Neuromuscular

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LIMB-GIRDLE MUSCULAR DYSTROPHY (LGMD) SYNDROMES2

Limb girdle dystrophies: Dominant
  1A: Myotilin; 5q31; Dysarthria
  1B: Lamin A/C; 1q21; + Cardiac
  1C: Caveolin-3; 3p25; Child onset
  1D: 7q
  Dilated Cardiomyopathy (?1E): 6q23
  1F: 7q32
  1G: 4q21
  Ankle contractures & High CK
  Bethlem: Collagen VI; 21q22 & 2q37
  Central core: Ryanodine receptor (19q13)
  Cytoplasmic body: 2q24; 2q21 + Other
  Distal myopathies
    MPD2: 5q31; ? Same locus as LGMD1A
  Emery-Dreifuss: Lamin A/C; 1q21
  Facioscapulohumeral: 4q35
  Myofibrillar (Desmin storage)
    Desmin: 2q35; AD or AR
    αB-crystallin: 11q22
    Filamin C: 7q32
    LGMD 1A: Myotilin; 5q31
    Congenital: SEPN1; 1p36
    ZASP myopathy: 10q22
    Other
  Myotonic (DM1): DMPK; 19q13
  Myotonic (DM2): ZNF9; 3q21
  Oculopharyngeal: PABP2; 14q11
  Skeletal + Myopathy
    Bone fragility: 9p21
    Paget disease: VCP; 9p13
Limb girdle dystrophies: Recessive
  2A: Calpain-3 ;15q15
  2B: Dysferlin; 2p13.1
  2C: γ-Sarcoglycan; 13q12
  2D: α-Sarcoglycan; 17q21
  2E: β-Sarcoglycan; 4q12
  2F: δ-Sarcoglycan; 5q33
  2G: Telethonin; 17q11-12
  2H: TRIM32; 9q31-q33
  2I: FKRP; 19q13.3
  2J: Titin; 2q24
  2K: POMT1; 9q34
  2L: 11p13
  2M: Fukutin; 9q31
  Merosin (Laminin α2)
    Absent: 6q2
    Reduced: 6q2
    Abnormal: LGMD 2I
  Caveolin-3 mutations

Limb girdle dystrophies: X-linked
  Barth: G4.5 (Tafazzins); Xp28
  Becker: Dystrophin; Xp21
  Duchenne: Dystrophin; Xp21
  Emery-Dreifuss: Emerin; Xq28
  Manifesting carriers
    Dystrophinopathy
    Myotubularin
  McLeod Syndrome: XK; Xp21.1;
  Vacuolar
    Danon's disease: LAMP-2; Xq24
    Excessive Autophagy: Xq28
    Mental retardation & Cardiomyopathy
Other inherited myopathy syndromes
  Barnes's myopathy
  Cardiac + Myopathy
    Cardiomyopathy-associated myopathy
    Cardiomyopathy (?LGMD1B)
    Dilated Cardiomyopathy: 6q23
  Congenital
    Myopathies: Late-onset
    Muscular dystrophies
  Cytoplasmic body myopathies
  Distal myopathies
  Excessive autophagy: Xq28
  Familial myasthenia gravis
  FSH dystrophy: 4q35
  Hereditary IBM syndromes
      IBM1: Dominant
      IBM2: GNE; 9p12; Recessive
      IBM3: MyHC-IIa; 17p13; Dominant
      IBM + Paget disease: 9p13; Dominant
  Metabolic myopathies
      Glycogen
      Lipid
  Mitochondrial
  Myopathy + PEO: 17p13; Recessive
  Myotonic dystrophy
  Other dystrophies
  Reducing body
  Respiratory failure
  Scapuloperoneal syndromes
  Skeletal + Myopathy
    Diaphyseal dysplasia: TGFB1; 19q13
    Epiphyseal dysplasia: COL9A3; 20q13
  Spheroid body (Myotilin)
  Tubular aggregates
  Tubular arrays
LGMD: General features

Muscle proteins
  Connective tissue
  Dystrophin & associated proteins
  Intermediate filaments
  Neuromuscular junction
  Structural & Contractile

alpha-Sarcoglycan: LGMD 2D gamma-Sarcoglycan: LGMD 2C delta-Sarcoglycan: LGMD 2F beta-Sarcoglycan: LGMD 2E Dystrophin: Duchenne & Becker MD Laminin-alpha2: Congenital muscular dystrophy Integrin, alpha7: Congenital muscular dystrophy Connective tissue Agrin alpha-Dystroglycan beta-Dystroglycan alpha-Dystrobrevin Syntrophins Sarcospan Filamin 2 Filamin 2 Integrin, beta1 Dystrophy-associated proteins DAG complex +



LGMD: General features

Inheritance
Myopathy: General features
Presenting features
Prevalence
Proteins: Subcellular location
Sarcoglycans
Weakness

From Bramwell:
Atlas of Clinical Medicine


MD: Toe walking




LGMD 1: Dominant inheritance


LGMD 1A
  l Myotilin (Titin immunoglobulin domain protein (TTID)) 19; Chromosome 5q31; Dominant or Sporadic

LGMD 1B17
  l Lamin A/C; Chromosome 1q21.2; Dominant
LGMD 1C 27
  l Caveolin-3 ; Chromosome 3p25; Dominant, Also Recessive

Caveolin protein
LGMD 1C
  Clinical
  Genetics
  Mouse models
Caveolin-3: Located on
muscle fiber sarcolemma

LGMD 1D:
  l Chromosome 7q; Dominant
Familial Dilated Cardiomyopathy with Conduction Defect & Muscular Dystrophy (?LGMD 1E)
  l Chromosome 6q23; Dominant
LGMD 1F35
  l Chromosome 7q32.1-32.2; Dominant
LGMD 1G
  l Chromosome 4q21; Dominant

LGMD2: Recessive Inheritance


LGMD 2A
  l Calpain-3 (p94 protein) ; Chromosome 15q15.1-q21.1; Recessive

Genetics
Calpain-3 protein
Clinical
Laboratory

From: C Angelini MD


LGMD 2B
  l Dysferlin ; Chromosome 2p13.3-p13.1; Recessive

Gene
Protein
Clinical
Laboratory
Pathology
Variant syndromes
Mouse model

From: C Angelini

LGMD 2C; Severe Childhood Autosomal Recessive (SCARMD)
  l γ Sarcoglycan ; Chromosome 13q12; Recessive
LGMD 2D
  l α-Sarcoglycan (Adhalin) ; Chromosome 17q21; Recessive

LGMD 2E
  l β-Sarcoglycan ; Chromosome 4q12; Recessive
LGMD 2F
  l δ-Sarcoglycan ; Chromosome 5q33-34; Recessive
LGMD 2G
  l Telethonin (Titin-Cap; TCAP) ; Chromosome 17q11-12; Recessive
LGMD 2H: Manitoba Hutterite Dystrophy
  l Tripartite-motif containing gene 32 (TRIM32) ; Chromosome 9q31-q33; Recessive Sarcotubular myopathy46
  l Tripartite-motif containing gene 32 (TRIM32) ; Chromosome 9q31-q33; Recessive
LGMD 2I18
  l Fukutin-related protein gene (FKRP) ; Chromosome 19q13.3; Recessive Myopathy with abnormal merosin (Laminin-2) 4
    l Fukutin-related protein gene (FKRP) ; Chromosome 19q13.3; Recessive
LGMD 2J
    l Titin ; Chromosome 2q31; Recessive
LGMD 2K : with Mental retardation and Reduced α-dystroglycan45
    l POMT1 ; Chromosome 9q34.1; Recessive
LGMD 2L 67
    l Chromosome 11p13-p12; Recessive
LGMD 2M 59
    l Fukutin (FCMD) ; Chromosome 9q31; Recessive

Other Dominant Myopathies

Bethlem myopathy : Several loci
  l Collagen, type VI, subunit α1 (COL6A1) ; Chromosome 21q22.3; Dominant
  l Collagen, type VI, subunit α2 (COL6A2) ; Chromosome 21q22.3; Dominant
  l Collagen, type VI, subunit α3 (COL6A3) ; Chromosome 2q37; Dominant
Multiple epiphyseal dysplasia with mild myopathy13 (EDM3)
  l Collagen, type IX, subunit α-3 (COL9A3) ; Chromosome 20q13.3; Dominant Dominant Myopathy with Bone Fragility 51
  l Chromosome 9p21-p22; Dominant Dominant Myopathy with Cardiomyopathy1
  l Autosomal dominant Dominant myopathy with Ankle contractures & High CK10
  l Autosomal Dominant Barnes's Myopathy

Other Recessive Myopathies



Familial Limb-Girdle Myasthenia
    l Dok-7 (C4ORF25) ; Chromosome 4; Recessive



LGMD 4
    l Autosomal Recessive

Metabolic myopathies

Infantile autophagic vacuolar myopathy56
    l Autosomal Recessive

Childhood autophagic vacuolar myopathy57
    l Autosomal Recessive or X-linked carrier

Adult-onset autophagic vacuolar myopathy with multiorgan involvement58
    l Sporadic

X-linked myopathies


X-linked myopathy with excessive autophagy5,16
  l Chromosome Xq28; Recessive

X-linked Vacuolar Cardiomyopathy and Myopathy (Danon's disease)
  l Lysosome-associated membrane protein 2 (LAMP-2) ; Chromosome Xq24; Dominant, more severe in males