Common LGMDs

Relative Prevalence in USA – 2000-2010 Calpain-3 = 25% Dysferlin = 15% Sarcoglycans = 15% FKRP = 15% Anoctamin-5 = 10% Lamin A/C = 10% All others 10% Extracellular matrix-related proteins RYR1-associated disorders Pompe disease VCP

SUBTYPE GENE GENE PRODUCT LGMD1B LMNA Lamin A/C LGMD1A MYOT Myotilin LGMD1B LMNA Lamin A/C LGMD1C CAPN3 Caveolin-3 LGMD1D DNAJB6 Molecular chaperone protein LGMD1E DES Desmin LGMD1F TNPO3 Transportin 3 LGMD1G HNRNPDL Heterogeneous nuclear ribonucleoprotein D-like protein LGMD1H Unknown LGMD1I CAPN3 Calpain-3 LGMD2A CAPN3 Calpain-3 LGMD2B DYSF Dysferlin LGMD2C SGCG g-sarcoglycan LGMD2D SGCA a-sarcoglycan LGMD2E SGCB b-sarcoglycan LGMD2F SGCD d-sarcoglycan LGMD2G TCAP Telethonin LGMD2H TRIM32 E3-ubiquitin-ligase LGMD2I FKRP Fukutin Related Protein LGMD2J TTN Titin LGMD2K POMT1 O-mannosyltransferase-1 LGMD2L ANO5 Anoctamin 5 LGMD2M FCMD Fukutin LGMD2N POMT2 O-mannosyltransferase-2 LGMD2O POMGnT21 O-mannose-b1,2-N-acetylglucosaminytranferase-1 LGMD2P DAG1 a-dystroglycan LGMD2Q PLEC1 Plectin 1f LGMD2R DES Desmin LGMD2S TRAPPC11 Transport protein particle complex, subunit 11 LGMD2T GMPPB GDP-mannose pyrophosphorylase B LGMD2U ISPD Isoprenoid synthase domain containing LGMD2V GAA a-1,4-glucosidase LGMD2W LIMS2 Lim and senescent cell antigen-like domains 2 LGMD2X BVES Blood vessel endothelial substance

LGMD2A - Calpain Posterior thigh involvement Overall most common LGMD, ~20% AR and AD (dominant negative effect on homodimer) Onset 2nd or 3rd decade 75% between 5-20 yo Range (2-72 yo) Posterior thigh involvement KF < KE, HE < HF, HAD < HAB CK – 1000-5000 U/L (450-12,500) Muscle biopsy – dystrophic ± lobulated fibers Fardeau et al Brain 1996;119:295-308

Vissing, J Curr Opin Neurol 2016, 29:635–641 Fardeau et al Brain 1996;119:295-308 Mercuri et al J of MRI 2007;25:433-440

Calpainopathy Scapular winging Finger extensor weakness Contractures Axial rigidity Medial gastrocnemius atrophy Asymmetries No significant heart involvement Gradual respiratory insufficiency very late in course (~10%) Pollitt et al Neuromusc Disord 2001;11:287-296

Assembly & remodeling of contractile proteins in the sarcomere Zatz & Starling NEJM 2005;352:2413-2423 Mechanisms of action: Assembly & remodeling of contractile proteins in the sarcomere Control of Ca2+-efflux from the sarcoplasmic reticulum Membrane repair Muscle regeneration

LGMD2B - Dysferlin Phenotype Limb girdle pattern (143/293 cases) Also distal myopathies: (150/293 cases) Miyoshi myopathy (gastrosoleus complex) Distal anterior compartment myopathy (tib ant) Scapuloperoneal or proximodistal pattern Biceps atrophy Bent spine syndrome Carriers may be symptomatic Identical genetic mutations may present with different phenotypes Even within the same family Mahjneh et al Neuromusc Disord 2001;11:20-26

Mechanism of action Dysferlinopathy Dysferlin-associated membrane repair Mitochondrial health Stabilizes stress-induced Ca2+ signaling in the T-tubule membrane Diltiazem ↓ muscle fiber inflammation & injury Bansal and Campbell Trends Cell Biol 2004;14:206-13

Dysferlinopathy Onset – mean 18-32 yrs (range 0-73 yrs) Most have: Some distal, calf weakness Calf atrophy common (inability to stand on toes) Asymmetries (side to side differences) No scapular winging, dysphagia, dysarthria, contractures or cardiac dysfunction PFTs ↓ over decades Rarely symptomatic Mahjneh et al Neuromusc Disord 2001;11:20-26

Dysferlinopathy Diamond on Quadriceps Sign - 21/33 cases Pradhan, S Neurology India 2009;57:172 Pradhan, S Neurology 2008;70:332

Dysferlinopathy Paradas, C Neurology 2010;75:316

Dysferlinopathy Paradas, C Neurology 2010;75:316

Dysferlinopathy Inflammation (common) CK may be markedly elevated Mean = 3800 U/L (generally 1,000-35,000 U/L) Biopsies: Inflammation (common) Treatment refractory polymyositis Deflazacort not effective Amyloid (20-30%) Gallardo, E Neurology 2001;57:2136 Spuler, S Ann Neurol 2008;63:323

LGMD2C-F - Sarcoglycans g-, a-, b- and d-sarcoglycan Form a tetrameric transmembrane subcomplex within the dystrophin glycoprotein complex links the extracellular matrix to the subsarcolemmal cytoskeletal proteins Bushby Brain 1999;122:1403-1420

LGMD2C-F - Sarcoglycans Onset in first decade in lower extremities Phenotypes: SCARMD (Duchenne-like) Mild, later onset (Becker-like) Aches / pains / cramps syndrome Recurrent myoglobinuria Asymptomatic hyperCKemia Dilated cardiomyopathy Calf hypertrophy in ½ Scapular winging frequent Bushby Brain 1999;122:1403-1420

LGMD2C-F - Sarcoglycans May develop cardiac dysfunction (conduction defect and/or dilated cardiomyopathy) CK markedly elevated 1,000-25,000 IU Khadikar and Singh J Clin Neuromusc Dis 2001;3:13-15

LGMD2I – FKRP Fukutin-related protein (FKRP) Highly prevalent LGMD subtype in Northern Europeans Phenotypes: Congenital muscular dystrophy – Fetal / neonatal LGMD – Onset 3-55 years Asymptomatic hyperCKemia Mercuri et al Ann Neurol 2003;53:537-542

LGMD2I - FKRP Cardiac dysfunction Respiratory involvement Highly variable progression Calf and tongue hypertrophy Muscle pain & cramps Cardiac dysfunction Respiratory involvement Nocturnal NIV in some Myoglobinuria not uncommon CK = NL => 50 x ULN May be confused with DMD/BMD

LGMD2I - FKRP Poppe et al Mercuri et al Neurology 2003;60:1246-1251 Ann Neurol 2003;53:537-542 Poppe et al Neurology 2003;60:1246-1251

a-dystroglycanopathies   1: POMT1   2: POMT2   3: POMGnT1   4: Fukutin   5: FKRP   6: LARGE   7: ISPD   8: GTDC2   9: DAG1   10: TMEM5   11: B3GALNT2   12: SGK196   13: B3GNT1   14: GMPPB Muscle biopsy: dystrophic Reduced Laminin a2 Glycosylated a-dystroglycan Brockington et al Am J Hum Genet 2001;69:1198-1209

LGMD2L – Anoctamin 5 More common than dysferlinopathy in Northern England AR inheritance: LGMD2L Distal myopathy (MMD3) Asymptomatic hyperCKemia LGMD clinical Onset 11-77 yo (70% < 40 yo) ↑ prevalence & severity in males Quadriceps & biceps atrophy Muscle pain in 85% No cardiorespiratory involvement Most remain ambulatory CK = 4-80 x ULN Bx = Dystrophic Patients with asymptomatic hyperCKemia were 61 and 67 with mild iliopsoas weakness Jarry et al Brain 2007;130:368-380

LGMD2L A-D – Atrophy of thighs & medial gastrocnemius E – Biceps atrophy F-H – Severe quad & hamstring wasting I – hyperextension of knee Patients with asymptomatic hyperCKemia were 61 and 67 with mild iliopsoas weakness Godfrey et al Ann Neurol 2006;60:603-610 Hicks et al Brain 2011;134:171–182

LGMD1B – Lamin A/C ~5-10% of LGMD Onset: Rigidity of the spine Congenital – 3rd decade Contractures Elbows Achilles Neck extensors Hip flexors Rigidity of the spine Scapular winging Variable rates of progression Frequent cardiac involvement Colomer et al Neuromusc Disord 2002;12:19-25

Localization and Interaction of LGMD Proteins

Lamin A/C Lamins A & C Mutations in LMNA also cause: Inner nuclear envelope proteins Mechanostructural functions, signaling and gene regulation Mutations in LMNA also cause: AR LGMD Familial partial lipodystrophy AD & AR axonal polyneuropathies Mandibuloacral dysplasia syndrome Progeria syndromes Isolated dilated cardiomyopathy with A-V block (CMD1A) Heart-hand syndrome of the Slovenian type Restrictive dermopathy Metabolic syndrome Cerebral white matter disease

Extracellular Matrix-Related Myopathies Collagen VI Bethlem and Ullrich COL6A1/A2/A3 Hyperlaxity => contractures Keloids Keratosis pilaris CK NL – 2,000 U/L Ultrasound “central cloud” MRI – “outside in” pattern Collagen XII Similar features

RYR1-associated Common in Italian cohort Onset: 0-70 years Multiple phenotypes Biopsy with cores and inflammation CK: Mostly NL (up to 10x ULN) Hyperlaxity and contractures Axial musculature Snoeck M, et al Eur J Neurol 2015 22 1094 Donkervoort S, et al. Am J Med Genet 2015 169C 23–42

Pompe Disease Affects all ages Treatable disorder Enzyme replacement therapy ~3% “LGMD” patients => Pompe disease “All undiagnosed LGMD patients should be tested for Pompe Disease.”

Myopathy with Paget’s Disease Mutations in VCP Adult onset – mean age of 42 years Slowly progressive proximodistal weakness Early onset Paget’s disease Premature frontotemporal dementia (FTD) VCP mutations also associated with: ALS sIBM Parkinsonism Kovach et al Mol Genet Metab 2001;74:458-475