Table 2.

Autosomal recessive limb–girdle muscular dystrophy

LGMD subtype	Gene	Onset	Phenotype
LGMD2A	CAPN3 Calpain 3	2–53 years	• 3 phenotypes:  ○ Pelvic–femoral LGMD or Leyden–Möbius   ■ BMD-like phenotype in 2/3   ■ DMD-like phenotype in 10%  ○ Scapulo-humeral LGMD (Erb) phenotype  ○ HyperCKemia (6%) • Early contractures of elbows/calves, scoliosis • Cardiomyopathy and respiratory dysfunction is rare • CK levels range from 4000 to >20,000
LGMD2B	DYSF Dysferlin	15–30 year	• 2 phenotypes:  ○ Limb–girdle syndrome (LGMD2B)   ■ Onset in adolescence or young adulthood   ■ Early weakness and atrophy of the pelvic and shoulder girdle muscles   ■ Slow progression   ■ No respiratory and cardiac muscle involvement  ○ Distal phenotype (Miyoshi myopathy)   ■ Onset in young adulthood   ■ Marked distal gastrocnemius–soleus weakness and atrophy with progression to the thigh/gluteal muscles   ■ Forearms may be mildly atrophic with decreased grip   ■ Small hand muscles are spared • CK: as high as 40,000 • Muscle biopsy: endomysial/perimysial infiltrates in up to 50%
LGMD 2C	SGCG Gamma-sarcoglycan		• Complete deficiency:  ○ Onset: 1–15 years of age  ○ Difficulty running/walking due to proximal weakness  ○ Calf hypertrophy  ○ Scapular winging  ○ Macroglossia  ○ Lumbar hyperlordosis  ○ Late contractures or scoliosis  ○May have cardiac and respiratory impairment  ○Wheelchair confinement by ~ 15 years old • Partial deficiency of sarcoglycans  ○Onset: adolescence to young adulthood  ○Cramps/exercise intolerance  ○ Asymptomatic hyperCKemia • CK levels range from 1000 to 25,000 U/L • Cardiomyopathy is common
LGMD 2D	SGCA α-sarcoglycan		• The same phenotypic features as LGMD 2C • Cardiomyopathy is rare
LGMD2E	SGCB β-sarcoglycan		• The same phenotypic features as LGMD 2C • Cardiomyopathy is common
LGMD 2F	SGCD δ-sarcoglycan		• The same phenotypic features as LGMD 2C • Cardiomyopathy is common
LGMD 2G	TCAP Titin-cap	9–15 years	• All have significant proximal weakness  ○ Weakness of the lower limbs   ■ Difficulty running due to early quadriceps weakness   ■ Footdrop from anterior tibialis weakness  ○ Proximal upper limb weakness • Significant variability in the phenotype:  ○ Some develop distal atrophy  ○ Others have calf hypertrophy • Cardiac involvement is seen in half of the cases • Females appear to be less severely affected than males
LGMD 2H	TRIM32 Tripartite motif- containing protein 32	8–27 years	• Slowly progressive weakness (wheelchair late in life)  ○ Early quadriceps and pelvic girdle weakness:   ■ Waddling gait   ■ Difficulty with stairs  ○ Trapezius and deltoid weakness  ○ Facial weakness  ○ Calf muscle wasting can be seen • No scoliosis or contractures • Variable severity • Severe end of phenotype: sarcotubular myopathy (STM)
LGMD 2I	FKRP Fukutin-related protein	Infancy–4th decade of life	• Difficulty running and walking due to hip girdle weakness with distal leg and proximal arms weakness • Calf hypertrophy • Tongue hypertrophy • Lumbar lordosis • Prominent respiratory and cardiac dysfunction with dilated cardiomyopathy in about 50% • Variable in severity
LGMD 2J	TTN Titin	Childhood–late adulthood	• Variable phenotype: any phenotype is possible  ○ Childhood-onset limb–girdle weakness (AR)  ○ Adult-onset (AD—more common) anterior tibial weakness, upper limb weakness with posterior calf atrophy and weakness
LGMD 2K	POMT1 Protein O-mannosyl-transferase 1	1–3 years	• Mild proximal > distal muscle weakness  ○ Increased fatigability  ○ Difficulty climbing stairs and running • Cognitive limitation • Language impairment • Hypertrophy of calves and thighs • Ankle contractures • CK: 20–40× normal range
LGMD 2L	ANO5 Anoctamin 5	10-20 years	• Distal leg phenotype • Prominent asymmetric thigh atrophy • No cardiac or respiratory dysfunction • CK: 200–35,000 U/L
LGMD 2M	FKTN Fukutin	4 months–4 years	• Early-onset proximal lower > upper limb weakness, leading to difficulties climbing stairs • Hypertrophy of calves, thighs, and triceps may be present • No scoliosis or contractures Note: common cause of Fukuyama muscular dystrophy
LGMD 2N	POMT2 Protein O- mannosyl-transferase 2	Early onset	• Phenotype of 2 cases:  ○ 5-year-old female, asymptomatic with normal intellect but neurological exam showed scapular winging, calf hypertrophy, and slowness in running and getting up  ○ 18 months old with developmental delay, intellectual disability, muscle hypertrophy, and right bundle branch block
LGMD 2O	POMGNT1 Protein O-mannose β-1,2-N-acetyl-glucos-aminyl-transferase 1		• LGMD phenotype is more benign and rare • One case report of a female: onset at 12 years old  ○ Normal cognition  ○ Progressive proximal > distal muscle weakness (difficulties rising from sitting and climbing stairs) with neck, hip girdle, and shoulder abductor muscles involved  ○ Hypertrophy of the calves and quadriceps  ○ Wasting of the hamstring and deltoid muscles  ○ Ankle contractures  ○ Severe myopia Note: common cause of muscle–eye–brain disease
LGMD 2P	DAG1 Dystrophin- associated glycoprotein 1		• Case report: cognitive delay
LGMD 2Q	PLEC1 Plectin		• PLEC-associated phenotypes:  ○ Epidermolysis bullosa simplex with late-onset progressive muscular dystrophy  ○ Myasthenic syndrome with late-onset myopathy  ○ Early childhood-onset progressive muscular dystrophy without skin involvement
LGMD 2R	DES Desmin	Early childhood–2nd decade	• Proximal muscle weakness, • Facial weakness • Respiratory muscle weakness • High arched palate • Scoliosis • Severe atrioventricular conduction defects requiring cardiac pacemaker placements
LGMD 2S	TRAPPC11 Trafficking protein particle complex, subunit 11	Early childhood	• Proximal weakness • Scapular winging • Mild myopathic facies • Global developmental delays • Infantile-onset hyperkinetic movements (dystonia/chorea) with truncal ataxia with myopathic EMG and cerebral volume loss on brain MRI • CK: as high as 10× normal
LGMD 2T	GMPPB GDP-mannose pyrophos- phorylase B	Birth–40 years	• Slow progression of proximal weakness • Early-onset cases: infantile hypotonia, intellectual disabilities, occasional seizures • Older patients: enlarged calves, rhabdomyolysis and cramps; some have cardiac involvement
LGMD 2U	ISPD Isoprenoid synthase domain-containing	Early childhood	• Hypotonia • Gait disorder • Gower’s sign due to predominantly proximal weakness • Muscle hypertrophy may be present as well as cardiac involvement with left ventricular dysfunction • CK: 3–50× normal
LGMD 2V	GAA α-1,4-Glucosidase	Infantile–adolescent–adult onset	• Phenotypes of Pompe Disease:  ○ Classic infantile form of cardiomyopathy and muscular hypotonia  ○ Adolescent and adult patients have proximal muscle weakness, thigh adductor weakness associated with respiratory insufficiency • EMG: CRDs or myotonic discharges specifically in the thoracic paraspinal muscles • Muscle biopsy: subsarcolemmal periodic-acid Schiff (PAS)-positive inclusions • Treatment: enzyme replacement therapy available Note: 8% of unclassified LGMD
LGMD 2W	LIMS2 Lim and senescent cell antigen-like domains 2	Childhood	• Severe proximal upper and lower extremity weakness • Slow progression • Distinctive features:  ○ Macroglossia  ○ Triangular tongue  ○ Calf hypertrophy • Cardiac involvement is seen by the 3rd decade of life with dilated cardiomyopathy • CK: up to 25× normal
LGMD 2X	BVES Blood vessel epicardial substance	Adulthood	• Slowly progressive proximal lower limb weakness • Cardiac arrhythmias may cause syncopal episodes • CK: elevated
LGMD 2Y	TOR1AIP1 Torsin A-interacting protein 1	1st–2nd decade	• Slowly progressive proximal lower limbs, followed by distal upper and lower limb muscle weakness and atrophy • Joint contractures—fingers (PIP and DIP), ankles • Rigid spine—cervical region • Restricted pulmonary function • May have mild cardiac involvement • CK: normal to elevated
LGMD 2Z	POGLUT1 Protein O-glucosyl-transferase 1	Young adult	• Slowly progressive proximal upper and lower limb muscle weakness and atrophy • Scapular winging • CK: mildly increased