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. 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

4. 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 – U/L (450-12,500)
Muscle biopsy – dystrophic ± lobulated fibers
Fardeau et al
Brain 1996;119:

5. Vissing, J
Curr Opin Neurol 2016, 29:635–641
Fardeau et al
Brain 1996;119:
Mercuri et al
J of MRI 2007;25:

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:

7. Assembly & remodeling of contractile proteins in the sarcomere
Zatz & Starling
NEJM 2005;352:
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

10. 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

11. 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

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

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

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

15. 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

16. 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:

18. 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:

19. 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

20. 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:

22. 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

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

24. 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:

25. LGMD2L – Anoctamin 5
More common than dysferlinopathy in Northern England
AR inheritance:
LGMD2L
Distal myopathy (MMD3)
Asymptomatic hyperCKemia
LGMD clinical
Onset 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:

26. 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:
Hicks et al
Brain 2011;134:171–182

27. 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

28. Localization and Interaction of LGMD Proteins

29. 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

31. 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

32. 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
Donkervoort S, et al.
Am J Med Genet C 23–42

33. 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.”

34. 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: