Limb Girdle Muscular Dystrophy (LGMD)
Before the advent of genetic testing, a group of disorders in patients commonly sharing a progressive pattern of proximal greater than distal muscular weakness with either autosomal-recessive (LGMD2) or -dominant (LGMD1) inheritance were termed limb girdle muscular dystrophies. Recent advances in molecular and genetic analyses have now identified a number of distinct genetic mutations in these patients. LGMD1 subtypes usually have later onset in adulthood. LGMD2 usually present during childhood or adolescence, although some may present in early adulthood. Many of the LGMD2 subtypes have been linked to gene defects causing abnormalities of the sarcolemmal associated proteins including sarcoglycans (alpha-SG, gamma-SG, beta-SG, and delta-SG), dystroglycans, Calpain-3, dysferlin, fukutin-related protein (FKRP), telethonin, and titin. The most common LGMD2 subtypes include sarcoglycanopathies, dysferlinopathies, calpainopathies, and FKRP deficiencies. The distribution and pattern of weakness at onset most often affects the pelvic or shoulder girdle musculature or both. The rate of progression is slower than DMD (87,89,90). Clinical features of the most common forms of LGMD2 are shown in Table 18.2.
SARCOGLYCANOPATHIES (LGMD 2C-2F). Disruption of the sarcolemmal membrane cytoskeleton is a common feature of sarcoglycanopathies. Most of the primary sarcoglycan abnormalities lead to secondary deficiencies of alpha-sarcoglycan. The CK levels are markedly elevated. A Duchenne-like phenotype in a female should raise a suspicion of a sarcoglycanopathy. Diagnosis of sarcoglycanopathies may be made with molecular genetic studies and immunohistochemical analysis of muscle biopsies. The age of onset of sarcoglycanopathies ranges from 2 to 15 years. Progression is variable with both more severe and milder phenotypes. Loss of ambulation may vary from 10 years to young adulthood. Weakness involves proximal greater than distal musculature. Calf pseudohypertrophy
TABLE 18.2 CHARACTERISTICS OF AUTOSOMAL-RECESSIVE LIMB GIRDLE MUSCULAR DYSTROPHIES (AR-LGMDS)
scapular winging, progressive contractures, and scoliosis often occur (89). A dilated cardiomyopathy may occur particularly in alpha-SG and delta-SG. Intelligence is often normal.
DYSFERLINOPATHIES (LGMD 2B). Dysferlin is a skeletal muscle protein localized in the muscle cell membrane (91). It is involved in muscle contraction and contains C2 domains that play a role in calcium-mediated membrane fusion events, suggesting that it may be involved in membrane regeneration and repair. Specific mutations in this gene have been shown to cause autosomal-recessive limb girdle muscular dystrophy type 2B (LGMD2B) with proximal muscle involvement as well as Miyoshi myopathy which presents with distal weakness involving the distal legs including the gastrocnemius and soleus muscles (89). In LGMD 2B no specific genotype-phenotype correlations have been established. Patients show markedly elevated CK from 10 times normal to approximately 30,000. Onset is from age 10 to 39 years. Mild weakness occurs in a distal lower extremity and/or pelvic-femoral distribution. Weakness is usually mild early in the course of disease. Proximal leg weakness associated with exercise is common. Asymmetrical weakness is common. Distally the gastrocnemius weakness may cause the inability to toe walk and run. Proximally the glutei, quadriceps, and psoas are affected. The lower limbs are involved 9 to 10 years before upper limbs. The shoulder girdle and biceps are often affected with sparring of the deltoids. In the trunk the erector spinae are affected. The face is generally normal. There is atrophy of the pelvic and shoulder girdle muscles. Equinus contractures are common. There is no scapular winging. Loss of ambulation is typically after 30 years. Respiratory muscles are affected with longer disease durations. Cardiac function is spared. Intelligence is normal.
CALPAINOPATHIES (LGMD 2A). Heterogeneous dystrophies due to mutation of the Calpain-3 gene are termed calpainopathy (90). Calpain-3 is a nonlysosomal calcium-dependent proteinase specifically expressed in muscle. Muscle biopsies reveal that calpainopathy patients have normal dystrophin and sarcoglycan labeling, but lack Calpain-3. Some may present with asymptomatic hyperCKemia. Labs show normal to markedly elevated CK up to 11,000. Toe walking is often a presenting sign. The age of presentation is 6 to 18 in 70% of patients. An early-onset form occurs before 12 years of age and has the most severe progression. The "Leyden-Mobius" subtype has an onset between 13 and 30 years and weakness is in the pelvic-femoral girdle distribution. In a rare subset with Erb dystrophy type there is scapular-humeral weakness, the onset age is 16 to 37 years, and weakness presents early in the shoulder girdle. The Miyoshi muscular dystrophy phenotype may be caused by Calpain-3 deficiency and those individuals present with gastrocnemius weakness and wasting. Others with later onset have been reported. The general pattern of symmetrical weakness in
Calpainopathy involves scapula, pelvic girdle and trunk weakness with normal facial strength. Milder distal weakness is common and lower extremity weakness is greater than upper extremity at the outset. Weakness of the rectus abdominis is common as is symmetric scapular winging. Lower extremity weakness affects the gluteus maximus, hip abductors, knee flexors, and ankle dorsiflexors while upper extremity weakness is seen in shoulder adduction; elbow flexion, and wrist extension. Hip adductors may be spared. The quadriceps, face, ocular and bulbar muscles are selectively spared. FVC declines over time but is rarely less than 80%. Progression is slow and patients demonstrate an inability to walk on heels, lumbar lordosis, and loss of walking typically occurs in the late second or third decade. Scapular winging is usually present from the early stages. The rate of deterioration varies between families. Wheelchair dependency typically occurs at 10 to 30 years after the onset of symptoms. The disease is predominantly symmetrical and atrophic, with prominent calves seen in only a minority of cases. Achilles tendon contractures may be an early sign, and spine deformity may also develop. Respiratory, but not cardiac, complications have been reported.
FUKUTIN RELATED PROTEIN—FKRP (LGMD 21). This dystrophy is caused by pathogenic mutations in the gene for FKRP, which is involved in the glycosylation of cell surface molecules in muscle fibers (91). The majority of the LGMD2I patients carry a common C826A missense mutation in the FKRP gene. In the LGMD 21 patients, different mutations in the FKRP gene are associated with several secondary muscle protein reductions and the deficiencies of oc2-laminin and a-DG on sections are prevalent, independent of the mutation type or the clinical severity. Onset ranges from 0.5 to 27 years with 61% less than 5 years. Onset may be at birth in patients with congenital muscular dystrophy syndrome (MDC1C), an allelic disorder. Weakness presents with waddling gait, difficulty with stairs, hypotonia, greater proximal than distal weakness of the legs and arms, and mild facial weakness in some older patients. Respiratory failure has been reported in 30%, occasionally occurring in the ambulant. The onset may be variable with intrafamilial variability described. Patients with early onset become nonam-bulant by teenage years. In those with later onset, they become nonambulant by the fourth to the sixth decade. Serum CK is elevated. Contractures are often at the ankles and more common in nonambulant patients. Scoliosis occurs in some. Cardiomyopathy is common in up to 80% and echocardiography may show a dilated left ventricle with mild LV failure. The cardiomyopathy shows no relation to skeletal muscle severity. Intelligence is preserved, although structural brain changes have been reported.
LAMIN A/C (LGMD 1B). Lamin A/C deficiency may present in those younger than 20 years with symmetric, proximal weakness of the lower limb, and slow progressive weakness. The upper limbs are involved by the third or the fourth decade. There are typically no contractures. Cardiomyopathy has been reported in approximately 60% manifested by A-V conduction block and occasional dilated cardiomyopathy. Serum CK is normal to mildly elevated.
CAVEOLIN-3 (LGMD 1C). Onset may occur from 5 years to adulthood. Weakness is usually proximal and moderate in severity, There is difficulty walking, progression is slow, and some adults may present with a Gower's maneuver. Calf hypertrophy is often observed and a history of cramps after exercise is reported. The CK values are elevated 3 to 40 times. Variable clinical manifestations may occur in a single family. Caveolin-3 mutations have been linked to variant syndromes including hyperCKemia, rippling muscle disease, distal myopathies, dilated hypertrophic cardiomyopathy, and long QT syndrome.