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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   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     POPDC3: 6q21   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

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   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

• Definitions
  • Dystrophy (Classic)
    • Tissue involved: Myopathy
    • Course: Progressive
    • Etiology: Genetic
  • LGMD ¹¹²
    • Tissue involved: Muscle
    • Etiology: Genetic
    • Weakness: Predominantly proximal
    • Serum CK: High
    • Muscle histology: "Dystrophic"
    • Course: Progressive
    • Atypical LGMD
      • 1A (Myotilin): Distal weakness
      • 1B (LMNA): Cardiac arrhythmias
      • 1C (CAV3): Mainly rippling muscles & Myalgias
      • 1E & 2R (Desmin): Distal weakness; Cardiomyopathy
      • 2V: Glycogen storage disease
    • LGMD: Previous classification
      • LGMD1: Dominant
        • 1A: Myotilin; 5q31; Dysarthria
          
        • 1B: Lamin A/C; 1q21; + Cardiac
          
        • 1C: Caveolin-3; 3p25; Child onset
          
        • 1D: DNAJB6; 7q36
          
        • 1E: Desmin; 2q35
          
        • 1F: TNPO3; 7q32
          
        • 1G: HNRPDL; 4q21
          
        • 1H: ? 3p23
          
        • 1I: Calpain-3; 15q15
          
      • LGMD2: Recessive
• Myopathies: General features
• Inheritance
  • LGMDD (LGMD1): Dominant
  • LGMDR (LGMD2): Recessive
  • X-linked
  • Other
• Weakness
  • Typical
    • Slowly progressive
    • Symmetric
    • Proximal
  • Severe: Duchenne; Sarcoglycanopathy (LGMD 2C, 2D, 2E, 2F); LGMD 2A (Some patients)
  • Mild: Becker; LGMD 1G, 2A, 2B, 2G
  • Distinctive, selective patterns
    • Extraocular
    • Arm
    • Quadriceps
    • Paraspinous: 2B
    • Distal: LGMD 1C; 2B
    • Asymmetric
    • Scapular
• Other distinctive features: Dystrophies may also present with
  • Myoglobinuria
  • Pain
  • Myotonia
  • Systemic signs
  • Contractures
  • CNS
  • Muscle hypertrophy
  • Cardiomyopathy
  • High serum CK: Especially DMD, Sarcoglycanopthies, LGMD 2B
  • Rippling muscles: LGMD 1C
  • Vacuoles
• Carriers: Have increased Serum CK in < 5% of cases
• Subcellular localization of myopathy-related proteins
  • Nucleus
  • Emerin: X-linked Emery-Dreifuss
  • Lamin A/C: Autosomal dominant Emery-Dreifuss
  • Nesprin (SYNE) 1 & 2: Autosomal dominant Emery-Dreifuss
  • Myotubularin: Myotubular myopathy
  • PABP2: Oculopharyngeal muscular dystrophy
  • VCP: IBMPFD
  • Matrin-3: MPD2
  • TNPO3: LGMD 1F
  • Cytosol
  • Calpain-3: LGMD 2A
  • Tafazzins: Barth
  • DMPK: Myotonic dystrophy
  • Zinc finger protein 9 (ZNF9): Proximal Myotonic Myopathy (PROMM; DM2)
  • TRIM32: LGMD 2H
  • Golgi
    • FKRP: LGMD2I; Congenital Muscular Dystrophy (MDC1C)
    • GOSR2: Congenital MD; Ataxia + Epilepsy
    • TRAPPC11: Myopathy with Movement Disorder & Intellectual Disability
    • GOLGA2: CNS + Muscle
  • Myofibrillar
  • Z-disk related
    • MYOT: LGMD1A
    • DNAJB6: LGMD1D
    • DES: LGMD1E; LGMD2R
    • TCAP: LGMD2G
    • TTN: LGMD2J
    • PLRC1: LGMD2Q
  • Cytoskeleton
  • Dystrophin: Duchenne; Becker
  • Telethonin (TCAP): LGMD 2G
  • Nebulin: Rod myopathy (NEM2)
  • Plectin: Congenital Muscular Dystrophy + Junctional Epidermolysis Bullosa
  • Titin: LGMD 2J
  • Contraction-related cytoskeleton
    • α-Actin (ACTA1): Rod myopathy
    • α-Tropomyosin 3 (TPM3): Rod myopathy (NEM1)
    • Troponin T1: Rod myopathy
    • Myosin: Acute quadriplegic myopathies; Hypertrophic cardiomyopathies; Hearing loss
  • Sarcolemma
  • Sarcoglycans
    • α: LGMD 2D (Adhalin deficiency)
    • β: LGMD 2E
    • γ: LGMD 2C
    • δ: LGMD 2F
    • e : Myoclonus-Dystonia syndrome (Dominant; Maternal imprinting) ²⁶
  • Caveolin-3: LGMD 1C; Hyper-CKemia; Rippling muscles
  • α7-Integrin: Congenital myopathy
  • Dysferlin: LGMD 2B; Miyoshi distal myopathy
  • Acetylcholine receptor subunits: Hereditary myasthenia gravis
  • Ion channels
    • Chloride Channel (CLCN1): Myotonia congenita; Myotonia levior
    • Sodium Channel - α subunit (SCN4A)
      • Paramyotonia
      • Acetazolamide-responsive Myotonia Congenita
      • Hyperkalemic periodic paralysis
      • Hypokalemic periodic paralysis
      • Myotonia Fluctuans
      • Myotonia Permanens
    • Potassium channels
      • KCNE3: Hyperkalemic periodic paralysis
      • KCNJ2 (Kir2.1): Andersen Syndrome
      • TREK-1 (KCNK2) regulators: POPDC1; POPDC3
  • Sarcoplasmic reticulum
    • Ryanodine receptor: Central core
    • Calcium ATPase (ATP2A1): Brody's syndrome
    • Calcium Channel, α1 subunit (Dihydropyridine Receptor) (CACNA1S)
      • Hypokalemic periodic paralysis
      • Malignant hyperthermia
  • Extracellular matrix
  • Laminin α2: Congenital muscular dystrophy
  • Collagen VI: Bethlem myopathy; Ullrich congenital muscular dystrophy
  • Laminin β1: Reduced around muscle fibers in Bethlem myopathy
  • Collagen IXα3: Epiphyseal dysplasia + Myopathy (EDM3):
  • Acetylcholinesterase, Collagen tail: Hereditary myasthenia gravis
  • ? Fukutin: Congenital muscular dystrophy
  • Perlecan: Schwartz-Jampel Syndrome (Chondrodystrophic myotonia)
  • α-dystroglycan ³³
    • Disorders
    • Abnormalities may involve DAG1 mutations or abnormal glycosylation due to other mutations
• Prevalence
  • LGMD general: 1 to 6 per 100,000
  • Recessive muscular dystrophies
    • LGMD 2A: Common on Réunion Island, Guipuzcoa, Northern Indiana, Russia
    • LGMD 2C: Most prevalent in Tunisia
    • LGMD 2D: Most prevalent in US, Europe & Brazil
    • Brazil: Relatively high frequencies of LGMD 2E (8%); 2F (6%); 2G
    • Manitoba Hutterites of Canada: LGD 2H
    • Denmark & England: LGD 2I
    • Finland: LGD 2J
    • French-Canadian: LGD 2L
• Dystrophin-associated glycoprotein (DAG; Sarcoglycan) mutations: Typical features
  • Mutations in one DAG often also result in reduced amounts of the others in muscle
  • Severe weakness
  • Very high serum CK
  • Complexes of DAGs are different in extrasynaptic muscle than at neuromuscular junctions
• Also see: Metabolic disorders
  • Lipid myopathies
  • Glycogen disorders
  • Mitochondrial disorders
    • LGMD 1H

LGMDD (LGMD 1): Dominant inheritance

• Nosology: Confused terminology
  • LGMD 1D: HUGO
  • LGMD 1E: OMIM & Some authors ³⁵
• Epidemiology
  • DNAJB6 mutations in > 20 families
  • US, Japan & Europe
  • 3% of LGMD
• Genetics
  • Mutations
    • Locations: G/F domain (Exon 5); J domain (A50V, E54A)
    • Types
      • Missense
      • Splice site: Removes glycine/phenylalanine-rich region (G/F domain)
      • Inframe deletion: Asp98del
    • Hotspot: Phe93
    • Clinical correlations ⁹⁹
      • Severe disease & Early onset: c.346+5G>A (ΔG/F); Phe91
      • Intermediate disease: Phe100, Pro96, Phe89
      • Milder disease: Phe93
      • Limb girdle phenotype: Proximal G/F domain mutations; Phe89, Phe91, Phe93
      • Distal onset: Distal G/F mutations; Pro96, D98del, Phe100
      • Bulbar: Phe100
  • Allelic with
    • Distal Dystrophy with Rimmed Vacuoles
    • Cardiomyopathy susceptibility
• DNAJB6 protein
  • Cell location
    • A isoform: Nucleus
    • B isoform: Cytoplasm; M-band > Z-band
  • Expression
    • Muscle: Z-disk
    • CNS
      • High levels
      • Inhibits polyglutamine (PolyQ) aggregation
      • Component of Lewy bodies
    • Other tissues
  • Chaperone-related
    • Protects client proteins from irreversible aggregation
    • Interacts with BAG3; HSP70
    • HSP40/DNAJ co-chaperone family: Features
      • Regulate molecular chaperone activity by stimulating ATPase activity
      • Associate with: HSP70 ATPases (e.g., HSPA4 )
      • Stimulate protein folding & remodeling reactions in endoplasmic reticulum
    • Other chaperone-related protein disorders
  • Ligands: MLF1 ; HSPA8 ; KRT18
  • Mutation effects
    • Reduced capacity to prevent protein aggregation
    • Enhanced GSK3β signaling
  • HSP40/DNAJ family: Other DNAJ disorders
    • DNAJB2: Motor neuropathy; CMT 2T
    • DNAJB5: Distal atrophy
    • DNAJC3: Diabetes Mellitus & Multisystem Neurodegeneration
    • DNAJC6 : PARK19
    • DNAJC7: ALS risk
    • DNAJC12 : Hyperphenylalaninemia, Dystonia & Intellectual Disability
    • DNAJC19: Dilated Cardiomyopathy with Ataxia
    • DNAJC21 : Bone marrow failure
• Clinical
  • Onset age
    • Mean: 38 years
    • Range: 8 to 50 years
  • Weakness
    • Distribution: Variable
      • Proximal > Distal or Distal > Proximal
      • Legs > Arms
      • Hamstring > Quadriceps: Some patients
      • Respiratory: Some childhood onset patients
    • Progression: Slow; Wheelchair after 20 to 30 years
  • Dysphagia (20%)
  • Muscle size: Atrophy in some patients
  • Cramps: Some patients
  • Systemic features: None
• Laboratory
  • Serum CK: Normal to 5x elevated
  • EMG: Myopathic; Some with irritability
  • MRI
  • Muscle pathology
    • Myopathic
    • Small muscle fibers: Rounded & Angulated
    • Endomysial fibrosis
    • Rimmed vacuoles: Associated with autophagy markers TDP-43, LC3, SQSTM1
    • Eosinophilic cytoplasmic bodies
    • Aggregates: Protein contents
      SMI-31, TDP-43, αB-crystallin, Myotilin, Desmin, DNAJB6
      Structural, RNA-binding stress-granule, Chaperones & Cochaperones
    • Small fibers express neonatal & fetal myosin
    • NMJs: Multisegmented

• Nosology: LGMD 1F
• Epidemiology 2 families
• Genetics
  • Mutation: c.2771delA; c.2757delC
  • Penetrance: 85%
  • Related features
    • IRF5-TNPO3 region: rs10488631 is risk locus for Systemic Lupus Erythematosus
    • c.2771delA mutation: Inhibits HIV-1 infection
• TNPO3 protein
  • Location: Nuclear
  • Transport into nucleus: Serine/arginine-rich proteins (Splicing factors)
  • HIV-1 infection cofactor: Through interaction with viral integrase & capsid
  • Karyopherin β superfamily of proteins
• Clinical
  • Weakness
    • Onset
      • Age
        • Mean: 16 years
        • Range: Congenital to 58 years
      • Hypotonia
      • Proximal leg
    • Distribution
      • Proximal: Early in disease course
      • Symmetric
      • Legs > Arms
      • Scapular winging: Some patients
      • Distal
        • Late in course
        • Muscles: Extensor digitorum, Tibialis anterior, Toe extensors
      • Face: Normal in most
      • Early-onset or More severe patients: Weakness
        • Face
        • Proximal & Distal
        • Respiratory: Younger onset patients; FVC 40%
        • Progression more rapid
      • Progression: Linear rate
        • Slow: Adult onset patients
        • More rapid: Juvenile onset patients
        • Wheelchair in 2nd or 3rd decade in younger onset patients
  • Muscle hypertrophy: Absent
  • Skeletal
    • Contractures: Occasional late; Ankles
    • Spinal deformity: Some younger onset patients
• Laboratory
  • Muscle pathology
    • Fiber size: Varied
    • Necrosis: Occasional
    • Type 1 predominance: Some patients
    • Connective tissue, Endomysial: Increased
    • Desmin: Mildly increased expression in some fibers
    • Nuclei: Abnormal morphology, Internal; TNPO3 perinuclear
    • Rimmed vacuoles (60%)
    • Ultrastructure: Autophagic vacuoles
  • Muscle MRI: Most involved muscles
    • Scapular girdle: Teres major (80%) > Pectoral (64%), Iinfraspinatus & Serratus anterior (55%), Deltoids (46%)
    • Lumbar: Paraspinal (90%) > Abdominal oblique (55%) Rectus abdominus (55%)
    • Thigh: Sartorius (100%) > Vastus lateralis, intermedius & medialis (73%), Biceps femoris, Semitendinosus (55%)
    • Lower leg: Peroneal (91%) & Gastrocnemius (91%) > Soleus (73%), Tibialis anterior (70%)
  • EMG: Myopathic or Neurogenic
  • Serum CK
    • Mean: 589
    • Normal: 40%
    • Range: 47 to 2,920
  • Cardiac: Normal EKG & Echocardiogram

• Nosology: LGMD 1G
• Epidemiology: Brazilian-Caucasian & Uruguayan families; 18 patients
• Genetics ⁹²
  • Mutations: Missense in same base pair; G>A (p.D378N), G>C (p.D378H)
• HNRPDL protein
  • HNRPDs: Participate in splicing of specific exons in premRNA of transcripts
  • Location
    • Normal muscle: Nuclei
    • Disease: Irregular nuclei; Also present around nuclei
  • May interact with: Transportin-1 (TNPO1) in RNA-processing events
  • Ribonuclear proteins & Disorders
• Clinical
  • Homogeneous phenotype
  • Onset
    • Age
      • Range: 15 to 53 years
      • Mean 37 years
      • Some mutation carriers asymptomatic > age 63
    • Weakness: Legs or Arms; Proximal
    • Cramps: Legs
    • Cataracts (50%)
  • Weakness
    • Proximal > Distal
    • Legs 100%; Arms 90%
    • Finger & Toe flexion: Limited
  • Muscle atrophy
  • Contractures: Limited flexion of fingers & toes
  • Progression
    • Slow
    • 50% walking at 10 years after onset
  • Eye: Cataracts
• Laboratory
  • EKG: Normal
  • Hand x-rays: Normal
  • Serum CK: Usually high (Up to 9x normal); Normal in 20%
  • Muscle biopsy
    • Fiber size variation
    • Perimysial fibrosis (Discrete)
    • Necrotic fibers
    • Vacuoles
      • Rimmed
      • Stain with dystrophin & sarcoglycans
    • Type 2 fiber predominance
    • Denervation-like
      • Small atrophic angulated fibers
      • Fiber type groups: Scattered
    • Milder patients: May be normal

Myofibrillar myopathy 3 (MFM3)

• Nosology: LGMD 1A
• Epidemiology
  • > 15 families described
  • Female = Male
  • 10% of myofibrillar myopathies
• Genetics
  • Mutations
    • Missense
      • Most common: Ser60Cys
      • Lys36Glu; Ser55Phe; Thr57Ile; Ser60Ile; Gln74Lys; Ser95Ile; Ala115Thr
    • Most common in: Exon 2; Serine rich region of myotilin
    • Other exon mutations: Arg6His (Exon 1); Arg405Lys (Exon 9)
  • ~50% of families have no family history: Not related to specific mutation
  • Allelic disorders
    • Spheroid body myopathy
    • Myofibrillar myopathy, Recessive
    • Homozygous Dominant mutation
    • MFM3
  • Also see: Myofibrillar myopathies
  • External link
    • Gene data base: Caveolin-3; Sequence variants
• Protein: Myotilin (Titin immunoglobulin domain protein; TTID)
  • Structure: Contains 2 Ig-like domains in C-terminus homologous to titin
  • Location
    • Sarcomere: In I-bands (Z-line); Bound to α-actinin
    • Sarcolemmal membrane
  • Interacts with: α-Actinin; Actin; Filaments (γ-Filamin)
• Clinical features ⁴⁰
  • Onset
    • Age: Variable
      • Young adults in Virginia family (Thr57Ile): Mean age 27 years
      • Other patients: 42 to 77 years
    • Weakness
      • Legs
      • Distal or Proximal
    • Myalgias & Stiffness: Some patients
  • Weakness
    • Legs & Arms
    • Distal
      • With disease progression in most
      • Many patients with early foot drop
    • Arms: Wrist & finger extensors + Deltoids most common
    • Neck extensors: Some patients
    • Face: 17%
    • Symmetric: Most patients
    • Respiratory failure: Some patients; At onset in 1 patient
  • Speech: Dysarthria, nasal (30%); ? Related to palatal weakness
  • Myalgias: 25%
  • Tendon reflexes: Reduced at knees & ankles (100%); Some with diffuse loss
  • Joint Contractures: Ankles (30%)
  • Cardiomyopathy: 50%; Onset in 6th or 7th decade
  • Neuropathy: Occasional patient
    • Sensory loss: Distal
    • Axonal loss
    • Demyelinating features: One patient
  • Progression
    • Slow
    • Late loss of ambulation (10 years after onset)
• Laboratory
  • Serum CK: Normal to 15-fold elevated; Commonly 2x high
  • EMG
    • Myopathic
    • Fibrillations: Some patients
    • Myotonia: Some patients
  • CT: Early posterior leg involvement
• Muscle pathology
  • Myopathic
  • Muscle fiber degeneration
  • Muscle fiber size: Varied
  • Fiber splitting
  • Central nuclei
  • Z-line streaming
  • Rimmed vacuoles: Numerous; Autophagic; No amyloid
  • Inclusions
    • Hyaline: Some congophilic; Composed of compacted, fragmented filaments
    • Rod-like inclusions: Z-band streaming
    • May be PAS positive
  • Inflammation: 1 patient; Mild
  • Immunocytochemistry
    • Myotilin
      • Normal levels
      • Abnormal muscle fibers often have patches of increased immunostaining
      • Co-localizes with ubiquitin & clusterin
    • Normal DAG staining
    • Increased staining: Other molecules in abnormal muscle fibers
      • Common to myofibrillar myopathies: Dystrophin; NCAM; Desmin; Plectin
      • More prominent than in other myofibrillar myopathies: Gelsolin; Ubiquitin
    • Reduced staining
      • Laminin γ1
  • Denervation: Small esterase positive muscle fibers
  
  
• Variant syndrome: Spheroid body myopathy ⁵²
    ● Myotilin ; Chromosome 5q31; Dominant
  • Epidemiology: Indiana & Oregon families
  • Genetics
    • Mutations: Missense; S39F in myotilin gene exon 2
  • Clinical: Variable within family
    • Onset: Teens to 80's; Mean 4th decade
    • Weakness
      • Proximal ± Distal
      • Legs
      • Symmetric
      • Dysarthria
      • Respiratory
    • Tendon reflex: Absent ankle
    • Prognosis
      • Usual: Benign; Little disability
      • Some patients: Rapid progression to wheelchair or respiratory failure
  • CK: Normal
  • Pathology
    • Variation in fiber size: Moderate
    • Inclusions
      • Aggregates of Gomori Trichrome + & Eosinophilic material
      • Contain Desmin & Ubiquitin
      • Type I > Type II fibers
      • Often subsarcolemmal; ± Associated with acid phosphatase staining
      • PAS -
• Variant syndrome: Myofibrillar myopathy, Recessive ⁹⁵
    ● Myotilin ; Chromosome 5q31; Recessive
  • Epidemiology: 1 German family, 2 patients
  • MYOT mutation: Arg6Gly, Homozygous
  • Clinical
    • Severe phenotype: Intrafamilial variability
    • Onset age: 3rd or 4th decade
    • Weakness: Proximal; Legs > Arms; Progressive
  • Laboratory
    • Serum CK: 1143
    • Muscle pathology: Myofibrillar myopathy
      • Fiber size: Varied
      • Subsarcolemmal & intracellular masses
      • Protein aggregates: Desmin; αB-crystalline; Myotilin
      • Ultrastructure: Myofibrillar damage
    • EMG: Myopathic
    • Muscle MRI: Vastus involvement
    • Cardiac: Mild EKG changes
• Variant syndrome: Homozygous Dominant disease
  • Genetics: Ser60Phe mutation
  • Clinical
    • Onset age: Adult
    • More severe disease
    • Proximal & Distal weakness

• Nosology: LGMD 1B
• Genetics
  • Lamin A/C gene mutation types
    • Missense & Deletion of codon in rod domain
    • Splice donor site: Protein lacking half of the globular tail domain
  • Lamin A/C gene mutations: Other clinical syndomes
• Lamin A/C protein
• Clinical
  • Onset: < 20 years
  • Weakness
    • Common: Symmetric; Proximal; Lower limb
    • Variant: Quadriceps with Arg377His mutation
  • Progression: Slow; Upper limbs involved by 3rd or 4th decade
  • No contractures
  • Associated systemic feature: Cardiomyopathy (62%)
    • A-V conduction block
    • Occasional dilated cardiomyopathy: Onset before weakness with Arg377His mutation
• Laboratory features
  • Serum CK: Normal to mildly elevated
  • Muscle
    • Myopathic changes, Mild
    • Aggregates: Desmin, Myotilin, α-B-Crystallin, Dystrophin
  • Lamin A subcellular localization
    • Normal: Nucleus; Co-localizes with Emerin
    • Mutated: May aggregate in nucleus & be present in cytoplasm
• Also see: Dominant myopathy with cardiomyopathy

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

• Genetics
  • Caveolin-3 gene mutations
    • General: Most commonly located in scaffolding domain of protein
    • Specific mutations
      • Arg26Gln
        • Caveolin levels reduced 60% to 80%
        • Disease associations
          • Idiopathic hyperCKemia
          • Rippling muscle disease
          • Distal myopathy
      • Asp27Glu
        • Rippling muscle disease ± Weakness (Distal or Proximal)
        • Variable clinical features in family
      • Pro28Thr
        • Onset 35 years
        • Rippling muscle disease
        • Fatigue: Exercise induced muscle pain, Cramps
        • Serum CK: 1100
      • Ala45Thr
        • N-terminal domain
        • Disease associations: LGMD1C; Rippling muscle disease
        • Caveolin levels reduced > 90%
      • Ala45Val: Rippling muscle disease
      • Ala46Thr: Rippling muscle disease; Distal myopathy
      • Ala46Val: Cardiomyopathy with Rippling muscles
      • Ser52Gly
        • Domain with role in homo-oligomerization
        • Rippling muscle disease
      • Gly55Ser
        • Caveolin scaffolding domain
        • Inheritance: Recessive
        • Caveolin levels: Normal
      • Val57Met: HyperCKemia
      • T63S: Cardiomyopathy
      • Cys71Trp: ? Disease association
        • Caveolin scaffolding domain
        • Caveolin levels: Normal
      • Homozygous: L86P or A92T
        • Rippling muscle disease: Severe, Recessive
      • Pro104 Leu
        • Missense mutation in membrane-spanning region
        • Disease associations: LGMD1C; Rippling muscle disease
        • Caveolin levels reduced > 90%
      • Arg125His: ? Disease association
        • C-terminal domain
        • Caveolin levels normal
      • 186Del9
        • Microdeletion in the scaffolding domain
        • Caveolin levels reduced > 90%
      • Splicing: IVS1+2T>C ⁶⁴
        • Homozygous
        • Intronic
        • Recessive inheritance
  • Caveolin-3: Allelic disorders
    • LGMD 1C
    • Rippling muscle disease: Dominant or Recessive
    • Increased CK with normal strength
    • Distal myopathy
    • Cardiomyopathy, familial hypertrophic
    • Long QT syndrome 9
  • External link: Leiden database
• Caveolin proteins
  • Caveolins: General
    • Integral transmembrane proteins
    • Principal protein components of caveolae
    • Caveolin-1 & Caveolin-3 generate caveola-like vesicles
    • Most of the functional domains in caveolins located in last exon
    • Functions
      • Signaling
        • Able to bind multiple components of a signaling pathway
        • Implicated in signal transduction: By receptor tyrosine kinases (RTKs) & G-proteins
        • Mechanism: Scafolding proteins; Organize & Concentrate molecules
          • Lipids: Cholesterol; Glycosphingpolipids
          • Lipid-modified signaling molecules in caveolar membrane
            • Src-like kinases, H-ras, eNOS, G proteins
      • Vesicular trafficking events
      • ? Tumor supressor (Caveolin-1)
  • Caveolae
    • Structural
      • 50 to 100 nm invaginations found in most cell membranes
      • Appendages or subcompartments of plasma membranes
    • Functional
      • ? Provide a scaffold
      • Place members of a signal-transduction pathway in close proximity to each other
    • Disease: Duchenne MD muscle has increased numbers of caveolae
  • Caveolin-3 protein
    • Tissue location: Muscle specific, Striated & Smooth
    • Cell localization
      • Sarcolemma (Adult)
      • T-tubules (Development & Adult): Concentrated in subsarcolemmal regions
    • Forms homo-oligomer: 14 to 16 subunits
    • Caveolin-3 interacts with
      • G-protein α subunits
      • Signaling molecules: Gl2α; Gβγ; c-Src; Src-like kinases
      • Dystrophin & Associated glycoproteins
        • Interaction not as strong as integral members of the DAG complex
        • Direct interaction with β-dystroglycan: Via WW-like domain
      • Dysferlin
      • PFK-M
        • Prominent caveolin-3 binding protein
        • ? Regulation of glycolysis by caveolin-3
      • nNOS (muscle-specific): Interaction inhibits nNOS enzyme activity
        • Cytokine-stimulated NOS activity: Increased in myotubes transfected with mutant CAV3
        • Transgenic CAV3 mutant mice (P104L): Increased nNOS activity in skeletal muscle
        • LGMD1C: Severe reduction of nNOS expression
      • Colocalizes with Na_v1.5 (SCN5A) in myocardium
    • Muscle functions
      • Required for myoblast fusion/myotube formation
      • Regulates myostatin signaling: Suppresses activation of type I myostatin receptor
      • Sarcolemma integrity
      • Electrical transmission of contractile impulse
      • Energy metabolism
  • Caveolin gene mutations & Other Disorders: Effects on caveolin-3 protein
    • LGMD 1C
      • Reduced Caveolin-3 levels in muscle: Membrane caveolin-3 especially reduced (~95%)
      • Mutations cause formation of unstable high molecular mass aggregates
      • Aggregates composed of normal & mutated caveolin-3: Dominant negative effect
      • Aggregates of normal & mutated caveolin-3
        • Cell location: Retained in Golgi; Not targeted to plasma membrane
        • Effect of aggregation on caveolin-3 protein: Misfolding; Degradation
        • Metabolism: Undergo ubiquitination & proteasomal degradation
        • Caveolin-3 Half-life: Shortened by 7 fold
        • ? Treatments rescue wild type caveolin-3
          • Inhibition of proteasomal degradation of caveolin-3 aggregates
          • Inhibition of caveolin-3 misfolding
      • Altered interactions of scaffolding region with muscle regulatory proteins
    • Duchenne MD: Caveolin-3 is upregulated
    • Denervation: Caveolin-3 aggregates are present inside targets
• LGMD 1C: Clinical features
  • Onset
    • Age: 4 to 71 years
    • Weakness
    • Difficulty walking
  • Weakness
    • Usual
      • Severity: Moderate
      • Pattern: Proximal
    • Distal
      • 2 families described
      • Also in recessive patients
    • Progression
      • Mild: Adults with Gower's maneuver
      • Variable among families
  • Calf hypertrophy
  • Exercise intolerance ± Weakness
    • Cramps: After exercise
    • Rhabdomyolysis
  • Variable clinical manifestations may occur in single family
• Caveolin-3 mutations: Variant syndromes
  • Recessive muscular dystrophy syndromes ⁶⁴
    • Mutations: Gly55Ser; Splice site (IVS1C2TOC)
    • Weakness
      • Proximal & Distal; Foot drop
      • Legs & Arms
    • Contractures: Ankles
    • Calf hypertrophy
    • MRI
      • Asymmetric
      • Muscles: Hip abductors & adductors, Rectus femoris, Hamstring, Tibialis anterior
    • Muscle biopsy
      • Chronic myopathy
      • Caveolin-3 absent: No 21 kD band on Western blot
  • Rippling muscle disease syndromes
  • Distal myopathy (MPDT)
    • Nosology: Tateyama myopathy
    • Epidemiology: 3 families
    • Genetics
      • Inheritance: Dominant
      • Mutations: Arg26Gln; N33K mutations
    • Clinical
      • Weakness
        • Onset age: 2nd to 5th decade
        • Isolated Hand & Foot muscles
        • Neck flexors: Mild
      • Muscle size
        • Calf hypertrophy
        • Distal wasting
      • Percussion induced muscle contractions: Distal hands
      • Some patients
        • Rippling
        • Myalgias
        • Pes cavus
    • Laboratory
      • Serum CK: High
      • EMG: Myopathic
      • Muscle
        • Internal nuclei
        • Type I predominance
        • Caveolin-3 nearly absent
        • Dysferlin: May be reduced or normal
  • Hyper-CKemia ⁶³
    • Mutations: Missense; Gly56Ser, Thr78Met
    • Frequency: 7% of Idiopathic Hyper-CKemia
    • Caveolin-3 staining of muscle: Normal
  • Cardiomyopathy: Varied types
    • Hypertrophic
    • Dilated
    • Long QT syndrome ⁶⁵
      • Mutations: Missense; T78M, A85T, F97C, S141R
      • Effect of mutations: 2- to 3-fold increase in late sodium current
      • Onset age: 8 to 40 years
      • Symptoms: Nonexertional syncope; Cardiac arrest; Shortness of breath
• LGMD 1C: Laboratory features
  • Serum CK: Increased 3 to 40-fold
  • Pathology ⁶⁶
    • Myopathic changes: Often mild
      • More severe with early disease onset
      • Muscle fiber size: Varied
      • Necrosis & Regeneration: Some patients
      • Endomysial connective tissue increased: Some patients
    • Caveolin-3
      • LGMD1C
        • Reduced on muscle fiber sarcolemma & by Western blot
        • May be normal or high on small, regenerating muscle fibers
      • Reduced on sarcolemma in other hereditary disorders
        • VCP myopathy (IBMPFTD)
        • Cavin-1
    • Dysferlin
      • Reduced on muscle fiber sarcolemma
      • Normal by Western blot
    • Ultrastructure
      • Reduction in caveolae
      • Loss of myofibrils
• Caveolin disorders: Mouse models
  • Overexpression of wild type caveolin-3
    • Myopathy
    • Reduced dystrophin
  • Overexpression of Pro104Leu mutant caveolin-3
    • Down regulation of wild type caveolin-3
    • Myopathy: Severe
  • Caveolin-null
    • T-tubule abnormalities
      • Mislocalized dihydropyridine receptor-1α & ryanodine receptor
      • Iregular orientation of T-tubules
    • Loss of caveolae at sarcolemmal membrane
    • Muscle fiber degeneration: Especially in soleus & diaphragm
    • No effect on dystrophin complex
• Links: Leiden

• Nosology: Confused terminology
  • LGMD 1E: HUGO
  • LGMD 1D: OMIM & Some authors ³⁵
  • Myofibrillar myopathy 1 (MFM1)
• Epidemiology: 1 Large family; French-Canadian descent
• Genetics
  • Desmin mutation: Intron splice donor site mutation (IVS3+3A>G)
  • Earlier incorrect chromosome localization at 6q23
  • Allelic disorders
• Desmin protein
• Clinical
  • Weakness
    • Onset: 2nd decade & later
    • Distribution: Proximal; Face normal
    • Calf hypertrophy: Occasional
    • Exertional dyspnea
    • Progression: Slow; All patients remain ambulatory
  • Cardiac
    • Arrhythmia: Earliest feature of cardiac disease; Onset 20 to 25 years
    • Congestive heart failure: 4 chamber enlargement; Onset 3rd to 5th decade
    • Sudden death without prior cardiac symptoms
• Laboratory
  • Muscle pathology
    • Variable fiber size
    • Increased endomysial connective tissue
    • Eosinophilic inclusions: Some reducing bodies
  • Serum CK
    • Usually increased 2x to 4x control
    • More likely high in males than females

• Epidemiology: 6 European families, 14 patients
• Genetics
  • Mutation: c.292C>T (p.His98Tyr)
• Myoglobin protein
  • Cytoplasmic globular hemoprotein
  • Highly expressed in: Cardiac myocytes & Oxidative skeletal myofibers
  • Binds O₂
  • Facilitates intracellular O₂ transport
  • Controller of nitric oxide & reactive oxygen species
• Clinical
  • Onset age: 33 to 49 years
  • Weakness
    • Proximal & Axial
    • Legs > Arms
    • Distal: With disease progression; Early hands in 2 patients
    • Respiratory
    • Dysphagia (33%)
    • Normal: Face & EOM
  • Muscle atrophy: Most
  • Cardiac: Dilated cardiomyopathy (45%)
  • Course
    • Slow progression
    • Wheelchair after 15 years
    • Death in some 18 to 30 years after onset
• Laboratory
  • Serum CK: Normal to 7x high
  • EMG: Myopathic with spontaneous activity
  • Muscle MRI
    • Proximal: Paraspinal, Gluteus maximus & medius
    • Thigh: Adductor magnus, Semimembranosus, Long head of biceps femoris & Vastus intermedius
    • Leg: Soleus
  • Muscle pathology
    • Sarcoplasmic bodies: Round; Autofluorescent; Also in heart
    • Vacuoles: Acid & LAMP1 phosphatase+
    • Fiber sizes: Varied
    • Internal nuclei
    • Type 1 fiber predominance

• Nosology: LGMD 1H
• Epidemiology: Southern Italian family
• Genetics: Incomplete penetrance
• Clinical
  • Onset
    • Age: 16 to 50 years
    • Weakness: Arms & Legs
  • Phenotype: Variable onset age & severity
  • Weakness
    • Proximal
    • Legs & Arms
    • More severe with younger onset
  • Muscle hypertrophy
    • Calves
    • Younger patients with no weakness
  • Muscle atrophy: Proximal
  • Tendon reflexes: Reduced
  • Progression: Slow
• Laboratory
  • EMG: Myopathic
  • Serum CK: 98 to 2300
  • Serum lactate: Normal
  • Muscle biopsy
    • Fiber size variation
    • Endomysial fibrosis
    • Mitochondrial
      • SDH+ & COX- muscle fibers
      • mtDNA deletions: Multiple

LGMDR (LGMD2): Recessive Inheritance

Genetics Calpain-3 protein Clinical Laboratory

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 is present by Western blot LGMD phenotype: Variable severity of weakness G222R mutation 54 Mutations: Compound heterozygote for R110X & G222R Loss of function: Size & Abundance normal Early onset weakness Disease foci Multiple mutations in some foci: Réunion island 60% have IVS6-1G>A Amish & Basque populations Digenic inheritance: ?? Single mutation Guipuzcoa (Basque Country, Spain) Exon 22, 2362AG[→]TCATCT in 76% US Northern Indiana Amish: R769Q in 100% Russia, Eastern Mediterrananean & North Italy 550delA: Mutation frequency 1/150 Venetian lagoon: R490Q Other foci: Brazil, Turkey, Japan 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 HGMD Leiden: Sequence variants 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 C-terminus of titin (connectin) in muscle Filamin C 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 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: Pelvic-femoral girdle Late onset Age: > 30 years Weakness: Pelvic girdle Erb dystrophy type (10%): Scapular-humeral phenotype Onset age: 16 to 37 years Weakness early in shoulder girdle Male = Female Calpain-3 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 Dystrophin; LGMD 1C; LGMD 2B (Dysferlin); LGMD 2I (FKRP); LGMD 2J (Titin) 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 Typical LGD 2A phenotype: May be dominant Western blot Calpain-3 enzyme activity: Reduced Mouse model: Calpain-3 knockout 42 Misaligned A-bands Abnormal sarcomere formation CAPN3 variant syndrome: LGMD, Dominant (LGMD D4) 104 Nosology: LGMD 1I Genetics Inheritance: Dominant Mutation: 21-bp, in-frame deletion (c.643_663del21) Clinical 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 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: Loss to< 15%

LGD 2A: Erb phenotype From: C Angelini

Gene Protein Clinical Laboratory Pathology Variant syndromes Mouse models

From: C Angelini

• Nosology: LGMD 2B
• Gene
  • 55 exons
  • Allelic with
    • Miyoshi distal myopathy (MM)
    • Distal myopathy with anterior tibialis onset (DMAT)
    • Variant syndromes
  • Locus near, but different from, Welander distal myopathy
• Gene mutations ²⁵
  • > 450 different mutations described
    • 18% of patients with dysferlin deficiency have only 1 (heterozygous) mutation identified on 1 allele
  • Mutation types
    • Types: Missense (26% to 46%); Nonsense (18% to 26%); Deletions; Insertions; Intron; Splice site
    • Distributed over entire coding sequence + Introns: Most mutations private variants
    • Most introduce stop codons or premature truncations of the dysferlin protein
    • Splice site (in-frame) mutation (A3443-33G) ⁵³
      • May allow some residual dysferlin protein production
      • Clinical phenotype: Milder
  • Mutation locations in gene: Widely dispersed over coding sequence
  • Variations in phenotype not well explained by mutation type
  • Geographic distribution
    • Mutations present at low frequency in many populations: Typically
      • 1% of recessive LGMD
      • 33% of distal myopathies
    • Common in Libyan Jews: 1624delG; Carrier frequency up to 10%
    • Japanese
      • G2997T (Trp999Cys); G3370T: Mild disease phenotype; Later onset
      • G3510A: More severe disease; Earlier onset; High CK
      • Other common mutations: 3746delG; 4870delT
      • 3373delG: Japanese Miyoshi
    • Sueca, Spain: Arg1905X ⁵⁰
  • External links
    • Mutation Databases: Leiden; Sequence variants
    • Diagnostic tool: Jain Foundation
• Protein: Dysferlin
  
  • Tissues: Skeletal muscle > Heart; Ubiquitously expressed at low levels
  • Size
    • 230 kDa + Multiple lower weight bands
    • 55 exons
  • Subcellular localization
    • Plasma membrane: Present at periphery of muscle fibers
    • T-tubules
    • Cytoplasmic vesicles: Trans-Golgi network secretory vesicles
  • Homology to
    • Nematode spermatogenesis factor (fer-1): Required for cell fusion
    • Myoferlin: Plasma membrane & Nuclear envelope
    • Otoferlin
  • Domains
    • Transmembrane: Short, C-terminal, hydrophobic
    • C2: 7 domains; Hydrophilic; Bind calcium & cellular membranes
    • Most of dysferlin protein intracellular
    • Extracellular domain: Small
  • Interactions: Binds to ⁶²
    • Caveolin-3
    • AHNAK
      • Interaction mediated by calpain-3
      • Levels reduced in dysferlinopathies
    • Annexins A1 & A2
    • S100 Calcium binding protein A10
    • Calpain 3 (CAPN3)
    • β-parvin
    • Dihydropyridine receptor (DHPR)
    • Mitsugumin 53 (MG53; TRIM72) : May play role in membrane repair
    • Other: Ca⁺⁺; Lipids
  • Functions
    • Membrane fusion or repair
    • Ca⁺⁺-mediated muscle membrane
      • Homeostasis processes
      • Signal transduction events
    • Myogenesis
    • Angiogenesis
    • Microtubule dynamics
  • Dysferlin turnover & levels
    • Half-life in membrane: ~ 3 hours
    • Upregulation: LARGE (myd) mouse
  • Dysferlin: LGMD 2B patients
    • Immunohistochemistry (IHC)
      • Sarcolemma: Absent or Reduced
      • Cytoplasm: Reduced or Increased
    • Western blot
      • Absence has more specificity for LGMD 2B than IHC changes
      • Dysferlin may be normal or increased
        • Some mutations produce cytoplasmic aggregates of normal sized dysferlin protein
• Clinical: Milder LGMD phenotype ⁸⁵
  

  LGMD 2B No calf hypertrophy

  • Onset
    • Age
      • Mean 19 to 27 years
      • Range
        • General: 10 to 39 years
        • Congenital & 8th decade onsets reported
      • Heterogeneity in single family may occur
    • Leg weakness
      • Proximal
      • May be associated with period of exercise
  • Weakness
    • Mild
    • Asymmetry: Common
    • Legs
      • Distal: Posterior muscles
        • Especially gastrocnemius
        • Early inability to walk on toes
        • Differential diagnosis: Distal myopathy with anterior leg sparing
      • Proximal
        • Anterior & Posterior muscle groups
        • Especially adductors, also psoas
      • Lower limbs involved 9 years before upper limbs
    • Arms
      • Especially biceps
        • Weakness
        • Atrophy: Distal predominant (boule du biceps) (MRC ≥ 4) ¹²⁶
      • Deltoid: Often spared
    • Trunk: Glutei, Erector spinae, Shoulder girdle involved
    • Face: Generally normal
    • Loss of ambulation: > 30 years
    • Respiratory
      • More with longer disease duration
      • Overall: 50% have VC < 80%
    • Wide inter- and intrafamilial variation
    • Progression: Slow; Most walk until > 33 years, some into 6th decade
  • Calf size
    • Hypertrophy: Some patients
      • Deltoid hypertrophy with biceps atrophy
      • Posterior leg (Calf): May be early in disease course
    • Occasional distal onset patients
      • Subacute, painful enlarged calves early in course ⁶⁰
  • Cramps & muscle discomfort: Some patients
  • No cardiomyopathy: Clinically preserved; EF generally > 50%
  • Same mutations may also produce Miyoshi distal myopathy
    • ? Modifier genes determine phenotype
• Laboratory features
  • CK
    • Typical
      • Very high
      • Range: 10x to 72x normal; Up to 27,000
      • Lowest: Normal
    • Presymptomatic: 343 to 3,000
    • ? Age-dependent increase
  • EMG: Myopathic
    • Motor units: Small amplitude; Short duration
    • No spontaneous activity
  • Imaging
    • Early involvement on MRI or CT
      • Posterior leg: Gastrocnemius atrophy, especially medial heads; soleus
      • Thigh: Hamstrings
      • Erector spinae
    • Late or minimal involvement: Gracilis; Sartorius; Glutei
  • Muscle
    

    Dysferlin staining in normal muscle

    • Pathology: Dystrophic Muscle
      • Necrosis & degeneration of muscle fibers
      • Endomysial connective tissue: Increased in more involved muscles
      • Muscle fibers: Size variation, may appear bimodal; Splitting
      • No vacuoles
      • Inflammation: Some mutations ²²
        • Perimysial & perivascular cell infiltrates: Some muscles
        • T-lymphocytes
        • No MHC class I antigen on muscle fibers
      • Complement: Membrane attack complex (but not C3) on muscle fiber surface
      • Amyloid
        • Present in muscle in some patients
          • Mutation locations: N-terminal or other regions
        • Location: Muscle fiber surface; Endomysial connective tissue; Perivascular
        • Amyloid may contain dysferlin
      • Ultrastructure
        • Sarcolemmal defects
        • Replacement of membrane by layers of small vesicles ²³
    • Dysferlin tissue staining ³⁰
      • Levels
        • Absent, Reduced or Normal
        • Absent staining: More specific for LGMD 2B than reduced, but present, staining
        • Retained staining: May be related to splice site mutations in dysferlin gene
        • No correlation between level of staining and clinical severity
      • Staining may be patchy among muscle fibers
      • Reduced dysferlin staining: Differential diagnosis
        • Not specific for dysferlinopathy: 30% to 60% with no DYSF mutation
        • Other disorders: CAPN3 (10%); CAV3 (2%); GNE; MYH2; ANO5
    • Dysferlin Western blot
      • Common & specific change in LGMD 2B: Dysferlin reduced to 0% to 20% of normal
      • Absent dysferlin on Western blot: Dysferlin gene mutations very common
      • Good correlation on WB between results in
        • Skeletal muscle (234 kDa)
        • Monocytes (doublet 224 to 234 kDa)
      • Increased dysferlin expression: Mutatons in exons 36 or 37
    • Other molecules
      • Calpain-3: Reduced especially with C2 domain mutations
      • Sarcoglycans & Dystrophin: Present
      • Aquaporin-4: Reduced
• Variant syndromes: Different phenotypes may occur in same family
  • General
    • Late in disease course: Varying weakness phenotypes merge
  • Distal myopathy: Miyoshi
  • Distal myopathy: Distal anterior dysferlinopathy (DMAT;DACM)
    • Onset: Foot drop; Steppage gait
    • Weakness
      • Legs
        • Anterior: Ankle > Knee
        • Distal > Proximal
      • Arms: Proximal
  • Myopathy: Proximal + Distal
    • Onset: Proximal weakness; Calf atrophy
    • Weakness: More rapidly progressive
    • Muscle pathology: Inflammation more common
  • Myopathy: Later onset, Proximal, Arms > Legs ⁸⁵
    • Mutation: Trp999Cys; Homozygous
    • Onset
      • Age: Mean 38 years; 16 years later than others average
      • Arm symptoms
    • Weakness: Proximal
    • Serum CK: High but lower than average
  • Pain syndrome
    • Onset: Distal leg (calf) painful swelling without weakness or atrophy
      • Unilateral or Bilateral
    • No weakness or atrophy
  • Asymptomatic with elevated serum CK levels
    • Frequency: 5% of dysferlinopathies
    • Mutations: Missense or Stop
    • Age: 28 & 50 years
    • MRI: Mild gastrocnemius pathology
  • Dysferlinopathy: Congenital myopathy ⁷⁰
    • Genetics
      • Mutation: p.Ala927LeufsX21 frameshift
      • Same mutation associated with: Asymptomatic high CK & LGMD syndromes
    • Clinical
      • Onset age: Congenital
      • Weakness
        • Birth: Hypotonia
        • Legs & Neck flexor ± Arms
        • Walking: At 19 to 30 months
        • Motor milestones: Delayed
      • Contractures: Ankles & Hips; Onset 3 years
      • CNS: Normal
    • Laboratory
      • Serum CK: Up to 5000; Normal or mildly high early
      • MRI: Pathology (STIR) in hamstring & gastrocnemius
      • Muscle
        • Myopathic: Fiber size varied; Endomysial connective tissue increased
        • Dysferlin absent; α-dystroglycan normal
  • Dysferlin: Mutation carriers ⁷⁴
    • May be symptomatic
    • Mutations: G519R; D625Y
    • Clinical
      • Weakness: Legs; Proximal or Distal; Progressive
      • Calf myalgias: 1 patient
    • Serum CK: High; 600 to 3000
    • Muscle
      • Myopathy
      • Dysferlin expression: Reduced & Patchy
• Mouse model: SJL
  • Mutation
    • Genomic: 141 bp intronic deletion involving tandem repeat
    • Effects of mutation
      • Alters 3' splicing site
      • Causes deletion of exon 45 in cDNA: 171-bp in-frame deletion
    • Protein results
      • Deletion of 57 amino acids
      • Reduced amount to 15% of normal
  • Pathology: Myopathy ± Inflammation
• Mouse model: A/J
  • Retrotransposon insertion in intron 4 (5' end) of dysferlin gene
  • Progressive myopathy: Proximal > Distal
  • Perivascular inflammation
  • Dysferlin: Absent by Western blot

• Nosology: LGMD2C
• γ Sarcoglycan gene
  • Promoters: Muscle, Brain & ? Heart-type
  • Mutations
    • Many mutations disrupt carboxyl-terminus
    • One Japanese patient with 73 base pair deletion
    • Gypsies: C283Y
    • Tunisia & North Africa: del521-T mutation ³⁶
    • Severe phenotype: May have null or missense mutation
    • Databases: Leiden; HGMD
• γ Sarcoglycan protein
  • 35 kD Dystrophin-associated glycoprotein
    • Peptide mass: 32 kDa
  • Acidic
  • Location: Subsarcolemmal
  • mRNA expressed
    • Strongly: Skeletal & cardiac muscles
    • Moderately: Lungs, Skin, Spinal cord & Olfactory bulb
    • Weakly: Cerebrum & Aorta
  • Sarcoglycan binding: Moderately to β-sarcoglycan
  • Homologous sarcoglycan: δ-sarcoglycan
  • See: Sarcoglycan complex
• Clinical features
  • Severity
    • Some with Duchenne-like course
    • Others intermediate between Duchenne & Becker phenotype
    • Mild Becker phenotype in occasional family
    • Variable: Interfamilial; Intrafamilial may be homogeneous or heterogeneous
    • Gypsies with C283Y mutation
      • Early Duchenne-like course but longer survival (50%)
      • Becker phenotype (13%)
      • Overall: More severe than North Africans with out of frame del521-T mutation
  • Weakness
    • Onset
      • Mean 5 to 6 years
      • C283Y mutation: < 2 years
    • Proximal > Distal
    • Patchy distribution with some mutations (C283Y)
      • Affected: Glutei, Adductors, Hamstrings, Spinalis, Abdominals, Subscapularis, Soleus
      • Spared: Quadriceps
    • Respiratory: Failure in 3rd decade
  • Muscle hypertrophy: Some patients (C283Y); Calf & Tongue
  • Hearing loss: Neurosensory
  • Cardiac
    • Occasional involvement: Especially late in disease course
    • C283Y mutation: Subclinical; EKG changes 60%; RVH; Diastolic dysfunction
  • Skeletal (C283Y): Lumbar hyperlordosis; Scapular winging
  • Intelligence: Normal
  • Course
    • Loss of ambulation: 10 to 37 years; Mean 16 years
    • No relation between severity of disease & age of onset
    • Death: Common in 2nd decade
• Laboratory features
  • Serum CK: Very high
  • Muscle pathology
    • Myopathic
    • Inflammation: Occasional
    • Sarcoglycan staining
      • Severe disease: Absent γ-sarcoglycan
      • Slowly progressive disease: Reduced γ-sarcoglycan
      • Other sarcoglycans: Levels not related to clinical phenotype
        • α: Normal or reduced
        • δ: Normal or reduced
        • β: Variable; May be reduced most or absent
    • Dystrophin: May be normal or reduced

• Nosology: LGMD 2D
• Genetics: α-Sarcoglycan gene
  • Promoters: 2
  • Mutations
    • Most mutations: Missense: In extracellular domain of SGCA
    • Arg77Cys most common mutation, independent of ethnicity
    • Mutation Databases: HGMD; Leiden
  • Allelic disorder: Exercise intolerance
• α-Sarcoglycan protein
  • 50 kD dystrophin-associated glycoprotein
    • Peptide size: 40.4 kDa
    • Homologous sarcoglycan: ε-sarcoglycan
    • Features distinct from non-homologous sarcoglycans
      • Cadherin-like domain: ? Function by associating with other glycoproteins
      • Calcium-binding pockets
  • Sarcoglycan binding: Moderately to β- & δ- sarcoglycans
  • Location: Expressed only in skeletal & cardiac muscle
  • See: Sarcoglycan complex
  • α-Sarcoglycan gene abnormalities
    • May produce absent or reduced level of α-Sarcoglycan in muscle
    • Levels of α-Sarcoglycan correlate roughly with gene structure
      • Null mutations: Often absent α-Sarcoglycan
      • Missense mutations: Reduced α-Sarcoglycan
    • Severity of myopathy correlates best with level of α-Sarcoglycan in muscle
      • Absent α-Sarcoglycan: Duchenne-like phenotype
        
      • Reduced α-Sarcoglycan: Later onset; Milder weakness
  • Other myopathies: α-Sarcoglycan may be reduced in other dystrophies
    • Especially other sarcoglycan disorders
    • Reduced α-Sarcoglycan in muscle (? gene defect): ? Related to dilated cardiomyopathy
      
• Clinical features: Severe or Mild phenotype
  • Onset
    • Variable: 2 to 15 years
    • Earlier onset
      • More rapidly progressive weakness
      • Absent α-Sarcoglycan
    • Later onset
      • Ambulation may be preserved
      • Occasional patients with only high CK, but no weakness
      • Reduced but present α-Sarcoglycan
  • Weakness
    • Proximal > Distal
    • Symmetric
    • Quadriceps: Severe phenotype
    • Scapular weakness & winging: Severe phenotype
  • Calf hypertrophy: Some patients
  • Systemic: Rare associated cardiomyopathy
• Laboratory features
  • Serum CK: Very high; Often > 5,000
  • Muscle biopsy
    • Myopathic
      • Fiber size variation
      • Endomysial connective tissue: Increased
      • Degeneration & Regeneration of muscle fibers
      • Myopathic grouping of degeneratiing & regenerating muscle fibers
    • Sarcoglycan staining
      • Absent α-sarcoglycan
      • Other sarcoglycans: Reduced or absent
• Treatment: Prednisone inproves motor function (Anecdotal reports)
• Heterozygotes (Ile124Thr missense mutation): Some patients have a clinical phenotype ³⁸
  • Myalgias
  • Scapular winging: 60%
  • Calf hypertrophy: 15%
  • Serum CK: Normal
  • Muscle biopsy: Fiber-size variability; Atrophic fibers; Normal α-sarcoglycan by IHC
• α-Sarcoglycan variant disorder: Exercise intolerance & Myalgias ¹⁰¹
  • α-Sarcoglycan genetics
    • Inheritance: Recessive
    • Mutations: V247M; R284C
  • Clinical
    • Onset age: 1st or 2nd decade
    • Myalgias: With exercise
    • Strength: Normal or Biceps weak
    • Scapular winging
  • Laboratory
    • Serum CK: 700 to 12,000; Higher with exercise
    • Muscle pathology
      • Histology non-diagnostic: Atrophic muscle fibers
      • α-Sarcoglycan: Reduced by Western blot
    • EMG: Normal

• Nosology: LGMD 2E
• Epidemiology: Common in Northern & Southern Indiana Amish; Bern, Switzerland
• β-Sarcoglycan gene
  • Promoters: 1
  • Mutations
    • Missense: Common
    • Common mutation: Ser114Phe
    • Also: Nonsense, Insertion & Deletion
  • Databases: Leiden; HGMD
• β-Sarcoglycan protein
  • 43 kD dystrophin-associated glycoprotein
    • Peptide size: 34.8 kDa
    • Binds to β-dystroglycan by extracellular domain
  • Sarcoglycan binding: Strongly to δ; Moderately to γ
  • Location: Subsarcolemmal
  • Expression patterns
    • Muscle: Skeletal & Cardiac
    • Only sarcoglycan expressed outside muscle: Brain; Kidney
  • See: Sarcoglycan complex
• Clinical features: Severe; Occasional mild phenotype
  • Onset age
    • < 3 years to Teens
    • Teen onset: Similar to "outlier" dystrophinopathy
    • Intrafamilial variability
  • Myopathy
    • Proximal weakness
    • Muscle hypertrophy: Prominent; ± Tongue
    • Shoulders: Scapular winging; Muscle wasting
    • Progression: Often in wheelchair by 10 to 15 years, usually by 25 years
  • Cardiomyopathy
    • Occasional patients
    • Mutation: 8 bp duplication in exon 3 of 1 allele
• Laboratory features
  • Serum CK: High; Often > 5,000
  • Muscle biopsy
    • Myopathic
    • Sarcoglycans: All usually absent or markedly reduced
    • Dystrophin: Often reduced but not absent
  • Cardiac muscle: Sarcoglycans reduced with cardiomyopathy
• β-Sarcoglycan knockout mouse
  • Myopathy with muscle hypertrophy
  • Cardiomyopathy with focal areas of necrosis
  • Reduced Sarcoglycan-Sarcospan complex in vascular smooth muscle: Vascular δ in heart, diaphragm & kidneys

• Nosology: LGMD 2F
• δ-Sarcoglycan gene
  • Promoters: 3; 1 predominantly in skeletal muscle
  • Mutations
    • Frameshift ® Premature truncation of protein: del656C: African-Brazilian ancestry
    • Missense: Glu262Lys (Near cysteine-rich region)
    • Nonsense ® Premature truncation of protein: E93Ter; Arg165Ter; Trp30Ter
    • Databases: HGMD; Leiden
  • Allelic with
    • Dilated cardiomyopathy 1L (CMD 1L)
    • LGMD, Mild phenotype
• δ-Sarcoglycan protein
  • 35 kD dystrophin-associated glycoprotein
  • Basic
  • Location: Subsarcolemmal
  • Sarcoglycan binding: Strongly to β- & γ- sarcoglycans
  • Homologous sarcoglycan: γ-sarcoglycan
  • See: Sarcoglycan complex
• Clinical: Severe phenotype with most mutations producing myopathy
  • Onset: 2 to 10 years
  • Weakness: Proximal; Symmetric
  • Other muscle change: Calf hypertrophy; Cramps
  • Progression: Wheelchair 9 to 16 years in most; One patient walking at 19 years
  • Death: 9 to 19 years
  • Intelligence: Normal
  • Cardiac
    • Often Normal
    • Dilated cardiomyopathy described : May occur without skeletal myopathy
• Laboratory features
  • Serum CK: High; 10x to 50x normal
  • Muscle biopsy
    • Myopathic: Degeneration & regeneration of muscle fibers
    • Immunostaining
      • δ-Sarcoglycan: Absent
      • Other sarcoglycans: α & β absent; γ reduced or absent
      • Dystrophin: Present but reduced
• Animal model
  • Syrian hamster cardiomyopathy: Deletion in promoter region of δ-Sarcoglycan gene
  • Boston terrier dogs: LGMD syndrome
• SGCD variant: LGMD, Mild phenotype

• Nosology: LGMD 2G
• Epidemiology: Brazil (Italian ancestry) & Europe
• Genetics
  • Mutations
    • Point mutations or small deletions
    • Produce stop codons
    • Ser11* (c.32C>A; Dravidian families); Trp25X (Bulgarian Muslims); Gln35X; g.637-640del2
  • Allelic with
    • Dilated cardiomyopathy 1N (DCM 1N): ? Polymorphism
    • Congenital muscular dystrophy with joint contractures
    • Hypertrophic cardiomyopathy 25 (CMH 25): Dominant; Missense mutations
    • Distal myopathy
• Telethonin (Titin-Cap) protein
  

  Telethonin in muscle fibers

  • Function
    • Substrate of serine kinase domain of titin
    • Titin phosphorylates C-terminal domain of telethonin
      • Occurs in early differentiating myocytes
  • Tissue localization: Cardiac & Skeletal muscle; GI smooth muscle
  • Cellular localization: Sarcomeric Z-disc
• Clinical features
  • Onset
    • Age: Mean 12 to 18 years; Range 1 to 25 years
    • Gait disorder: Toe walking
  • Weakness:
    • Extremities: Legs > Arms
      • Legs
        • Proximal: Glutei; Hamstrings; Hip adductors
        • Distal: Foot drop; Some patients
      • Arms: Proximal
      • Asymmetry: Some patients
    • Face: Normal or mildly weak
    • Neck: Normal
    • Progression: Slow; 40% non-ambulatory in 3rd or 4th decade
  • Muscle size
    • Calf hypertrophy 50%
    • Calf atrophy 50%
  • Discomfort: Occasional patient
    • Cramps
    • Myalgias
  • Cardiac involvement 55%
  • Contractures: Ankles
• Laboratory
  • Serum CK
    • Increased 3- to 30-fold
    • Lower with greater age
  • Muscle imaging
    • More involvement: Quadriceps; Anterior tibial; Posterior pelvic
    • Asymmetry: Some
    • Preservation: Adductor longus; Biceps femoris
    • Hypertrophy: Sartorius; Gracilis
  • EMG: Small myopathic potentials ± Large potentials
  • Muscle pathology
    • Myopathic: Degeneration & Regeneration
    • Rimmed vacuoles: Some patients
    • Lobulated muscle fibers: Especially type 1
    • Cytoplasmic bodies
    • Telethonin protein: Absent from muscle
• Variant telethonin syndrome: Congenital Muscular Dystrophy ⁸⁰
  • Epidemiology: French male
  • Genetics
    • TCAP mutation: Gln58X; Homozygous
    • Inheritance: Recessive
  • Clinical
    • Motor
      • Milestones: Delayed head control & sitting
      • Weakness
        • Proximal (Psoas; Adductors) > Distal
        • Anterior tibial
        • Neck flexion
        • Course: Minimal progression
      • Gait: Waddling; Falling
      • Muscle size: Glutei wasting; Calf hypertrophy, mild
    • Skeletal
      • Scapular winging
      • Scoliosis
      • Joint laxity: Distal arms
      • Contractures: Ankles
    • Heart: Normal
  • Laboratory
    • Pathology: Muscle
      • Fiber size: Varied
      • Internal nuclei
      • Necrosis & Regeneration: Some clusters
      • Type I fibers: Small
      • Telethonin: Absent
      • α-Dystroglycan: Normal
    • Serum CK: 600 to 1300
• TCAP variant: Distal myopathy ¹¹⁷
  • Epidemiology: 1 patient
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous; Stop; c.256C>T
  • Clinical
    • Onset age: 50 years
    • Weakness
      • Symmetric
      • Legs: Distal > Proximal; Anterior > Posterior
      • Arms: Normal
  • Laboratory
    • Serum CK: < 300
    • EMG: Myopathic
    • Muscle MRI: Involvement of adductors & hamstrings
    • Muscle: Vacuoles; Varied fiber size

• Nosology: LGMD 2H
• Epidemiology
  • Focus: Hutterite
  • Other: 16 patients
• Genetics: Mutations
  • Homozygous for D487N point mutation
    • All Hutterite patients
    • Mutation localized in NHL domain
  • Other mutations: Deletions, Frameshift, Nonsense
  • Same gene as
    • Sarcotubular myopathy: Same D487N mutation
    • Bardet-Biedl syndrome 11
• Protein
  • Function
    • E3-ubiquitin ligase
    • Labeling of proteins with ubiqutin for proteasome degradation
  • Homo-multimer: Self-association via CC regions
  • Concentrated in cytoplasmic & nuclear bodies
  • Tissue localization: Muscle; Testis; Heart; Skin
• Clinical
  • Variable phenotype
  • Onset
    • Age: 3 to 45 years; Usual 2nd or 3rd decade; Some asymptomatic in 3rd decade
    • Proximal weakness; Back pain; Fatigue; Gait change
  • Weakness
    • Proximal leg: Quadriceps & Pelvic girdle
    • Some patients with: Axial, Face, Periscapular, Distal arm weakness
    • Mild
    • Respiratory: Often spared
    • Progression: Slow; Ambulatory > 50 years of age
  • Heart: Not involved
• Laboratory
  • Serum CK: High; 250 to 4,500 U/L
  • EMG: Myopathic
  • Muscle MRI
    • Thigh: Posterior > Anterior
    • Lower leg: Posterior; Anterior tibial; Peronei
• Muscle biopsy: Mild dystrophic changes
  • Fiber size variation
  • Muscle fiber degeneration & regeneration
  • Other: Fiber splitting; Internal nuclei
  • Endomysial fibrosis
  • Vacuoles: Few patients

• Epidemiology
  • Hutterite brothers from South Dakota
  • Non-Hutterite brothers from Germany
• Genetics
  • Same mutation as LGMD 2H: Homozygous missense (D487N)
• Clinical
  • Onset: Congenital, Childhood or Adult (31 years)
  • Weakness
    • Proximal: Symmetric; Mild
    • Face: Mild
  • Muscle size
    • Hypertrophy: Calf
    • Atrophy: Proximal
  • Myalgias: Exercise induced
  • Scapular winging
  • Tendon reflexes: Normal or Reduced
• Pathology
  • Vacuoles
    • Multiple small rounded
    • In type 2 > type 1 fibers
    • Sarcoplasmic reticulum membranes
  • Varied fiber size
  • Z-disk streaming

• Nosology
  • LGMD 2I
  • Muscular dystrophy-Dystroglycanopathy
• Epidemiology
  • > 40 familes
  • Carrier risk: ~ 1:400
  • Common in Denmark & parts of England
• Genetics
  • Point mutations most common: Missense
  • Common mutation in 1 allele (> 90%): Leu276Ileu (C826A)
  • Disease severity correlates with mutation in 2nd allele
  • Leu276Ileu (c.826>>A) homozygosity: Correlates with less severe phenotype
  • Mexico founder mutation (c.1387A>G): More severe disease
  • Allelic with
    • Congenital muscular dystrophy with muscle hypertrophy & Normal CNS (MDC1C)
    • Myopathy with abnormal merosin (Laminin-2)
    • Walker-Warburg syndrome: Homozygous FKRP mutations; Met1Val & Cys318Tyr
• FKRP protein
  • Ubiquitous
  • Highest levels: Skeletal muscle; Heart; Placenta
  • Subcellular
    • Golgi
    • Skeletal and cardiac muscle
      • Surrounds myonuclei
      • No change in location with disease mutations
      • Absent from the nuclei of interstitial cells
    • Targeted by N-terminus & tm domain
    • Not secreted
  • Glycosyltransferase
  • Colocalizes with α-Mannosidase II
  • Associated with dystroglycan processing
• Clinical
  • Onset
    • Age
      • Range 0.5 to 27 years; 61% less than 5 years
      • Birth: Patients with Congenital muscular dystrophy syndrome (MDC1C)
    • Weakness: Waddling gait; Difficulty with stairs; Hypotonia
  • Weakness
  • Proximal > Distal
  • Legs & Arms
  • Legs: Thigh adductors; Psoas; Quadriceps
  • Arms: Periscapular; Deltoid; Biceps; Triceps
  • Face: Mild weakness in some older patients
  • Respiratory failure (30%)
    • May occur while patient still ambulant
    • DMD-phenotype: Onset in later teens
  • Severity
    • Variable: DMD-like to Adult onset myopathy
    • Intrafamilial variability described
  • Asymmetry: Some patients
  • Progression
    • Early onset: Non-ambulant by teens
    • Later onset: Slow; Variable; Some (28%) non-ambulant by 4th to 6th decade
  • Muscle size
    • Wasting: In regions of weakness; Arms > Legs
    • Hypertrophy: Calves 77%; Thighs; Tongue
  • Other occasional muscle features
    • Exertional pain: Early symptom,: Mean 14 years, Range 2 to 45 years
    • Cramps: Limbs & Tongue described
    • Myoglobinuria (25%)
      • Multiple episodes
      • Related to physical activity
      • Can occur at time with mild or no weakness
      • Frequent in patients with homozygote common mutation (Leu276Ileu)
  • Tendon reflexes: Preserved; Knee mildly reduced
  • Intellect: Normal
  • Skeletal
    • Contractures: Often at ankles; More common in non-ambulant patients
    • Scoliosis
  • Cardiomyopathy
    • Common: 30% to 80%; Often seen on echocardiography
    • Type: Dilated
    • Usually mild
    • Left ventricular failure
    • May be isolated feature: Homozygous C826A mutation
    • No relation to skeletal muscle severity
  • Skin: May be soft or hyperextensible
  • Variable severity
    • Severe: Onset < 2 years; Never run; Lose ambulation in teens
    • Milder: Later onset; Cramps; Muscle hypertrophy
    • Consistent phenotype within individual families
• Laboratory
  • Serum CK: Very high; 1,000 to 8,000
  • Muscle biopsy
  • Endomysial connective tissue: Mildly increased
  • Muscle fibers
    • Size: Variation
    • Necrosis & Regeneration
    • Type 1 predominance: Some patients
    • Muscle fiber staining
      • α-Dystroglycan: Reduced, especially in severe disease
        • Selective loss of higher MW forms
        • Less severe loss than in MDC1C
        • Some patients have normal staining
        • DDx: Reduced α-Dystroglycan
      • α2-laminin: Moderate loss in some patients: May be absent on Western blot
      • Normal: Dystrophin, Sarcoglycans & β-Dystroglycan
  • Nerve conduction studies: Normal
  • EKG: Normal
  • MRI: Normal CNS or minimal atrophy

• Genetics: Allelic with LGMD 2I
• Clinical
  • Onset
    • Usually adult: 11 to 40 years
  • Female preponderance
  • Weakness
    • Cranial: Eye closure; Neck flexion
    • Upper extremity: Proximal; No scapular winging
    • Lower extremity: Especially hamstrings + hip adductor & flexors
    • Vital capacity: Reduced to 30% to 93% of normal
    • Asymmetry: Some
    • Progressive
  • Muscle hypertrophy: Calves; Brachioradialis
  • Cramps: Occasional
  • Skeletal: Lumbar lordosis; No contractures
  • CNS (MRI) & cardiac: Normal
• Laboratory
  • Serum CK: 1,100 to 3,700
  • EMG: Myopathic
  • Muscle histology
    • Variation in fiber size
    • Muscle fiber necrosis
  • Muscle merosin
    • Normal immunocytochemistry of muscle section (80 kDa & 300 kDa fragments)
    • Absent on Western blot

• Nosology: LGMD 2J
• Epidemiology
  • > 10 patients
  • May occur in families with other members having: Dominant distal weakness syndrome
• Genetics
  • Mutations
    • Homozygous or Compound heterozygous for titin mutations
    • Mutation types
      • 11 bp insertion-deletion (Finnish; FINmaj): Final exon (363)
      • Missense: Leu293,356Pro (French); Arg32,936His
      • Common patterns
        • Homozygous: Exon 364 mutations
        • Compound heterozygous: Exon 364 + Truncating mutation
    • Genotype-Phenotype corelations
      • Homozygous 11 bp deletion: Severe, Childhood onset
      • French missense mutation: Onset 3rd decade, Proximal Arms
    • Disease relevance of mutations: General ¹¹⁰
      • Truncating mutations most strongly associated with myopathy
      • Biallelic truncating mutations
        • Primary cardiac common
        • Wide range of phenotypes
      • Single heterozygous truncating mutations
        • Skeletal muscle disorders common
        • Also associated with: Dominant dilated cardiomyopathy
        • Western blot analysis: May identify further truncating variants in trans
  • Allelic disorders
    • Dominant
      • Distal myopathy, Finnish (Tibial MD)
      • Myopathy with Early Respiratory failure (HMERF)
        • Cytoplasmic aggregate myopathy
        • Cytoplasmic body myopathy
      • Dilated cardiomyopathy 1G
      • Hypertrophic cardiomyopathy (CMH 9)
    • Recessive
      • Congenital myopathies
        • Multicore disease: Congenital myopathy + Fatal dilated cardiomyopathy (EOMFC)
        • Centronuclear myopathy
        • Fiber type size disproportion
      • LGMD 2J
      • Distal myopathy, Adult onset
      • Proximal adult-onset rimmed vacuolar myopathy
      • Emery-Dreifuss without cardiac involvement
      • Lethal congenital contracture syndrome (LCCS)
• Titin protein
• Clinical
  • Onset age
    • Usual: Childhood
    • Range: < 10 years to 3rd decade
  • Weakness
    • Proximal > Distal
    • More severe than in allelic distal myopathy
    • Face: Normal or Weak
    • Asymmetric: Some patients
  • Muscle size
    • Smallness: Anterior tibial
    • Hypertrophy: Some patients
  • Progression
    • Usual: Wheelchair < 30 years, within 20 years of onset
    • Some patients ambulatory at 60 years
  • Some patients
    • Cardiomyopathy
    • Developmental delay
    • Skeletal: Clinodactyly; Narrow face; Microcephaly
• Laboratory
  • Serum CK: High
  • Muscle biopsy
    • Myopathic
    • No vacuoles
    • Loss of calpain-3
    • Western blot: Severely reduced C-terminal titin fragments
    • Obscurin: Mislocalization
• Titin variant syndrome: Proximal adult-onset rimmed vacuolar myopathy
  • Genetics
    • Inheritance: Recessive
    • Mutations: Compound heterozygous; Exon 364 + Missense
  • Clinical
    • Onset age: Adult
    • Weakness: Quadriceps & Soleus; Tibial spared
  • Laboratory
    • Muscle: Rimmed vacuoles
• Titin variant syndrome: Emery-Dreifuss syndrome without cardiac involvement ¹⁰²
  • Epidemiology: 3 families; French & Algerian
  • Genetics
    • Inheritance: Recessive
    • Mutations: Truncating; Mex3 exon in sarcomeric M-band
  • Titin protein
    • Mutated protein: Truncation of M-line
  • Clinical
    • Onset age: 3 to 10 years
    • Weakness
      • Limb-Girdle: Proximal > Distal
      • Respiratory: Vital capacity reduced in some (67%)
      • Trunk: Scapular winging; Abdominal
      • Symmetric
      • Course: Progressive to wheelchair by 13 to 36 years
    • Large muscles: Calf; Tongue
    • Contractures
      • Arms & Legs
      • Proximal & Distal
      • C-spine & Masseter in some
    • Cardiac: Normal
  • Laboratory
    • Serum CK: 1.5x to 10x high; Lower with increased age
    • EMG: Myopathic
    • Muscle pathology
      • Fiber size: Varied
      • Necrosis: Scattered
      • Immature muscle fibers
      • Internal nuclei
      • Internal architecture: Irregular
      • Rimmed vacuoles
      • Rods or Cytoplasmic bodies
      • Calpain-3: Absent or very reduced
      • Ultrastructure: M-bands abnormal
    • Muscle MRI: Posterior thigh, Gastrocnemius & Glutei most involved
• Titin variant syndrome: Distal myopathy ¹⁰⁹
  • Epidemiology: Serbian families
  • Genetics
    • Inheritance: Recessive
    • Mutations
      • General: Stop-gain variants
      • Common: c.107635C4T (p.Gln35879Ter); Founder mutation
      • Other: Stop codons in TTN exons 286 to 358
    • Allelic disorders
  • Titin protein
  • Clinical: Similar to Dominant Finnish Tibial MD
    • Onset: Adult; 14 to 44 years
      • Later onset: Founder mutation, homozygous
    • Weakness
      • Distal (100%) > Proximal (60%)
      • Legs > Arms: Foot & toe dorsiflexors > plantarflexors
      • Proximal involvement: Hip & shoulder girdle
      • Asymmetry: 30%
      • Scapular winging: 40%
      • Course: Most patients remain ambulant
    • Contractures: Ankle
    • Respiratory: Normal
    • Cardiomyopathy: Uncommon
  • Laboratory
    • Serum CK: Normal to Mildly high
    • EMG: Myopathic
    • Muscle MRI: Similar to Tibial MD, Dominant
    • Muscle biopsy: Dystrophic
      • Muscle fibers: Hypertrophic; Atrophic
      • Endomysial connective tissue: Increased
• Titin variant syndrome: Lethal congenital contracture syndrome (LCCS) ¹¹¹
  • Epidemiology: 1 family
  • Genetics
    • Mutations: Homozygous c.36122delC (p. P12041Lfs*20) variant (In exon 167 in fetal IC isoform of TTN)
    • Inheritance: Recessive
  • Clinical
    • Intrauterine: Reduced movement; Death
    • Neonatal respiratory distress
    • Spontaneous movement: Reduced
    • Contractures: Large joints
    • Death: < 17 weeks
  • Laboratory
    • Bone: Multiple fractures
• Mouse model: Homozygous knockout
  • Severe: Lethal
  • Weakness: Distal > Proximal

LGMD R11 (MDDGC1) : with Mental retardation and Reduced α-dystroglycan

• Nosology
  • LGMD 2K
  • MDDGC1: Muscular dystrophy-Dystroglycanopathy
• Epidemiology: 15 patients
• Genetics
  • Mutations: Missense mutations most common; Turkish Ala200Pro
  • Allelic disorders
    • Walker-Warburg syndrome: MDDGA1
    • Disease related mutations: > 76
• POMT1 protein
  • Clinical phenotype severity: Inversely correlated with POMT1 activity
• Clinical
  • Onset
    • Ages: 1 to 33 years
    • Motor: Fatigue; Difficulty climbing stairs & running; Early milestones normal
  • Muscle
    • Size: Mild pseudohypertrophy
    • Weakness: Proximal
    • Course: Slow progression
  • Skeletal
    • Joint contractures (50%): Ankles
    • Scoliosis
  • CNS (60%)
    • Mental retardation, IQ 50 to 76
    • Microcephaly
  • Cardiomyopathy (30%): LV dilatation
• Laboratory
  • Serum CK: Very high (9x to 40x elevated)
  • Muscle
    • Fiber size: Varied
    • Fibeer types: 1 predominance
    • Cores: Some patients
    • α-Dystroglycan: Reduced glycosylation
  • MRI: Normal CNS

• Nosology: LGMD 2L
• Epidemiology
  • May be 10% to 20% of LGMD families
  • Females: Less commonly or less severely affected
• Genetics
  • Mutations: > 20 identified
    • Splice site (C1295G; Aberrant splicing of Exon 13)
    • Duplication (c.191dupA (p.Asn64Lysfs*15) in exon 5): Common in Northern Europe
    • Arg758Cys in exon 20: Common mutation
    • Missense: G231V in exon 8
    • Locations: Distributed all along gene
  • Allelic disorders
    • Gnathodiaphyseal dysplasia : Dominant
    • Distal myopathy (MMD3): Recessive
    • LGMD R12
    • Myalgia & High CK
  • Genotype-Phenotype correlations
    • Variable phenotypes, mild & severe, with most mutations
• Anoctamin 5 protein
  • Member of family of proteins with 8 transmembrane domains
    • Anoctamins 1, 2 &3 are calcium-activated chloride channels (CaCC)
    • ANO3 mutatins cause: Dominant Craniocervical Dystonia (DYT23)
  • Integral membrane glycoprotein
  • Intracellular
  • Functions: Myogenesis; Osteogenesis
  • Mutations may cause: Defective membrane repair
• Clinical
  • Variability
    • Intrafamilial: Prominent
    • Variant syndromes
      • Distal myopathy
      • Normal strength with high CK
  • Onset
    • Age: Mean = 33 to 43 years; Range 11 to 70 years
    • Weakness: Quadriceps, Asymmetric
  • Muscle
    • Atrophy: Quadriceps; Biceps brachii; Lower leg
    • Asymmetric
    • Weakness
      • Legs > Arms
      • Scapular: Biceps
      • Pelvic: Psoas; Quadriceps
      • Posterior leg: See MMD3
      • Distal arms: Normal strength
      • Face: Few patients
      • Progression: Slow
    • Muscle discomfort
      • Frequency: 86%; 50% with, or after, exercise
      • Common: Calf; Myalgia or Burning
    • Fatigue: May occur before weakness
    • Calf hypertrophy or atrophy: Some patients
    • Rhabdomyolysis: Few patients
    • Course
      • Slowly Progressive
      • Walking retained in most
    • Respiratory: Normal or Mild changes
  • Contractures: Unusual
  • Cardiac
    • Atrial: Arrhythmias; Bradycardia; Some patients
    • Cardiomyopathy: Dilated or Hypertrophic
• Laboratory
  • MRI: Early atrophy of medial quadriceps, hamstrings & adductor magnus
  • Serum CK: Normal to 35,000
  • EMG: Myopathic; Some with spontaneous activity or myotonia
  • MRI: Asymmetric involvement
• Pathology: Muscle
  • Muscle fibers
    • Size: Varied
    • Necrosis & Regeneration
    • Internal nuclei
    • Splitting
    • Internal architecture: Irregular; Whorled
    • Vacuoles: 2 patients
    • Ultrastructure: Multifocal sarcolemmal lesions
  • Endomysial connective tissue: Increased
  • Inflammation: In severe cases; Endomysial
  • Amyloid
    • Frequency: 50%
    • Location: Peri-Vascular & Muscle fiber
    • No relation to mutation location or clinical features
  • Dystrophy proteins
    • Dystrophin reduced: 40%
    • Calpain-3 reduced: 45%
    • Dysferlin: Normal
• ANO5 Variant syndrome: Distal Miyoshi-like myopathy 3 (MMD3)
  • Epidemiology: Dutch & Finnish families
  • Genetics
    • Inheritance: Recessive
    • ANO5 Mutations
      • Missense: Arg758Cys in exon 20
      • Duplication (c.191 dupA in exon 5)
    • Allelic with: LGMD 2L
  • Clinical
    • Onset
      • Age: 2nd & 3rd decade
      • Difficulty running & standing on toes
    • Weakness
      • Calf: Early; Difficulty running & walking on toes
      • Proximal: Ileopsoas; Hamstrings, Gluteus maximum, Hip adductors
    • Hypertrophy: Calf; Extensor digitorum brevis
    • Muscle discomfort: Calves
    • Asymmetry
  • Laboratory
    • Serum CK: 1,500 to 16,000
    • Muscle pathology
      • Cell membrane repair defect
    • Imaging: Medial gastrocnemius & soleus involvement
• ANO5 Variant syndrome: Normal strength + High serum CK ¹⁰⁶
  • Epidemiology: Males & Females
  • Clinical
    • Myalgias
    • Exercise intolerance
    • Calf: Hypertrophy or Atrophy
    • Some patients asymptomatic
    • Course: May remain with few, or mild, symptoms for long periods
  • Laboratory
    • Serum CK: High; 200 to 40,000 U/L; Vary over time
    • EMG: May be normal or myopathic
    • Muscle imaging: Medial gastrocnemius involved (55%)
    • Muscle biopsy: Non-specific or Normal

• Nosology
  • LGMD 2M
  • Muscular dystrophy-Dystroglycanopathy
• Epidemiology: 5 families; Portuguese, Turkish, French, Israeli Jewish & Indian
• Genetics
  • Mutations
    • Types: Stop & Missense
    • 1167dupA; 1363delG; Arg47X; Ala170Glu; Arg246Gly; Arg307Gln; Tyr371Cys
  • Allelic disorders
• Clinical
  • Onset
    • Age: Less than 6 months
    • Hypotonia
    • Motor delay
    • Deterioration with acute febrile illness
  • Weakness
    • General: Diffuse; Variable severity
    • Distribution: Axial & Proximal > Distal
    • Legs > Arms
    • Face: Mild to Moderate
    • Improves with corticosteroid treatment
    • Many patients ambulant
    • Course: Progressive
  • Muscle size
    • Wasting: Most muscles
    • Hypertrophy: Posterior leg ± Tongue & other
  • CNS
    • Normal in mildest patients
    • Reduced intelligence: Variable association with degree of weakness
  • Skeletal
    • Spinal rigidity
    • Joint contractures
  • Cardiomyopathy: Some patients
• Laboratory
  • Serum CK: Very high
  • Muscle biopsy
    • Morphology: Dystrophic; Muscle fiber necrosis
    • Endomysial connective tissue: Increased
    • Glycosylated α-dystroglycan: Nearly absent
    • Laminin-α2, β1 & γ1: Mildly reduced
  • MRI: May show cortical & posterior fossa pathology
    • Vermis hypoplasia
    • Polymicrogyria

• Epidemiology: 5 families from UK & Finland
• Genetics
  • Compound heterozygous
  • Mutation type: Truncating
  • Allelic disorders
• MYH2 protein
  • Myosin subtype
  • Location: Type 2A muscle fibers
• Clinical
  • Onset age: Early childhood
  • Weakness
    • Generalized
    • Mild
    • Proximal > Distal
    • Face & Neck
    • Extraocular muscles
      • Severe ophthalmoplegia
      • Ptosis 20%
    • Prognosis: Slow progression with age
  • Muscle wasting
  • Joints: Hypermobility
• Laboratory
  • Muscle pathology
    • Type 2A fibers: Absent
    • Fiber size: Varied
    • Internal nuclei
    • Endomysial connective tissue: Increased
  • EMG: Myopathic
  • Serum CK: Normal
  • Muscle imaging: Selective nvolvement of
    • Leg: Medial gastrocnemius
    • Thigh: Semitendinosus, Gracilis & Vastus lateralis
• Also see: Myopathies with Ophthalmoplegia

• Nosology: Same as MYH2 mutations
• Epidemiology: Israeli-Arab inbred families
• Genetics
  • MYH2 mutation: c.2400delG in exon 19
  • Allelic disorders
  • Variant syndrome: Juvenile-onset myopathy with PEO
• Clinical
  • Onset age: Early childhood
  • Ocular: External ophthalmoplegia (100%)
    • Conjugate
    • Non-restrictive
    • Impairment greatest in upgaze
    • No ptosis or aberrant eye movements
  • Weakness
    • Symmetric
    • Severity: 4/5
    • Face: Mild; Eyes > Mouth
    • Voice: Nasal
    • Neck: Flexors (100%)
    • Limbs
      • Proximal arms: Most common (75%)
      • Distal arms (50%)
      • Proximal legs (30%)
      • Distal legs: Normal
    • Associated with wasting
    • Progression: Slow
  • Skeletal
    • Face: Dysmorphism
    • Scoliosis (73%)
• Laboratory
  • Orbital MRI: Fatty replacement of oculorotatory muscles
  • EMG: Myopathic (50%)
  • Serum CK: Usually normal; Occasional <2x normal in younger patients
• Muscle biopsy
  • Muscle fiber types
    • Type 1 muscle predominance
    • Type 2A absent
  • Core-like changes
• MYH2 variant syndrome: Juvenile-onset myopathy with PEO ⁹⁷
  • Epidemiology: Australian patient
  • Genetics
    • Mutation: c.5630T>C, p.(Leu1877Pro)
    • Inheritance: Sporadic
  • Clinical
    • Onset age: 16 years
    • Weakness
      • Distal: Hands most severe; Feet
      • Proximal: Hip & knee flexion
      • Scapular winging
      • Bulbar: Hypophonia; Palatal movements reduced; Dysphagia
      • Face
      • Respiratory
    • Eyes
      • Ophthalmoplegia: Progressive to severe with some preserved downgaze
      • Ptosis
    • Atrophy: Upper extremities
    • Tendon reflexes: Absent proximally
    • Contractures: Ankles
  • Laboratory
    • EMG: Myopathic
    • Serum CK: 153 to 806
    • Muscle MRI
      • Extensive fat replacement
      • Relative sparing: Deltoid & Anterior legs
    • Muscle
      • Fiber size: Varied; Small to Hypertrophy
      • Internal nuclei
      • Endomysial fibrosis. Dystrophic features were present, being
      • Lobulated fibers & Core-like structures
      • Fiber types: Most type 1, Few small type 2
      • Dystrophy related protein staining: Normal
      • No vacuoles

• Epidemiology: 1 family
• Genetics
  • Mutation: Q819X; Homozygous
  • Allelic disorders
• Clinical
  • Onset
    • Age: Childhood; 2 to 4 years
    • Contractures
  • Weakness
    • Distribution: Proximal + Distal
    • Severity: Mild to Moderate
    • Vital capacity: Reduced
  • Contractures
    • All joints: Limbs; Jaws; Spine
    • Progressive
    • No hypermobility
• Laboratory
  • Serum CK: Mildly high (1.5x)
  • Muscle biopsy
    • Endomysial connective dissue: Diffusely increased
    • Muscle fibers
      • Size: Varied
      • Internal nuclei
      • Laminin β1: Reduced on extrajunctional basal lamina
      • Collagen VI
        • Discontinuous on muscle basal lamina
        • Absent from capillaries
        • Reduced on Western blot
    • Ultrastructure
      • Basement membrane defects: Thickening & Duplication
      • Pericytes: Increased numbers

• Nosology: LGMD 2P
• Epidemiology: Turkish & British families
• Genetics
  • Mutation: Thr192Met; Homozygous
  • Mutation in 1 patient of original series
  • Allelic disorders
    • Asymptomatic high CK
    • Congenital muscular dystrophy MDDGA9
• DAG 1 protein
  • Mutation: Alters DAG1 glycosylation & interaction with LARGE
• Clinical
  • Onset
    • Age: 1st decade
    • Fatigue
    • Weakness: Stairs; Running
  • Muscle
    • Weakness: Proximal > Distal
    • Size: Normal or Mild increase in thigh or calves
    • Progression: Slow: Patients remain ambulant
  • Contractures: Ankles (50%)
  • CNS
    • Mental retardation: Mild to severe
    • Head size: Small
• Laboratory
  • Serum CK: Very High
  • Muscle
    • Fiber size: Varied
    • Regeneration & Occasional necrosis
    • Endomysial connective tissue: Increased
    • α-Dystroglycan: Reduced
  • Brain MRI: Normal
• DAG1 variant syndrome: High CK, Asymptomatic ⁹⁶
  • Epidemiology: 1 patient
  • Mutations: c.220G>A (Val74Ile) & c.331G>A (Asp111Asn)
  • Clinical
    • Strength: Normal
    • Pseudohypertrophy: Calf
  • Laboratory
    • Serum CK: 1,855 to 6,512
    • Muscle
      • Fiber size: Varied
      • Regenerating fibers: Few
      • Internal nuclei
      • Endomysial fibrosis: Mild
      • α-Dystroglycan: Reduced glycosylation
    • Muscle CT
      • Low intensity: Rectus femoris, Semimembranosus, Gastrocnemius
• DAG1 variant syndrome: Congenital muscular dystrophy MDDGA9
  • Epidemiology: 2 families, Israeli-Arab & Libyan
  • Genetics
    • Inheritance: Recessive
    • Mutations: Homozygous; Cys669Phe, 1-BP del, 743C
  • Clinical
    • Onset: Congenital
    • CNS: Developmental delay; Mental retardation
    • Eye: Cataract, Retinal dystrophy, Myopia, Buphthalmos
    • Motor: Hypotonia; Reduced movements; Respiratory failure
    • Death: Infancy; Respiratory failure
  • Laboratory
    • Serum CK: High, 800 to 2,000
    • Muscle: Fiber size varied; α- & β-dystroglycan absent
    • Brain MRI: Brainstem kinking; Cerebellar vermis atrophy; White matter cysts;
        Hydrocephalus; Polymicrogyria; Corpus callosum thin; Calcifications

• Nosology: LGMD 2S
• Epidemiology: Syrian, Turkish, Han Chinese & Hutterite families
• Genetics
  • Mutations
    • Missense, Deletion or Splice site
    • Gly980Arg (Syrian); Ala372_Ser429del (Hutterite); c.661-1G>T, splice site
• TRAPPC11 protein
  • TRAPP multisubunit tethering complex
  • Function: ER to Golgi vesicle trafficking (ERGIC)
  • Expression: Ubiquitous
  • Mutations
    • Disrupt Golgi apparatus architecture
    • Slow exit of proteins from Golgi to cell surface
    • LAMP1 & LAMP2: Abnormal; Increased glycosylation
• Clinical
  • Myopathy (60%)
    • Onset: Infant or Childhood
    • Proximal
    • Legs > Arms
    • Face: Mildly myopathic
    • Scapular winging: Mild
    • Discomfort: Myalgia; Cramps
    • Fatigue
    • Progressive: Reduced ambulation
  • CNS
    • Intellectual disability: Moderate; Global or Motor delay
    • Variable features
      • Seizures
      • Ataxia: Truncal
      • Leg spasticity
      • Hyperkinetic movements
        • Infantile onset
        • Choreiform, Athetoid or Dystonia
      • Tendon reflexes: Reduced
  • PNS: Variable
    • Tendon reflexes: Reduced
    • Autonomic: Alacrima; Achalasia
  • Skeletal
    • Hip dysplasia
    • Scoliosis
  • Systemic: Variable among families
    • Cardiac: Usually normal
    • Eye: Cataracts, infantile-onset; Strabismus
    • Hepatomegaly with steatosis
• Laboratory
  • Serum CK: High in 100%; 300 to 9000
  • Brain MRI: Normal or Mild cerebral or cerebellar atrophy
  • Muscle
    • Myopathic
      • Fiber size: Varied
      • Necrosis & Regeneration
      • Internal nuclei
      • Endomysial connective tissue: Increased
      • Lipid increased: 1 family
      • α-Dystroglycan: Normal or Reduced
    • Neuropathic: Fiber type grouping in 1 family
  • Muscle MRI: Gluteal & Posterior leg muscle involvement

Other Dominant Myopathies

• Nosology: LGMD D5
• Gene mutations: >50 identified
  • Most mutations located between Exons 3 and 14
  • Most are amino acid substitutions: Glycine most common (Gly-X-Y)
    • Usually in triple helix region
    • Some mutations in globular region
    • Disease pathogenesis: ? Dominant negative effect
  • Inframe deletion in exon 14 of Collagen α1 (IVS14DS, G-A, +1): Common mutation
  • Can also cause disease by stop codon : Produces haploinsufficiency
    • Lower incidence of contractures
  • Other disease correlations
    • Most severe disease: COL6A1 multi-exon out-of-frame deletion; Mutations inside triple helix
    • Milder: Exon-skipping mutations; N-terminal globular region
    • Recessive COL6A2 mutations: Stop & Splicing (c.1770delG & R784H in cis) + Missense (R830W)
  • Allelic disorders
    • Bethlem myopathy: Dominant
    • Ullrich Scleroatonic muscular dystrophy
      • Same 3 COL6A subunit genes mutated
      • Recessive
    • Myosclerosis: COL6A2 mutations
    • Ossification of posterior longitudinal ligament: Mutations in different part of COL6A1 gene
    • Early-Onset Isolated Dystonia 27 (DYT27) : COL6A3, Recessive
    • Landseer Dogs, Early-onset MD: COL6A1 mutations; Recessive ¹⁰⁰
  • Also see: Bethlem myopathy, Collagen XII
• Protein: Collagen VI
  • Collagen
  • Location
    • Extracellular matrix: In most connective tissues
    • Basement membrane
      • Abundant around fat cells, nerves & muscle
      • Normal: Co-localizes with perlecan & collagen IV
      • Mutant: Variable co-localization with perlecan & collagen IV
    • Synthesized by: Interstitial fibroblasts
    • Sources of other collagens
      • Collagens I, III & V: Skeletal muscle
      • Collagen IV & Laminin: Fibroblasts & Mononucleated myoblasts
  • Collagen VI synthesis in muscle: By Interstitial fibroblasts
  • Monomer: Contains 3 subunits α1 (140kD), α2 (140 kD) & α3 (260kD)
  • Subunit domains
    • Short collagenous triple helix of repeating Gly-X-Y sequence
    • Large N- & C-terminal globular regions: Homology to von Willibrand factor type A
  • Assembly of monomers: Intracellular
    • First, into antiparallel overlapping dimers
    • Then dimers align in parallel to form tetramers
    • Assembly stabilized by disulfide bridges
    • Forms microfibrillar network
  • Possible functions of Collagen VI
    • Anchor basement membranes in extracellular matrix: Interacts with
      • Proteoglycans: Perlican; Decorin; Biglycan; Fibromodulin
      • Other extracellular matrix components: Fibrillar collagens I & II; Fibronectin
    • Bridges cells with the extracellular matrix: Mediated by
      • Integrins: α1β1, α2β1 & α3β1
      • Cell surface proteoglycan: NG2
    • Cell differentiation
    • Apoptosis: Suppression
  • Disease mechanisms ¹⁵
    • Glycine mutations: May impair assembly pathway
      • Mildly affected patients (Bethlem): Normal amounts of collagen VI in fibroblast matrix
      • Severely affected patients (Ullrich): Reduced amounts of collagen VI in fibroblast matrix
    • Collagen VI point mutations (G1679E and G1679Q in α3): May produce
      • Lower protein levels
      • Misfolded protein
• Clinical features
  • Onset
    • Age: Variable within families
      • Prenatal: Fetal movements reduced
      • Neonatal: Hypotonia
      • Early childhood (< 2 years): Common with Weakness or Contractures
      • Adult: As late as 6th decade
    • Motor: Hypotonia
    • Joints: Laxity or Contractures
  • Clinical
    • Weakness
      • Diffuse; Proximal > Distal
      • Progressive
        • Usually mild in childhood
        • May become severe & disabling in adulthood
      • Occasional respiratory muscle weakness: Severe cases
      • Falling common in children
      • Face: Spared
    • Muscle cramps or pain: Some patients
    • Muscle size
      • Wasting: Proximal muscles; Distal in legs
      • No muscle hypertrophy
    • Contractures
      • Distribution
        • Flexion: IP joints medial 4 fingers, wrists, elbows, ankles
        • Proximal: Pectorals, Knees, Shoulders, Hips
        • Truncal
          • Congenital: Torticollis
          • Disease progression: Restrictive lung disease correlates with weakness & contractures
          • Spine
        • Dorsiflexion contractures at ankles in COL6A2 (G250S) mutation
      • Course
        • After birth: Often spontaneously improve
        • Joints: Some are initially hypermobile May develop contractures over time
        • Childhood & Adult: May progress independent of weakness
        • Some patients in families may never have contractures
      • No functional impairment
    • Skin
      • Follicular hyperkeratosis (Keratosis pilaris)
      • Keloid formation
      • 'Cigarette paper' scarring over knees
    • Course
      • Early: Benign
      • Improvement in function around puberty
      • Adult
        • Progression in weakness common between 25 & 40 years
        • Many wheelchair-bound in adulthood: Usually 6th or 7th decade
        • Others work into old age
        • Cramps in some patients
    • Cardiac disease
      • Conduction abnormalities described in 10% ³²
    • Differential diagnosis: Emery Dreifuss MD
• Laboratory
  • CK: Normal or Elevated to 1,750
  • EMG: Myopathic; Sparse fibrillatons
  • Cardiac: Normal
  • MRI: T1W sequences ³¹
    • Vastus lateralis & hamstrings: Peripheral involvement, Central sparing ³⁷
    • Paravertebral involvement
  • Muscle ultrasound: "Central cloud"
  • Muscle biopsy
    • Non-specific myopathy
      • Fiber size variation
      • Fiber Splitting
      • Internal nuclei
      • Connective tissue increased
    • Lobulated type I muscle fibers
    • Collagen VI
      • Levels: Usually normal; May be reduced
      • Localization: Reduced co-localization with basal lamina (Collagen IV & Perlecan)
    • Laminin β1
      • Reduced in muscle fiber basal lamina but not vessels
      • May also be reduced in Lamin A/C mutations

• Epidemiology: 4 families
• Genetics
  • Mutations: Gly2786Asp; Arg1965Cys; Gly2777Arg
  • Allelic with: Ullrich CMD2
  • Also see: Bethlem myopathy 1, Collagen 6
• COL 12A1 protein
  • FACIT collagen
  • Interacts with: Collagen I; Decorin; Tenascin X
  • Regulates fibrillar scaffolds
  • Location: Perimysium
  • Mutation: Collagen XII
    • Less abundant
    • Disorganized
    • Intracellular retention
• Clinical
  • Onset
    • Age: Congenital
    • Hypotonia
    • Distal laxity
  • Weakness
    • Motor milestones: Delayed
    • Generalized: Proximal > Distal; Neck
    • Improves: During childhood & teenage years
    • May progress in later decades
  • Scapular winging
  • Skeletal
    • Joint hypermobility
    • Contractures: Long finger flexors; Proximal
    • Spine: Kyphosis or Scoliosis
    • Facial dysmorphism: Long face, Micrognathia, High-arched palate
  • Skin: Atrophic scarring
  • Progression: Mild or Improvement
  • Heart: Normal
• Laboratory
  • Serum CK: Normal to 1300
  • EMG: Normal or Myopathic
  • MRI
    • Common: Rectus femoris atrophy
    • More severe disease: Quadriceps, Adductors & Medial gastrocnemius
    • Asymmetry: Some muscles
  • Muscle
    • Collagen: XII reduced in muscle membranes; VI normal
    • Myopathic
    • Endomysial connective tisssue: Increased
    • Laminin B1 reduced
  • EM skin fibroblast
    • Col XII retained intracellulary
    • Endoplasmic reticulum: Distorted
• Collagen 12A1 variant syndrome: Ullrich congenital muscular dystrophy 2 (UCMD2)
  • Epidemiology: 1 family
  • Genetics
    • Inheritance: Recessive
    • Mutations: Homozygous; Frameshift
    • Allelic with: Bethlem myopathy 2
    • Also see: Ullrich 1
  • Clinical
    • Onset age: Congenital
    • Hypotonia
    • Distal laxity
    • Facial weakness
    • Palate: High arched
    • Skin: Normal in childhood
  • Laboratory
    • Muscle & Fibroblasts: Collagen 12 absent

• Genetics
  • COL9A3
    • Mutation: Splice acceptor mutation in intron 2
    • Mutant collagen IX is poorly cross-linked
    • Allelic with: Intervertebral disk disease, tendency
  • COL9A2 mutations
    • Splice donor site of exon 3: c.186G>A; c.186+2T>C
    • Cause skipping of exon 3 from COL9A2 mRNA
    • Allelic with: Intervertebral disk disease, tendency
  • COMP mutations
    • C-terminal domain
  • Myopathy present with some, but not all, mutations
• Type IX collagen proteins
  • Collagen
  • Fibril-associated collagen with interrupted triple helices
  • Chain structure: 4 Noncollagenous domains (NC1-4) separated by 3 triple helical collagenous domains (COL1-3)
  • Location (Tissue-specific isoforms): Cartilage; Eye vitreous; Myotendinous junction
  • Function: Organization & spacing of type II collagen fibrils
  • Modifications: NC3 domain of 2(IX) chain can be modified by a single glycosaminoglycan
• COMP protein
  • Extracellular matrix protein
  • Present at myotendinous junction
  • Interacts with cell surface integrin receptors
  • Suppresses apoptosis: Blocks activation of caspase-3
  • Mutations produce: EDM1
• Clinical
  • General
    • Onset: Childhood; Knee pain
    • ? Males worse than females
  • Weakness: Mild; Symmetric
    • Neck flexion
    • Arms
      • Shoulder abduction
      • Elbow extension
    • Legs
      • Proximal
      • Hamstrings weaker than Quadriceps
      • Waddling gait
  • Joints
    • Early onset degenerative disease
    • Especially knees: Pain
    • Sparing: Hips; Distinguishes conditions from Ribbing & Fairbank types of MED
    • Osteoarthritis
      • Joint space narrowing; Femoral condylar bony flattening; Osteophytes & subchondral cysts
      • Onset: Mid-adulthood
  • Skeletal: No short stature or brachydactyly
• Laboratory
  • Serum CK: Mildly elevated
  • X-rays: Epiphyses
    • Delayed ossification
    • Small & Irregular
  • Muscle biopsy
    • Mild myopathic changes: Varied muscle fiber size
    • Perimysial collagen: Normal
    • Immunostaining: Normal dystrophin, merosin & sarcoglycans
  • Epiphyseal chondrocytes: Intracytoplasmic inclusions

• Nosology: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH)
• Clinical
  • Weakness
    • Proximal
    • Onset: Mean 29 years
    • Progressive
  • Skeletal
    • Fractures, easy
    • Poor healing of long bones
    • Onst: Mean 18 years
  • Other
    • Skin: Thin
    • Hair: Premature gray
    • Hernias
• Laboratory
  • Clotting disorders
  • EMG: Myopathic
  • Bones: Coarse trabeculation, Patchy sclerosis, Cortical thickening, Narrowing of medullary cavities

• Epidemiology: Chinese Han family, 15 patients
• Clinical
  • Onset age
    • 4th to 6th decade
    • Earlier in males
  • Weakness
    • Early: Proximal legs; Neck flexion; Axial
    • Proximal arms: With disease progression
    • Distal extremities: Occasional; Usually mild
    • ? More severe in males
  • Course: Slowly progressive; Walking preserved
• Laboratory
  • Muscle
    • Necrosis & Regeneration
    • Fiber size: Varied; Some angular fibers
    • Rimmed vacuoles: In atrophic fibers
    • No inflammation
    • Congophilic inclusions: Few
    • Myofibfillar stains: Rare desmin & αB-crystallin aggregates
    • Ultrastructure: Cytoplasmic inclusions, 15–21 nm filaments
  • Serum CK: Mildly high; 300 to 400
  • EMG: Myopathic; Irritable
  • NCV: Normal
  • MRI: Medial & Lateral thigh atrophy

• Nosology: ? LGMD 1B
• Clinical
  • Onset: 4 to 38 years
  • Weakness
    • Proximal; Symmetric
    • Lower > upper extremity
    • Biceps involved @ 40 years
  • Contractures: Mild or absent
  • Cardiac
    • Dysrhythmias & conduction disturbances
    • Sudden death
• Laboratory
  • Serum CK: Median 3x normal; Range - normal to 25x
  • EMG & biopsy: Myopathic

• Clinical
  • Male predominance
  • Onset: 2nd or 3rd decade
  • Weakness: Proximal; Symmetric
  • Joint contractures: Ankles
  • Progression: Often disabled by 6th decade
  • Cardiac: Normal
• Laboratory
  • Serum CK: Very high; 12x to 55x normal
  • Muscle biopsy
    • Variation in muscle fiber size
    • Occasional necrotic muscle fibers

• Dominant; ? LGMD 1

Other Recessive Myopathies

• Nosology: Congenital disorder of glycosylation, Type 1o (CDG1O)
• Epidemiology: 2 patients
• Genetics
  • Mutation: Leu85Ser, Leu44Pro; Homozygous
• DPM3 protein
  • Binds DPM1
  • Accessory protein DPM3 of Dol-P-Man synthase
    • Dol-P-Man: Glycosyl donor for all mannosylation reactions on luminal side of ER
• Clinical
  • Onset
    • Age: 11 to 42 years
    • Weakness: Proximal
    • Waddling gait
  • Weakness
    • Proximal
    • Progression: Slow
  • Pseudohypertrophy: Gastrocnemius
  • Tendon reflexes: Reduced or Normal
  • Contractures: Ankle
  • Cardiomyopathy in 1 patient
    • Dilated
    • Stroke-like episodes
  • Short stature
  • CNS & Eye: Normal
• Laboratory
  • Serum CK: 1500 to 4300
  • CDG type I: Defective N-glycosylation in Endoplasmic reticulum
    • Increased ratio of mono- versus diglycosylated transferrin
    • Partial absence of complete biantennary N-glycans
  • EMG: Myopathic
  • Muscle MRI, Thigh: Hamstring; Adductors; Rectus femoris
  • Muscle: Myopathic
    • Fiber-size variation
    • Internal nuclei
    • Necrotic fibers
    • Rimmed vacuoles
    • Fiber splitting
    • Endomysial fibrosis
    • α-Dystroglycan: Reduced

• Epidemiology: 1 Canadian family
• Genetics
  • Mutations: Missense; L345P, P119L, N114K
• LIMS2 protein
  • Z-disk
  • Functions: Adhesion; Integrin signalling
• Clinical
  • Onset age: Childhood
  • Weakness
    • Severe
    • Arms & Legs
    • Face spared
  • Tongue
    • Triangular
    • Macroglossia
  • Muscle size: General atrophy; Calf hypertrophy
  • Cardiomyopathy: LV dysfunction; Onset in 3rd decade
• Laboratory
  • Serum CK: Very high; Up to 5,000
  • MRI: Muscle atrophy
  • Muscle
    • Fiber size: Varied
    • Internal nucle
    • Endomysial connective tissue: Increased
    • PINCH2 staining: May be reduced

• Nosology: LGMD 2X
• Epidemiology: 7 families
• Genetics
  • Mutations
    • Often: Loss of function; Homozygous
    • Missense: c.602C>T, p.Ser201Phe; Pseudo-dominant
    • Splice site: c.1A>G; c.816 + 2T>C
    • Stop: c.262C>T
• POPDC1 protein
  • Localization: Plasma membrane; T-tubule; Nuclear envelope
  • cAMP-binding & effector protein
  • Expressed in cardiac & skeletal muscle
  • Cell adhesion molecule
  • Formation & regulation of tight junction paracellular permeability barrier in epithelial cells
  • VAMP3-mediated vesicular transport
  • Interactions: Caveolin-3; TREK-1 (KCNK2)
  • Nosology: Blood vessel epicardial substance (BVES)
• Clinical
  • Onset age: 2nd to 5th decade
  • Weakness (60%): Proximal; Legs; Symmetric
  • Exercise intolerance
  • Myalgia
  • Cardiac: Syncope; A-V block; Palpitations
• Laboratory
  • Serum CK: 700 to 8000
  • EMG: Myopathic or Normal
  • Muscle biopsy
    • Fiber size: Varied
    • Internal nuclei
    • Necrosis & Regeneration: Scattered
    • Sarcolemma: Reduced POPDC1 & POPDC2
  • Muscle MRI
    • Posterior thigh involvement
    • Asymmetric
    • Distal leg spared
    • Often normal
  • Holter monitor: A-V block

• Epidemiology; 3 families; 5 patients
• Genetics
  • Mutations: Homozygous; p.Leu155His, p.Leu217Phe, p.Arg261Gln
• POPDC3 protein
  • Expression: Heart; Skeletal muscle
  • Transmembrane
  • Bind: cAMP (Popeye domain); TREK-1 (KCNK2)
  • Modulate membrane trafficking of interacting proteins
  • POPDC proteins: Other
    • POPDC1: LGMD R25
    • POPDC2 : AV block
• Clinical
  • Onset age: Adult; 20 to 40 years
  • Weakness: Proximal; Legs > Arms; Poor running
  • Calf hypertrophy
  • Cardiac: Normal
• Laboratory
  • Serum CK: Mean 3500; Range 1050 to 9200
  • Muscle MRI
    • Involvement: Paraspinal; Proximal leg; Medial gastrocnemius
    • Spared: Gracilis; Sartorius; Rectus femoris
  • Muscle pathology
    • Muscle fibers: Varied size; Necrosis; Whorled; Internal nuclei
    • Endomysial connective tissue: Increased
    • POPDC3 protein: Reduced
  • EKG & Echocardiography: Normal

• Epidemiology: 2 families, 4 patients
• Genetics
  • Mutation: Frameshift; Homozygous c.186delG
  • Allelic disorders ¹²⁴
    • Dystonia, Cerebellar atrophy, Cardiomyopathy
    • Multisystem disorders, Progeroid appearance, Early death
    • Multisystem disorder: Developmental delay, Hearing Loss, Cataracts, Cardiac, Skeletal, Muscle atrophy
• LAP1B protein
  • Location: Inner nuclear membrane
  • Binds type A & B lamins
  • ? Regulates TorsinA ATPase
• Clinical
  • Onset age: 1st decade
  • Contractures
    • Rigid spine
    • Interphalangeal joints: Distal & Proximal
  • Weakness
    • Limb-Girdle: Legs > Arms
    • Dysphagia
    • Respiratory insufficiency
    • Progressive
  • Cardiomyopathy, dilated: 1 patient
• Laboratory
  • Serum CK: 80 to 10,000
  • EMG: Irritable myopathy
  • Muscle MRI
    • Trunk: Rectus abdominus, Glutei, Obturator internus, Obliques, Iliacus
    • Thigh: Medial (Adductors & Gracilis & Posterior (Bicceps fermoris & Semitendinosus)
  • Muscle pathology
    • Muscle fibers: Varied size; Internal nuclei; Necrosis & Regeneration
    • Endomysial connective tissue: Increased
    • C_5b-9 on sarcolemma
    • TOR1AIP1: Absent
    • Nuclei: Irregular
    • Ultrastructure: Abnormal nuclear envelope

• Nosology: LGMD 2Z
• Epidemiology: 9 families
• Genetics
  • Mutations: Homozygous; Missense; D233E, R98W, Y57C, I129T, Y156N, R183W
  • Allelic disorder: Galli-Galli/Dowling-Degos disease (DDD4)
• POGLUT1 protein
  • Notch posttranslational modification
    • Notch pathway: Maintains Satellite cell quiescence
  • O-Glucosyltransferase activity on Notch
  • Specifically adds O-glucose or O-xylose to properly folded EGF repeats containing CXSX(P/A)C consensus sequence
  • Glycosyltransferase: Directly add sugar molecules to an amino acid & not to other sugars
  • Mutation: Impairs muscle development
• Clinical
  • Onset age: Congenital to 5th decade
  • Weakness
    • Proximal
    • Legs > Arms
    • Scapular winging
    • Respiratory: 4th decade
  • Course: Slow progression; Some require wheelchair
• Laboratory
  • Brain MRI: Normal
  • Muscle MRI: Internal thigh muscle pathology
  • Muscle
    • Fiber size: Varied
    • Endomysial connective tissue: Increased
    • Nuclei: Internal in some muscle fibers
    • α-Dystroglycan: Hypoglycosylation
    • Satellite cells: Reduced numbers
  • Serum CK: Normal or Mildly high

• Epidemiology: 5 patients
• Genetics
  • Mutations: c.86-1G>A; Arg74*; Arg56Cys; Arg145*
• PAX7 protein
  • Satellite cells
  • Muscle development
• Clinical
  • Onset age: Birth to Few months of age
  • Hypotonia: Especially axial
  • Ptosis
  • Muscle
    • Atrophy
    • Weakness
      • Distal or Diffuse
      • Respiratory: More severe patient
      • Course: Progressive
    • Gait: Abnormal in most
  • Tendon reflexes: Normal or Reduced
  • Skeletal
    • Scoliosis
    • Short stature
  • Face: Mild dysmorphism
  • Systemic: Renal in patient with severe disease
• Laboratory
  • Muscle pathology
    • Fiber size variation: Atrophic fibers
    • Myonuclei: Number reduced
    • Replacement by fat
    • PAX 7 & MYF5 expression: Absent
  • Serum CK: Normal
  • EMG: Early normal; Teens myopathic
  • Brain MRI: Normal

• Epidemiology: 2 paatients
• Genetics
  • Mutation: p.Q247X, Homozygous
  • Variant: Digenic syndrome
• Trim63 protein
  • Regulator of muscle atrophy
  • Expression: Skeletal & Cardiac muscle
• Clinical
  • Onset age: 6th decade
  • Strength: Normal
• Laboratory
  • Cardiac hypertrophy
  • Serum CK: 700
  • EMG: Myopathy, Mild
  • Muscle MRI
    • Patchy asymmetric changes
    • Muacles involved: Gluteus minimus„ Vastus lateralis, Semimembranosus, Medial gastrocnemius
  • Muscle biopsy
    • Necrotic fibers: Few
    • Muscle fiber size: Varied
    • Internal nuclei
    • Internal capillaries: 5–10% of muscle fibers
• TRIM63 variant syndrome: Cardiac & Skeletal Aggregate Myopathy with Combined MuRF1 & MuRF3 mutations ¹¹⁶
  • Epidemiology: 1 patient
  • Genetics: Digenic
    • Murf1 (TRIM63) mutations: p.Q247X, Homozygous
    • Murf3 (TRIM54) mutation: p.Asp106Asn, Heterozygous
  • Clinical
    • Onset age: 15 years
    • Weakness
      • Distribution: Arms & Legs; Proximal; Symmetric
      • Gait: Waddling
      • Respiratory: Moderate reduction
      • Course: Slow progression
    • Muscle hypertrophy: Deltoids, Biceps, Calf
    • Scapular winging
    • Rigid spine, hypertrophy
  • Laboratory
    • Echocardiogram: Hypertrophic cardiomyopathy
    • EKG: Atrial flutter & enlargement
    • Serum CK: 2x to 6x high
    • EMG: Myopathic
    • Muscle MRI
      • Subcutaneous tissue: Reduced
      • Fat replacement: Lumbar paraspinous; Glutei; Thigh, anterior & posterior
      • Hypertrophy: Rectus femoris, Sartorius, Gracilis
    • Muscle biopsy
      • Fiber sizes: Some small fibers
      • Fiber aggregates
        • Location: Sub-sarcolemmal
        • Type I fibers
        • Components: MyHC, MuRF3, M-protein, Myomesin
        • Ultrastructure: Aberrantly oriented sarcomere fragments
      • Nuclei: Large
      • Endomysial connective tissue: Mildly increased

• Epidemiology: 2 Sicilian families
• Genetics
  • Mutations: c.4-1G>C (Disrupts acceptor splice site of exon 2; Y23C
• DPM2 protein
  • Dolichol-phosphate-mannose (Dol-P-Man; DPM) synthase complex component
  • Catalyzes synthesis of DPM at cytosolic face of ER membrane
• Clinical
  • Onset age: Congenital
  • Microcephaly, progressive
  • Visual defect, Severe
  • Epilepsy
  • Muscular dystrophy: Hypotonia
  • Liver involvement
  • Death: < 18 months
• Laboratory
  • Coagulation factors: Decreased
  • Serum CK: High; 1,200 to 1,400
  • EMG: Myopathic
  • Muscle
    • Fiber-size variation
    • Internal nuclei
    • Endomysial fibrosis
    • Reduced: α-Dystroglycan; Laminin-α2
  • Transferrin: Abnormal N-glycosylation
  • Brain MRI: Cerebellar vermis hypoplasia

• Epidemiology
  • 5 unrelated Japanese families
  • Omani & UK families
• Genetics: Mutations
  • Homozygous or Heterozygous
  • c.525delG, c.696_697insC, c.160delG, c.362dupT
• PTRF protein
  • Termination of RNA polymerase I (Pol I)
  transcription
  • Release of both pre-rRNA & Pol I from template
  • Required for caveola formation & sequestration of mobile caveolin into immobile caveolae
• Clinical
  • Onset
    • Age: Infancy or early childhood
    • Lipodystrophy
  • Lipodystrophy
    • Generalized
    • Loss of adipose tissue in several regions including face
  • Weakness
    • Mild
    • Distal dominant or Generalized
  • Muscle
    • Muscle hypertrophy
    • Muscle activity
      • Muscle mounding
      • Rippling
      • Electrically silent
    • Myalgias: Occasional
  • Cardiac
    • Tachycardias: Supraventricular & Ventricular
    • Bradycardia
    • Long-QT syndrome
    • Sudden cardiac death: Teens
  • GI
    • Smooth muscle hypertrophy
    • Hypertrophic pyloric stenosis
    • Impaired gastrointestinal motility: Constipation
    • Chalasia
  • Bone
    • Impaired bone formation
    • Osteopenia
    • Osteoporosis
    • Atlanto-axial instability
    • Skeletal: Lordosis or Scoliosis
  • Other systems
    • Acromegaloid features
    • Umbilical prominence
  • Immune: Some patients
    • Transient immunodeficiency (IgA)
    • Recurrent pneumonia
  • Not present
    • Intellectual deficit
    • Acanthosis nigricans
• Laboratory
  • Serum CK: High; 500 to 2600
  • Muscle
    • Chronic dystrophic changes
      • Variation in fiber size: Marked
      • Enlarged fibers
      • Internal nuclei
      • Endomysial fibrosis
      • Necrotic & Regenerating fibers: Few
    • Caveolin family members
      • Deficiency & Mislocalization of all 3
      • Caveolin-3: Reduced on sarcolemma: Increased in cytoplasm
      • Caveolin-1 & Caveolin-2: Reduced in blood vessels
      • Caveolae structure: Reduced
    • Dysferlin: Decreased in sarcolemma; Mislocalized into cytoplasm
    • PTRF: Absent from muscle by Western blot
    • Normal: Dystrophin, Sarcoglycans, Dystroglycans, Emerin, Merosin, Collagen VI

• Epidemiology: 2 patients
• Genetics
  • Mutations
    • 30 kb deletion: Leads to fusion gene with pseudogene TNXA; Truncating
    • Arg4072Cys
  • Allelic with: Ehlers-Danlos syndrome, autosomal dominant, hypermobility type
• TNXB protein
  • Extracellular matrix of muscle & Blood vessels
  • Regulator of collagen deposition by dermal fibroblasts
• Clinical
  • Weakness
    • Onset age: 4th decade
    • Proximal & Axial
    • Symmetric
    • Weakest muscles: Abdominal; Knee extensors
    • Scapular winging
    • Functional: Difficulty running
    • Muscle bulk: Reduced
    • Course: Slowly progressive
  • Tendon reflexes: Reduced
  • Skin: Hyperextensible
  • Hematomas: After minimal trauma
  • Contractures: Fingers or None
• Laboratory
  • EMG: Myopathic; Pseudomyotonic discharge
  • NCV: Normal
  • Serum CK: High; Up to 5x normal
  • CT: Rectus femoris most preserved in Thigh; Distal legs normal
  • Cardiac echo: Systolic function mildly reduced
  • Platelet aggregation: Mildly abnormal
  • Muscle
    • Soft consistency
    • Fiber size: Varied
    • Internal nuclei
    • Fiber type groupisng
    • Myotendinous junctions: Increased
    • Endomysial connective tissue: Normal
    • Tenascin-X staining: Reduced in muscle & skin
    • Ultrastructure: Plasma membrane focally disrupted; Basal lamina abnormally folded

• Northern Indiana Amish
• Linked to LGMD 2E

• Lipid Storage
  • Carnitine Deficiency
  • Riboflavin Responsive (multiple enzyme deficiencies)
• Acid Maltase deficiency & other Glycogen storage syndromes

• Epidemiology: 2 Japanese patients
• Onset: Congenital Hyoptonia
• Clinical
  • Progression: Developmental delay
  • Cardiomyopathy: Cardiomegaly
  • Death: 2 to 30 months
• Muscle: Vacuoles, autophagic
  • LAMP-2 staining
  • Contain glycogen granules

• Epidemiology: 1 family; 2 British females
• Onset: 12 years
• Clinical
  • Early developpment: Normal
  • Weakness
    • Legs > Arms
    • Proximal > Distal
    • Neck flexor
  • Contractures: Knee
• Laboratory
  • Serum CK: High, 500 to 700
  • EMG: Myopathic
  • MRI: Wasting of thigh muscles sparing adductors
  • Muscle
    • Autophagic vacuoles
    • Endomysial connective tissue: Mildly increased

• Epidemiology: 1 Japanese male
• Onset: Myopathy as adult
• Clinical
  • Ocular
    • Achromatopsia: From childhood
    • Retinal pigmentary degeneration: Blindness in 3rd decade
    • Optic atrophy
  • Weakness
    • Proximal > Distal
    • Scapular winging
  • Other muscle
    • Exertional pain
    • Dyspnea
  • Cardiomyopathy
    • EKG: Bradycardia with transient sinus arrest & prolonged PQ interval
    • Echocardiography: Hypertrophy & partial dilatation of left ventricular wall; Decreased ejection fraction
  • Lung: Fibrosis
• Laboratory
  • Serum CK: High, 500
  • IgG & IgE: High
  • ⁶⁷Ga uptake in skeletal muscles
  • Muscle
    • Autophagic vacuoles
    • Fiber size: Moderate variation
  • Liver: Vacuoles in hepatocytes
  • Renal: Proteinuria

• Epidemiology: 4 families, 5 patients
• Genetics
  • Mutations: Missense (Gly165Glu), Splice & Stop; Common 1 kb deletion
  • Allelic disorder: Neuronal ceroid lipofuscinosis, juvenile form
• CLN3 protein
  • Organs: Brain + other tissues
  • Subcellular: Nucleus & Cytoplasm; Lysosomal
  • Cellular: Astrocytes & Endothelium
• Clinical
  • Onset age: 6 to 9 years
  • Eye
    • Early in disease course
    • Retinitis pigmentosa
    • Visual loss
  • CNS
    • Epilepsy: Tonic-clonic
    • Cognitive: Mild impairment of verbal fluency & executive functions
  • Cardiac
    • Hypertrophic cardiomyopathy
    • Sick sinus syndrome
    • Conduction defect
    • Onset: Later in disease course
  • Motor function: Normal
  • Course: Slow progression over decades
• Laboratory
  • Serum CK: Up to 600
  • Muscle
    • AVSFs
    • Autophagic debris: Acid phosphatase +
    • Autofluorescent material
  • EMG: Myopathy, mild
  • EEG: Spikes & sharp waves
  • Blood lymphocytes: Cytoplasmic vacuolization
  • Brain MRI: Cerebral & Cerebellar atrophy

X-linked myopathies

• Becker muscular dystrophy
  ● Dystrophin partial deficiency; Chromosome Xp21; Recessive
• Emery-Dreifuss: Contractures & Cardiac
  ● Emerin; Chromosome Xq28; Recessive
  
• McLeod Syndrome: Acanthocytosis & Chorea
  
• Barth syndrome
• X-linked myopathy with excessive autophagy
  

• Epidemiology: Families in Europe & North America, ~14
• Genetics
  • VMA21 mutations ⁷¹
    • Single nucleotide substitutions
    • Locations: Intron; Splice site; 3' UTR
    • Mutation effects: Reduced VMA21 abundance
    • c.164-7T>G: Childhood & adult onset patients
    • Non-coding microdeletions (c.54-16_54-8del; c.*13_*104del): More severe, early-onset disease
  • Allelic with: Congenital Autophagic Vacuolar Myopathy (CAVM): c.16426t>g mutation
• VMA21 protein (Vacuolar H⁺-ATPase homolog)
  • Assembly chaperone for: V-ATPase
    • Principal mammalian proton pump complex
    • May pump 2-3 H⁺ per ATP hydrolyzed
    • Acidify vesicles: Golgi-derived, Clathrin-coated, Synaptic
    • Inhibitor: Bafilomycin
  • Decreased VMA21
    • Raises Lysosomal pH: Increased from 4.7 to 5.2
    • Lysosomal degradative ability: Reduced
    • Autophagy: Blocked
    • Cellular free amino acids: Reduced
    • mTOR pathway & mTOR-dependent macroautophagy: Down regulated
    • Proliferation of large & ineffective autolysosomes
      • Engulf sections of cytoplasm, merge & form vacuoles
  • Disease mechanism
    • Macroautophagic overcompensation: Leads to cell vacuolation & tissue atrophy
• Clinical: Similar patterns among families
  • Onset
    • Age: Range Neonatal to 50 years; Typical 5 to 10 years
    • Weakness: Difficulty climbing stairs & running
    • Neonatal onset: Hypotonia; Rapid progression
  • Weakness
    • Common: Limb-Girdle; Mild
      • Proximal
      • Symmetric
      • Legs > Arms
    • Distal: Ankles
    • Eyes: Up & Lateral movements limited in more severe patients
  • No muscle hypertrophy or clinical myotonia
  • Progression
    • Common: Very slow or Stable
    • Longevity: Not altered
    • Many patients in wheelchair by 6th decade
  • Cardiac: Normal
  • CNS
    • Intellect: Normal
    • Seizures: More severe patients
  • Female carriers: Normal or Mildly affected
• Laboratory
  • Serum CK: 2x to 15x elevated; Higher in adolescence than childhood
  • EMG
    • Myopathic
    • Motor units: High amplitude; Polyphasic; Normal duration
    • Spontaneous activity
      • Myotonic & High frequency discharges
      • May occur in clinically unaffected muscles
    • Most affected muscles: Psoas; Anterior thigh; Posterior leg
• Muscle biopsy
  • Muscle fibers
    • Variable fiber size
    • Necrosis: Little or None
    • Vacuoles: Autophagic with sarcolemmal features (AVSF)
      • Excessive autophagic activity
      • Location: Sarcoplasm; Internal or Near surface
      • Size: 2 to 10 μm
      • Basophilic granules
      • Contents
        • Lysosomal enzymes (Hydrolases)
        • Calcium
        • C_5b-9 complement components
        • Cellular debris
        • Acid phosphatase: Variably present
      • Immunostaining
        • Dystrophin: Vacuolar membrane staining
        • LAMP-2 & Sarcoglycans
        • Caveolin-3
        • α1-Antitrypsin: Within vacuoles
      • Vacuolated fibers express polysialylated isoform of NCAM
      • Unable to complete digestion of contents
        • Migrate to myofiber surface
        • Fuse with sarcolemma
        • Exocytosis of phagocytosed material: To extracellular space
      • Differential diagnosis
  • Basal lamina
    • Affected fibers surrounded by multiple layers
    • Contains Granular material
  • Complement deposits
    • Sarcolemma & vacuoles
    • Granular pattern

• Epidemiology
  • Occurrence: Infrequent
  • ~500 patients reported worldwide
  • Hypertrophic cardiomyopathy: Higher frequency of LAMP2 mutations; 4% to 30%%
• Genetics
  • Mutations
    • Frameshift; Nonsense; Insertion
    • Cause protein truncation
    • Usually cause absent LAMP-2 in muscle: 1 family with some residual LAMP-2
    • May affect
      • LAMP-2B only: No mental retardation in males; Milder or no signs in females
      • Both LAMP-2 isoforms: Most common pattern; Typical disease manifestations
  • Allelic disorders
    • Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy
    • Weakness with no mental retardation
    • Carrier females
• LAMP-2 protein
  • Type 1 membrane protein: 3 domains; Luminal, Transmembrane, Cytoplasmic
  • Lysosomal: Coats inner side of membrane
  • Highly glycosylated
    • LAMP1 & LAMP2 most densely glycosylated proteins known
    • N-glycosylations: Luminal domain
    • O-glycosylations: Hinge region
  • 3 Isoforms: Lysosomal
    • LAMP-2A: Ubiquitous
      • Chaperone-mediated autophagy
      • Oxidized proteins
      • Increased during starvation
    • LAMP-2B
      • Cardiac & Skeletal muscle
      • Macroautophagy
    • LAMP-2C: ?
  • LAMP-2 deficiency: Affects
    • Chaperone-mediated autophagy
    • Lysosomal biogenesis
    • Lysosome-autophagosome fusion
    • Lysosomal movement along microtubules
    • Disease mechanisms
      • Block in autophagy
      • Impaired fusion of autophagosome-lysosome
      • Inefficient lysosome biogenesis & Maturation
• Clinical ²⁹
  • Onset
    • Age
      • Range: Infantile to 5th decade
      • Childhood most common
      • Mean 13 years
      • Latest: 45 years (Mutation in exon 9b)
    • Cardiac
  • Weakness
    • Frequency: Most patients; 80% to 100%
    • Often mild: Most patients remain ambulatory
    • Distribution
      • Symmetric
      • Proximal ± Distal
      • Arms & Legs
      • Trunk: Neck; Scapular winging
      • Face
    • Fatigability without fixed weakness: 10%
    • Wasting: 15%
    • Monophasic severe post-operative weakness: 1 patient ⁸⁴
  • Cardiomyopathy (Nearly 100%) ⁷²
    • Symptoms: Chest pain, Palpitations, Syncope, Fatigue; Heart murmurs; Cardiac arrest (Syncope)
    • Hypertrophic: Concentric; Impaired LV function; Thick IV septum & posterior walls
    • Left ventricular systolic dysfunction, ejection fraction ~25%
    • Left ventricular cavity enlargement
    • Treatment: Pacemaker or Heart transplantation
    • EKG
      • Abnormal in 100%: Arrhythmia; Startsx before symptoms
      • Ventricular preexcitation
      • Wolff-Parkinson-White (69%)
      • Other: Short PR intervals; High precordial voltage; Arrhythmias
      • Echocardiography: Concentric left ventricular hypertrophy
    • Prognosis: Poor
      • Progression to end stage heart failure in early adulthood
      • Sudden death
    • Treatment: Heart transplant
  • CNS
    • Mental retardation: 80%; Mild or absent in 40%
    • Ischaemic thromboembolic strokes
  • Hepatomegaly: 35%
  • Foot deformities: 38% of males
  • Retinopathy
    • Loss of pigment in retinal pigment epithelium
    • Reduced visual acuity: Mild
  • Polyneuropathy (38%): Sensory > Motor
  • Course
    • Some with death in 2nd to 5th decade
    • Males < 30 years
    • Females: 4th & 5th decade
    • Cause of death: Cardiac failure
• Laboratory
  • Serum CK
    • High in most (4x to 35x normal; 300 to 3,000)
    • May be normal (10% to 20%)
    • Patients may present with asymptomatic high CK
  • EMG: Myopathic (100%); Myotonia (30%); Spontaneous activity (30%)
  • Nerve conduction tests: Normal
  • EEG: Mild abnormalities in 28%
  • Liver enzymes: High
  • CNS: Normal brain MRI
• Muscle pathology
  • Vacuoles: Similar to XMEA
    • Autophagic: Contain lysosomal enzymes & LC3
    • Cytoplasmic: Small solid basophilic granules
    • Histochemistry: Acid phosphatase, Nonspecific-esterase & Acetylcholinesterase staining
    • Immunocytochemistry: Stain for Dystrophin; Laminin; limp-1
    • Ultrastructure: Vacuoles contain glycogen particles & cytoplasmic debris
    • Present in males & females
  • Myopathy: Varied muscle fiber sizes
  • Glycogen: Increased or Normal amount; Free & membrane bound
  • Lamp-2 protein staining: Absent with most mutations; Rarely residual LAMP-2A isoform
  • Molecular, other
    • VPS15 (PIK3R4) : Accumulation & Altered localization
    • TFEB : Activation
    • LC3-II & p62: Increased
  • Heart: Fibrosis; Intracytoplasmic vacuoles
• Danon syndrome variant: Early weakness but no retardation ⁵⁵
  • Mutation: Gly384Arg
  • Onset
    • Age: Childhood to 4th or 5th decade
    • Leg weakness
  • Clinical
    • Weakness
      • Legs: Distal > Proximal
      • Arms
      • Face
      • Sleep apnea
    • Gynecomastia
    • Cardiac: Some patients
      • Sick sinus syndrome
      • Atrial fibrillation
    • No mental retardation
    • Female carriers
      • Cardiac disease: Arrhythmias
      • One with weakness
  • Pathology: Muscle
    • Autophagic vacuoles
    • Glycogen: Increased
    • LAMP-2: Normal staining
• LAMP2 variant: Carrier females
  • Frequency
    • > 70% of carriers
    • All eventually have abnormal EKG
  • Clinical
    • Onset
      • Age: 12 to 53 years
      • Cardiac signs
    • Weakness: 33%; Mild; Proximal limb & Neck
    • Cardiomyopathy
      • Dilated > Hypertrophic
      • Arrhythmia: Pacemaker in 17%
      • WPW (30%)
      • May present during pregnancy
    • Retinopathy (64%)
      • Pigmentary changes: Peripheral
      • Electroretinogram: Abnormal
      • Visual fields: May be abnormal central region
    • Cognitive: Learning disability (50%)
    • Polyneuropathy & Muscle cramps
    • Course: Some with death in 4th & 5th decade
  • Laboratory
    • Serum CK: 76 to 643
    • Muscle biopsy
      • Vacuoles
      • LAMP-2 staining: Absent or Reduced
  • Treatment: Cardiac transplantation or Pacemaker
• Danon syndrome: Variant
  • Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy

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     8: PYROXD1; 12p12     MFM: ACTA1; 1q42   Myopathy & Respiratory Δ     Type 1: Titin; 2q31     Type 2: 2q21   Other     Distal myopathy: HSPB8; 12q24     DMRV: SQSTM1 + TIA1     LGMD       1B; LMNA; 1q21       1D: DNAJB6; 7q36       2Q: Plectin; 8q24     Polyglugosan body: RBCK1; 20p13     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

• Clinical features
  • Weakness
    • Proximal & Distal
    • May present with respiratory failure
  • Cardiomyopathy (50%)
  • EMG
    • Myopathy
    • Irritability: Fibrillations; Positive sharp waves
    • Myotonia
    • Complex repetitive discharges
  • Serum CK: Normal, or Elevated < 5x
• Pathological features
  • Initial: Centered on Z-disc
  • Degradation (focal) primarily affecting myofibrils
    • Lytic lesions depleted of actin, α-actinin ± titin, nebulin, or myosin
    • Inappropriate expression of
      • Cell division cycle (CDC) 2 kinase
      • Cyclin-dependent kinases (CDK) 2, 4 & 7
  • Hyaline spheroid & granular structures: Staining patterns
    • Gomori trichrome: Amorphous, hyaline, or granular material
    • Contain compacted & degraded myofibrillar structures
    • NADH: Circumscribed reduced staining
    • React intensely for actin
    • Congo red positive
  • Numerous proteins accumulate in lesions & muscle fibers
    • Desmin, lamin-B, gelsolin, ubiquitin, α₁-antichymotrypsin, NCAM, N-terminal β-AP, myotilin (90%)
    • Ectopic dystrophin & γ-sarcoglycan
    • Ectopic expression of lamin B & nuclear matrix protein in cytoplasm
    • Amyloid deposits

Myofibrillar myopathies: Specific syndromes

Myofibrillar myopathy 1 (MFM1)

• Nosology
  • Myofibrillar myopathy with desmin mutations
  • One family originally identified as: HIBM1
• Gene mutations
  • Location
    • Most mutations: Carboxy-terminal of rod domain (Helixes 1B & 2B)
    • Occasional mutations in head or tail domains
  • Types
    • Usually: Missense
    • Occasional: Splice site with exon skipping; In-frame deletion; Small insertion
  • Recessive mutations: 6%; Mean onset = 5 years
  • Mutation Database: HGMD
  • Allelic with
    • Dominant
      • Myopathies
        • Kaeser scapuloperoneal syndrome
        • Myofibrillar myopathy 1 (MFM1)
        • LGMD 1E
        • Distal myopathy, Cardiomyopathy & Autophagic vacuoles
      • Cardiomyopathies
        • Dilated: 1F, 1I
        • ARVD7
    • Recessive
      • LGMD 2R
      • Myopathy, Early onset
      • Myopathy, Adult onset
      • Myopathy + Ophthalmoparesis, Infant onset
• Desmin protein features ⁴³

  From C Weihl MD

  • Vimentin-like intermediate filament
    • Appearance follows vimentin in development
    • 53 kDa monomer
    • Domains: Head; Rod; Tail
    • Assembles into 10nM diameter filaments
    • Non-polar filament
  • Location
    • Cytoplasm: Subsarcolemmal; Z-band encircled
  • Tissues: Muscle specific
    • Skeletal
      • 0.35% of total cell protein
      • Major intermediate filament in muscle
      • Increased amounts at: Myotendinous & Neuromuscular junctions
      • Development
        • Low in replicating myoblasts & satellite cells
        • High in differentiated myotubes
      • Mutations
        • Levels of mutant protein: Vary within regions of single fibers
    • Cardiac: 2% of total cell protein
    • Smooth: Especially resistance-sized mesenteric microarteries
  • Functions
    • Overall: Links myofibrils to sarcolemma, nucleus & mitochondria
    • Contractile apparatus in muscle
      • Role in maintenance of structural & mechanical integrity
      • Force transmission
    • Mitochondrial function
      • Influences: Position, Movement & Respiratory activity
  • Desmin interactions: Binding to
    • Ankyrin
    • Spectrin
    • Synemin : Interacts with α-dystrobrevin, vinculin & α-actinin
    • Desmuslin
    • Syncoilin
    • Plectin: Links cytoskeleton & intermediate filaments
    • Nebulin: C-terminus
  • Inclusions
    • Cytoplasmic, Spheroid, Mallory, Lewy bodies
    • Associated with: Actin; Ubiquitin; Heat shock proteins (α-B crystallin); Amyloid proteins
  • Mutant desmin
    • Abnormal assembly of intermediate filaments
    • Produces fragility of myofibrils
• Myopathy + Cardiomyopathy (MFM1)
  • Genetics
    • Inheritance: Dominant
    • Mutations: Heterozygous; Ala337Pro; Leu345Pro; L370P
    • Mechanism: ? Dominant negative effect on filament formation
  • Clinical
    • General
      • Syndromes may involve skeletal muscle, heart or both
      • Smooth muscle involved in some syndromes
      • Inter- and intra-familial variability with same mutation
    • Skeletal myopathy
      • Onset: 20's & 30's
      • Early: Distal progressing to Proximal weakness
      • Patterns of weakness
        • Scapuloperoneal
        • Limb-Girdle
        • Distal
        • Distal + Proximal
        • Also see: R350P (Kaeser scapuloperoneal syndrome)
      • Progression of weakness
        • Limbs; Neck; Pectoral; Bulbar & Facial
        • Disability: Wheelchair, walker or braces in 75%
        • Respiratory failure in some families
    • Cardiac involvement (60%)
      • EKG: Right bundle branch block; ST segment elevation
      • Syncopal episodes: Pacemaker often required (40%)
  • Laboratory
    • Serum CK: Mildly elevated in 50%
    • EMG: Myopathic; Fibrillations
    • Muscle pathology
      • Variable fiber size
      • Internal nuclei: Increased
      • Storage: Desmin, Vimentin & Nestin accumulate in muscle fibers
        • Location
          • Cytoplasmic
          • Subsarcolemmal & some sarcoplasmic aggregates
        • Accumulations also contain dystrophin
        • Aggregates may have different shapes in type 1 & 2 muscle fibers
        • Ultrastructure: Granulofilamentous material
      • Occasional: Rimmed vacuoles; Small rods
• Desmin variant syndrome: Distal myopathy, Cardiomyopathy & Sarcolemmal Vacuoles ⁹⁸
  • Epidemiology: 2 families
  • Genetics
    • Inheritance: Dominant
    • Mutations: R454W (Tail domain); I402N
  • Clinical
    • Onset age: 3rd to 5th decades
    • Myopathy
      • Weakness
        • Distal > Proximal
        • Respiratory
        • Symmetric
      • Atrophy: Distal
    • Cardiac
      • Conduction block
      • Cardiomyopathy: Dilated
  • Laboratory
    • Serum CK: Mildly high; 280 to 810
    • EMG: Myopathic; Fibrillations, distal
    • NCV: Normal
    • Muscle
      • Fiber size: Varied; Clustered atrophy
      • Internal nuclei
      • Ensomysial connective tissue: Increased
      • Aggregates: Desmin
      • Cytoplasmic bodies
      • Vacuoles: Autophagic with Sarcoplasmic features (AVSF)
• Desmin variant syndrome: LGMD 2R
  • Genetics
    • Inheritance: Recessive
    • Mutations: Compound heterozygosity (Type 3); Ala360Pro & Asn393Ile
    • Heterozygote carriers: Not involved
  • Clinical
    • Cardiac
      • A-V conduction block: Require pacemaker at ages 2 to 10
      • Cardiomyopathy onset: Childhood to 20's
    • Weakness
      • Proximal & Facial
      • Onset 20's
      • Respiratory involvement
    • Skeletal
      • High arched palate
      • Scoliosis
  • Pathology
    • Hyaline/desmin plaques (Mallory body-like)
    • Amorphous subsarcolemmal material
      • Desmin- & dystrophin-immunoreactive
• Desmin variant syndrome: Scapular myopathy, Early onset ⁷³
  • Genetics
    • Inheritance: Recessive
    • Mutation: Homozygous in-frame deletion; p.R173_E179del
  • Desmin: Mutated protein
    • No assembly of desmin filaments
    • Reduced ability to form intermediate filament network
  • Clinical
    • Onset
      • Age: 6 months
      • Syncope
    • Cardiomyopathy
    • Weakness: Progressive
      • Face & Ptosis
      • Proximal & Distal
      • Scapular winging
    • Tendon reflexes: Reduced
    • Death: 20 years
  • Laboratory
    • EMG: Complex repetitive discharges; Myotonic discharges; Fibrillations
    • EKG: Ventricular tachycardia, QT interval prolonged; 2nd degree AV block
    • Muscle: Desmin aggregates, subsarcolemmal (Cap-like); Small vacuoles
• Desmin variant syndrome: Myopathy, Adult onset ⁸⁷
  • Epidemiology: Turkish family
  • Genetics
    • Inheritance: Recessive
    • Mutation: c.1289-2A>G (Tail domain; Lamin B interaction)
    • Homozygous splice site mutation
  • Clinical
    • Onset age: 2nd or 3rd decade
    • Weakness
      • Distribution: Proximal; Symmetric; Face, mild
      • May be severe
      • Scapular winging
      • Course: Wheelchair in 2 decades
    • Contractures: Elbow
  • Laboratory
    • Muscle pathology
      • Fiber size: Varied
      • Necrosis: Occasional
      • Endomysial connective tissue: Increased
      • Type 2 predominance
      • Desmin staining: Present; No aggregates
    • Serum CK: Normal
    • EKG: Right bundle branch block
    • Cardiac echo: Normal
• Desmin variant syndrome: Myopathy + Ophthalmoparesis ¹²⁰
  • Epidemiology: 1 family, 2 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations: Loss-of-function; Homozygous; c.345dupC (p.N116Qfs*2)
  • Clinical
    • Onset age: Infancy; Fetal movements reduced
    • Motor milestones: Delayed
    • Weakness
      • Generalized
      • Face
      • Respiratory
    • Eye: Ptosis; Ophthalmoparesis
    • Cardiomyopathy: Left ventricular Hypertrophy
    • Face: Long; Hypertelorism
    • Treatment: Salbutamol (2 mg tid), Partial response
  • Laboratory
    • EMG: Myopathic
    • RNS: Decrement
    • NCV: Normal
    • Muscle
      • Myopathy: Internal nuclei, Abnormal structure, Clumped
      • Desmin: Absent
      • Ultrastructure: Myofibril degeneration; Autophagic vacuoles; Rods
    • Serum CK: 4x elevated
• Desmin variant syndrome: Cardiomyopathies
  • Types
    • Familial hypertrophic
      • Desmin point mutation; Dominant
    • Dilated Cardiomyopathy 1I
    • Restrictive
  • Other features
    • Atrioventricular conduction abnormalities: Require pacemaker
    • Sudden death
    • Heart disease eventually in > 60% of desminopathies
    • Earlier onset in cases without skeletal myopathy

• Genetics
  • MFM2 Inheritance: Autosomal Dominant
  • Mutations: Myopathy
    • Missense: D109H, D109A, Arg120Gly
    • Truncating: C-terminal; 464delCT & Gln151X
  • Allelic disorders
    • Dominant Congenital Posterior Polar Cataract: 1-BP Del, 450A
    • Fatal infantile hypertonic myofibrillar myopathy, Recessive
    • CMD 1II: Cardiomyopathy, Familial dilated
• CRYAB protein
  

  From HPRD αB-crystallin

  • Type: Heat shock protein 20 (HSP20) family
  • Amount: 3% of soluble protein in heart & skeletal muscle
  • Location
    • Tissues: Muscle (Especially slow fibers); Lens; Myocardium; Kidney epithelium
    • Subcellular: Cytosol
  • Functions
    • Chaperone: Multifunctional; Desmin, Tubulin & Actin (pH & Temperature dependent)
    • Lens: Forms aggregates with αA-crystallin; Maintains lens transparency
    • Cytoprotective: Target of p53
    • Apoptosis regulation
    • Muscle
      • Stabilizes cytoskeletal & sarcomeric proteins
      • Modulates titin elasticity
  • Major component of Rosenthal fibers in Alexander's disease
  • Mutant protein
    • Expressed
      • Even with truncation mutations
      • Lower levels than normal protein
    • Forms complexes with wild type protein
    • Probably exerts dominant negative effect
  • External link: HPRD
• Clinical: Variable
  • General
    • Some families with only single system involved: Cataracts, Myopathy or Cardiomyopathy
    • Multisystem disease: D109H; R120G
  • Onset: Early to middle adulthood
  • Progression: Slow; Sudden cardiac death
  • Weakness
    • Proximal: Most patients
    • Distal: Legs; Most patients
    • Cranial nerve: Face, Bulbar (Dysphagia; Dysarthria)
    • Respiratory: Later in disease course
  • Chest pain
  • Cardiac: Arrhythmia, Conduction block, Congestive failure
  • Other systems
    • Lens opacities: Posterior polar cataracts
    • Intestinal malabsorption
  • ± Neuropathy
• Laboratory
  • Serum CK: Normal to 7x normal
  • EMG: Myopathic; Irritable
• Muscle pathology
  • Myopathic
    • Varied fiber size
    • Scattered degenerating & necrotic fibers
  • Accumulations of granulofilamentous material in muscle & heart
    • Present in type 1 & 2 fibers
    • Subsarcolemmal & intermyofibrillar
    • Contain phosphorylated desmin
    • Molecular components: Desmin, aB-crystallin, Myotilin, Dystrophin, NCAM, CDC2 kinase
    • Molecules not present: Ubiquitin, Gelsolin, and α1-antichymotrypsin
    • Rubbing out of intermyfibrillar network in type I fibers
    • Trichrome: Regions of dark blue staining
    • Congo red: Some regions congophilic (Amyloid-like)
  • Autophagocytosis
  • Nuclei: 7% to 8% show early apoptotic changes
  • Denervation: Scattered esterase+ angular muscle fibers
  • NOTE: αB-crystallin also accumulates in muscle fibers in inclusion body myositis
• CRYAB Variant syndrome: Fatal infantile hypertonic myofibrillar myopathy, Recessive
  • Epidemiology: Canadian aboriginals
  • Genetics: 1 bp deletion; 60delC
  • Clinical
    • Stiffness
      • Limb & Axial
      • Progressive
    • Respiratory insufficiency
    • Death: Infancy to 3 years
    • Cognition: Normal
  • Laboratory
    • Serum CK: 15x to 25x high
    • Brain MRI: Normal
    • Heart: Usually normal
  • Muscle
    • Fiber size: Varied
    • Endomysial connective tissue: Increased
    • Gomori trichrome: Dark-staining inclusions
    • Myofibrillar myopathy: Patchy cytoplasmic desmin staining
    • CRYAB: Reduced staining; Staining peresent for AA 1-10
  • Heterozygous parents: Usually not affected
• CRYAB Variant syndromes: Other recessive
  • Mutations: R56W, S115fs129X, S21Afs24X
  • Clinical
    • Cataracts
    • Myopathy: Early onset

• Genetics
  • 16 exons: Several tissue specific splice variants
  • Mutations: Missense
    • A147T and A165V: Myopathy; Near or within motif important in linking ZASP to Z-disk
    • R268C: Exon 9; Oldest at myopathy disease onset
    • Cardiomyopathy: Mutations
      • Often in linker region between the PDZ and LIM domains
      • Exon 4: Isolated non-compaction of the left ventricular myocardium (INLVM)
      • Exon 6: INLVM or Dilated cardiomyopathy
      • Exon 10: Dilated cardiomyopathy
  • Allelic disorders
    • Myofibrillar myopathy 4 (MFM4)
    • Markesbery distal myopathy
    • Dilated cardiomyopathy (CMD1C)
    • Isolated non-compaction of left ventricular myocardium
    • Hypertrophic cardiomyopathy 24 (CMH 24)
  • ~16% of myofibrillar myopathies
• ZASP protein (Z-band alternatively spliced PDZ motif-containing protein)
  • Subcellular localization: Cytoplasm
  • Tissue expression: Predominantly in cardiac & skeletal muscle.
  • Binds to: α-actinin (Structural component of Z-filaments that cross-links thin filaments of adjacent sarcomeres)
  • Structure
    • N-terminal PDZ domain: Important for protein–protein interactions
    • ZASP-like motif (ZM motif): In exons 4 and 6; 26-residues; Needed for interaction with α-actinin
    • Long isoforms: Contain LIM domains that interact with protein kinase C subtypes
  • Splice variants
    • Skeletal muscle: 3 isoforms
      • Longest isoform: Lacks exons 4 and 9
      • 2nd long isoform: Lacks exons 4, 9, and 10
      • Short isoform: Lacks exon 4; Stop codon in exon 9
    • Cardiac muscle isoforms
      • Often contain exon 4 instead of exon 6
      • Mutations in exon 6 cause cardiomyopathy in humans
• Clinical
  • Onset
    • Age: Child to 73 years
    • Weakness: Most common early feature
  • Weakness: May be proximal or distal
    • Proximal or Distal
      • Proximal > Distal (45%)
      • Proximal + Distal (27%)
      • Distal only (9%)
      • Proximal only (18%)
    • Legs: Posterior
    • Scapular, Selective: 1 patient
    • Respiratory: Not prominent
  • Cardiac (27%)
  • Polyneuropathy (45%)
• Laboratory
  • Serum CK: Normal to 6x elevated
  • EMG: Myopathic; Irritable (Fibrillations & Myotonic discharges)
  • Muscle pathology
    • Trichrome stain: Pleomorphic hyaline, granular & amorphous deposits
    • Congo red: Hyaline structures often Congophilic
    • Abnormal fiber regions wthout oxidative enzyme activity
    • Vacuoles: Small, Few fibers
    • Partial denervation & reinnervation: Some biopsies
    • Necrosis or Regeneration: Common
    • Chronic changes: Splitting; Internal nuclei
    • Immunocytochemistry: Aggregates may contain Myotilin, Desmin, αB-Crystallin, Dystrophin, NCAM
    • Ultrastructure: Z-disk streaming & disintegration; Disorganized sarcomeres & myofibrils
  • MRI
• Mouse variant: ZASP deletion (Cypher or Oracle)
  • Causes skeletal & cardiac myopathy with fragmented Z-disks

• Epidemiology: Swedish family
• Genetics
  • Previously localized to 10q22.3
  • ARVD7
  • Allelic with: Desmin myopathies
• Clinical
  • Onset: Adult; 20 to 60 years
  • Intrafamilial variability inn severity
  • Weakness
    • Mild: Axial
    • Moderate: Distal predominant
    • Severe: Generalized
    • May be asymmetric
  • Cardiac
    • Episodes of chest pain or palpitations
    • Cardiomyopathy
      • Arrhythmia: Nonsustained ventricular tachycardia; Atrial flutter
      • Ventricular dilation: Especially Right
• Serum CK: Mildly elevated in 50%
• EMG
  • Myopathic: Proximal & Distal
  • Spontaneous activity: Fibrillations; Positive sharp waves
• Muscle pathology
  • Myopathic
    • Fiber size: Varied
    • Internal nuclei
    • Endomysial connective tissue: Increased
  • Myofibrillar disorganization (NADH stain)
  • Rimmed vacuoles
  • Protein accumulation
    • Desmin storage
    • NCAM upregulation: All fibers in severe patients
  • Ultrastructure
    • Intermyofibrillar accumulation of granulofilamentous material
    • Myofibrillar disorganization
    • Z-band streaming
    • Occasional: Cytoplasmic bodies; Autophagic vacuoles

• Onset age
  • Variable; 3 to 92 years
  • Most with onset by 42 years
  • Occasional asymptomatic carriers
• Cardiomyopathy
  • Restrictive (Reduced myocardial compliance)
  • Dyspnea
  • Edema: Pleural effusion; Anasarca
  • Venous hypertension
  • Hepatomegaly
  • EKG: Atrial flutter/fibrillation; ST/T wave changes
  • Echocardiogram: Atrial enlargement, left & right
  • Cardiac biopsy: Interstitial fibrosis
• Skeletal muscle: No myopathy
• Cataracts: None
• Desmin accumulation: Cardiac muscle; Demonstrated by immunocytochemistry

• Onset: Adult; 5th decade
• Clinical
  • Weakness: Distal > Proximal; Respiratory insufficiency
  • Cardiomyopathy: Systolic dysfunction; A-V conduction block
  • Course: Life span limited by respiratory function
• Laboratory
  • Serum CK: Normal or high
  • Cervical spine: Vertebral fusion
• Muscle pathology
  • Fiber size: Varied; Small to Hypertrophic
  • Hyaline masses
    • Location: Type I muscle fibers
    • Congophilic
    • Contain: Desmin; αB-Crystallin; Ubiquitin; α₁-Antichymotrypsin
  • Nemaline rods: Usually in fibers with hyaline masses
  • Vacuoles
  • Lobulation: Some type I muscle fibers

• Clinical
  • Onset: Child - Adult
  • Weakness: Distal & Proximal
  • Fatigability
  • Dysphagia
  • Cardiac: Occasional
• Pathology: Cytoplasmic or Spheroid bodies associated with desmin

• Epidemiology: Northeastern Germany & Polish families
• Genetics
  • Inheritance: Recessive
  • Allelic disorders
    • CM with rigid spine
    • Minicore syndromes
• SEPN1 protein
  • Description
• Clinical
  • Onset
    • Age: Birth or Early infancy
    • Hypotonia
  • Weakness
    • Proximal
    • Axial
    • Face
  • Muscle size: Small
    • Thin inner thighs
    • Straight calves
    • Flat feet
  • Cardiac
    • Right ventricular hypertrophy
    • Cardiac failure in 1st 2 decades
    • Normal in some families
  • Scoliosis
    • Dorsal lordosis
    • Trunk deviation: Lateral
    • Hips: Balanced
    • Spine rigidity
    • Onset: 8 to 14 years
  • Joint contractures: Correlate with degree of weakness
  • Course
    • Weakness: Progressive
    • Death: May occur in 1st or 2nd decade due to respiratory failure or pneumonia
• Laboratory
  • Serum CK: Normal or Mildly high
  • Serum aldolase: Normal or Mildly high
• Muscle pathology
  • Desmin-containing inclusions
    • Present in 10% of muscle fibers
    • Mallory body-like
    • Immunoreactive for: Desmin; Dystrophin; Ubiquitin
    • Ultrastructure: Composed of helical filaments, 10 to 12 nm diameter
  • Fiber size variability
  • Internal nuclei
  • Vacuoles: Occasional rimmed
  • Connective tissue: Mildly increased
  • Type I muscle fiber predominance