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1. 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 muscular dystrophies. LGMD refers to a broad and increasingly heterogeneous group of genetic disorders characterized by postnatal onset an progressive weakness. In most cases, the weakness is predominantly symmetric and typically effects the pelvic and/or shoulder girdle musculature. LGMD is autosomally inherited and classified into two major subtypes: Autosomal dominant LGMD type 1 (LGMD1), and autosomal recessive LGMD type 2 (LGMD2) .1 LGMD is distinct 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, even though there is some overlap in the causative genes for CMD and EDMD in particular.

Etiology

Currently, there are more than 30 different known LGMDs including the eight dominant (LGMD1A-H) and 23 recessive (LGMD2A-Y) types. In naming, the terminal letter is added based on the identification of a distinct familial phenotype and/or gene locus. Note that the same letter used for LGMD1 and LGMD2, does not indicate the same gene;  LGMD1A has a different genetic defect than LGMD2A.  Lettering will probably go from Z to AA, AB, etc. once the limit of the current system is exceeded.

Epidemiology including risk factors and primary prevention

LGMDs are individually rare diseases but combined represent the fourth most common form of muscular dystrophy with a minimum prevalence ranging from 0.07 per 100,000 to 0.43 per 100,000.  Variable specific diagnostic criteria for LGMD makes accurate reporting of prevalence complicated. The incidence of each subtype varies geographically. LGMD2A (calpainopathy) is thought to be the most common form of LGMD in the United States and accounts for 12-30% of all LGMD cases. The second most common LGMD is sarcoglycanopathy including  2C-2F; 2B (dysferlinopathy) and 2I (FKRP) are also relatively common. Of the dominant LGMDs, LGMD1B is the most common. More discoveries of genetic variations may alter prevalence estimates in the future. Table 1 summarizes the specific typical features of LGMD1 and LGMD2. Of note, phenotypic presentation may be variable depending on location and type of mutation within the gene or even within families.1

Patho-anatomy/physiology

A wide variety of cellular functions may be affected in each of the LGMDs, depending on the genetic defect. The following table lists known defects. 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.

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. 2,3,4,5

Table 1: Limb-girdle muscular dystrophy type 1: Autosomal dominant

DiseaseGene / defective proteinOnsetCK LevelProgressionMuscular FindingsExtramuscular Findings
LGMD1AMYOT/MyotilinAdulthoodNormal to HighSlowScapular-humeral-pelvic

Distal Weakness;

Rimmed vacuole;

Ankle contractures

Peripheral Neuropathy;

Cardiomyopathy;

Nasal speech / dysarthria

LGMD1BLMNA/Lamin A/CYoung child- to adulthoodNormal to Mildly HighSlowSymmetric weakness;

lower limb early;

upper limb late; Spinal rigidity; late contractures

 

Cardiomyopathy;

Arrhythmia

LGMD1CCAV3/Caveolin-3childhood to adulthoodMildly High to Very HighSlow / ModerateRippling muscles; percussion induced rapid contractions;

Distal or proximal weakness;

Calf hypertrophy;

Rhabdomyolosis

Cardiomyopathy;

Long Q-T syndrome

 

LGMD1DDNAJ or HSP40 /

heat shock protein 40

Childhood to late AdulthoodNormal to moderately HighSlowLower limb>upper limb;

Proximal>distal or distal >proximal;

Cramps;

Rimmed Vacuoles

Dysphagia (20%)

 

LGMD1EDES/Desmin

 

AdulthoodMild to moderately elevatedSlowProximal weakness;

Calf hypertrophy;

Rimmed vacuoles

Cardiomyopathy;

Arrhythmia;

Respiratory insufficiency;

Sudden death without prior cardiac symptoms

LGMD1FTMPO3/Transportin-3Young child- to adulthoodNormal to mildly highRapid in youngerEarly proximal weakness;

Legs>Arms

contractures;

Spinal deformities;

Rimmed vacuoles

Respiratory insufficiency in younger onset
LGMD1GHNRNPDL/

Heterogenous ribonucleoprotein D-like protein

Adolescence to AdulthoodNormal to very highSlowProgressive finger and toe flexion limitation; Cramps;

Rimmed vacuoles

Cataracts
LGMD1HUnknown, localized to

3p25.1-p23

Child- to adulthoodNormal to highSlowProximal; lower>upper limbs;

Calf hypertrophy; ragged red fibers; multiple mitochondrial DNA deletions in muscle

 

Table 2: Limb-girdle muscular dystrophy type 2: Autosomal Recessive

DiseaseProtein DefectOnsetHyper
CKemia
ProgressionMuscular FindingsExtramuscular findings
LGMD2ACAPN3 / Calpain-3AdolescenceHigh to very highModerate / rapidProximal legs / Rectus abdominus / Peri-scapular; contracturesNormal or mild cognitive impairment
LGMD2BDYSF / DysferlinYoung adulthoodVery highSlowAsymmetric weakness; preference for biceps with spared deltoid;

Absent or reduced dysferlin staining on muscle biopsy

Respiratory insufficiency with earl onset;
LGMD2CSGCG / γSarcoglycanEarly childhood 

 

 

 

 

Very high

Moderate / RapidCalf hypertrophy; lumbar hyperlordosis; scapular winging;  tongue hypertrophy; sparing of quadricepsRespiratory insufficiency; Hearing loss; Cardiomyopathy later in disease course
LGMD2DSGCA / αSarcoglycanEarly childhoodVery highRapidQuadriceps involvement; calf hypertrophyCardiomyopathy
LGMD2ESGCB / βSarcoglycanEarly childhoodVery highRapidTongue hypertrophy; Muscle hypertrophyCardiomyopathy
LGMD2FSGCD / δSarcoglycanEarly childhoodVery highRapidCalf hypertrophy; crampsCardiomyopathy
LGMD2GTCAP / Telethonin or titin-capAdolescenceHigh to very highSlowCalf hypertrophy or atrophy; normal or weak facial muscles; crampsCardiomyopathy
LGMD2H (Manitoba Hutterite Dystrophy)TRIM32 / tripartite motif containing protein-32AdulthoodHighSlowVariable 
LGMD2IFKRP / fukutin releated proteinLate child- to adulthoodVery highVariableFacial involvement later in disease; can be asymmetric; exertional pain / cramps limbs; myoglobinuriaRespiratory failure -30%
LGMD2JTTN / TitinYoung adulthoodHighRapidCan be asymmetric 
LGMD2KPOMT1 / protein O-manno syltransferase 1ChildhoodVery highSlowAnkle joint contractures – 50%Impaired cognition
LGMD2LANO5 / Anoctamin 5Young to late adulthoodNormal to very highSlowAsymmetric; legs > arms;  can have facial involvement; normal strength in distal arms; 
LGMD2MFKTN / FukutinEarly childhoodVery highModerateLegs > arms; mild to moderate facial involvement 
LGMD2NPOMT2 / protein O-mannosyl transferase 2Early childhoodHighSlowCalf hypertrophy; scapular winging; skeletal lordosis 
LGMD2OPOMGnT1 / protein O-glucosaminyl transferaseEarly to late childhoodMildly elevatedModerateCongenital hypotoniaMyopia; glaucoma; juvenile cataracts; retinal dysplasia; severe mental retardation;
LGMD2PDAG1 / Alpha dystroglycanEarly childhoodVery HighSlowContractures commonMental Retardation (mild-severe); small head circumference
LGMD2QPLEC/PlectinEarly childhoodModerate to highModerateAtrophic musculature and  contractures late 
LGMD2RDES / DesminEarly adulthoodModerate to highModerateProximal and distal weakness; facial muscle involvement; scapular wingingHigh arched palate; scoliosis; A-V block; cardiomyopathy; Respiratory insufficiency
LGMD2STRAPPC11 / Trafficking particle subunit complex, subunit11Early to late childhoodHighModerateLegs>ArmsMovement disorder and intellectual disability; seizures
LGMD2TGMPPB / GDP-mannose pyrophosphorylase, beta subunitBirth to adulthoodModerate to highSlowRhabdomyolysis and crampsCardiomyopathy-rare; impaired cognition (50%)
LGMD2UISPD / isoprenoid-synthase domain-containing protein<1 year oldVery HighModerateProximal weaknessMyopia; Oculomotor apraxia; cerebellar hypoplasia;
LGMD2VGAA / Acid maltase (late-onset Pompe variant)Late childhood to early adulthoodVariableVariableRigid spine; distal contractures; scapular winingPtosis; bulbar weakness; Respiratory insufficiency; diaphragm involvement; cardiomyopathy
LGMD2WLIMS2 / LIM and senescent cell antigen-likedomain 2, aka  PINCH2 / Particularly interesting CYS-HIS protein 2ChildhoodVery HighVariableGeneral atrophy;

Calf hypertrophy

Macroglossia / Triangular shaped tongue; cardiomyopathy
LGMD2XBVES / Blood vessel- epicardial substance aka POPDC1 / Popeye domain-containing protein 1AdulthoodHighVariableSymmetric proximal weaknessCardiac syncope; A-V block
LGMD2YTOPAIP1 / TorsinA-interacting protein 1First decadeNormal to moderately elevatedVariableContractures of distal and proximal interphalangeal joints

Rigid Spine

Cardiomyopathy

 

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: Cardiomyopathy ranges from rare (e.g., LGMD2A) to common and severe (e.g., LGMD2C-LGMD2, LGMD2R, LGMD2T, LGMD2V-LGMD2Y).5 Rhythm disturbances are less common but may also occur in these types. Patient’s should be followed regularly, at least annually, by cardiology. An echocardiogram should be performed at disease onset and routine screening echocardiograms and/or holter monitor studies should be performed routinely. Afterload reducing and cardio-protective agents may be considered.

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: Patient 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).

2. 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. Both males and females are equally affected, in contrast to dystrophinopathy.
  • Development: in children, note time to attain developmental milestones (eg, rolling, sitting, cruising, walking, speaking). [changed order]
  • 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 System:

  • 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.

Neurological:

  • 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:

  • Distance able to walk and rate of speed if ambulatory.
  • Quality of gait: proximal weakness typically results in waddling (Trendelenberg) 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:

  • Question regarding 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): normal to very high (e.g. 80-100 times normal), depending on subtype. May decline with age due to a decrease in muscle mass. Aldolase is usually proportional to CPK expect in primary inflammatory disease where it may be the more substantially elevated.
  • Note that SGOT and SGPT are also muscle enzymes and will be elevated proportionally to the CPK. GGT is more specific to liver disease and is recommended if there is any concern for hepatic disease. Alkaline phosphatase and bilirubins can also be checked, but unnecessary infectious and autoimmune hepatitis panels and liver biopsies should be avoided.
  • Gene panels for sequencing and deletion-duplication in the known genes causing limb girdle muscular dystrophy may be ordered, and whole exome sequencing (WES) and other next-generation sequencing may be considered. An option with no cost to the patient/family is currently available through LGMD.org for a basic sequencing panel currently including 35 genes.

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, myotonic, 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.

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. 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.

3. 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.

Corticosteroid treatment is the mainstay of management of Duchenne muscular dystrophy. It may be indicated in a few subtypes of LGMD, most notable, LGMD2I, at half the dose for dystrophinopathy. 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. 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,7 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. [omit] 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 as long as 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 the North Star 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

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 common known phenotype (e.g., Duchenne or Becker muscular dystrophy, FSHD, spinal muscular atrophy, congenital or [omit] 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.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Whole genome sequencing (WGS) and other next generation sequencing including “exome slices” may allow for accurate and early diagnosis especially if the clinical picture and initial studies are negative or unclear.  It is important to differentiate between pathologic and benign mutations in each gene for the various LGMDs.8 Family “trio” sequencing may be helpful in that regard, as well as various online protein predictive tools. Also, reanalysis of WES and WGS can be requested as new causative genes are regularly discovered.  Searches of and contribution to online databases such as Leiden and HGVS may also be helpful.

Genetic therapies are being offered in clinical trials and some may soon be available for clinical use with these conditions, as has begun for dystrophinopathy.

  • Examples of other molecularly targeted therapies being assessed in human trials include:
  • Neutralizing antibody to myostatin, an endogenous inhibitor of muscle growth, may increase muscle mass in some LGMDs. Phase 1 clinical trials have been completed for safety and tolerability.6
  • Epicatechin is a compound found in dark chocolate and green tea which may improve mitochondrial function in some forms of limb-girdle muscular dystrophy. It has been studied in sarcoglycan null mouse models and found to slow heart and skeletal muscle degeneration.9
  • Enzyme replacement therapy is available for late-onset Pompe disease (LGMD2V.)

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

A recent Cochrane review found limited evidence for the benefit of serial casting in Duchenne muscular dystrophy, but it is more challenging to provide evidence-based treatments for specific rare disorders. Evidence for rehabilitation therapies for more common disorders may need to be extrapolated to LGMD. Optimal routes to early diagnosis and the continuing role of electrodiagnosis, biopsy, and muscle imaging are not currently well defined. WES and WGS currently take several months to be completed, and indications may continue to change as that interval is reduced.

REFERENCES

Bibliography

Mah JK, Korngut L, Fiest KM. A Systematic Review and Meta-analysis on the Epidemiology of the Muscular Dystrophies. Can J Neurol Sci. 2016 Jan;43(1):163-77. doi: 10.1017/cjn.2015.311.

Thompson R, Straub V. Limb-girdle muscular dystrophies— international collaborations for translational research. Nat Rev Neuro 2016;12:294-309.

Wicklund MP, Kissel JT. The limb-girdle muscular dystrophies. Neurol Clin 2014;32:729-749.

Liewluck T. Genetics of Limb-Girdle Muscular Dystrophies. AANEM Course Book. 2016.

Limb-Girdle Muscular Dystrophy (LGMD) Syndromes. neuromuscular.wustl.edu.

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.

Hornyak JE, Pangilinan PH Jr. Rehabilitation of children and adults who have neuromuscular diseases. Phys Med Rehabil Clin N Am. 2007;18:883-897.

Reddy HM, Cho KA, Lek M. The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States. J Hum Genet. 2016 Oct 6. doi: 10.1038/jhg.2016.116.

Ramirez-Sanchez I, De los Santos S, Gonzalez-Basurto S. –)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic d-sarcoglycan null mouse striated muscle. FEBS. 2014. 281; 5567-5580.

Darin N1, Kroksmark AK, Ahlander AC, Moslemi AR, Oldfors A, Tulinius M., Inflammation and response to steroid treatment in limb-girdle muscular dystrophy 2I, Eur J Paediatr Neurol. 2007 Nov;11(6):353-7. Epub 2007 Apr 18.  https://www.ncbi.nlm.nih.gov/pubmed/17446099/

OMIM, http://omim.org/

Leiden Muscular Dystrophy Pages, http://www.dmd.nl/

Original Version of the Topic

James T. Eckner, MD. Limb Girdle Muscular Dystrophies. 03/28/2013.

Author Disclosure

Lisa Williams, MD
Nothing to disclose