Limb Girdle Muscular Dystrophies

Disease/Disorder

Definition

Muscular dystrophy is defined as muscle disease featuring degeneration and regeneration of muscle with fibrosis and fatty replacement. Historically, cases that did not fit other, better-defined disorders were labeled

Limb-Girdle Muscular Dystrophy (LGMD), specifically to be distinguished from the more common X-linked Becker and Duchenne dystrophies refers to a broad and increasingly heterogeneous group of genetic disorders characterized by postnatal onset and progressive weakness. In most cases, the weakness is predominantly symmetric and typically affects the pelvic and/or shoulder girdle musculature. In 2017, the 229^th ENMC consortium proposed an update to the definition of LGMD. The consensus definition describes LGMD as meeting the following criteria: protein abnormality must be described in at least two unrelated families, affected individuals achieve independent walking, elevated serum creatinine kinase level, progressive degenerative changes over time on muscle imaging, and dystrophic changes on muscle histology.¹ This criterion further defines LGMD as a distinct entity from the congenital muscular dystrophies (CMD), Emery-Dreifuss muscular dystrophies (EDMD), facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM1, DM2 and PROMM), and myopathic mitochondrial DNA depletion syndromes. Previously there was causative overlap between LGMD and CMD/EDMD, however this new definition separates them as distinct diagnoses. Additionally, LGMD 2V is now known as Pompe Disease to more correctly categorize it as a metabolic myopathy.

Nomenclature

The above stated definitional change to LGMD resulted in the creation of a new classification system. Several diseases previously classified as LGMD are no longer known as such and conversely several diseases not originally classified as LGMD are now given this designation. These changes can be viewed in the following Tables 1 and 2.

Table 1: Previous LGMD that no longer carry LGMD classification

Table 2: Non-LGMD diseases now reclassified as LGMD

The previous classification was developed in 1954 by 2 British neurologists, Walton and Natrass, neuromuscular disease experts. This system relied on the notation of a number to signify the inheritance pattern (1= autosomal dominant, 2= autosomal recessive) followed by a letter to denote the order in which the specific LGMD was discovered. With advances in molecular genetics, the classification system was revised so that more LGMD could be included. The major changes that were made include the following:

• Genetic inheritance designation: D = autosomal dominant, R= autosomal recessive
• Order of discovery: numbered list beginning at 1 for each mode of inheritance
• Genetic pathology- explicit naming of the affected protein involved in the disease

The new nomenclature can be thought of as summation of the elements described above, this is shown below:

NAME= “LGMD” + inheritance (D/R) + order of discovery (1, 2, 3…) + affected protein “-related”

When this is applied to the existing LGMD, it results in the nomenclature described in Tables 3 and 4.

Table 3: Reclassification of autosomal dominant LGMD

Table 4: Reclassification of autosomal recessive LGMD

Epidemiology including risk factors and primary prevention

LGMDs are individually rare diseases that affect males and females equally. The estimated incidence is 1to 6 in every 100,000 however this is suspected to be an underestimated value.³ Although the exact prevalence is unknown, estimates range from 1 in 14,500 to 1 in 123,000 with a variable age of onset.⁴ Variable specific diagnostic criteria for LGMD makes accurate reporting both incidence and prevalence complicated. LGMD R1 calpain3-related (calpainopathy) is thought to be the most common form of LGMD in the United States and accounts for 15-40% of all LGMD cases. It is most prevalent in Eastern Europe, Netherlands, Czech Republic, Spain, Italy, and Brazil. Sarcoglycan-related LGMD including R3/R4/R5 (sarcoglycanopathy) is the second most common subtype and are more common in Turkey, North Africa, and Brazil; LGMD R2 dysferlin-related (dysferlinopathy) and LGMD R9 FKRP-related are also relatively common. The recessive forms are more common than the autosomal dominant types.⁴ More discoveries of genetic variations may alter prevalence estimates in the future. Table 5 summarizes the specific typical features of LGMD dominant and recessive subtypes. Of note, phenotypic presentation may be variable depending on location and type of mutation within the gene or even within families.

Patho-anatomy/physiology

A wide variety of cellular functions may be affected in each of the LGMDs, depending on the genetic defect. The genetic variants result in abnormal protein synthesis in various parts of the muscle fiber. CPK levels vary with the amount of muscle cell breakdown and release of the enzyme into the circulation and may decrease over time as muscle bulk is lost. Tables 5 and 6 list known defects.

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

All variants of LGMD present with a limb-girdle weakness pattern, however, some may have a distal weakness, atrophy/hypertrophy, or muscle sparing as detailed in the tables below. Scoliosis and joint contractures are more common with earlier disease onset. Extramuscular findings including cardiac, respiratory, ocular and CNS may occur with specific variants as detailed in the tables below. (WUSTL(=),⁴

Table 5: Limb-girdle muscular dystrophy: Autosomal dominant

Table 6: Limb-girdle muscular dystrophy: Autosomal Recessive

Specific secondary or associated conditions and complications

Early onset disorders may result in developmental delays in gross motor skills (e.g., walking, alternating steps on stairs).

Orthopedic: Contractures may occur, but generally are less common and less severe than in other dystrophies. There is increased a risk of scoliosis in childhood onset LGMD. Routine monitoring clinically and with radiographic assessment is important along with referral to orthopedic spine surgery for consideration of surgical intervention if indicated. Weakness in the shoulder girdle may result in scapular winging and shoulder instability; in some cases, a surgical stabilization of the shoulder girdle may improve function.

Cardiac: The presence of cardiomyopathy is variable and depends on the LGMD variant. Severe cardiac involvement can be seen more with those variants with sarcoglycanopathy.⁵ Rhythm disturbances are less common but may also occur. Patients should be followed regularly by cardiology. An echocardiogram should be performed at disease onset and routine screening echocardiograms and/or holter monitor studies should be performed routinely. Consideration should be given to appropriate pharmacologic therapies or device placement for optimization of cardiac function

Pulmonary: Some subtypes are at increased risk for restrictive lung disease leading to respiratory insufficiency due to respiratory muscle weakness; these patients plus those with scoliosis should have routine pulmonary function tests. Non-invasive ventilation may improve both length and quality of life.

Nutritional: Patients may have dysphagia or inability to feed themselves due to upper limb weakness. Referral for swallow evaluation and optimization of nutrition is important. Diet texture modifications and/or physical maneuver may improve swallow and reduce aspiration. Alternative nutritional support such as gastrostomy tubes should be considered if nutritional requirements cannot be met orally.

Cognitive: Intellectual disability and learning differences are seen in some types of LGMD, most commonly with the dystroglycanopathies and may need individualized educational programs (IEP).

Essentials of Assessment

History

• Age of Onset: Infancy through adulthood.
• Progression of weakness: slow versus rapid.
• Family History: Often negative in recessive cases, other than siblings if any; inquire sensitively about consanguinity. Draw a pedigree if there is a positive one. Male to male transmission indicates dominant inheritance.
• Development: in children, note time to attain developmental milestones
• Mobility: Include walking, running, stair climbing, rising from chairs, keeping up with peers and athletic participation history.
• Self-care: Include ability to open doors and containers and manage feeding and dressing.
• Academic achievement and any practical difficulties in the classroom.
• Nutrition: the ability to chew and swallow different textures.
• Pain: history of muscle pain, cramping, other musculoskeletal pain.
• Fatigue and/or sleep disturbances
• Surgical or anesthetic complications, episodes of rhabdomyolysis (abdominal pain, discolored urine, extremely high CPK that trends back to baseline)
• Cardiac and pulmonary symptoms

Physical examination

• Assess muscle bulk for patterns of hypertrophy and atrophy. Look for any asymmetry.
• Manual muscle testing with focus on distribution of weakness. Include neck flexors, look for scapular winging with shoulder abduction and flexion, test the deltoid separately, and specifically, test proximal hip muscles. Observe for Gower maneuver if unable to perform MMT.
• Assessment of joint range of motion for contractures, including the spine, and assess for scoliosis.
• Cranial nerve examination to assess for facial, extraocular, or bulbar involvement; note hearing, visual or eye abnormalities.
• Sensory testing to differentiate myopathic versus neuropathic process.
• Evaluation of gait.
• Note micro- or macrocephaly, stature, overweight or underweight status.

Functional assessment

Musculoskeletal and Neurological Assessment:

• As above through comprehensive physical examination

Evaluation of gait

• Distance able to walk and rate of speed if ambulatory.
• Quality of gait: proximal weakness typically results in waddling (Trendelenburg) gait and toe walking.
• Gower maneuver may be present.
• Frequency of trips and falls.
• Ability to do stairs, alternating versus non-alternating.

Self-care

• Ability to open/close jars and doors.
• Ability to reach top and back of head for hygiene and to get the hand to mouth for self-feeding.
• Difficulties with bathing/showering.
• Any difficulty arising from chair or commode.

Nutrition

• Difficulties with chewing and swallowing.

Communication

• Difficulties with speech, writing, and/or keyboarding.

Affect

• Presence of dysthymia (sadness, anger, depression, mood) and coping mechanisms.

Social

• Ability to maintain social interaction with family, friends, and community participation.

Laboratory studies

• Differential diagnosis includes other myopathies and dystrophies, and inflammatory muscle disease (polymyositis/dermatomyositis – PMS/DMS).
• Creatine phosphokinase (CPK): Variable. Can be normal to very high (e.g., 80-100 times normal), depending on the subtype. The CK levels are higher in autosomal recessive forms than the dominant forms. The CPK may decline with age due to a decrease in muscle mass.⁵
• Genetic panels for sequencing and deletion-duplication in the known genes causing limb girdle muscular dystrophy may be ordered. Single gene analysis can be performed to target specific gene in question, if unrevealing then next-generation sequencing of larger LGMD panels may be considered with whole exome sequencing (WES) as another option if unrevealing. Presently, there are several sponsored panels that allow for expanded access to genetic testing for LGMD; this has allowed for increased amount of testing in order to identify specific gene mutations.

Imaging

Magnetic resonance imaging and ultrasound have been used to evaluate dystrophic muscles and help to distinguish fatty infiltration seen in dystrophy from inflammation seen in PMS/DMS. Radiographs of the spine may be necessary to assess scoliosis.

Supplemental assessment tools

Electrodiagnostic testing may be helpful to rule out other neuromuscular disorders including neuropathy, metabolic, myotonia, and neuromuscular junction disorders. Findings may be normal or demonstrate a myopathic process. Normal findings are more likely in younger patients with less severe phenotype. Electrodiagnostic findings are summarized below in table 7. When performing electrodiagnostic testing, it is important to consider leaving certain muscle groups unexamined by needle electromyography for consideration of potential muscle biopsy.

Table 7: Electrodiagnostic findings in LGMD

• Muscle biopsy usually demonstrates degeneration and regeneration of skeletal muscle fibers, with variations in the levels of inflammation and fibrosis. Immunofluorescence for specific gene products may lead to diagnosis from biopsy, but patterns are not entirely specific to the single protein affected and can lead to diagnostic error without gene test confirmation.⁷ Electron microscopy is strongly indicated especially if light microscopy findings are limited or non-specific, to look for structural myopathies and myofibrillar effects.
• Electrocardiogram and echocardiogram should be performed to evaluate for arrhythmias and cardiac involvement in subtypes where the heart may be affected.
• Pulmonary function should be performed even in the absence of symptoms and should include expiratory function such as peak cough flow.

Early predictions of outcomes

Outcomes have marked variation between and among the different disorders, ranging from early childhood onset with severe weakness and rapid progression with severe cardiomyopathy to a much more benign adult onset with mild weakness and slow progression. Lifespan is largely dependent on cardiac and pulmonary involvement and its proactive management.

Environmental

Understanding the patient’s environment will assist with functional assessment.

• Type of home: ranch versus multistory, steps to enter, owning versus renting for modifications.
• Setting of home: urban versus rural may affect availability of services.
• Work Environment: Office work versus manual labor.

Social role and social support system

Assessment of the patient’s social status and interactions including:

• Living arrangements: single, married, parent/child.
• Educational history and current educational placement for children.
• Employment status and work history (adults).
• Social activities.
• Financial resources (income, insurance benefits, eligibility for social services).
• Connection with national or worldwide support groups and registries.

Professional issues

• Genetic counseling should be offered for family planning; benefits depend on the specific LGMD type and whether other family members could be affected or carriers who are considering having children. Patient and family belief systems may affect the willingness to obtain and their response to testing. Relieving false guilt or blame about carrying a recessive gene or passing on a dominant one needs to be sensitively addressed.
• End of life issues needs to be addressed with more rapidly progressive disorders to assure patient autonomy with these decisions, while also clarifying more normal lifespan expectations for families where long-term survival is likely.

Rehabilitation Management and Treatments

Available or current treatment guidelines

Practice guidelines were published by the American Academy of Neurology. These guidelines focus more on medical management and less on rehabilitation. There is level B evidence for the following management strategies: Referral to cardiology for evaluation even in asymptomatic patients; periodic pulmonary function tests for patients with a known high risk for respiratory failure; referral to a multidisciplinary clinic. Genetic testing may assist with guiding disease management, especially for extra muscular involvement. Further efficacy and safety studies should be performed on therapies including gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone, and many other approaches.⁶

Corticosteroid treatment is the mainstay of management of Duchenne muscular dystrophy. It may be indicated in a few subtypes of LGMD, most notable, LGMD R9 FKRP-related, at half the dose for dystrophinopathy.⁸ It should be avoided for dysferlinopathy, which can be mistaken for polymyositis based on biopsy findings alone. The risks and benefits of steroids must be intricately weighed and discussed with the patient and family prior to initiating treatment with steroids.

At different disease stages

Physical therapy involvement is needed for issues related to weakness, mobility, contractures, and pain. Deconditioning will worsen overall function, and therefore physical activity should be maintained. Strength-training and cardiovascular training vary in benefit and limitations, so global recommendations cannot be made. Passive range of motion is important for prevention of contractures.⁹ For children, therapy services are available and funded through the schools under the Individuals with Disabilities Education Act (IDEA) if they are in special education, and adaptive physical education or PT consultation if not formal therapy can be part of a Section 504 plan for reasonable accommodations.

• Contracture management: In addition to therapy, splinting, and serial casting, surgical interventions such as Achilles lengthening procedures may be beneficial to improve positioning, but goals must be realistically assessed. Botulinum toxin use is considered relatively contraindicated.
• Occupational therapy can be useful for maintaining and maximizing self-care. Adaptive equipment is available for grooming, hygiene, dressing, and other activities of daily living, plus accessibility and safety in the home; families may be unaware of these options.
• Bracing and Orthotics may be useful to maintain ambulation and slow the progression of contractures. Upper-extremity bracing (e.g., balanced forearm orthoses) may improve self-care. Bracing of the spine may limit the progression of scoliosis.
• Rehabilitation Engineering can provide technology to maximize function [omit] in the home, as part of education, or employment.
• Educational, vocational, psychologic, and family counseling may be beneficial for respective issues, depending on stage of life.
• Disabled parking may provide significant functional benefits and aid with maintaining community involvement.
• Exercise and conditioning: Aerobic and strength training are safe if submaximal effort is performed. Gentle aerobic training can improve cardiovascular health. If there is concern for osteoporosis, exercise can be low impact such as swimming and stationary bicycle. Educate patients on the warning signs of over exertion such as dark colored urine (indicating myoglobinuria), muscle pain or cramps. Eccentric contraction should generally be avoided.

Coordination of care

For the more involved LGMD, a team approach may be most beneficial to patients and their families. Multidisciplinary clinics allow coordination of care between specialists while adding convenience. Appropriate team members will be dependent on patient needs but may include physiatrist, neurology, genetics, orthopedics, cardiology, pulmonology, physical therapy, occupational therapy, psychology, and social services. Depending on the patient’s age, educational and vocational counseling should be available. Accurate and open discussion about progression of the disease is needed, with end-of-life discussions and referral to palliative and hospice care when appropriate.

Patient & family education

LGMDs are genetic conditions, therefore it is important for patients and families to understand the implications of the disorders for subsequent generations. Patients and family members should be able to make informed decisions regarding family planning. While a genetic diagnosis may or may not change current treatment, future options may depend on specific diagnosis or even specific genetic variation. Involvement with registries and other online resources for clinical trials such as clinicaltrials.gov can be encouraged, and families need to understand that research participation is voluntary, separate from clinical care, and may or may not result in direct benefit if they participate. They also should know that legitimate researchers will never ask them to pay for participation, but instead, their study-related expenses should be compensated. For the more severe forms, family members may need education in caring for the involved family member. This may range from passive stretching to total care.

Emerging/unique interventions

Manual muscle testing should be performed routinely. The 0 to 5 Medical Research Council Scale is commonly used to assess strength, but it is a gross measure. A hand-held dynamometer may be used to more objectively follow changes in strength. A ten-meter walk time, six-minute walk test, time to rise from the ground, time to rise from a chair, or similar mobility inventory may be used to follow functional strength.

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

LGMD are relatively rare disorders that may not fit a specific pattern. When evaluating a patient with a myopathic process that does not fit with a more commonly known phenotype (e.g., Duchenne or Becker muscular dystrophy, FSHD, spinal muscular atrophy, congenital or myotonic muscular dystrophy), a diagnosis of LGMD should be considered. Referral to a neuromuscular specialist for further diagnostics is warranted. Specific diagnosis is critical to accurate genetic counseling, prognostication, and in many cases, treatment options.

Cutting Edge/Emerging and Unique Concepts and Practice

Next-generation sequencing techniques have been established to aid in the diagnosis of LGMD. These include PCR and MLPA based analysis of specific genes of interest, including some options for free panel testing; whole exome sequencing (WES) targeting approximately 1.5% of the human genome; and whole genome sequencing (WGS). Sequencing alone does not target copy number variation which is usually included in MLPA-based systems. Details should be available for all commercially offered options and the help of a genetic counselor or geneticist for test selection. Sponsored next generation genetic testing panels are also available and have been invaluable in expanding access to testing and broadening our knowledge base of genetic conditions. Additionally, various online tools can be used to help distinguish between benign and pathogenic mutations.

An increasing number of clinical trials are currently active for LGMD with the hope of future treatment options on the horizon. Some recent examples include:

• Deflazacort in patients with LGMD R9 FKRP-related⁸
• AAV1 gamma-sarcoglycan gene therapy for patients with LGMD R5 gamma sarcoglycan-related⁸
• Gene delivery of signal recognition protein 9003 for patients with LGMD R4 beta sarcoglycan-related⁸
• Bidridistrogene xeboparvovec, an adeno-associated virus based gene therapy, for LGMD type R4 (beta-sarcoglycan)¹⁰

References

1. Straub V et al. 229^th ENMC international workshop: Limb girdle muscular dystrophies – Nomenclature and reformed classification Naarden, the Netherlands, 17–19 March 2017. Journal of Neurmomuscular Disorders. Vol 28. Issue 8. 702-710. 2018.
2. Bouchard C, Tremblay JP. Limb-Girdle Muscular Dystrophies Classification and Therapies. J Clin Med. 2023 Jul 19;12(14):4769. Doi: 10.3390/jcm12144769. PMID: 37510884; PMCID: PMC10381329.
3. Chu ML, Moran E. The Limb-Girdle Muscular Dystrophies: Is Treatment on the Horizon? Neurotherapeutics. 2018 Oct;15(4):849-862. Doi: 10.1007/s13311-018-0648-x. PMID: 30019308; PMCID: PMC6277288.
4. https://rarediseases.org/rare-diseases/limb-girdle-muscular-dystrophies/#disease-overview-main. Last updated 10/1/2019
5. Limb-Girdle Muscular Dystrophy (LGMD) Syndromes. neuromuscular.wustl.edu.
6. Narayanaswami P, Weiss M, Selcen D. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. 2014 Oct 14;83(16):1453-63.
7. Tesi Rocha, C., Hoffman, E.P. Limb–Girdle and Congenital Muscular Dystrophies: Current Diagnostics, Management, and Emerging Technologies. Curr Neurol Neurosci Rep 10, 267–276 (2010). https://doi.org/10.1007/s11910-010-0119-1
8. Limb-Girdle Muscular Dystrophy, https://my.clevelandclinic.org/health/diseases/limb-girdle-muscular-dystrophy-lgmd
9. Hornyak JE, Pangilinan PH Jr. Rehabilitation of children and adults who have neuromuscular diseases. Phys Med Rehabil Clin N Am. 2007;18:883-897.
10. Mendell, J.R., Pozsgai, E.R., Lewis, S. et al. Gene therapy with bidridistrogene xeboparvovec for limb-girdle muscular dystrophy type 2E/R4: phase 1/2 trial results. Nat Med30, 199–206 (2024). https://doi.org/10.1038/s41591-023-02730-9

Original Version of the Topic

James T. Eckner, MD. Limb Girdle Muscular Dystrophies. 3/28/2013

Previous Revision(s) of the Topic

Lisa Williams MD. Limb Girdle Muscular Dystrophies. 4/5/2017

Lisa Williams, MD, Shailesh Reddy, MD, Olivia Tong, MD. Limb Girdle Muscular Dystrophies. 6/29/2021

Author Disclosure

Jasmina Solankee, MD
Nothing to Disclose

Rajashree Srinivasan, MD, MBBS
Nothing to Disclose