Table 1.

Autosomal dominant limb–girdle muscular dystrophy

LGMD subtype	Gene	Onset	Phenotypes
LGMD 1A	MYOT Myotilin	18–35 years	• Weakness of the scapular–humeral–pelvic muscles • Distal leg weakness, occasional arm weakness • Cardiomyopathy may be seen • Distinct feature: nasal dysarthria and hypophonia • CK: normal or elevated (up to 9× normal) • Muscle biopsy: rimmed vacuoles often seen, occasional nemaline rod-like inclusions may have features of myofibrillar myopathy
LGMD 1B	LMNA Lamin A/C	5–25 years	• Weakness in scapular and pelvic girdle muscles—usually early in the second decade of life • Contractures affecting posture and gait—can precede muscle weakness • Dilated cardiomyopathy and conduction system defects associated with high risk of cardiac sudden death, may precede muscle weakness • CK: normal or mildly elevated (< 5× upper limit of normal) • Muscle biopsy: usually nonspecific; may have dystrophic features Note: LMNA mutations can present with variable phenotypes including LGMD, AD-EDMD, DCM (dilated cardiomyopathy), heart–hand syndrome, Dunnegan lipodystrophy, mandibuloacral dysplasia, restrictive dermopathy, axonal neuropathy (CMT2B1), and metabolic syndrome. 3 myopathic phenotypes of LMNA: LGMD1B, EDMD2, and LMNA-CMD
LGMD 1C	CAV3 Caveolin 3	1st decade–late adulthood	• 6 distinct phenotypes:  ○ Proximal weakness or exertional myalgias associated with calf hypertrophy  ○ Rippling muscle disease  ○ Distal myopathy  ○ Asymptomatic hyperCKemia  ○ Familial hypertrophic cardiomyopathy without skeletal muscle weakness  ○ Muscle pain, exercise intolerance and rhabdomyolysis [8] • Intra-familial variability and rate of progression • Cardiac involvement is common • CK: elevated (450–5000) • Muscle biopsy: generally normal but may include variability in fiber size, muscle degenerating/regenerating fibers with an increased number of central nuclei, and a mild increase in connective tissue
LGMD 1D	DNAJB6 DNAJ/HSP40 homolog, subfamily B, member 6	2nd decade–upper middle age	• Adult-onset: slowly progressive proximal weakness, ambulation to 60s • Childhood onset: (2 presentations)  ○ Distal involvement of muscles  ○ Loss of ambulation in early adulthood and respiratory involvement • CK: normal or elevated • Muscle biopsy: myopathic or dystrophic pattern. Rimmed vacuolar pathology (predominant with disease progression) myofibrillar aggregates
LGMD 1E	DES Desmin	Classic AD form: Puberty–50 years AR cases reported earlier	• Distal myopathy (usual presentation) • Generalized myopathy • Proximal weakness • Scapuloperoneal syndrome • Associated dilated cardiomyopathy and cardiac conduction defects • Dysphagia is common • Respiratory insufficiency in 25% of patients • Severe generalized myopathy • CK: normal or slightly elevated • Muscle biopsy: (EM) abundant accumulation of desmin- immunoreactive deposits and granulofilamentous material
LGMD 1F	TNPO3 Transportin 3	Infancy–late adulthood	• Adult onset:  ○ Weakness of pelvic and shoulder girdle muscles  ○ Variable rate of disease progression and severity  ○ Generally benign course • Childhood or juvenile onset:  ○ Some with severe myopathy  ○ Wheelchair dependency  ○ Respiratory insufficiency  ○ Suggestion of genetic anticipation with earlier onset in subsequent generations • Muscle biopsy: rimmed vacuoles and filamentous inclusions
LGMD 1G	HNRNPDL Heterogeneous nuclear ribonucleo-protein D-like	Adult	• Variable proximal weakness, lower > upper limbs • Slowly progressive • Distinctive feature: limitation of finger and toe flexion • Muscle biopsy: predominantly myopathic, rimmed vacuoles
LGMD 1H	Mapped to chr3p23-p25.1	2nd–5th decade	• Slowly progressive weakness • Decreased reflexes • Proximal muscle atrophy • Calf hypertrophy ± muscle weakness • Occasionally high CK and serum lactate levels • Muscle biopsy: compatible with muscular dystrophy associated with subsarcolemmal accumulation of mitochondria and the presence of multiple mitochondrial DNA deletions in muscle