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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   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     Satellits 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
  • 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 12 families
  • US, Japan & Europe
• Genetics
  • Mutations
    • Location: G/F domain (Exon 5)
    • Types
      • Missense
      • Splice site: Removes glycine/phenylalanine-rich region (G/F domain)
      • Inframe deletion: Asp98del
    • Hotspot: Phe93
    • Clinical correlations ⁹⁹
      • Severe disease: 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, 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
  • HSP40/DNAJ family: Other DNAJ disorders
    • DNAJB2: Motor neuropathy; CMT 2T
    • DNAJB5: Distal atrophy
    • DNAJC3: Diabetes Mellitus & Multisystem Neurodegeneration
    • DNAJC6 : PARK19
    • 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: Contain SMI-31, TDP-43, αB-crystallin, Myotilin, Desmin, DNAJB6
    • Small fibers express neonatal & fetal myosin

• Nosology: LGMD 1F
• Epidemiology 2 families
• Genetics
  • Mutation: c.2771delA; c.2757delC
  • Penetrance: 85%
  • IRF5-TNPO3 region: rs10488631 is risk locus for Systemic Lupus Erythematosus
• TNPO3 protein
  • Location: Nuclear
  • Transport into nucleus
    • Serine/arginine rich proteins
    • HIV
• 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: 30% to 40%; Most cause frameshift & premature 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[rarr]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
  

  LGD 2A: Erb phenotype From: C Angelini

  • 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 cellularity
          • 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: Highly specific (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%

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
      • 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
• Genetics
  • Mutations
    • Homozygous or Compound heterozygous for titin mutations
    • Mutation types
      • 11 bp insertion-deletion (Finnish; FINmaj): Final exon (363)
      • Missense: Leu293,356Pro (French)
      • 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
  • Usually occurs in families with other members having dominant distal weakness syndrome
  • Onset age
    • Usual: Childhood
    • Range: < 10 years to 3rd decade
  • Weakness
    • Proximal > Distal
    • More severe than in allelic distal myopathy
    • Face: Normal
    • Asymmetric: Some patients
  • Wasting: Anterior tibial
  • Progression
    • Usual: Wheelchair < 30 years, within 20 years of onset
    • Some patients ambulatory at 60 years
  • No cardiomyopathy
• 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 with
    • Gnathodiaphyseal dysplasia : Dominant
    • Distal myopathy (MMD3): Recessive
  • 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 51 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 pain: 86%; 50% with, or after, exercise
    • Fatigue: May occur before weakness
    • Calf hypertrophy or atrophy: Some patients
    • Rhabdomyolysis: Occasional patient
    • Course: Progressive; Walking retained
    • 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: 4 families
• Genetics
  • Mutations
    • Often loss of function
    • Missense: c.602C>T, p.Ser201Phe; Homozygous; Pseudo-dominant
    • Splice site: intron 8 (c.816 + 2T>C).
• 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
  • Nosology: Blood vessel epicardial substance (BVES)
• Clinical
  • Onset age: 2nd to 5th decade
  • Weakness: Proximal; Legs; Symmetric
  • Exercise intolerance
  • Myalgia
  • Cardiac: Syncope; A-V block
• Laboratory
  • Serum CK: 700 to 8000
  • EMG: Myopathic
  • Muscle biopsy
    • Fiber size: Varied
    • Internal nuclei
    • Necrosis & Regeneration: Scattered
    • Sarcolemma: Reduced POPDC1 & POPDC2

• Epidemiology: 1 Turkish family, 3 patients
• Genetics
  • Mutation: Frameshift; Homozygous c.186delG
• 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
  • Cardiomyopathy, dilated: 1 patient
• Laboratory
  • Serum CK: 80 to 500
  • Muscle
    • Muscle fibers: Varied size; Internal nuclei; Mild necrosis
    • Endomysial connective tissue: Increased
    • TOR1AIP1: Absent
    • Ultrastructure: Abnormal nuclear envelope

• Nosology: LGMD 2Z
• Epidemiology: Spanish family, 4 siblings
• Genetics
  • Mutation: Homozygous; Missense; D233E
  • 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: 3rd decade
  • Weakness
    • Proximal
    • Legs > Arms
    • Scapular winging
    • Respiratory: 4th decade
  • Course: Slow progression; Some rrequire 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
    • Gait: Abnormal in most
  • Tendon reflexes: Normal or Reduced
  • Skeletal Scoliosis short stature
  • Face: Mild dysmorphism
• 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

• 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 disorder: Scapuloperoneal muscular dystrophy with mental retardation & lethal cardiomyopathy
• LAMP-2 protein
  • Type 1 membrane protein: 3 domains; Luminal, Transmembrane, Cytoplasmic
  • Lysosomal: Coats inner side of membrane
  • Highly glycosylated
  • 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
• Clinical ²⁹
  • Onset
    • Age: Infantile to 2nd decade; Childhood most common; Mean onset 13 years
    • Cardiac
  • Weakness
    • Often mild: All patients remain ambulatory
    • Distribution: Symmetric; Shoulder girdle & Neck; Proximal ± Distal
    • Frequency: Most patients; 85%
    • Fatigability without fixed weakness: 10%
    • Wasting: 15%
    • Monophasic severe post-operative weakness: 1 patient ⁸⁴
  • Cardiomyopathy (Nearly 100%) ⁷²
    • Symptoms: Chest pain, Palpitations, Syncope, Cardiac arrest.
    • 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
      • Ventricular preexcitation
      • Wolff-Parkinson-White; Short PR intervals; High precordial voltage
    • Echocardiography: Concentric left ventricular hypertrophy
    • Prognosis: Poor
      • Progression to end stage heart failure in early adulthood
      • Sudden death
  • Mental retardation: 80%; Mild or absent in 40%
  • Hepatomegaly: 35%
  • Foot deformities: 38% of males
  • Retinopathy
    • Loss of pigment in retinal pigment epithelium
    • Reduced visual acuity: Mild
  • Course
    • Some with death in 2nd to 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
    • 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: Variation in muscle fiber size
  • Glycogen: Increased or Normal amount; Free & membrane bound
  • Lamp-2 protein staining: Absent with most mutations; Rarely residual LAMP-2A isoform
  • Heart: Fibrosis; Intracytoplasmic vacuoles
• Danon syndrome: Variant with 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
• Variant: Carrier females
  • Frequency
    • > 70% of carriers
    • All eventually have abnormal EKG
  • Clinical
    • Onset
      • Age: 12 to 53 years
      • Cardiac signs
    • Weakness: 33%; Proximal limb & Neck
    • Cardiomyopathy
      • Dilated > Hypertrophic
      • Arrhythmia: Pacemaker in 17%
    • Retinopathy
      • Pigmentary changes: Peripheral
      • Electroretinogram: Abnormal
      • Visual fields: May be abnormal central region
    • 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
• 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
    • Homozygous in-frame deletion
    • Mutation: 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 syndromes: 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

• Genetic: Autosomal dominant
  • Mutations: Myopathy
    • Missense: Arg120Gly
    • Truncating: C-terminal; 464delCT & Gln151X
  • Other mutations in same gene
    • 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
  • Location
    • Tissues: Muscle; Lens; Myocardium; Kidney epithelium
    • Subcellular: Cytosol
  • Functions
    • Chaperone: Desmin& Actin
    • Lens: Forms aggregates with αA-crystallin; Maintains lens transparency
    • Cytoprotective: Target of p53
  • 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
  • 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
• SEPN1 protein
  • Description
  • Other SEPN1 disorders
    • CM with rigid spine
    • Minicore syndromes
• Onset
  • Age: Birth or Early infancy
  • Hypotonia
• Clinical
  • 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

• Epidemiology: German & Chinese families
• Genetics: Truncation mutation
  • Mutations
    • German: W2710X
    • Chinese: 2695–2712 del/GTTTGT ins (Exon 18; In-frame)
    • 12-nucleotide deletion in exon 18
    • Filamin C rod & dimerization domains
  • Truncated protein: Abnormal folding; Unable to dimerize properly
  • Allelic disorders
    • Distal myopathies
      • Distal myopathy with Spared anterior leg muscles (Williams myopathy)
      • Distal myopathy with Upper limb predominance
    • Cardiomyopathy, familial hypertrophic, 26 (CMH26)
    • Myofibrillar myopathy 5 (MFM5)
• Filamin C protein
• Clinical
• Onset
  • Age: 35 to 57 years
  • Weakness: Usually proximal legs
  • Back pain
• Weakness
  • Legs > Arms
  • Usually: Proximal > Distal
  • Respiratory: 50%
  • Other: Hands; Calf weakness, Selective; Neck flexor
• Polyneuropathy: 40%
• Cardiac
  • Some patients
  • Often mild
  • Bundle branch block; Reduced ejection fraction
• GI: Chronic diarrhea in some patients
• Laboratory
  • Serum CK: Mildly elevated, 2x to 8x
  • EMG: Myopathic; Myotonic discharges
  • Muscle pathology: Myofibrillar myopathy
    • Internal nuclei
    • Fiber splitting
    • Necrosis: Isolated fibers
    • Gomori trichrome stain: Hyaline masses; Vacuoles; Rods
    • Aggregates
      • Contain: Filamin C, Desmin, Myotilin, Dystrophin, Sarcoglycans; Dysferlin; Not α-actinin
      • Cytoplasmic
      • Spheroid bodies

• Epidemiology: 2 families
• Genetics
  • Mutation: Pro209Leu in both families
  • Allelic disorders
    • CMD 1HH, Cardiomyopathy, Familial dilated
    • Polyneuropathy, Demyelinating
    • CMT2
• Protein: Family of Hsp70/Hsc70 molecular chaperone regulators
  • Anti-apoptotic activity
    • Binds to Bcl-2 and PLC-γ
  • Chaperones
    • Binds to the ATPase domain of HSP70 & HSC70 chaperones
    • Inhibits chaperone activity of HSP70 & HSC70: Promotes substrate release
  • Muscle: Z-disk (Colocalizes with myotilin)
• Clinical
  • Onset: Childhood
  • Weakness
    • Proximal > Distal
    • Limb & Axial
    • Respiratory
  • Cardiomyopathy
    • Onset: Teens
    • Restrictive or Hypertrophic
  • Skeletal
    • Rigid spine
    • Scoliosis
    • Contractures
  • Polyneuropathy (1 patient)
    • Axonal & Demyelinating
    • Some Giant axons
• Laboratory
  • Serum CK: High, 3- to 15-fold
  • EMG: Myopathic
  • Muscle
    • Histology
      • Fiber size: Varied
      • Splitting
      • Necrosis & Regeneration
      • Abnormal staining: Bag3, αB-crystallin, Desmin, Gelsolin, NCAM, Myotilin, Ubiquitin, Dystrophin
      • Other immunoreactivity in muscle fibers: Hsp27, HspB8, Bcl-2
      • Congophilia
    • EM
      • Z-disk disintegration
      • Accumulation of granualar debris & larger inclusions
      • Apoptosis
    • BAG3: Abnormal aggregation
• BAG3 Variant: Dilated cardiomyopathy
  • Mutations: Frameshift, Deletion, Nonsense & Missense
  • Adult onset
• BAG3 Variant: CMT2 ¹⁰⁸
  • Epidemiology: 2 families, 5 patients
  • Genetics
    • Inheritance: Dominant
    • Mutation: c.625C>T; p.Pro209Ser
  • Clinical
    • Onset ages: Adult; 3rdc to 5th decade
    • Weakness: Distal; Legs > Arms
    • Sensory loss: Pan-modal; Legs; Distal
    • Dyspnes: 5th decade
  • Laboratory
    • Electrodiagnostic
      • NCV: Velocity nomal
      • Axon loss: Low amplitude CMAPs & SNAPs
    • Serum CK: Normal or Mildly high

• Desmin knockout mouse
  • Exercise intolerance
  • Cardiomyopathy: Dilated; Cardiomyocyte hypertrophy
  • Skeletal myopathy
    • Location: Weight-bearing muscles & Diaphragm
    • Anatomy: Loss of anchorage of myofibrils to plasma membrane at costameres
  • Vasculopathy: Lower passive & active tension in vessel walls
  • Life span: Shortened
  • Regeneration: Adipocytes tend to accumulate
• Desmin-containing inclusions
  • Scapuloperoneal muscular dystrophy
  • Inclusion body myositis
  • Enlinafide (Topoisomerase II inhibitor; Cancer chemotherapy) myopathy ¹²
  • Emetine: Painful myopathy ± Rhabdomyolysis

Intermediate filaments & Disorders ²⁰

• Intermediate filaments: General features
  • Family
    • ~ 65 functional genes
    • Most are unique to multicellular organisms
    • ? Ancestor protein in unicellular organism: Crescentin (In bacteria)
  • Structure
    • Fibrous proteins
    • Central rod domain
      • Coiled coil α-helical
      • Similar structure in most IFs: Different 1° sequences
      • Heptad repeats: Contain Acidic residues
    • amino- & carboxy- termini: Various lengths and sequence
    • 10-nm diameter
    • Soluble unit: Tetramer with two antiparallel dimers
  • Post-translational modifications
    • Farnesylation
    • Phosphorylation: Regulates
      • Filament organization & solubility
      • Association with interacting proteins
      • Susceptibility to degradation during apoptosis
    • Glycosylation
    • Transglutamination:
      • Formation of protective, cornified cell envelope contributing to skin barrier
  • Interactions with other proteins
    • Actin microfilaments (7 nm)
    • Microtubules (24 nm)
  • Locations
    • Most are cytoplasmic
    • Lamins in nucleus
    • Some are integral membrane proteins
  • Functions: Mediate cell-type-specific features of cytoarchitecture
    • Interconnected: With same, or other accessory proteins
    • Form cytoskeletal scaffolding in eukaryotic cells
    • Dynamic: Some are motor proteins
    • No known enzymatic activity
  • Mutation effects
    • Often disrupt aggregation of intermediate filament proteins
  • Neurofilaments ¹⁰⁷
    • General
      • Major intermediate filament in neurons
      • Up to 85% of protein content
    • Composition: Usually 4 subunits
      • NF subunits have tripartite structure
        • Central α-helical rod region
          • Conserved
          • Shared with other IF family proteins
          • Contain long stretches of hydrophobic heptad repeats
        • Head domain at amino-terminal
          • Variable
          • Rich in serine & threonine residues
          • Contains consensus sites for O-linked glycosylation or phosphorylation
        • Tail domain at carboxy-terminal
          • Repeats of Lys–Ser–Pro ("KSP") motif: 6 to 15 in NF-M; 40 to 51 in NF-H
          • Longer in NF-H & NF-M than in other intermediate filaments
      • Proteins
        • NF light chain (61.5 kDa; 68 on SDS-PAGE): Forms backbone & initiates assembly of NF
        • NF medium chain (102.5 kDa; 160 on SDS-PAGE)
        • NF heavy chain (112.5 kDa; 200 on SDS-PAGE)
        • α-internexin: CNS neurons
        • Peripherin: PNS neurons
      • Subunits form heteropolymers to assemble into 10 nm filaments
    • Structure: Carboxy terminals of NFH & NFM form side arm projections
      • Allow interactions among neurofilaments
      • Underlie the "cross links" between adjacent filaments
      • KSP (Lys-Ser-Pro) repeat motif: Size is ALS risk factor
    • Location
      • Exlusively in neurons
        • Perikarya: Sparse & Tortuous
        • Dendrites: Sparse & Tortuous
        • Axons
          • Numerous
          • Straight & Unbranched
          • Long (mean 118 mm)
          • Peripheral axons: 2x more in proximal than distal axons
          • Optic nerve axons: 3x more in distal than proximal axons
        • Large myelinated axons
          • Organization: Parallel arrays
          • Distance from each other: Determined by side arms projecting perpendicularly from filament core
          • Increase in number proportionate to radial growth of axon
          • More concentrated at: Nodes of Ranvier; Demyelinated regions of axons
    • Metabolism
      • Half-life: 55 days
      • Degradation: Multiple systems
      • NF assembly: Confers proteolytic resistance
    • Axon transport
      • Most NF network is stationary in axons
      • Small proportion of NF moves down axon by slow transport
      • Subunits required for NF transport: NF-M or α-internexin
      • Nonfilamentous heterooligomers assemble into filaments as they are transported
      • Motors
        • Anterograde transport: Kinesin-I
        • Retrograde transport: Dynein–Dynactin complex
      • Reduced NF transport
        • Toxin: IDPN
        • NF-H: Increased phosphorylation
    • IF association molecules
      • Plectin; BPAG1
      • Mediate the cross-linking of NF & microtubules
      • Produce the cytoskeletal lattice
      • Cross bridges associated with
        • Actin filaments
        • Microtubules
        • Cross bridge proteins: Spectrin; Bullous pemphigoid antigen; Plectin; tau; MAP1; MAP2
    • Post-translational modifications
      • Phosphorylation
        • Location
          • 40 to 70 Lys-Ser-Pro (KSP) repeats
          • C-terminus domains
        • Mediated by
          • Protein kinase A (PKA)
          • Protein kinase C (PKC)
          • Calcium/calmodulin-dependent protein kinase type II (CAMKII)
        • Probable roles
          • NF assembly & disassembly
          • NF transport from perikaryon to the axon through slow transport mechanisms
          • NF incorporation into a cytoskeletal network
      • O-linked N-acetylglucosamine (O-GlcNAc)
    • NF functions
      • Determine axonal caliber & conduction velocity
        • Neurofilament numbers
        • Tail domains of NF-H & NF-M
      • Structural support & docking sites for reversible interactions with vesicular organelles & molecular motors
      • Synaptic plasticity
    • Neurofilament Disorders: NF-L; NF-M; NF-H
      • Genetic
        • ALS, Sporadic & Familial
          • NF-H tail deletions
          • Peripherin
        • CMT: NF-H
        • CMT: NF-L
          • 1F
          • 2E
          • AR (2B5)
          • Mutations may be in head, coil or tail domains
        • Mutations in associated proteins
          • AR-CMT: TRIM2 - NFL are target of ubiquitination
          • CMT 2F/dHMN: HSPB1
          • CMT 2B: RAB7A
          • Giant axonal neuropathy: Gigaxonin - Impaired NF degradation
          • ALS: SOD1
          • Dementia/Parkinsonism: PRKAR1B
        • Linkage to CNS disorders
          • Parkinson disease: NF-M rod domain point mutations
          • Alzheimer disease: NF-M & NF-H mutations; Hyperphosphorylation of KSP domains
      • Immune Polyneuropathy: Anti-Neurofilament Antibodies
      • Toxic polyneuropathies
        • β,β-Iminodipropionitrile: Rat models
        • 2,5-Hexaneidone (Glue-sniffing)
        • DMAPN
      • CSF NF levels: May be high in ALS, Parkinson disease
      • Pathology: Accumulations in axons
• Intermediate filament proteins & mutations
  • α-Internexin : Neurons
  • Keratin family: Epithelial cells; > 20 proteins
    • Protect from mechanical & nonmechanical forms of stress
    • Numerous Keratinopathies
      • Epidermolysis bullosa & hyperkeratosis syndromes
      • Corneal dystrophy: Keratins 3 & 12
      • Alopecia (Monilethrix): Hair keratins 1 & 6
      • Pachyonychia congenita: Keratins Keratins 6a, 16, 6b, 17
  • Desmin (2q35): Dominant myopathy
    • Myopathy + Right ventricular cardiomyopathy
  • Desmuslin : Muscle; Co-localizes with desmin
  • Filensin : Lens; Cataracts
  • FHL1: Scapuloperoneal muscular dystrophy
  • Glial fibrillary acidic protein (GFAP) : Alexander disease
  • α-Internexin : CNS
  • Lamins: Nuclear
    • Lamin A/C: Emery-Dreifuss muscular dystrophy; Differentiated cells
    • Lamin B : All cell types
  • Nestin : Neuroepithelial stem cells; Muscle cells (Z-band); Fibroblasts
  • Neurofilaments: NF-L; NF-M; NF-H
  • Paranemin : Muscle cells; Co-polymer with desmin
  • Peripherins: Neuronal cells
    • Peripheral nerve : Sporadic ALS
    • Photoreceptor : Retinitis pigmentosa; Macular dystrophy
  • Phakinin : Lens; Co-polymer with Filensin
    • Juvenile & Congenital cataract
  • Syncoilin: Muscle, Cardiac & Skeletal
  • Synemin : Muscle cells; Co-polymer with desmin
  • Titin: Proximal & Respiratory muscle weakness
  • Vimentin : Mesenchyme; Null mutation has no phenotype
• Intermediate filament-associated proteins & mutations
  • αB-crystallin (11q22): Dominant myopathy
  • Bullous pemphigoid antigen 1
  • Desmoplakin : Keratosis palmoplantaris striata II; Cardiomyopathies
  • Emerin: Emery-Dreifuss muscular dystrophy
  • Gigaxonin: Giant axonal neuropathy
  • Plectin: Congenital Muscular Dystrophy with Familial Junctional Epidermolysis Bullosa
• Neurofilament accumulations in acquired neuropathies
  • Giant axonal neuropathy
  • Hexacarbon intoxication
  • Disulfiram
  • Acrylamide
  • β,β-iminodipropionitrile (Proximal initial axon segments; Animal model only)
  • Dimethylaminopropionitrile (Distal intramuscular nerves)
  • Carbon disulfide
  • Diabetes (Distal intramuscular nerves)
  • Non-specific: Chronic neuropathy
  • Motor neuron disease (ALS): Cell body & Initial segment
• Other
  • α-Actin: Nemaline (Rod) Myopathy
  • Dystrophin: Duchenne muscular dystrophy