory studies.
Muscle enzymes such as serum creatinine kinase (CK) and aldolase: these are usually elevated in MD. The degree of elevation is not consistent with disease severity. Some conditions may present with normal or moderately elevated CK (FSHD, EDMD). Others may present with markedly elevated CK levels (Miyoshi myopathy, a form of LGMD). It is common to have elevated transaminases of muscle origin which may give the false impression of liver disease.15
Molecular genetic studies: These are available for some MD subtypes, yet do not always lead to a diagnosis, as a single genotype can lead to multiple phenotypes and some mutations are of unclear significance. These are available for some LGMD syndromes, FSHD, and EDMD.22,23
Muscle Biopsy: the most commonly used muscles include vastus lateralis, triceps, biceps and posterior deltoid. Typical hematoxylin and eosin (H&E) findings include variable fiber size, hypercontracted (opaque) muscle fibers, myopathic grouping, muscle fiber degeneration, and regeneration (early stages). Specific muscle proteins such as dystrophin and sarcoglycan can be measured, which can be diagnostic. Immunofluorescence examination can also be performed for specific muscle proteins.24
Magnetic resonance imaging (MRI) is used increasingly to determine distributions of muscle inflammation or dystrophic changes. Musculoskeletal ultrasound presents an emerging and cost-effective screening technique for detection of dystrophic changes in striated muscle, but is limited to the evaluation of superficial muscle groups and requires further research.25,26
Supplemental assessment tools
Electrodiagnostic studies (EDX) have decreased in popularity and been replaced by DNA testing in some cases. In cases where DNA testing is too expensive or not available, EDX is a useful diagnostic tool. It can help differentiate between MD and motor neuron disease or neuromuscular junction disorders for example. Nerve conduction studies (NCS) are usually normal, unless there is a coexistent neuropathy. If the myopathy is severe enough, motor studies might show decreased compound muscle action potential (CMAP) amplitudes. Repetitive stimulation studies can assess for neuromuscular junction pathology that might mimic a myopathy.
The most important part of the study is needle electromyography (EMG). Usually, one side of the body is sampled. This allows the electromyographer to assess which muscles show greater pathologic findings, highlighting potential muscles to biopsy on the contralateral side. It is important to avoid sampling muscles tested by EMG as there is resulting needle artifact that could interfere with biopsy results. Evaluation should include distal muscles, proximal muscles, and cervical, thoracic, and lumbar paraspinals, as well as facial muscles if clinically involved. The myopathic process and muscle necrosis may cause functional denervation with resultant fibrillation potentials and positive sharp waves. Complex repetitive discharges can be seen as well. As with other myopathies, motor unit action potentials (MUAPs) will typically show decreased duration and amplitude with increased polyphasicity. Chronic myopathies like adult-onset MDs may have large MUAPs, making them susceptible to confusion with neuropathic conditions. Early (increased) MUAP recruitment is also evident at low force thresholds.27,28,29
Evaluation for cardiac pathology with tests such as electrocardiogram, Holter monitor, or echocardiogram can help in establishing conduction defects, arrhythmias and cardiomyopathies that are associated with some MDs. Pulmonary function tests can also be used for evaluation of decreased functional vital capacity.30,31 Due to the substantial cardiopulmonary disease risk with many types of MD, the American Heart Association has published clinical practice guidelines for cardiac management.32
Early predictions of outcomes
While age of onset or loss of ambulation may have prognostic utility for the dystrophinopathies, the adolescent and adult-onset muscular dystrophies are too genotypically and phenotypically varied for use of consistent clinically significant milestones. After performing the initial work-up and establishing the correct diagnosis, it is possible to educate the patient about the usual disease progression associated with his/her particular variation of MD. Because of varying degrees of penetration, the same disease in different family members may present and progress differently.16
Evaluation of the patient’s home, school, or work should be performed to identify any possible barriers to participation. This includes the presence of stairs, having to walk long distances, uneven terrain, and inaccessible bathroom facilities. Education regarding assistive devices and structure modifications such as ramps or railings should be performed. The patient’s driving capability, possible vehicle modifications, and alternative means of transport should be discussed as well.
Social role and social support system
It is essential to assess the support structure that friends and family members might provide. This structure is vital for ensuring proper care and adaptation to society, including transportation, employment, and adaptive recreational activities. It is important to discuss what to expect in terms of disease progression, proper care, or adaptations required.
Evaluation by genetic specialists and subsequent counseling should be considered to discuss family planning and the implications of genetic testing on insurability and employment.
Rehabilitation Management and Treatments
See Adult and Adolescent Muscular Dystrophies Part 2: Rehabilitation Management and Treatments
Cutting Edge/ Emerging and Unique Concepts and Practice
See Adult and Adolescent Muscular Dystrophies Part 2: Rehabilitation Management and Treatments for more details
The goals of the NIH’s Therapeutics for Rare and Neglected Diseases (TRND) Program is to foster and promote development of new treatments for rare and neglected diseases. Currently, there are no active TRND projects focusing on the aforementioned adolescent and adult-onset muscular dystrophies, however their gene therapy platform includes a project regarding nanotherapy for Duchenne Muscular Dystrophy.33
Gaps in the Evidence- Based Knowledge
See Adult and Adolescent Muscular Dystrophies Part 2: Rehabilitation Management and Treatments for more details
There is increasing evidence to suggest that aerobic exercise in neuromuscular disorders is not only safe but likely of benefit. On the other hand, evidence on the effect of strength training is insufficient. Regardless of the type of exercise, more research is needed to study not only the effects but also their mechanisms of action.34
There is insufficient and low-quality RCT evidence to determine the effect of interventions for dysphagia in long-term, progressive muscle disease. 35
- Norwood FL, Harling C, Chinnery PF, Eagle M, Bushby K, Straub V. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. Nov 2009;132(Pt 11):3175-3186.
- Hilton-Jones D. Myopathies in the adult patient. Medicine. 2012;40(10):558-565.
- Tesi C, Hoffman E. Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies. Curr Neurol Neurosci Rep. 2010;10(4):267-276.
- Myotonic Dystrophy. (2017, January 04). Retrieved March 28, 2021, from https://rarediseases.org/rare-diseases/dystrophy-myotonic/
- Bonne G, Quijano-Roy S. Emery-Dreifuss muscular dystrophy, laminopathies, and other nuclear envelopathies. Handb Clin Neurol 2013; 113:1367.
- Facioscapulohumeral muscular dystrophy. (2020, May 06). Retrieved March 28, 2021, from https://rarediseases.org/rare-diseases/facioscapulohumeral-muscular-dystrophy/
- Wicklund MP. The Limb-Girdle Muscular Dystrophies. Continuum (Minneap Minn) 2019; 25:1599.
- Emery Dreifuss Muscular Dystrophy. (2015, June 22). Retrieved March 28, 2021, from https://rarediseases.org/rare-diseases/emery-dreifuss-muscular-dystrophy/
- Massa R, Panico MB, Caldarola S, Fusco FR, Sabatelli P, Terracciano C, Botta A, Novelli G, Bernardi G, Loreni F. The myotonic dystrophy type 2 (DM2) gene product zinc finger protein 9 (ZNF9) is associated with sarcomeres and normally localized in DM2 patients’ muscles. Neuropathol Appl Neurobiol. 2010 Jun;36(4):275-84. doi:10.1111/j.1365-2990.2010.01068.x. Epub 2009 Nov 20. PMID: 20102514
- Myotonic Dystrophy. (2019, July 01). Retrieved March 27, 2021, from https://www.mda.org/disease/myotonic-dystrophy/causes-inheritance
- Emery-Dreifuss Muscular Dystrophy. (2016, January 18). Retrieved March 27, 2021, from https://www.mda.org/disease/emery-dreifuss-muscular-dystrophy
- Facioscapulohumeral Dystrophy. (n.d.). Retrieved March 27, 2021, from https://www.mda.org/disease/facioscapulohumeral-muscular-dystrophy/causes-inheritance
- Limb-Girdle Muscular Dystrophy. (2019, October 04). Retrieved March 27, 2021, from https://www.mda.org/disease/limb-girdle-muscular-dystrophy/causes-inheritance
- Cohn R, Campbell K: Molecular basis of muscular dystrophies. Muscle Nerve. 2000; 23(10):1456-1471.
- Wicklund M: Approaches to diseases of muscle. In Tawil R, Venance S (ed): Neuromuscular Disorders. Oxford, Eng: Wiley-Blackwell, 2011;9-14.
- Norwood F, Visser M, Eymard B, et al. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol. 2007;14(12):1305-1312.
- Tawil R, Van Der Maarel SM: Fascioscapulohumeral muscular dystrophy, Muscle Nerve 34:1-15, 2006.
- Bushby K, Norwood F, Straub V. The limb-girdle muscular dystrophies: diagnostic strategies. Biochim Biophys Acta. 2007;1772(2):238-242.
- Bushby K. The limb-girdle muscular dystrophies-diagnostic guidelines. Eur J of Pediatr Neurol. 1999;3(2): 53-58.
- Guglieri M, Bushby K. How to go about diagnosing and managing the limb-girdle muscular dystrophies. Neurol India. 2008;56(3):271-280.
- D’Angelo MG, Bresolin N. Cognitive impairment in neuromuscular disorders. Muscle Nerve. 2006; 34(1):16-33.
- Krajewski K, Shy M. Genetic testing in neuromuscular disease. Neurol Clin. 2004;22(3):481-508.
- Greenberg SA, Walsh RJ. Molecular diagnosis of inheritable neuromuscular disorders. Part II: Application of genetic testing in neuromuscular disease. Muscle Nerve. 2005;31(4):431-451.
- Jaradeh S, Ho H. Muscle, nerve and skin biopsy. Neurol Clin. 2004;22(3): 539-561.
- Wattjes MP, Kley RA, Fischer D. Neuromuscular imaging in inherited muscle diseases. Eur Radiol. 2010;20(10):2447-2460.
- Lovitt S, Marden F, Gundogdu B, et al. MRI in myopathy. Neurol Clin. 2004;22(3):509-538.
- Barboi A, Barhaus P. Electrodiagnostic testing in neuromuscular disorders. Neurol Clin. 2004;22(3):619-641.
- Preston DC, Shapiro BE. Myopathy. In: Preston DC, Shapiro BE, eds. Electromyography and Neuromuscular Disorders. 2nd ed. Philadelphia, PA: Elsevier; 2005:575.
- Paganoni S, Amato A. Electrodiagnostic evaluation of myopathies. Phys Med Rehabil Clin N Am. 2013;24(1):193-207.
- Bhakta D, Groh WJ. Cardiac function tests in neuromuscular diseases. Neurol Clin. 2004;22(3):591-617.
- Goodwin FC, Muntoni F. Cardiac involvement in muscular dystrophies: molecular mechanisms. Muscle Nerve. 2005;32(5):577-588.
- Management of Cardiac Involvement Associated with Neuromuscular Diseases: A Scientific Statement From the American Heart Association. Brian Feingold, William T. Mahle, Scott Auerbach, Paula Clemens, Andrea A. Domenighetti, John L. Jefferies, Daniel P. Judge, Ashwin K. Lal, Larry W. Markham, W. James Parks, Takeshi Tsuda, Paul J. Wang and Shi-Joon YooOn behalf of the American Heart Association Pediatric Heart Failure Committee of the Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Radiology and Intervention; Council on Functional Genomics and Translational Biology; and Stroke Council. Circulation. 2017;136:e200-e231, originally published August 24, 2017
- Nance ME, Hakim CH, Yang NN, Duan D. Nanotherapy for Duchenne muscular dystrophy. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017 Apr 11. doi: 10.1002/wnan.1472.
- Voet NBM. Exercise in neuromuscular disorders: a promising intervention. Acta Myol. 2019;38(4):207-214. Published 2019 Dec 1.
- Jones K, Pitceathly RDS, Rose MR, McGowan S, Hill M, Badrising UA, Hughes T. Interventions for dysphagia in long-term, progressive muscle disease. Cochrane Database of Systematic Reviews2016, Issue 2. Art. No.: CD004303. DOI: 10.1002/14651858.CD004303.pub4.
Amato A, Rusell JA. Neuromuscular Disorders. 1st ed.; New York City, New York. McGraw Hill; 2008.
Murphy KP, McMahon MA, Houtrow AJ. (2021). Pediatric rehabilitation. New York: Publishing Company, LLC.
Original Version of the Topic
Edwardo Ramos, MD, Manuel F. Mas, MD, Fernando L. Sepúlveda, MD. Adult and adolescent onset muscular dystrophies: evaluation and diagnosis. 8/30/2013.
Previous Revision(s) of the Topic
Rajashree Srinivasan, MD, Saylee Dhamdhere, MD, and Sebastiaan Bens, MD. Adult and adolescent onset muscular dystrophies: evaluation and diagnosis. 2/13/2018.
Amy Tenaglia, MD
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