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MUSCULAR DYSTROPHY SYNDROMES 2

Limb Girdle Dystrophies
  Dominant (LGMDD)
    1: DNAJB6; 7q36
    2: TNPO3; 7q32
    3: HNRPDL; 4q21
    4: Calpain-3; 15q15
    5 (Bethlem 1)
      COL6A1: 21q22
      COL6A2: 21q22
      COL6A3: 2q37
    Previous classification
Myopathies, Dominant
  1H: 3p23
  Ankle contractures & High CK
  Bethlem 2: COL12A1; 6q13
  Central core: RYR1; 19q13
  Cytoplasmic body
  Distal myopathies
    MPD2: MATR3; 5q31
  Emery-Dreifuss
    Lamin A/C; 1q21
    SYNE1; 6q25
    SYNE2; 14q23
  Facioscapulohumeral
    1A: DUX4; 4q35
    1B: DUX4; 10qter
    2: SMCHD1; 18p11
  Myofibrillar (Desmin storage)
  Myoglobinopathy: MB; 22q12
  Myosin storage: MYH7; 14q11
  Myotonic (DM1): DMPK; 19q13
  Myotonic (DM2): ZNF9; 3q21
  Oculopharyngeal: PABP2; 14q11
  Tremor: MYBPC1; 12q23
 		Limb Girdle Dystrophies
  Recessive (LGMDR)
  1 (2A): Calpain-3; 15q15
  2 (2B): Dysferlin; 2p13
  3 (2D): α-Sarcoglycan; 17q21
  4 (2E): β-Sarcoglycan; 4q12
  5 (2C): γ-Sarcoglycan; 13q12
  6 (2F): δ-Sarcoglycan; 5q33
  7 (2G): Telethonin; 17q12
  8 (2H): TRIM32; 9q33
  9 (2I; MDDGC5): FKRP; 19q13
  10 (2J): Titin; 2q24
  11 (2K; MDDGC1): POMT1; 9q34
  12 (2L): ANO5; 11p14
  13 (2M; MDDGC4): Fukutin; 9q31
  14 (2N;MDDGC2): POMT2; 14q24
  15 (2O; MDDGC3): POMGnT1; 1p32
  16 (2P; MDDGC9): DAG1; 3p21
  17 (2Q): Plectin 1f; 8q24
  18 (2S): TRAPPC11; 4q35
  19 (2T): GMPPB; 3p21
  20 (2U): ISPD; 7p21
  21 (2Z): POGLUT1; 3q13
  22: COL6A2; 21q22
  23: LAMA2; 6q22
  24: POMGNT2; 3p22
  25: POPDC1; 6q21
  26: POPDC3; 6q21
  Other
    Pompe (2V): GAA; 17q25
    2W: LIMS2; 2q14
    2Y: TOR1AIP1; 1q25
    MDDGC12: POMK; 8p11
    Caveolin-3
    Merosin (Laminin α2)
      23 (Absent): 6q22
      Reduced
      Abnormal: LGMD 2I
    MFM (2R): Desmin; 2q35
    PYROXD1: 12p12
  Myopathy +
    Cardiomyopathy
      Arrhythmia: POPDC1; 6q21
      Dilated: DPM3; 1q12
      Hypertrophic: TRIM63; 1p36
        Digenic: + Murf3 heterozygous
      Triangle tongue (2W): LIMS2; 2q14
    Contractures: TOR1AIP1; 1q25
    Epilepsy: DPM2; 9q34
    Infant stiffness: CRYAB; 11q22
    Lipodystrophy: PTRF; 17q21
    MR & Eye (2T): GMPPB; 3p21
    Ophthalmoplegia: MYH2; 17p13
    Satellite cell loss
      POGLUT1
      PAX7
 		Limb Girdle Dystrophies: X-linked
  Barth: G4.5 (Tafazzins); Xp28
  Becker: Dystrophin; Xp21
  Duchenne: Dystrophin; Xp21
  Emery-Dreifuss
    Emerin; Xq28
    FHL1: Xq26
  Manifesting carriers
    Dystrophinopathy
    Myotubularin
  McLeod Syndrome: XK; Xp21.1;
  Vacuolar
    Danon's disease: LAMP-2; Xq24
    Excess Autophagy: VMA21; Xq28
    MR & Cardiac: LAMP-2; Xq24

LGMD: General features
  Muscle pathology

Muscle proteins
  Connective tissue
  Dystrophin & associated proteins
  Intermediate filaments
  Neuromuscular junction
  Nuclear envelope
  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 + 		Other inherited myopathy syndromes
  α-Dystroglycan disorders (MDDGC)
  Aggregates
    Cytoplasmic body
    Hyaline body: MYH7; 14q11; Dominant
    KFS4: MYO18B; 22q12; Recessive
    Myofibrillar (Desmin)
    Reducing body
    Spheroid body (Myotilin)
    Tubular
    Tubular arrays
    VMCQA: CASQ1; 1q23; Dominant
  APECED: AIRE; 21q22; Recessive
  Autophagy
    Excessive: VMA21; Xq28
    Multisystem: CLN3; 16p11; Recessive
    Other
  Barnes myopathy: Dominant
  Cardiac + Myopathy
    Cardiomyopathy-associated
    Cardiomyopathy (? LGMD1B)
    LGMD 1E: Desmin; 2q35; Dominant
  Congenital
    Myopathies: Late-onset
    Muscular dystrophies (MDDG)
  Distal myopathies
  Ehlers-Danlos: Recessive
    TNXB; 6p21
    FKBP14; 7p14
 		  FSH dystrophy: Dominant
    FSHD1: D4Z4 deletion; 4q35
    FSHD2: SMCHD1; 18p11 & 4q35
  Glycogenoses
  Glycosylation
  Hearing loss & Ovarian Failure: GGPS1
  Inclusion Body (IBM)
    HMERF: TTN; 2q31; Dominant
    IBM1: Desmin; 2q35; Dominant
    IBM2: GNE; 9p12; Recessive
    IBM3: MYH2; 17p13; Dominant
    IBM4: 7q22; Dominant
    LGMD 1D: DNAJB6; 7q36; Dominant
    IBM + Paget
  Lipid
  Mitochondrial
  Myasthenia gravis, Familial
  Myotonic dystrophy
  Ophthalmoplegia: MYH2; 17p13; Recessive
  Other dystrophies
  Respiratory failure
  Scapuloperoneal syndromes
  Skeletal + Myopathy: Dominant
    Bone fragility: MTAP; 9p21
    Paget (VCP; HNRNPA2B1; HNRNPA1)
    Dysplasia
      Diaphyseal: TGFB1; 19q13
      Epiphyseal (COL9A3; COL9A2; COMP)
  Strongman: DCST2; 1q22; Dominant


LGMD: General features

Inheritance
Myopathy: General features
Presenting features
Prevalence
Proteins: Subcellular location
Sarcoglycans
Weakness
From Bramwell:
Atlas of Clinical Medicine

MD: Toe walking

LGMDD (LGMD 1): Dominant inheritance

LGMD D1 82
  ● DNAJ/HSP40 Homolog, subfamily B, Member 6 (DNAJB6) ; Chromosome 7q36.3; Dominant
LGMD D2 35
  ● Transportin 3 (TNPO3) ; Chromosome 7q32.1; Dominant
LGMD D3 128
  ● Heterogeneous nuclear ribonucleoprotein D-like protein (HNRNPDL; HNRPDL) ; Chromosome 4q21.22; Dominant
Myofibrillar myopathy 3 (MFM3)
  ● Myotilin (Titin immunoglobulin domain protein (TTID); MYOT) 19; Chromosome 5q31.2; Dominant or Sporadic
Myopathy, Dominant 17
  ● Lamin A/C ; Chromosome 1q21.2; Dominant
LGMD 1C 27
  ● Caveolin-3 ; Chromosome 3p25.3; Dominant, Also Recessive

Caveolin protein
LGMD 1C
  Allelic disorders
  Clinical
  Genetics
  Laboratory
  Mouse models
Caveolin-3: Located on
muscle fiber sarcolemma
Familial Dilated Cardiomyopathy with Conduction Defect & Muscular Dystrophy 81
  ● Desmin; Chromosome 2q35; Dominant
Myopathy with Sarcoplasmic Inclusions & Dilated Cardiomyopathy 118
  ● Myoglobin (MB) ; Chromosome 22q12.3; Dominant
Myopathy, Dominant 77
  ● ? Chromosome 3p25.1–p23; Dominant

LGMDR (LGMD2): Recessive Inheritance

LGMD R1
  ● Calpain-3 (CAPN3; p94 protein) ; Chromosome 15q15.1; Recessive or Dominant

Recessive
  Genetics
  Calpain-3 protein
  Clinical
  Laboratory

Dominant
From: C Angelini MD
  • Nosology: LGMD 2A
  • Epidemiology
    • Most common recessive LGMD worldwide
      • Especially: Eastern Europe, Spain, Italian
      • Denmark: Less common than 2I & 2L
  • Genotype & Phenotype
    • Mutations: > 500 identified 7
      • Mutation patterns
        • Private variant mutations in 70%
        • Recurrent mutations
          • Founder effect 1.5x more frequent than than recurrent
      • Single base pair: 60% to 70%
        • Missense: Most, ~80%
        • Stop codons: Few
        • Splicing defects: ~15%
      • Small insertions or deletions
        • Frequency: 30% to 40%
        • Most cause frameshift & stop codon
      • 1 Large genomic deletion
        • 2° to unequal recombination between two intragenic Alu elements
      • Overall ~45% of mutations are truncating
      • Location: Present through most of gene
        • Excess of mutations: Exon 21
        • Excess of point mutations
          • Exons 5, 11 (11 amino acid span with multiple CpG sites) & 21
        • Excess of deletions/insertions: Exons 15, 17, & 22
        • R490Q mutation
          • Located in catalytic site
          • Protein
            • Present by Western blot
            • Autolytic activity: Lost
              • CAPN3 protein remains after incubation of muscle without EDTA 130
          • LGMD phenotype: Weakness severity Variable
        • G222R mutation 54
          • Mutations: Compound heterozygote for R110X & G222R
          • Loss of function: Size & Abundance normal
          • Early onset weakness
      • Disease foci: Geography
        • Europe
          • Réunion island
            • 60% have IVS6-1G>A
            • Amish & Basque populations
            • Digenic inheritance: ??
          • Guipuzcoa (Basque Country, Spain)
            • Exon 22, 2362AG[→]TCATCT in 76%
          • Italy
            • Mocheni, Italian Alps: c.1193+6T>A
            • Venetian lagoon (Chioggia): Arg490Gln
          • Russia, Eastern Mediterrananean & North Italy
            • 550delA: Mutation frequency 1/150
        • North America
          • US Northern Indiana Amish: Arg769Gln
          • Tlaxcala, Mexico: Ala116Asp
        • Asia
          • China: c.2120A>G
          • Japan: c.1795_1796insA
          • Northern India: p.Asp780His, c.2099-1G>T, c.2051-1G>T, c.2338G>C
        • Large (31,012-bp) deletion (Exons 2-8) (c.309+4469_c.1116-1204del)
          • Occurs in different ethnic backgrounds
      • Clinical correlations
        • Severe phenotype
          • Homozygous null mutations: Often but not always
          • NS1 domain mutations; S86F
        • Least severe phenotype: Homozygous missense mutations
        • S86F heterozygotes: Mildly high serum CK; Normal strength
    • Allelic disorder: LGMD, Dominant
    • Mutation Databases
  • Calpain-3 (p94) protein
    • Functions
      • General
        • Ca++ activated non-lysosomal cysteine thiol-protease
        • Cleaves proteins into short polypeptides, not single amino acids
        • Activity may not be Ca++ dependent
        • Use cysteine as active site residue
        • Limited proteolytic cleavage of substrate
      • Role in cytoskeletal remodeling
        • Assembly & remodelling of contractile proteins in sarcomere
        • Can bind & cleave titin
      • Control of Ca++-efflux from the sarcoplasmic reticulum
      • Membrane repair
      • Muscle regeneration
      • Mutations: Reduced affinity of calpain-3 for titin
    • Localization
      • Expressed prominantly in skeletal muscle: N2-line region
      • Associates with
      • Subcellular: Nucleus ± Cytosol; Not membrane related
    • Halflife
      • Short (< 10 minutes)
      • Rapid turnover related to insertion sequences (IS) not present in other calpains
    • Disease mutations: Effects on calpain function vary, may be selectve for
      • Proteolytic activity vs fodrin substrate: Reduced
      • Autolysis capacity: Reduced
      • Titin binding: Reduced
      • Altered maintenance & remodelling of contractile apparatus
        • Abnormal calpain-3 proteolysis & cleavage of titin
  • LGD 2A: Clinical features 21
    • Onset
      • Early motor milestones: Most normal; Toe walking common
      • Range: 2 to 45 years; Median = 14 to 20 years; 71% between 6 to 18 years
      • Weakness: Proximal legs; Rectus abdominus
      • No clear sex differences; ? Females slightly younger than males
    • Disease patterns: Various phenotypes
      • General pattern: Scapula, pelvic girdle & trunk weakness with normal face
      • Differential Diagnosis: FSH; LGMD 2I
      • HyperCKemia, asymptomatic (14%): Male > Female 3:1
      • Limb girdle types (76%)
        • Early onset: < 12 year
          • Group with most homogeneous progression
          • Contractures more common
          • Null mutations: Common
        • Leyden-Mobius type
          • Onset 13 to 29 years
          • Weakness
            • Early: Pelvic-Femoral girdle
            • Later: Shoulders
        • Late onset
          • Age: > 30 years
          • Weakness: Pelvic girdle
      • Erb dystrophy type (10%): Scapular-Humeral phenotype
        • Onset age: 16 to 37 years
        • Weakness early: Shoulder girdle
        • Male = Female
        • Calpain-3 protein in muscle: Often normal
      • Miyoshi muscular dystrophy phenotype
    • Weakness
      • General
        • Symmetrical
        • Proximal + Milder Distal
        • Legs > Arms at onset: Most patients
        • May be asymmetric
        • Progressive
        • Severity
          • Heterogeneous: Mild to Early onset severe
          • Mild phenotype in majority
          • Male = Female
      • Trunk
        • Peri-Scapular
          • Latissimus dorsi; Serratus magnus
          • Scapular winging (83%): Symmetric
        • Rectus abdominus
        • Pelvic girdle
        • Gluteus maximus
      • Legs
        • Most severe: Adductors; Knee flexion
        • Ankle dorsiflexion: Some patients
      • Arms
        • Most severe: Shoulder adduction; Elbow flexion
        • Wrist extension: Some patients
      • Respiratory
        • Vital capacity: Declines over time; Rarely < 80%
        • No nocturnal hypoventilation
      • Quadriceps: May be selectively spared
      • Gait
        • Inability to walk on heels
        • Lumbar lordosis
        • Loss of walking: Mean late 2nd or 3rd decade
      • Normal: Face; Ocular & Bulbar
      • Some patients are asymptomatic with elevated serum CK levels
    • Muscle size
      • Atrophy
        • Early in posterior compartments of limbs
          • Different from Quadriceps wasting in Sarcoglycanopathies
          • May be apparent on CT
        • Most affected: Gluteus maximus & Thigh adductors
        • Pelvic; Shoulder; Proximal limbs; Trunk; May be scapuloperoneal
      • Hypertrophy
        • Some patients: Especially in Brazil
        • Calf most common: Not prominent
    • Contractures
      • Onset: May occur early in disease course
      • Calf: Toe walking may be presenting sign
      • Other: Elbow, Wrist & Finger flexion
      • Common late in disease progression: Rigid spine
      • May be severe & require surgery
      • Differential diagnosis: Emery-Dreifuss
    • CNS
      • Normal, or
      • Mild mental retardation: Average IQ = 77
    • Cardiac: No involvement
    • Progression
      • Slow: Earlier onset more rapid
      • Loss of walking
        • 10 to 30 years after onset
        • 50% in 3rd decade
        • Most by age 40 years
      • Many patients can still stand, even when in wheelchair
    • Syndrome variation
      • Intrafamilial
        • Similar onset age & severity in some families with null mutations
          • Onset at 15 years
        • Variation in others with
          • 2 Missense mutations or
          • Compound heterozygotes for missense & null mutation
          • Onset 2.5 to 45 years
      • Interfamilial: Prominent
  • LGD 2A: Lab features
    • Serum CK: Normal to 80 times normal; 190 to 11,000
    • MRI
      • Thigh: Varies with degree of function
        • Prominent in most patients: Posterior
        • Early involvement: Adductors; Semimembranosus
        • Restricted ambulation
          • Diffuse involvement: Posterolateral thigh & Vastus intermedius
          • Sparing: Vastus lateralis, Sartorius & Gracilis
      • Calf
        • Involvement: Soleus; Gastrocnemius, Medial head
        • Relative sparing: Gastrocnemius, Lateral head
    • Muscle Biopsy
      • Myopathic
        • Muscle fibers
          • Necrosis & Regeneration
            • Active myopathic changes
            • Eosinophils in some associated cell foci
            • Myopathic groups
              • May involve clusters or whole fascicles early in disease 34
          • Size: Variable; Small rounded to Hypertrophic
          • Internal architecture
            • Usually unremarkable
            • Regenerating fibers: Coarse internal architecture
            • Lobulation of Type I fibers: Later in disease course
            • Nuclei: Internal; Apoptosis with altered IκBα/NF-κB pathway
            • Groups of atrophic (type 2) muscle fibers
        • Endomysial fibrosis: Increased with longer disease course
      • Fiber types
        • Type 2 hypertrophy: Some patients
        • Type I predominance: With increasing weakness
        • Type 2C: Common
      • Inflammation
        • Some biopsies
        • May be perivascular or endomysial
      • Dystrophy-related proteins
        • Calpain-3: Western blot patterns
          • Loss of all calpain-3 bands (94 kDa, 60 kDa & 30 kDa)
            • High specificity for LGMD2A: Frequency 23%
            • May have null or missense mutations
          • Absence or reduction of 60 kDa bands
            • High specificity (94%)
            • Sensitive (64%)
          • Absence or reduction of 30 kDa bands
            • Specific (88%)
            • Sensitive (58%)
          • Increased lower MW 60 kDa region bands
            • No mutations (92%)
            • Suggests protein degradation artifact
          • Normal full-sized calpain-3 protein
            • Occurs in 23% of patients with 2 calpain-3 mutations
            • Often have loss of autocatalytic function
          • Abnormal Western blot with only 1 calpain-3 mutation
            • Similar phenotype to patients with 2 mutations found
          • Calpain-3 reduction may occur in other myopathies
        • Dysferlin: Reduced or absent in some patients; Western blot normal
        • Sarcoglycans & Dystrophin: Normal
      • Ultrastructure: Patchy damage to myofibrillar Z, I & A bands
    • Diagnosis 41
      • Genetics
        • Difficult due to many different mutations
        • More common in some regions of gene
          • 87% of mutant alleles exons 1, 4, 5, 8, 10, 11 & 21
        • Some common mutations: 61% have one of eight mutations
        • Directed mutation analysis: Geographic groups
        • Some patients with only 1 detected mutation have
      • Western blot
      • Calpain-3 enzyme activity: Reduced
  • Mouse model: Calpain-3 knockout 42
    • Misaligned A-bands
    • Abnormal sarcomere formation
  • CAPN3 variant syndrome: LGMD, Dominant 4 (LGMD D4) 104
    • Nosology: LGMD 1I; LGMD D4
    • Epidemiology: 36 families
    • Genetics
      • Inheritance: Dominant
      • Mutations: 21-bp in-frame deletion (c.643_663del21); c.598_612del15; c.1333G>A [p.(Gly445Arg)
    • Clinical: Milder than recessive CAPN3 mutations
      • Onset age
        • Mean 34 years: 16 years later than Recesive LGMD 2A
        • Range: 13 to 84 years
      • Pain (50%): Muscle; Back
      • Weakness
        • Severity: Milder than LGMD 2A
        • Pattern: Similar to LGMD 2A
          • Paraspinal: Lumbar
          • Leg: Proximal
          • Distal leg: Gastrocnemius, medial
          • Arms: Proximal
        • Normal strength: Some patients
        • Course: Variable
          • Severe disability: Some patients
          • Asymptomatic: Some patients
      • Muscle wasting: Proximal arms
    • Laboratory
      • Serum CK: High in 90%; Range 169 to 9,000
      • Muscle MRI: Fat replacement
        • Trunk: Paraspinal
        • Pelvis: Glutei
        • Thigh: Hamstring
        • Leg: Gastrocnemius, medial
      • Muscle pathology
        • Myopathic
          • Internal nuclei
          • Fiber size: Varied
          • Necrosis: Scattered
          • Endomysial connective tissue: Increased
        • Calpain-3 protein: Reduced; < 15% of control levels
LGD 2A: Erb phenotype



From: C Angelini

LGMD R2
  ● Dysferlin ; Chromosome 2p13.2; Recessive

Gene
Protein
Clinical
Laboratory
Pathology
Variant syndromes
Mouse models
From: C Angelini
LGMD R5; Severe Childhood Autosomal Recessive (SCARMD)
  ● γ Sarcoglycan ; Chromosome 13q12.12; Recessive
LGMD R3
  ● α-Sarcoglycan (Adhalin; SGCA) ; Chromosome 17q21.33; Recessive
LGMD R4
  ● β-Sarcoglycan ; Chromosome 4q12; Recessive
LGMD R6
  ● δ-Sarcoglycan (SGCD) ; Chromosome 5q33.3; Recessive
LGMD R7
  ● Telethonin (Titin-Cap; TCAP) ; Chromosome 17q12; Recessive
LGMD R8: Manitoba Hutterite Dystrophy 113
  ● Tripartite-motif containing gene 32 (TRIM32) ; Chromosome 9q33.1; Recessive Sarcotubular myopathy 46
  ● Tripartite-motif containing gene 32 (TRIM32) ; Chromosome 9q31-q33; Recessive
LGMD R9 (MDDGC5) 18
  ● Fukutin-related protein gene (FKRP) ; Chromosome 19q13.32; Recessive Myopathy with abnormal merosin (Laminin-2) 4
    ● Fukutin-related protein gene (FKRP) ; Chromosome 19q13.3; Recessive
LGMD R10
    ● Titin ; Chromosome 2q31.2; Recessive
LGMD R11 (MDDGC1) : with Mental retardation and Reduced α-dystroglycan 45
    ● O-mannosyltransferase 1 (POMT1) ; Chromosome 9q34.13; Recessive
LGMD R12 67
    ● Anoctamin 5 (ANO5, TMEM16E, GDD1) ; Chromosome 11p14.3; Recessive
LGMD R13 (MDDGC4) 59
    ● Fukutin (FCMD; FKTN) ; Chromosome 9q31.2; Recessive
Myopathy, Early-onset with Ophthalmoplegia 78
    ● Myosin, heavy chain 2, skeletal muscle, adult (MYH2) ; Chromosome 17p13.1; Recessive
Early-onset Myopathy with External ophthalmoplegia 78
  ● Myosin, heavy chain 2, skeletal muscle, adult (MYH2) ; Chromosome 17p13.1; Recessive
Myosclerosis (LGMD R22) 69
    ● Collagen, type VI, subunit α2 (COL6A2) ; Chromosome 21q22.3; Recessive
Limb Girdle Dystrophy with Mental Retardation (MDDGC9; LGMD R16) 79
  ● Dystrophin-associated glycoprotein 1 (Dystroglycan 1; DAG1) ; Chromosome 3p21.31; Recessive
LGMD R18: Limb Girdle Dystrophy with Movement Disorder & Intellectual Disability 89
  ● Transport (Trafficking) protein particle complex, Subunit 11 (TRAPPC11) ; Chromosome 4q35.1; Recessive

Other Dominant Myopathies

Bethlem myopathy : Several loci
  ● Collagen, type VI, subunit α1 (COL6A1) ; Chromosome 21q22.3; Dominant
  ● Collagen, type VI, subunit α2 (COL6A2) ; Chromosome 21q22.3; Dominant or Recessive
  ● Collagen, type VI, subunit α3 (COL6A3) ; Chromosome 2q37; Dominant
Bethlem myopathy 2 (BTHLM2) 90
  ● Collagen, type XII, subunit α-1 (COL12A1) ; Chromosome 6q13-q14; Dominant
Multiple epiphyseal dysplasia with mild myopathy (EDM3) 13
  ● Collagen, type IX, subunit α-3 (COL9A3) ; Chromosome 20q13.3; Dominant
  ● Collagen, type IX, subunit α-2 (COL9A2) ; Chromosome 1p34.2; Dominant
  ● Cartilage oligomeric matrix protein (COMP) ; Chromosome 19p13.1; Dominant
Dominant Myopathy with Bone Fragility 51
  ● Methylthioadenosine phosphorylase (MTAP) ; Chromosome 9p21.3; Dominant
Hereditary Inclusion Body Myopathy 4 (HIBM4) 83
  ● Chromosome 7q22.1-31.1; Dominant
Dominant Myopathy with Cardiomyopathy 1
  ● Autosomal dominant
Dominant myopathy with Ankle contractures & High CK 10
  ● Autosomal Dominant
Barnes's Myopathy

Other Recessive Myopathies


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


MDDGC15: Myopathy ± Dilated Cardiomyopathy 75
  ● Dolichyl-phosphate mannosyltransferase 3 (DPM3) ; Chromosome 1q22; Recessive

LGMD 2W: Myopathy with Cardiomyopathy & Triangular Tongue (MDRCMTT) 91
  ● Lim and senescent cell antigen-like domains 2 (LIMS2; PINCH2) ; Chromosome 2q14.3; Recessive
LGMD R25: Myopathy with Arrhythmias 103
  ● Popeye domain–containing 1 gene (POPDC1; BVES) ; Chromosome 6q21; Recessive
LGMD R26: Myopathy 121
  ● Popeye domain–containing 1 gene (POPDC3) ; Chromosome 6q21; Recessive
Myopathy with Contractures (LGMD 2Y; MRRSDC) 125
  ● Torsin A-interacting protein 1 (TOR1AIP1; LAP1B) ; Chromosome 1q25.2; Recessive
Myopathy with Satellite cell loss (LGMD R21) 105
  ● Protein O-glucosyltransferase 1 (POGLUT1) ; Chromosome 3q13.33; Recessive
Myopathy with Scoliosis & Satellite cell loss (MYOSCO) 119
  ● Paired Box Gene 7 (PAX7) ; Chromosome 1p36.13; Recessive
Cardiomyopathy + Myopathy 115
  ● Tripartite motif-containing protein 63 (TRIM63; Murf1) ; Chromosome 1p36.11; Recessive

Congenital disorder of glycosylation, Type Iu (CDG1U; DPM2-CDG): Myopathy with Epilepsy & Microcephaly
  ● Dolichyl-phosphate mannosyltransferase 2 (DPM2) ; Chromosome 9q34.13; Recessive

Myopathy with Lipodystrophy (Congenital generalized lipodystrophy, Type 4; CGL4) 76
  ● Polymerase I and transcript release factor (PTRF; Cavin-1; FKSG13) ; Chromosome 17q21.31; Recessive

Ehlers-Danlos with Myopathy 88
  ● Tenascin-XB (TNXB) ; Chromosome 6p21.33; Recessive

LGMD 4
    ● Autosomal Recessive

Metabolic myopathies

Infantile autophagic vacuolar myopathy 56
    ● Autosomal Recessive

Childhood autophagic vacuolar myopathy 57
    ● Autosomal Recessive or X-linked carrier

Adult-onset autophagic vacuolar myopathy with multiorgan involvement 58
    ● Sporadic

Cardiomyopathy, Retinal degeneration & Epilepsy 93
    ● CLN3 ; Chromosome 16p11.2; Recessive

X-linked myopathies

X-linked Myopathy with Excessive Autophagy (MEAX; XMEA) 5, 16
  ● VMA21 vacuolar H+-ATPase homolog (VMA21; ATP6V0E1; LOC203547) ; Chromosome Xq28; Recessive

X-linked Vacuolar Cardiomyopathy and Myopathy (Danon disease) 122
  ● Lysosome-associated membrane protein 2 (LAMP-2) ; Chromosome Xq24; Dominant, more severe in males

Myofibrillar (Desmin -storage) Myopathies 3,11

MFM: Hereditary types
  Congenital
    Cap
      TPM2: 9p13
      TPM3: 1q22
      ACTA1: 1q42
    MD: SEPN1; 1p36
    MD + JEB: Plectin; 8q24
    Myopathy: CCDC78; 16p13
  Childhood
  MFM
    1 (LGMD 1E): Desmin; 2q35
    2: αB-crystallin; 11q22
    3 (LGMD 1A): Myotilin; 5q31
    4: ZASP; 10q23
    5: Filamin C; 7q32
    6: BAG3; 10q25
    7: KY; 3q22; Recessive
    8: PYROXD1; 12p12
    9: Titin; 2q31
    10: SVIL; 10p11; Recessive
    MFM: ACTA1; 1q42
  Other
    Distal myopathy: HSPB8; 12q24
    DMRV: SQSTM1 + TIA1
    DNAJB4
    LGMD
      1B; LMNA; 1q21
      1D: DNAJB6; 7q36
      2Q: Plectin; 8q24
    Polyglugosan body: RBCK1; 20p13
    PYGM, Dominant: 11q13
    Respiratory Δ: 2q21
    Restrictive cardiomyopathy
    Scapuloperoneal: FHL-1; Xq26
 		MFM
  Clinical features
  Pathological features

Also see
  Contractures + Weakness: KY; 3q22
  Desmin knock-out mouse
  Inclusion body myositis
  Intermediate filament disorders

Desmin aggregates


Myofibrillar myopathies: General 114

Myofibrillar myopathies: Specific syndromes

Myofibrillar myopathy 1 (MFM1)
  ● Desmin ; Chromosome 2q35; Dominant or Recessive
Myofibrillar myopathy 2 (MFM2) (Type 1) 39
  ● αB-crystallin (CRYAB; HSPB5) ; Chromosome 11q23.1; Dominant or Recessive
Myofibrillar myopathy 4 (MFM4) 44
  ● ZASP (Lim domain-binding 3 (LDB3)) ; Chromosome 10q23.2; Dominant
Myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVD7) 14
  ● Desmin (DES) ; Chromosome 2q35; Dominant
Desmin-associated restrictive cardiomyopathy 28
  ● Autosomal Dominant
Cardioneuromyopathy with Hyaline masses and Nemaline rods
  ● Autosomal Recessive
Desmin myopathy (Type 2)
  ● Autosomal Dominant
Congenital muscular dystrophy with Desmin inclusions
  ● Selenoprotein N, 1 (SEPN1) ; Chromosome 1p36-p35; Recessive
Myofibrillar myopathy 5 (MFM5) 47
  ● Filamin C (Filamin 2; FLNC) ; Chromosome 7q32.1; Dominant
Myofibrillar myopathy 6 (MFM6) 68
  ● BCL2-associated athanogene 3 (BAG3) ; Chromosome 10q25.2-q26.2; Dominant
Myofibrillar myopathy 10 (MFM10)
  ● Supervillin (SVIL) ; Chromosome 10p11.23; Recessive
Desmin disorders: Other

Intermediate filaments & Disorders 20

General features
Proteins & Mutations

CYTOPLASMIC BODY MYOPATHIES (Also see Distal myopathies)

Severe limb-girdle: ? Recessive
Mild limb-girdle: Dominant
Desmin myopathies
Myopathy + Respiratory weakness
  Type 1: Titin; 2q31; Dominant
  Type 2: 2q21; Dominant
Distal: Dominant
  Gowers-Laing: MYH7; 14q12
Plectin deficiency
Congenital
  ACTA1: 1q42

Pathology
  Cytoplasmic bodies
Gomori trichrome
Phalloidin

MYOPATHIES WITH TUBULAR AGGREGATES

General features
Pathology
Syndromes
  Myopathy, Proximal
    TAM1: STIM1; 11p15; Dominant
    TAM2: ORAI1; 12q24; Dominant
    TAM (VMCQA): CASQ1; 1q23; Dominant
  Myasthenic disorders
    Limb Girdle MG 1: GFPT1; 2p13; Recessive
    Limb Girdle MG 2: DPAGT1; 11q23; Recessive
    CMS 14: ALG2; 9q22
    Slow channel MG: AChR mutations
    CMG, Recessive: SYT2; 1q32
  Rhabdomyolysis & Cramps
    PGAM2; 7p13; Recessive
  Neuromuscular, Other
    Gyrate atrophy: OAT; 10q26; Recessive
    Periodic paralysis
      Hypokalemic
      Andersen
    Paramyotonia congentia: Some patients
  Occasional: Differential Diagnosis
Gomori trichrome

Tubular aggregates: General features Tubular aggregates: Proximal myopathy syndromes Tubular aggregates: Other Neuromuscular Disorders Tubular aggregates: Other occasional associations Tubular Aggregates: Mouse models
Myopathy with Tubular Arrays 48
Myopathy, vacuolar, with CASQ1 aggregates (VMCQA) 94
  ● Calsequestrin 1 (CASQ1) ; Chromosome 1q23.2; Dominant
Myopathy + Hearing loss & Ovarian Failure 127
  ● Geranylgeranyl Diphosphate Synthase 1 (GGPS1) ; Chromosome 1q42.3; Recessive
Congenital Myopathy Syndromes: Late onset or progressive
Animal models with Myopathy
Also see: Other Dystrophies

Return to Myopathy & NMJ Index

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