Adult and Adolescent Onset Muscular Dystrophies Part 1: Evaluation and Diagnosis

Disease/Disorder

Definition

Adult and adolescent onset muscular dystrophies (MDs) are characterized by progressive muscle weakness and loss of muscle mass with degeneration or degeneration/regeneration due to mutations in one or more genes which code for proteins required for normal muscle function, structural support and homeostasis.¹ Other organ systems can be affected directly or indirectly as many of these proteins are not localized to just skeletal muscle and other body systems are affected by lack of muscle strength or mass. Muscular dystrophies can present with proximal and symmetric muscle weakness, asymmetrical weakness, scapulohumeral, scapuloperoneal, or distal weakness. and inheritance may be autosomal dominant, autosomal recessive, or X-linked.

This article will focus on muscular dystrophies more commonly presenting in adolescence or adulthood. Those which will be briefly reviewed here include the following: myotonic dystrophy, Emery-Dreifuss muscular dystrophy (EDMD), facioscapulohumeral dystrophy (FSHD), and limb-girdle muscular dystrophies (LGMDs). Dystrophinopathies (Duchenne and Becker MD) are discussed as their own subcategory, as are congenital muscular dystrophies such as merosin-deficient congenital muscular dystrophy (CMD), alpha-dystroglycanopathies, and Collagen VI related CMD (Bethlem-Ullrich). These and the non-dystrophic myotonic syndromes, myasthenic syndromes, inflammatory or metabolic myopathies, channelopathies. later-onset anterior horn cell disease and other rare neuromuscular conditions are clinically separate and are also discussed elsewhere.²

Muscular dystrophies can also be classified by age of presentation such as congenital versus childhood or early versus later onset. Diagnosis of early onset conditions may be delayed, sometimes remarkably so; a recent case of FSHD presented as a Case Record of the Massachusetts General hospital went undiagnosed until age 80³ .Though it has been increasingly recognized that different mutations can present with similar phenotypes, while mutations in a specific gene can lead to different phenotypes, In general, mutations causing more severe consequences to protein structures present earlier with greater clinical severity and progression. Yet even the identical mutation may show variation in phenotype between different individuals, even in the same family.

Etiology

Most MDs are heritable disorders, and spontaneous mutations (“de novo”) can occur. The dystrophinopathies and the majority of EDMD cases are X-linked, FSHD and myotonic dystrophies are autosomal dominant, as are some LGMDs and EDMDs, and others are autosomal recessive such as most LGMDs and rare forms of EDMD. Careful history of family members must be a part of medical evaluation, bearing in mind that before the advent of genetic testing, misattributed diagnoses commonly occurred.

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 DM1 is less common among non-white populations, andDM2 is much less common than DM1 except possibly in Nordic countries such as Germany and Finland.

The overall incidence and prevalence of EDMD is not known but estimates are around 0.4 to 1/100,000.⁵ FSHD has an estimated prevalence of between 4 and 10 per 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 0.8 to 6.9 in 100,000.⁷ Approximately 250,000 people in the United States have some form of MD according to Muscular Dystrophy Epidemiology – Rare Disease Advisor but the true incidence and prevalence are not clearly known.⁸

Identifying risk factors other than consanguinity for autosomal recessive conditions and providing primary prevention for patients is difficult due to variable inheritance patterns, possibility of spontaneous mutations, and irregular phenotypic expression. Cases with anticipation in particular DM1 and FSHD can result in the less severe phenotype of the parent going unrecognized. Genetic counseling should be made available for parents and patients to understand their genetic characteristics and the risk of their offspring inheriting MD.

Patho-anatomy/physiology

Myotonic dystrophy: There are two types of myotonic dystrophy, DM1 and DM2, both caused by an abnormal nucleotide repeats in two unrelated genes. Though they exhibit a similar phenotype, in DM1 this is an unstable CTG repeat expansion in the C’ untranslated end of the DMPK protein kinase gene, creating an abnormal RNA which causes alternative splicing and reduced transcription of that gene and also sequesters transcription factors for other genes including CLCN1 and in cortical and subcortical locations. In DM2 it is a larger but more stable CCTG repeat in intron one of the ZNF9 (zinc finger protein 9, aka CNBP for cellular nucleic-acid binding) gene and is similarly widely expressed; there is more proximal and distal weakness, but less facial weakness and little to no increase in severity over generations. Both types present with muscle pain and stiffness, progressive muscle weakness, myotonia, male hypogonadism, hypothyroidism, cardiac arrhythmias, diabetes due to insulin resistance, and early cataracts. Other features may include cognitive dysfunction, hypersomnia, tremor, and hearing loss.¹¹ In myotonic dystrophy type I, there may be a history of learning disabilities and executive dysfunction as well.

Emery-Dreifuss muscular dystrophy: In EDMD, defects in one of multiple genes can lead to loss of proteins essential for proper function of a cell’s nuclear envelope including inner and outer membranes and related structures. More research is needed to elucidate why malfunction of these specific proteins affect primarily skeletal muscle and cardiac conduction systems though these proteins are found in multiple tissue types.¹¹ More causative genes have been identified recently, making autosomal dominant inheritance nearly as common as x-linked. A current listing is as follows:¹²

Facioscapulohumeral dystrophy: The genetics of FSHD are more complex, with the majority of patients having FSHD1 with contraction of the D4Z4 repeat on chromosome 4q resulting in inadequate suppression of DUX4 which is normally active briefly in fetal development but is toxic to skeletal muscle. This form is inherited as an autosomal dominant with anticipation. FSHD2 is digenic, requiring one mutation in SMCHD1 which normally hypermethylates the D4Z4 region, and a 4a (“permissive”) allele.¹³ Testing methods screen for the size of the D4Z4 area, and then the presence of the 4a allele before sequencing of SMCHD1. FSHD must be suspected by phenotype and the specific testing ordered.

Limb-girdle muscular dystrophies: LGMDs are diverse, with over 30 identified types. Many of the associated genes code for proteins essential to the sarcolemma, or muscle cell membrane, but others include an enzyme (calpain), myofibrillar proteins, and those associated with Golgi or endoplasmic reticulum (FKRP, FKTN). LGMDs are named depending on the inheritance pattern (AD or AR) and the specific gene and protein that is defective or missing. For example, disease due to biallelic mutation in CAPN3 which codes for calpain is labeled LGMD2a/R1 and termed calpainopathy; there are monoallelic cases of affected carriers labeled LGMDD4.¹⁴ An up to date chart is available at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783424/.

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.In cases related to abnormal glycosylation of alpha-dystroglycan, there are types A, B, and C, where type C is a primarily limb-girdle phenotype but A and B have CNS involvement and A has eye involvement as well. An example of this is for FKRP-related conditions as referenced at Entry – *606596 – FUKUTIN-RELATED PROTEIN; FKRP – OMIM (https://www.omim.org/entry/606596).

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Adult-onset MDs generally begin with loss of strength and endurance with symptoms which can develop at different ages. Patients may experience falls, difficulty ascending stairs, clumsiness, exercise intolerance, muscle cramps, episodic weakness, focal wasting of muscle groups, contractures, cardiac symptoms, and/or breathing difficulties.¹⁵

Specific secondary or associated conditions and complications

Although symptoms tend to be primarily neuromuscular in nature, manifestations in additional organ systems can be prominent especially for DM1 and DM2 as described above as well as gastrointestinal and pulmonary complications.¹⁶ Many but not all LGMD subtypes are associated with cardiomyopathy and respiratory involvement. Patients with more severe FSHD can have sensorineural hearing loss and more rarely a bilateral Coates-like retinopathy.¹⁷ Individuals with EDMD can have multiple cardiac issues, with arrhythmia more common than cardiomyopathy. 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

History

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 pain and cramps, and breathing difficulties. Some patients may notice atrophy in affected muscles or scapular winging.^15,18-20

Physical examination

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 different 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. Grip myotonia with delayed relaxation as well as percussion myotonia should be assessed. Abnormal gait pattern can also help localize areas of weakness, for example a Trendelenburg gait for gluteus medius and minimus muscles or foot drop in distal dystrophies. 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, 18-20} Specific muscle groups less commonly tested such as neck flexion and extension, finger extension, and abdominals, plus looking for specific patterns such as scapular winging with shoulder flexion and abduction and good deltoid strength in the lower half of the shoulder range typical for FSHD.

Functional assessment

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 may additionally affect endurance or lead to changes in sleeping position. Some patients will have given up activities rather than make efforts to obtain mobility aids that would allow them to continue. There may be 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

Diagnostic studies

A number of tools which can be divided into general and specific diagnostic studies are used to diagnose muscular dystrophy, including genetic testing, blood tests that identify signs of muscle damage, electrodiagnostic studies (EDX), muscle biopsy, pulmonary function tests or spirometry (PFT) electrocardiogram (ECG), and/or echocardiogram (ECHO).

Muscle enzymes such as serum creatinine kinase (CK) and aldolase are usually elevated in MD. The degree of elevation is not consistent with disease severity. Some conditions with less muscle cell breakage may present with normal or moderately elevated CK (FSHD, EDMD). Others may present with markedly elevated CK levels (e.g. calpainopathy or dysferlinopathy two forms of LGMD). It is common to have elevated transaminases of muscle origin which may give the false impression of liver disease in which case GGT can be measured instead as it is specific to the liver. ²¹

Molecular genetic studies are more specific and are available for EDMD, FSHD, and LGMD. They do not always lead to a diagnosis, as various changes in a single gene can lead to multiple phenotypes, and some variants are of unclear significance.^22,23

Muscle biopsy is less specific but can at least categorize the type of neuromuscular disease. 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 versus neuropathic grouping, muscle fiber degeneration and regeneration in early stages of dystrophy. Specific muscle proteins such as dystrophin and sarcoglycan can be measured, which can be diagnostic. Immunofluorescence examination should also be performed for specific muscle proteins.²⁴ Electron microscopy can determine the presence of inclusions or myofibrillar changes specific to some forms of LGMD.

Imaging

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) are likewise not very specific, have decreased in popularity and have 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, 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. Myotonia will typically be visible if present. Nerve conduction studies (NCS) are usually normal, unless there is a coexistent neuropathy.

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 early and increased recruitment at low force thresholds. Chronic myopathies like adult-onset MDs may have large and even polyphasic MUAPs, making them susceptible to confusion with neuropathic conditions.^27,28,29

Evaluation for cardiac pathology with tests such as electrocardiogram, Holter monitor, or echocardiogram is also used to monitor for the development of treatable conduction defects, arrhythmias and cardiomyopathies that are associated with some MDs. Pulmonary function tests can also be used for evaluation of decreased inspiratory and expiratory function and determining need for intervention, and polysomnography (PSG) may be more sensitive to these needs as well.^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 and the American College of Chest Physicians has guidelines for respiratory 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

Environmental

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. Some adults may be caregivers for more severely affected children as well. These considerations are vital for ensuring proper care and optimal participation in the community and society, including transportation, employment, and adaptive recreational activities. It is important to discuss what to expect in terms of disease progression, changing care needs and adaptations that may be required.

Professional issues

Evaluation by genetic specialists and subsequent counseling should be considered to discuss family planning and the implications of genetic testing on insurability and employment. Confidentially and the voluntary nature of genetic testing is essential and must be addressed and respected. Sensitivity to blame being assigned by other family members or general shame and guilt about genetic diagnosis is also important in many cases. Recognition of patterns specific to these conditions and sensitivity to past non-diagnosis or misdiagnosis earlier in the course of disease may allow for people to make different reproductive decisions and to have explanations for symptoms previously attributed to “clumsiness” or lack of effort.

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 including both genetic and small molecule therapeutics, clinical trial readiness, and platforms for optimizing gene therapes.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

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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, Ray Stanford, MD, Jeremy Roberts, MD, Vera Tsetlina, MD, Hana Azizi, MD. Adult and Adolescent Onset Muscular Dystrophies Part 1: Evaluation and Diagnosis. 5/18/2021

Author Disclosures

Vikki A. Stefans, MD
Nothing to Disclose