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Common LGMDs

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

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Common LGMDs

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  1. Common LGMDs

  2. 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

  3. SUBTYPEGENEGENE PRODUCT • 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

  4. LGMD2A - Calpain • 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. Dysferlinopathy • Mechanism of action • 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

  10. 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

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

  12. Dysferlinopathy Paradas, C Neurology 2010;75:316

  13. Dysferlinopathy Paradas, C Neurology 2010;75:316

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

  15. 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

  16. 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

  17. 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

  18. 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

  19. LGMD2I - FKRP • 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

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

  21. a-dystroglycanopathies • Muscle biopsy: dystrophic • Reduced • Laminin a2 • Glycosylated a-dystroglycan a-dystroglycanopathies 1: POMT12: POMT23: POMGnT14: Fukutin5: FKRP6: LARGE7: ISPD8: GTDC29: DAG110: TMEM511: B3GALNT212: SGK19613: B3GNT114: GMPPB Brockington et al Am J Hum Genet 2001;69:1198-1209

  22. 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 Jarry et al Brain 2007;130:368-380

  23. LGMD2L • A-D – Atrophy of thighs & medial gastrocnemius • E – Biceps atrophy • F-H – Severe quad & hamstring wasting • I – hyperextension of knee Godfrey et al Ann Neurol 2006;60:603-610 Hicks et al Brain 2011;134:171–182

  24. LGMD1B – Lamin A/C • ~5-10% of LGMD • Onset: • 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

  25. Localization and Interaction of LGMD Proteins

  26. Lamin A/C • Lamins A & C • 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

  27. 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

  28. 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

  29. 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.”

  30. 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

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