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Sections Limb-Girdle Muscular Dystrophy
Overview
Presentation
- History
- Causes
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DDx
Workup
Treatment
Guidelines
Follow-up
Questions & Answers
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Tables
References

Treatment

Medical Care

No specific treatment is available for any of the LGMD syndromes, though aggressive supportive care is essential. The AAN developed guidelines for treatment of LGMDs.^[65]

Cardiac involvement

Many LGMDs have associated cardiac disease. Newly diagnosed patients with LGMDs known to have cardiac involvement (LGMD1A, LGMD1B, LGMD1C, LGMD1E, LGMD2C-F, LGMD2G, LGMD2I, LGMD2M, LGMD2N, LGMD2R, LGMD2T, LGMD2U, LGMD2W, LGMD2X) should have early referral to a cardiologist. Cardiology referral should also be made for undiagnosed patients with LGMD.

Testing should include EKG and echocardiography. If these are abnormal or if cardiac symptoms develop, other tests may be needed including cardiac MRI, Holter monitoring, and event monitoring. Cardiac arrhythmias can be a major cause of morbidity and mortality (sudden cardiac death) and placement of a pacemaker can be a life-saving procedure.

Respiratory failure

Many LGMDs may have early respiratory involvement (LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD1F, LGMD2B, LGMD2C-F, LGMD2G, LGMD2I, LGMD2J, LGMD2K, LGMD2M, LGMD2N, LGMD2O, LGMD2R, LGMD2T, LGMD2U, LGMD2V, LGMD2W).

Pulmonary function testing should be done in the neurology clinic or through referral to a pulmonologist in most LGMD patients at time of presentation or when symptomatic.

Patients with excessive daytime sleepiness, frequent arousals, morning headache, or with shortness of breath or abnormal pulmonary function tests should be referred to a pulmonary or sleep medicine clinic for consideration of non-invasive ventilation.

Early intervention to treat respiratory insufficiency with non-invasive ventilation can help improve function and prolong the patient's life expectancy.

Dysphagia and nutrition

Patients with dysphagia, aspiration, or weight loss should be evaluated with a modified barium swallow by a speech pathologist.

Nutritional supplementation or enteral feeding (gastrostomoy tube) may be needed to maintain optimal nutrition and reduce the risk of aspiration pneumonia.

Spinal deformities

Skeletal abnormalities, such as scoliosis and contractures can result in discomfort and impairment of gait or activities of daily living.

Neurologists should monitor for these and refer appropriate patients to a physical therapist, orthotist, or orthopedic surgeon

Passive stretching, bracing, and orthopedic procedures can help to allow the patient to remain independent for as long as possible.

As for other hereditary myopathies, a team approach, including a neurologist, pulmonologist, cardiologist, orthopedic surgeon, physiatrist, physical/occupational/speech therapist, nutritionist, orthotist, and counselors, ensures the best therapeutic program.

Exercise can help to counteract the loss of muscle tissue and strength in LGMD. Though there is no certain evidences about the type, frequency, or intensity, a training with moderate (less than 70% of predicted maximal aerobic capacity) aerobic exercise seems to be useful and safe in muscular dystrophies.^[75]

Gene therapy using vectors based on the adeno-associated virus may become a viable treatment option in the future. Preliminary data using adeno-associated virus to deliver full-length α-sarcoglycan to the extensor digitorum brevis muscle in patients with LGMD2D resulted in 6 months of sustained α-sarcoglycan gene expression in 2 of 3 patients.^[76]Muscle fiber size increased, and, in the patients with sustained expression, there were no neutralizing antibodies or T-cell immunity to adeno-associated virus.

A phase 1 trial of a neutralizing antibody against myostatin provided evidence of safety and tolerability.^[77]

Surgical Care

Orthopedic surgery may be needed to help correct or prevent contractures and scoliosis.

Consultations

Guidelines issued by the American Academy of Neurology and the American Association of Neuromuscular & Electrodiagnostic Medicine call for referral of patients suspected of having MD to a specialist center for evaluation and genetic testing. Patients at high risk for cardiac complications should be given a cardiology evaluation, even if asymptomatic and those at known risk for respiratory failure should receive periodic pulmonary function testing.^{[64, 65]}

Additional consultation with the following may prove helpful:

Orthopedic surgeon
Pulmonologist
Cardiologist
Physiatrist
Physical/occupational therapist
Orthotist
Speech therapist/nutritionist

Activity

In general patients with LGMD lead a sedentary lifestyle due to their weakness. The effect of endurance training has been only rarely studied.

A study of endurance training on patients with LGMD2I and mild weakness was carried out. The patients cycled for 30 minute training sessions progressing up to a maximum of 5 sessions per week over 12 weeks at 65% of their maximum oxygen uptake. Training significantly improved work capacity, paralleled by self-reported improvements. Creatine kinase levels did not increase significantly, and muscle morphology was unaffected. The authors concluded that moderate-intensity endurance training is a safe method to increase exercise performance and daily function in patients with LGMD2I.

However, this was a small study, performed in only one form of LGMD, has not been replicated and lasted only 12 weeks. The long-term repercussions of endurance training in LGMD are not known and caution should be used in recommending endurance training for patients with LGMD.

Guidelines

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Media Gallery

Dystrophin-glycoprotein complex bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all sarcoglycans, dysferlin, and caveolin-3, as well as mutations that cause abnormal glycosylation of alpha-dystroglycan can result in limb-girdle muscular dystrophy syndrome. Reprinted with permission from Cohn RD. Dystroglycan: important player in skeletal muscle and beyond. In: Neuromuscular Disorders. Vol. 15. Cohn RD. Elsevier; 2005: 207-17. 7, 20
Schematic of the sarcomere with labeled molecular components that are known to cause limb-girdle muscular dystrophy or myofibrillar myopathy. Mutations in actin and nebulin cause the congenital myopathy nemaline rod myopathy, and the mutations in myosin cause familial hypertrophic cardiomyopathy. Image courtesy of Dr F. Schoeni-Affoher, University of Friberg, Switzerland.
Top: Photomicrograph shows normal alpha-sarcoglycan staining of a myopathic biopsy specimen. Note dark staining around the rims of the muscle fibers. Bottom: Alpha-sarcoglycan stain of a muscle biopsy specimen from a patient with alpha-sarcoglycan deficiency. Note the absence of staining at the rims of the muscle fibers. Patterns of staining similar to these are observed in all the sarcoglycanopathies, dysferlinopathy, calpainopathy and limb-girdle muscular dystrophy type 2I (LGMD2I, Fukutin-related proteinopathy). However, staining may be variably reduced or absent.
Gomori trichrome–stained section in patient with myofibrillar myopathy. Note the abnormal accumulations of blue-red material in several muscle fibers.
Immunohistochemical staining by using an anti-desmin antibody in a patient with a myofibrillar myopathy. Courtesy of Alan Pestronk.

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Table 1. Conditions that are no longer considered LGMD, as per the definition proposed by the 229th ENMC international workshop, 2017

Previous name	Gene	Reason for exclusion	Proposed new name
LGMD1A	Myot	Distal weakness	Myofibrillar myopathy
LGMD1B	LMNA	High risk of cardiac arrhythmias; EDMD phenotype	Emery–Dreifuss muscular dystrophy (EDMD)
LGMD1C	CAV3	Main clinical features rippling muscle disease and myalgia	Rippling muscle disease
LGMD1E	DES	Primarily false linkage; distal weakness and cardiomyopathy	Myofibrillar myopathy
LGMD1H	—	False linkage	Not confirmed
LGMD2R	DES	Distal weakness	Myofibrillar myopathy
LGMD2V	GAA	Histological changes	Pompe disease
LGMD2W	PINCH2	Reported in a single family	PINCH2-related myopathy
LGMD2X	BVES	As above	BVES-related myopathy
LGMD2Y	TOR1AIP1	As above	TOR1AIP1-related myopathy

Table 2. New classification of LGMD with relevant affected protein

LGMDD (previous name)

LGMDR (previous name)

LGMD D1-DNAJB6; 7q36 [LGMD1E, 1D]

LGMD D2-TNPO3; 7q32 [LGMD1F]

LGMD D3-HNRPDL; 4q21 [LGMD1G]

LGMD D4-Calpain-3; 15q15 [LGMD1I]

LGMD D5 (Bethlem):

COL6A1: 21q22

COL6A2: 21q22

COL6A3: 2q37

R1 (2A): Calpain-3; 15q15

R2 (2B): Dysferlin; 2p13

R3 (2D): α-Sarcoglycan; 17q21

R4 (2E): β-Sarcoglycan; 4q12

R5 (2C): γ-Sarcoglycan; 13q12

R6 (2F): δ-Sarcoglycan; 5q33

R7 (2G): Telethonin; 17q12

R8 (2H): TRIM32; 9q33

R9 (2I; MDDGC5): FKRP; 19q13

R10 (2J): Titin; 2q24

R11 (2K; MDDGC1): POMT1; 9q34

R12 (2L): ANO5; 11p14

R13 (2M; MDDGC4): Fukutin; 9q31

R14 (2N; MDDGC2): POMT2; 14q24

R15 (2O; MDDGC3): POMGnT1; 1p32

R16 (2P; MDDGC9): DAG1; 3p21

R17 (2Q): Plectin 1f; 8q24

R18 (2S): TRAPPC11; 4q35

R19 (2T): GMPPB; 3p21

R20 (2U): ISPD; 7p21

R21 (2Z): POGLUT1; 3q13

R22: COL6A2; 21q22

R23: LAMA2; 6q22

R24: POMGNT2; 3p22

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