Limb-Girdle Muscular Dystrophy (LGMD)

Genetically transmitted neuromuscular disorder characterized by progressive proximal muscle weakness.

There are two types and numerous variants of LGMD.

Type I

• Limb-Girdle Muscular Dystrophy Type IA (Proximal Muscular Dystrophy): Autosomal dominant disorder characterized by adult onset of proximal muscle weakness, beginning in the hip girdle region and later progressing to the shoulder girdle region. Distal muscle weakness may occur later. Some affected individuals exhibit a distinctive nasal, dysarthric pattern of speech.
• Limb-Girdle Muscular Dystrophy Type IB: Characterized by cardiac involvement and symmetrical weakness in the proximal lower-limb muscles before age 20 years. In the third or fourth decade, upper-limb muscles gradually become affected. Early contractures of the spine and contractures of elbows and Achilles tendons are minimal or late, distinguishing this disorder from Emery-Dreifuss muscular dystrophy.
• Limb-Girdle Muscular Dystrophy Type IC: Characterized with onset of disease around age 5 years. Calf hypertrophy, mild-to-moderate proximal muscle weakness, multiple episodes of muscle cramps after physical effort, and serum creatinine kinase levels more than 4to 25-fold normal values are present.
• Limb-Girdle Muscular Dystrophy Type ID: Characterized with a slowly progressive LGMD. Onset is believed to occur between the second and sixth decade, with hip girdle involvement preceding shoulder girdle involvement. It is inherited as an autosomal dominant pattern.
• Limb-Girdle Muscular Dystrophy Type IE: Characterized by severe dilated cardiomyopathy with conduction defect. The age of onset is during the adulthood period and most often presents as progressive and severe muscle weakness of the lower extremities. Other clinical features include progressive dyspnea over years, becoming very severe even at rest, syncopal episodes due to complete heart block, and sudden death. An echocardiography always demonstrates dilatation of all four chambers of the heart.
• Limb-Girdle Muscular Dystrophy Type IF: Characterized by pelvic and shoulder girdle proximal weakness. Pelvic girdle impairment is more severe and occurs earlier than shoulder girdle weakness. Distal weakness often occurs later. Respiratory muscles are clinically affected, especially in the juvenile onset group.

Type II

• Limb-Girdle Muscular Dystrophy Type IIA (Pelvofemoral Muscular Dystrophy; Leyden-Moebius Muscular Dystrophy; Calpainopathy): Occurs usually in childhood but sometimes in young adult or middle age period. Muscular involvement is first evident in either the pelvic or, less frequently, the shoulder girdle. It manifests often with asymmetry of muscle wasting when the upper limbs are first involved.
• Limb-Girdle Muscular Dystrophy Type IIB: Characterized by slowly progressive muscular weakness of the lower limbs (distal and proximal) beginning in the late part of the second decade of life. Patients had markedly elevated serum creatine kinase levels, and two of the four patients from whom muscle biopsies were available demonstrated an inflammatory process, a finding not previously described in LGMD.
• Limb-Girdle Muscular Dystrophy Type IIC (Duchenne-like Muscular Dystrophy; Secondary Adhalin Deficiency; North African Severe Childhood Autosomal Recessive Muscular Dystrophy type; Sarcoglycan Deficiency): Autosomal recessive inheritance of muscular dystrophy resembling the X-linked Duchenne type with onset before 5 years, confinement to wheelchair by 12 years, and death usually before 20 years. Pseudohypertrophy is present. Chronic congestive heart failure and severe arrhythmias have been described.
• Limb-Girdle Muscular Dystrophy Type IID (Duchenne-like Autosomal Recessive Muscular Dystrophy; Primary Adhalinopathy): Characterized by a progressive form of muscular dystrophy including proximal muscle weakness beginning at approximately age 10 years, associated with calf hypertrophy and elevated serum creatine kinase.
• Limb-Girdle Muscular Dystrophy Type IIE: Characterized by severe cardiomyopathy resulting from mutations in β-sarcoglycan. Cardiac function should be monitored in patients with LGMD and defective sarcoglycan expression.
• Limb-Girdle Muscular Dystrophy Type IIF: Characterized by a severe clinical phenotype and muscle biopsy revealing the absence of α-sarcoglycan.
• Limb-Girdle Muscular Dystrophy Type IIG: Characterized by early involvement of the distal muscles, mildly elevated serum creatine kinase levels, and rimmed vacuoles in muscle biopsies. It has been suggested that this form resembled autosomal recessive Kugelberg-Welander disease. The mean age at onset has been 12.5 years in most patients. All had difficulty with walking, running, and climbing stairs. Extraocular and facial muscles are spared.
• Limb-Girdle Muscular Dystrophy Type IIH (Hutterite Muscular Dystrophy): Characterized by the combination of a slowly progressive muscular dystrophy with facial features of the facioscapulohumeral type and the proximal distribution of the limb-girdle type. Onset is between 1 and 9 years of age, and the quadriceps and pelvic girdle musculature are most involved. Waddling gait and difficulty rising from the squatting position result.
• Limb-Girdle Muscular Dystrophy Type II I: Characterized by late clinical onset with absence of merosin on immunoblotting but normal merosin on immunocytochemistry. It involves muscle weakness, initially the proximal muscles of the lower limbs between the ages of 17 and 40 years. Hypertrophy of the calf muscles, absence of scapular winging, and predominant involvement of hip flexors and hamstrings more than quadriceps. Serum creatine kinase is at least 10 times normal, and muscle biopsies show nonspecific dystrophic features.
• Limb-Girdle Muscular Dystrophy Type IIJ: Characterized by late-onset distal tibial myopathy. It is confirmed by nonspecific myopathic changes on muscle biopsy and progressive fatty infiltration of involved muscles. Onset of the severe LGMD phenotype form usually presents between the first and third decades and involves weakness of all proximal muscles. Within 20 years, patients present with severe disability and complete loss of ambulation. There is no facial muscle involvement or cardiomyopathy in this type of muscular dystrophy. It has been suggested that the mild form of the disease is inherited as an autosomal dominant pattern, whereas the severe limb-girdle muscular dystrophy is inherited as an autosomal recessive pattern.
• Limb-Girdle Muscular Dystrophy Type IIK: Characterized by an autosomal recessive muscular dystrophy and severe mental retardation. All patients acquire early motor milestones; however, there is no congenital muscular dystrophy. The age at onset ranges from 1 to 6 years, and the clinical presentation is confirmed by difficulty in walking and climbing stairs. Other clinical features include slow progression, proximal muscle weakness, mild muscle hypertrophy, increased serum creatine kinase, microcephaly, and mental retardation (IQ range 50-76). Magnetic resonance imaging of the brain shows normal structures in all cases. Skeletal muscle biopsy shows dystrophic changes, including mild fibrosis with many regenerating and few necrotic fibers, increased fiber size variability, and multiple central nuclei.

Overall frequency ranges between 5 and 70 per one million population. No sex or racial predominance in either autosomal dominant or recessive forms.

LGMDs are classified as autosomal dominant (LGMD I, A-F) and recessive (LGMD II, A-H) syndromes. Additionally, there are rare X-linked forms (Barth syndrome, McLeod syndrome). Autosomal dominant, recessive, and familial variants. Type I is familial and is transmitted as an autosomal dominant trait: type IA is linked to the chromosome 5 (gene unidentified); type IB to chromosome 1 (gene unidentified); type IC to chromosome 3 (caveolin-3 gene); and type ID to chromosome 7 (gene unidentified). Type II is transmitted as an autosomal recessive trait: type IIA is caused by a mutation in the calpain-3 gene of chromosome 15 (15q15.1-q21.1); type IIB is caused by a mutation in the dysferlin gene on chromosome 2; type IIC is caused by a mutation in the γ-sarcoglycan gene on chromosome 13; type IID is caused by a mutation in the α-sarcoglycan (adhalin) gene on chromosome 17; type IIE is caused by a mutation in the β-sarcoglycan gene on chromosome 4; type IIF is caused by a mutation in the δ-sarcoglycan gene on chromosome 5; type IIG is caused by an unidentified gene mutation on chromosome 17; and type IIH is caused by an unidentified gene mutation on chromosome 9 in Manitoba Hutterites.

Bethlem myopathy is caused by mutations on either chromosome 21 or 2 in one of the three subunits of type VI collagen; dilated cardiomyopathy with conduction defect and muscular dystrophy has been linked to chromosome 6 (gene unidentified).

LGMD result in abnormal dystrophin-glycoprotein complex that bridges the inner cytoskeleton (F-actin) and the basal lamina. Mutations in all the sarcoglycans and several other members of the complex result in a muscular dystrophy. Limb-girdle muscular dystrophy is a generic term for muscular dystrophies that are distinct from the much more common X-linked dystrophinopathies (Duchenne muscular dystrophy). Patients with LGMD generally show weakness and wasting restricted to the limb musculature, proximal greater than distal. Most patients with LGMD show relative sparing of the heart and bulbar muscles, although exceptions occur, depending on the genetic subtype. Onset, progression, and distribution of the weakness and wasting vary considerably among patients and genetic subtype. This produces a progressive disorder involving pelvic and scapular girdle muscles marked by weakness of proximal muscles of hip and shoulder areas with variable psychiatric disorders and occasional mild mental retardation. The disorder is bilateral, symmetrical, and very selective; the face muscles are not affected. The muscle selectivity persists throughout the course of the disease. Muscle wasting tends to be asymmetrical when the upper limbs are first involved. The progression of the disease varies with inability to walk, usually occurring approximately 20 to 30 years after onset. Facial weakness and contractures may occur later. Limb-girdle muscular dystrophy Type II I is a slowly progressive form of muscular dystrophy that involves the pelvic girdle, with onset in the late teens.

Elevated creatine phosphokinase (CPK) in plasma. Limb-girdle muscular dystrophy typically shows degeneration/regeneration of muscle (dystrophic biopsy) without dystrophin disorders. Biochemical testing (i.e., protein testing by immunostaining) performed on a muscle biopsy can establish the diagnosis of sarcoglycanopathy, calpainopathy, dysferlinopathy, and telethoninopathy. Demonstration of complete or partial deficiencies of any particular protein can be followed by mutation studies of the corresponding gene on a research basis only.

Progressive dystrophy of muscles forming the pelvic and shoulder girdles, pseudohypertrophy of calves, facial weakness, and weakness of proximal leg, shoulder, biceps, and brachioradialis muscles. Mental retardation, with depression, substance abuse, depersonalization, psychotic disorders, dysthymia, and obsessive behavior are frequent. Difficulty in climbing stairs and holding hands above head are typical.

There does not appear to be any literature specifically about this condition and anesthesia, but certain considerations are very important to mention. Weakness of muscles can be extensive and generalized. Complete workup is required, including neurologic and motor milestones, family history, and previous problems. Cardiac function should be assessed in light of the potential for cardiomyopathy (although rare with limb-girdle variants). Respiratory function should be checked by chest radiographs and arterial blood gas analysis the need for physiotherapy preoperatively likely will be of benefit to those with affected respiratory muscles (rare).

Postoperative mechanical ventilation may be necessary in severe patients. Delayed respiratory failure may occur. Favor regional techniques whenever possible for postoperative pain relief instead of opiates. Remember the possibility of severe cardiac disease. There may be a need for pacing and pharmacological therapies, so equipment for pacing should be ready. However, these interventions may not be necessary because there is a low incidence of cardiac and respiratory muscle disease. Realize that cardiac, respiratory, and other system involvement is common with closely related syndromes and should be planned for if not ruled out.

Succinylcholine use may cause rhabdomyolysis, cardiac arrest as a result of hyperkalemia, and possibly malignant hyperpyrexia, so it is not recommended. Use minimal drug dosages. Avoid respiratory depressants or muscle relaxants as much as possible.

Duchenne and Becker Muscular Dystrophies: X-linked recessive inherited dystrophinopathies (dystrophin is normal in LGMD patients).

Fascioscapulohumeral Muscular Dystrophy (FSH): Autosomal dominant disorder, often included in LGMD, that is characterized by marked weakness of the facial muscles and the stabilizers of the scapula or the dorsiflexors of the foot. The diagnosis is established by molecular genetic testing. Approximately 95% of patients have detection of integral copies of a 3.3-kb DNA repeat motif termed D4Z4.

Emery-Dreifuss Muscular Dystrophy (EDMD): Often included in LGMD. It can be inherited as an autosomal recessive, autosomal dominant, or X-linked recessive manner. It is a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system. It is caused by an autosomal dominant mutation in the laminin A/C gene (LMNA). There is an autosomal recessive form without cardiac involvement that is caused by a mutation in the emerin gene.

Congenital Muscular Dystrophy: Dystrophy caused by a complete loss of function of the laminin alpha 2 gene in 50% of cases. Patients typically have white matter changes in the brain that are visible on MRI as a result of altered water distribution in the white matter secondary to blood-brain barrier dysfunction, which is a result of merosin deficiency in the vasculature.