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Muscle NMJ Nerve Spinal Ataxia Antibody & Biopsy Patient Information

CONGENITAL MYOPATHIES & WEAKNESS

CONGENITAL WEAKNESS Absent muscles Actin aggregate: ACTA1; 1q42 Apoptosis Arthrogryposis Autophagy, high: VMA21; Xq28  Broad A band Cap CARDAR: TRDN; 6q22 Carey-Fineman-Ziter: TMEM8C; 9q34 Central core: RYR1; 19q13 Centronuclear (Myotubular) CMH4: MYBPC3; 11p11 CMND: SPTBN4; 19q13 Collagens   Bethlem   COL12A1: 6q13   MED: COL9A2 & COL9A3   P4HA1   Ullrich Core Cylindrical spirals Cytoplasmic Body (Spheroid) Danon: LAMP2; Xq24 Diarrhea & Deafness DOPA-responsive dystonia Ehlers-Danlos: FKBP14; 7p14 EMARDD: MEGF10; 5q23 Fiber Type   Size Δ (CFTD)   Type I predominance     ZAK: 2q31   Type 2 atrophy: MYL1; 2q34 Fingerprint body Focal FSH dystrophy: 4q35 Hyaline body: MYH7; 14q11   IBM3: MYH2; 17p13 Lethal congenital: CNTN1; 12q11 Mallory body: SEPN1; 1p36 Mental retardation: CUL4B; Xq24 Metabolic disorders MFM11: UNC45B; 17q12 Mitochondrial Multicore (Minicore) Muscular Dystrophy (CMD)   α-Dystroglycan   CDG Myasthenic Syndromes Myofibrillar Myopathy: CACNA1S; 1q32 Myosin storage: MYH7; 14q11 Myotonic dystrophy 1: DMPK; 19q13 Native American: Stac3; 12q13 Nemaline rod Neuropathic syndromes NMOAS: DHX16; 6p21 Ophthalmoplegias Perifascicular myopathy, neonatal Reducing body: FHL1; Xq26 Sarcotubular (LGD 2H): TRIM32; 9q31 Shwachman–Diamond: SBDS; 7q11 Skeletal disorders + Weakness Spheroid body: MYOT; 5q31 Spindle excess: HRAS; 11p15 Tel Hashomer camptodactyly Thin filaments, Excess: α-Actin; 1q42 Trilaminar myopathy Type 1 fiber smallness Williams-Beuren syndrome Woods-Black-Norbury syndrome Zebra body: α-Actin; 1q42

CONGENITAL MUSCULAR DYSTROPHY Adducted thumbs & Ophthalmoplegia Axon loss, Large myelinated & CNS Δ α-Dystroglycan disorders (MDDG) Cataracts & ID: INPP5K; 17p13 Cerebellar atrophy CMD + Cardiomyopathy: Titin; 2q24 CMS10: DOK7; 4p16 Desmin inclusions: SEPN1; 1p36 Dysferlin: 2p13 EBSMD: Plec1; 8q24 Fukuyama: Fukutin; 9q31 Glycosylation disorders   Muscle (MDDGA) Integrin α-7: 12q13 Integrin α-9: 3p23 Laminin-α2 (Merosin)   Deficient (MDC1A): 6q22   Normal: "Pure" form Marinesco-Sjögren: SIL1; 5q31 MDCDC: TRIP4; 15q22 MDDGA3: POMGnT1; 1p34 Mitochondrial structure: CHKB; 22q13 Multisystem: PIGY; 4q22 Muscle-Eye-Brain (MEB) Muscle hypertrophy   MDDGA6 (MDC1D): LARGE1; 22q12   MDDGB5 (MDC1C): FKRP; 19q13   Mental retardation   Respiratory failure (MDC1B): 1q42 Nuclear membrane   LMNA; 1q22   SYNE1; 6q25 Rigid spine with CMD   SEPN1: 1p36   Lamin A/C: 1q21   SECISBP2: 9q22 Telethonin: 17q12 Ullrich   1: COL6A     6A1; 21q22     6A2; 21q22     6A3; 2q37   2: COL12A1; 6q13 Walker-Warburg (MDDGA) Batten

ABSENT or WEAK MUSCLES Abdominal Brachial plexus Cardiofacial syndrome Depressor anguli oris Diaphragm Eye (Extraocular muscles)   Blepharophimosis   Congenital fibrosis   Duane's syndrome   Horizontal gaze     HGPPS: 1; 2   Möbius syndrome   Ptosis   Superior rectus Finger extensors Holt-Oram Palmaris longis Pectoral Peroneus tertius Poland syndrome Prune belly Psoas (CHILD) Thenar eminence Trapezius

Congenital Weakness: General Hypotonia: Clinical assessment Traction response Maneuver Grasp child's hands Pull to sitting position Newborn: Head Lags behind Drops forward suddenly when upright posture is reached Normal at 1 month Minimal head lag Flexion at the elbows, knees, and ankles Premature infants < 33 weeks' gestation: Absent Suspension: Vertical & Horizontal Assessment of mother History Delayed walking or other motor functions; Skeletal or joint deformity Strength Myotonia CNS disease is the most common cause of congenital hypotonia Common features of presentation of Neuromuscular disorders in infants Hypotonia 152 Posture with normal tone Flexion at knees, hips, & elbows Hips internally rotated Posture with reduced tone Head lag Legs & arms extended Weakness: Similar degrees in facial, appendicular, & axial muscles Muscle mass: Reduced Normal sensation Skeletal disorders Rigid spine syndromes Contractures Best defined neuromuscular causes of congenital weakness include Congenital Myopathies Centronuclear (myotubular) myopathy Nemaline rod myopathy Similar genes: Zebra body; Cap myopathy Central core disease Congenital fiber type disproportion Hyaline body (MYH7) Congenital muscular dystrophies Congenital presentations of adult dystrophies Myotonic dystrophy FSH dystrophy Myasthenic syndromes Neuropathic syndromes Diagnosis of syndromes with congenital weakness Often based on morphological findings on muscle biopsy Clinically distinctive congenital weakness syndromes Centronuclear myopathy (X-linked) EOM limitation Respiratory failure Mental changes EMG: Fibrillations; PSW RNS: Decrement in some Nemaline myopathy (Severe infantile) Facial & Axial weakness High-arched narrow palate Central core Dominant inheritance: Often History of malignant hyperthermia in family Proximal weakness Congenital muscular dystrophy Severe weakness Creatine kinase: High Myopathy with early fibrosis Spinal muscular atrophy Proximal > Distal weakness Tongue fasciculations Respiratory dysfunction DTR reduced Face spared Congenital hypomyelinating neuropathy Distal > Proximal weakness Sensory loss DTR reduced Cervical myelopathy Quadriplegia, sparing face Sphincter function abnormal Disease Mechanisms Membrane remodelling defects & Phosphoinositide phosphatases BIN1: Centronuclear myopathy 2 DNM2: Centronuclear myopathy 1 MTM1: Centronuclear myopathy X MTMR14: CNM1 modifier SPEG: Centronuclear myopathy + Dilated cardiomyopathy PIP Phosphatases Excitation-contraction coupling, Transverse-tubule & Sarcoplasmic reticulum Δ RYR1: Central Core CCDC78: Centronuclear myopathy 4 STAC3: Native American myopathy Muscle force generation molecules ACTA1: Nemaline rod 3 CFL2: Nemaline rod 7 LMOD3: Nemaline rod 10 MYH7: Multicore/Minicore, Hyaline body NEB: Nemaline rod 2 TNNT1: Nemaline rod 5 TPM2: Nemaline rod 4 TPM3: Nemaline rod 1 Atrophy: Skeletal muscle protein synthesis & degradation KBTBD13: Nemaline rod 6 KLHL40: Nemaline rod 8 MEGF10: Early-onset Myopathy + Areflexia, Respiratory Δ & Dysphagia SEPN1: Rigid spine; Desmin inclusions Additional NMJ involvement DNM2: Centronuclear myopathy 1 MTM1: Centronuclear myopathy X RYR1: Central Core TPM3: Nemaline rod 1 Connective tissues Congenital muscular dystrophies Glycosylation Collagen

from A Kornberg MD Congenital Myopathies Clinical Disorder Eye MTM1, DNM2, RYR1 Respiratory weakness   > Limbs ACTA1, NEB, SEPN1, TPM3   Birth MTM1, DNM2, NM, RYR1 Face   Weak MTM1, DNM2, NM, RYR1   Dysmorphic Hypotonia   Congenital MTM1, NM, RYR1, DM1, UNC45B   Axial RYR1, SEPN1 Features   Bulbar weak MTM1, NM, RYR1   MH RYR1   Tremors TNNT1   Slow movement KBTBD13   Cardiac ACTA1, MYH7, TTN,   MYPN, BIN1   CNS CMD (MDDGA), MTM1   Spine & Skeletal     Foot drop/     Pes cavus DNM2, MYH7, NEB,   TPM2, TPM3     Rigid RYR1, SEPN1, LMNA     Scoliosis NM, RYR1, SEPN1     Arthrogryposis KLHL40, BIN1 Other   Dominant   inheritance RYR1, DNM2, DM1   Adult onset RYR1, MYH7, ACTA1

Central Core Disorders ± Malignant Hyperthermia ¹⁷⁰

RYR1 Genetics RyR protein Clinical Laboratory Pathology Variants   RyR clinical syndromes     Dominant       Central core diseases         Congenital myopathy         Cores, Rods & Malignant Hyperthermia         Limb-Girdle Syndrome: Onset in teens         Minicores, Transient         Fetal akinesia       Malignant Hyperthermia: Onset in teens       King-Denborough Syndrome       Type 1 fiber predominance         Congenital (CNMDU1)         Hypotonia, Benign       Axial myopathy, Adult onset       Serum CK high: Asymptomatic     Recessive       Dusty Core       Central core diseases         Minicores, Transient         Fetal akinesia         Mild phenotype & Recessive inheritance         Samaritan myopathy       Nemaline rods + External ophthalmoplegia       Congenital myopathy         Centronuclear myopathy         Fatigable weakness         Focal lost striations         Hypotonia & Cardiac       Periodic Paralysis

Multicore/Minicore   RYR1   SEPN1   ACTN2   CCDC78   FXR1   MYH2   MEGF10 Core-Rod   NEB   ACTA1   KBTBD13 (NEM6)   CFL2 (NEM7)   TRIP4   TNNT1 Cores: Other   MYH7   Myopathy +     Myofibril Δ: PYROXD1     Eccentric core: UNC45B

NADH Stain

• History
  • Described by: Shy & Magee
• Epidemiology
  • Pediatric point prevalence: 1:90,000
• Genetic features ¹¹
  • 106 exons
  • > 300 mutations identified
  • Central core families: Most linked to Ryanodine receptor mutations
  • Mutation types
    • Most: Missense
    • Few: Small deletions
    • Rare: Splice or Insertion
  • Dominant mutations
    • Most: Missense
    • Location: Hotspots on gene
    • de novo: May cause core-rod myopathy
    • Dominant variant disease mechanisms: Sarcoplasmic reticulum Ca⁺⁺ release dysfunction
      • RyR1 channel hyper/hyposensitivity
      • Ca⁺⁺ leak: Chronic
  • Recessive mutations
    • Present along entire gene
    • More common with severe phenotype
    • Large deletions reported: Compound heterozygous
      • 54 of 106 RYR1 exons: Congenital lethal myopathy with atypical histopathologic features
      • Exon 91 to 98: Recessive late-onset core myopathy
      • Exons 70-71: Arthrogryposis multiplex congenita, Severe
    • Recessive variant disease mechanisms
      • Hypomorphic RyR1 protein expression
      • RyR1-Dihydropyridine (DHPR) misalignment
    • Tissue-specific epigenetic silencing of maternal RYR1 allele: Recessive core myopathies
  • Mutation hot spots
    • Cytosolic region of protein
      • Cytoplasmic N terminus: Malignant hyperthermia phenotype mutations in this region
      • Central cytoplasmic region: Gene segment 6400-6700
      • Mutations often occur at CpG dinucleotide sequences on coding or anti-sense DNA strand
    • 3' Transmembrane domain (Exons 93-105): 30% of cases
      • Malignant hyperthermia by IVCT
      • But no clinical complications with exposure to MH triggering agents
  • Mutations: Other
    • 2 different mutations in codons 614 (Same as pig 615), 2163, 2454 & 2458
    • 1 Mutation in C-terminus: Severe phenotype
    • Dutch allele with 3 different mutations: Ile1571Val, Arg3366His, Tyr3933Cys ¹⁵⁹
      • Heterozygous: MH susceptbility
      • Compound heterozygous with Val4849Ile: MH + Myopathy with cores & rods
  • Clinical-Genetic correlations
    • Central core disease (CCD), Dominant mutations
      • C terminal region of RYR1: Typical CCD; Early onset, Cores well-formed
      • Outside C terminal region: Clinically Milder; Atypical cores
    • Central core disease (CCD), Recesive mutations
      • Mutations: All through coding sequence
      • Severe phenotype
      • Muscle fibers: Internal nuclei
    • MH alone mutations: Most in N-terminus region
      • Arg614Cys: Common (4% to 9%)
        • Also produces porcine MH
        • Higher thresholds & Smaller contractures compared to other mutations
      • Gly2433Arg: Common (4% to 7%)
      • Gly341Arg: 5% to 6% of British & Irish families
      • Arg2454Cys: Low trigger thresholds
      • Other: Gly248Arg; Arg552Trp; Arg614Leu; Val2168Met; Thr2206Met
    • Central core disease & MH mutations
      • Arg163Cys; Ile403Met; Tyr522Ser; Arg2434His; Arg2454His
      • Severe & penetrant phenotype: Ile4898Thr
        • Mexican pedigree
        • C-terminal transmembrane/luminal region
        • Channel properties
          • Leaky
          • Activated by Ca⁺⁺ concentrations 4-fold lower than normal
  • Allelic disorders
• Ryanodine receptor protein ⁸¹
  • Size
    • 560 kDa
    • Largest ion channel protein
  • Location: Sarcoplasmic reticulum, terminal cisternae
  • Structure
    • Homo-Tetrameric
    • Transmembrane domains: 6 to 8
    • C-terminal 20% of molecule forms transmembrane Ca⁺⁺ channel
    • N-terminal: Contains most ligand binding sites; Cytoplasmic domain
    • Isoforms
      • RYR1: Skeletal muscle; Purkinje cells; Gastric; B-lymphocytes
      • RYR2 : Cardiac & Smooth muscle
      • RYR3 : CNS & Muscle
  • Ryr1 activation by: Ca_v1.1 voltage sensor proteins
    • Location: Transverse tubule membrane
    • During Excitation-Contraction
  • RyR1 Functions
    • Structural: In skeletal muscle
      • Foot: Bridges gap between sarcoplasmic reticulum & T-tubule
    • Calcium release channel
      

      Excitation-Contraction Coupling: Muscle

      • Major Ca⁺⁺ channel expressed in skeletal muscle
      • Calcium release, Calcium-induced
        • With Ca⁺⁺ channels in plasma membrane
      • Excitation-Contraction coupling
      • Rise in Ca⁺⁺ required for muscle fiber contraction
        • Skeletal muscle Ca⁺⁺ release channel
        • Provided by activation of sarcoplasmic reticulum Ca⁺⁺ release channels in RyRs
        • Ca⁺⁺ release: From sarcoplasmic reticulum stores (lumen) into cytoplasm
    • Functionally coupled to changes in sarcolemmal membrane potential
      • Through L-type VGCC (DHPR)
      • RyR1 opening
        • Induced by: Conformational changes in DHPR (Physical interaction)
        • Stimulus: Membrane depolarization
      • RyR2 activation in heart
        • Activation of L-type Ca⁺⁺ channels
        • Induces Ca⁺⁺-induced Ca⁺⁺ release (CICR)
    • Regulatory molecules
      • Activation during excitation-contraction: Ca_v1.1 voltage sensor proteins
      • Ca⁺⁺
      • Mg⁺⁺: Inhibitory
      • Adenine nucleotides & Cyclic ADPribose: Channel activation
      • Oxidation
      • Nitrosylation
      • Caffeine & 4-chloro-m-cresol (CmC)
        • Activate RyR channels
        • Facilitate channel opening: ↑ Sensitivity of RyR to Ca⁺⁺-dependent activation
      • RyR blockers; Ruthenium red; Local anesthetics (Procaine; Tetracaine)
      • Dantrolene: Inhibits SR Ca⁺⁺-leak via mutant RyR1; Used to prevent MH crises
  • Associated proteins
    • Dihydropteridine receptor (DHPR)
    • FK506 binding protein 1A (FKBP1A)
    • Calmodulin (CaM): Participates in Ca⁺⁺-dependent regulation of channel activity
      • Ca⁺⁺-free CaM: Activates RyR
      • Ca⁺⁺-bound CaM: Inhibits RyR channel function
    • Triadin
    • Calsequestrin
    • Phosphatases: PP1 , PP2A
    • Phosphodiesterase PDE4D
    • Muscle A-kinase anchoring protein (mAKAP; AKAP6)
    • Stac3
    • Kinases: PKA; CamK
  • Mutation effects on protein function: More MHS + CCD with
    • Greater Sensitivity of mutant RYR protein to agonists caffeine & halothane
    • Higher resting Ca⁺⁺ in sarcoplasm
    • Lower endoplasmic reticulum Ca⁺⁺ stores
    • Reduced Size of releasable Ca⁺⁺ stores
    • Y522S: Leaky RyR1
    • C-terminus (14895T & other): Uncouple EC coupling
• Central core congenital myopathy: Clinical features
  • Genetics
    • Mutation hotspot: C-terminal exons 101–102
    • Inheritance: Dominant
  • Clinical
    • Onset age: Childhood or Congenital
    • Developmental
      • Fetal movements: Reduced
      • Breech presentation
    • Motor
      • Hypotonia
      • Weakness
        • Proximal: Hips
        • Legs > Arms
        • Axial
        • Face: Mild weakness
        • Extraocular movements: Normal
    • Discomfort
      • Cramps
      • Myalgias
    • Skeletal
      • Congenital hip dislocation
      • Scoliosis
      • Foot deformities
    • Malignant hyperthermia
    • Cardiac: Normal
    • Course: Non- or Slowly Progressive
  • Muscle pathology
• Variants: Central core syndromes & Other RyR disorders
  • RYR1 variant: Malignant Hyperthermia, Onset in teens
  • RYR1 variant: King-Denborough Syndrome
  • RYR1 variant: Limb-Girdle Syndrome
    • Inheritance: Dominant
    • Clinical
      • Onset age: Teens
      • Weakness: Proximal; Symmetric
      • Malignant Hyperthermia
      • Course: Slowly progressive
  • RYR1 variant: High serum CK: Asymptomatic
  • RYR1 variant: Central core disease, Rods & Malignant Hyperthermia with RYR1 mutation
    • Mutations
      • Y4796C: C-terminal channel forming domain
      • Thr4637Ala: Transmembrane region
    • Epidemiology: 2 families
    • Clinical
      • Onset: Infantile
      • Weakness: Non-progressive; Hypotonia; Walk at 2.5 years
      • Contractures: Ankles
      • Course: Still walking in 3rd & 4th decades
    • Laboratory
      • Serum CK: Normal
      • Muscle biopsy: Central cores; Rods in areas without cores
      • In vitro contracture test: Positive
    • Other Rod-Core syndrome: Nebulin mutations
  • RYR1 variant: Nemaline (Rod) Myopathy With Ophthalomoplegia, Severe Congenital ¹⁰⁰
    • Genetics
      • Inheritance: Recessive
      • Mutations: Pro1573Leu & Asp2529Asn
    • Clinical
      • Fetal akinesia
      • Hypotonia & Weakness
        • Neonatal
        • Severe
        • Generalized
        • Face
        • Respiratory insufficiency
        • Swallowing disturbance
      • Ophthalomoplegia
      • Face: Narrow
    • Laboratory
      • Muscle histology
        • Nemaline bodies: Cytoplasmic
        • Type 1 fibers: Small; Predominant (70%)
        • No central cores or minicores
      • EMG: Myopathic; Small, short action potentials
  • RYR1 variant: Dusty Core Syndromes ¹⁴⁸
    • Epidemiology: Common RYR1 Recessive syndrome
    • Genetics
      • Inheritance: Recessive
      • Mutations
        • Nonsense & Missense
        • Especially in Bridge solenoid & Pore domains
    • Clinical
      • General: More severe & earlier onset vs other RYR1 recessive syndromes
      • Onset ages: Median 1 year; Range = Antenatal to 66 years
      • Motor milestones: Delayed; May not walk
      • Eye (50%): Ptosis; Ophthalmoplegia; More with severe disease
      • Weakness
        • General: Often more proximal
        • Face: Weak; May be long & narrow
        • Arms & Legs
        • Respiratory (40%)
      • Skeletal: Scoliosis; contractures
    • Laboratory
      • Muscle
        • Muscle fiber lesions
          • Irregular areas of myofibrillar disorganisation
          • Gomori trichrome: Red-purple granular deposition
          • Uneven oxidative stains: Clear center; Radial strands
          • ATPase stain: Reduced or Absent in center of fibers
          • Central cores (10%)
          • Desmin, Myotilin, RYR1, DHPR & αB-crystallin: Central staining
          • May be more prominent with increasing age
        • Lowest levels of RyR1 expression
        • Type 1 fiber predominance
        • Internal nuclei
        • Fiber sizes: Varied
        • Ultrastructure
          • Sarcomere disorganization
          • Osmophilic filamentous smeared material
          • Short thickened darker fragments
  • RYR1 variant: Central core disease with transient Minicores ³⁰
    • Nosology
      • Multicore syndrome: Mild phenotype
      • Multicore syndrome: "Central core-like"
    • Epidemiology: Algerian, Turkish & German families
    • Genetics
      • Inheritance: Recessive
      • RYR1 mutation: Homozygous; Missense; P3527S
      • Overlap with phenotype for central core syndrome: Missense V4849I
    • Clinical
      • Onset
        • Age: Infancy or childhood
        • Hypotonia
      • Weakness
        • Severity
          • Usually Moderate
          • Variable in families: Some patients with severe disability
        • Distribution
          • Proximal > Distal
          • Axial muscles: Neck; Trunk flexors
          • Pelvic girdle
          • Hands: Moderate weakness; Wasting
          • Face: Some patients
          • Respiratory
            • Vital capacity variably reduced: 50% to 100% of normal
            • No respiratory failure
        • Course: Stable or Slowly progressive
      • Other muscle
        • Preserved bulk
        • Pain on exertion
        • Ophthalmoplegia: Some patients
      • Joints
        • Hyperlaxity: Hand involvement; Other joints also involved; Patellar, Hip & Knee dislocations
        • Contractures: Some patients; Mild; Mainly at heels
        • Arthrogryposis: Some patients
    • Laboratory
      • Serum CK: Normal
      • Cardiac: Normal
      • MRI: Gluteus maximus & Quadriceps preferentially involved
    • Muscle biopsy
      • Childhood: Multiple minicores
      • Minicores or Cores: Larger than with SEPN1 mutations
      • Adult: Central cores; Muscle fiber loss
      • Type 1 muscle fiber: All or Predominance
      • Myopathic changes
  • RYR1 variant: Central core disease with Fetal Akinesia (FADS) ⁴⁵
    • Epidemiology
      • Frequency: Up to 8% of FADS
    • Genetics
      • Inheritance: Dominant or Recessive
      • Mutations
        • Recessive
          • R614C (Often associated with MH) & G215E
          • L4650P & K4724Q
          • In-frame deletion: c.2097_2123del
          • Nonsense: c.6721C>T
        • Dominant: G4899E (Mother less severely affected)
    • Clinical
      • Pregnancy
        • Fetal akinesia
          • Differential Dx in NM disorders: Nemaline & Myotubular myopathies; Pena-Shokeir
        • Fetal movements: Reduced
        • Arthrogryposis: Multiple
        • Hydramnion
      • Post-natal
        • Hypotonia: Severe
        • Respiratory distress
        • Multiple malformations
      • Course
        • Death in some
        • Others with stable weakness after prolonged respiratory support
        • Ocular: Strabismus & Ptosis may develop
    • Muscle pathology
      • Central cores: Eccentric; Some patients
      • Fiber size: Varied
      • Type 1 fibers: Small
      • Central nuclei: Some patients
      • Endomysial connective tissue: Increased
      • Fiber types: May be uniform & abnormal
      • Ultrastructure: Myofibrillar disorganization
  • RYR1 variant: Central core disease: Mild phenotype & Recessive inheritance
    • RYR1 Genetics
      • Missense V4849I mutation
      • Same mutation also found in dominant malignant hyperthermia family
    • Disease pattern overlaps with mild phenotype of multicore disease
  • RYR1 variant: Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1) ⁶⁹
    • RYR1 genetics: Mutations
      • Inheritance: Dominant or Recessive
      • Heterozygous
      • Missense or Deletion
      • Location
        • Common: C-terminal domain of RYR1; Pore forming segment
        • Other: Arg2615Cys; Arg4893Trp
      • Mutations found in 40% of patients with CNMDU1
        • None in patients with mental retardation
    • Clinical
      • Onset: Congenital or Childhood
      • Weakness
        • Mild to Severe
        • Proximal ± Axial
        • Face: Some patients
        • Progressive
      • Tendon reflexes: Reduced or Absent
      • CNS: No mental retardation
    • Laboratory
      • Serum CK: Normal
      • EMG: Myopathic
      • Muscle biopsy
        • Fiber type: All, or most, type 1
        • No cores
        • Endomysial connective tissue: Normal or Mild increase
  • RYR1 variant: Benign Samaritan congenital myopathy ⁹²
    • Epidemiology: Samaritan Israeli family, inbred
    • Genetics
      • Inheritance: Recessive
      • RYR1 Mutation: Homozygous; Missense; Tyr1088Cys
    • Clinical
      • Onset
        • Age: Congenital
        • Hypotonia: Severe
      • Weakness
        • Birth: Severe; Diffuse; Respiratory failure; Hypotonia
        • Improves with age
        • Adults: Mild proximal weakness in arms & legs
      • Eye movements: Normal
      • Face: Dysmorphic
        • Hypertelorism
        • Epicanthal folds
        • Nasal bridge: Broad
        • Mouth: Small
      • Hyperthermia with anesthesia: Mild in 1 patient
    • Laboratory
      • Serum CK: Normal
      • EMG: Mild myopathy
    • Muscle pathology
      • Internal nuclei
      • Core-like structures: In type I muscle fibers
      • Fiber types: Types I & II present
      • Internal architecture: Irregular; Moth-eaten
      • RYR1 staining: Reduced; Irregular; Aggregates with Caveolin-3
  • Central core disease or Multicores
    • Genetics: Missense mutation Arg 4893Trp; Heterozygous
    • Dominant inheritance
  • RYR1 variant: Congenital myopathy with focal loss of cross-striations ⁹⁸
    • Genetics
      • Inheritance: Recessive
      • RYR1 mutations: Heterozygous; Arg3539His, c.10627-2A>G splice site
    • Clinical
      • External ophthalmoplegia: No ptosis
      • Motor development: Delayed
      • Weakness: Generalized; Proximal > Distal
      • Progression: Minimal
      • Contractures: Long finger flexors
    • Muscle
      • NADH stain irregular
      • Type 1 predominance
  • RYR1 variant: Bent spine syndrome (Axial myopathy, Adult onset) ¹⁰¹
    • Genetics
      • Inheritance: Dominant
      • RYR1 Mutations: Heterozygous; Missense; Varying gene regions
    • Clinical
      • Onset ages: 3rd to 7th decade
      • Weakness
        • Axial
          • Lumbar: Lumbar hyperlordosis
          • Neck
          • Shoulder fixators (Scapular winging)
          • Camptocormia 10%
        • Proximal limb: Mild
      • Myalgia: Common; Exercise related
    • Laboratory
      • Serum CK: High; Up to 1,400
      • Malignant hyperthermia testing: Positive in 1 patient
      • Muscle
        • Varied fiber size
        • Internal nuclei
        • Internal architecture: Irregular
        • Cores: 10% of patients
        • Type 1 predominance: 10%
      • Muscle imaging: Lumbar paraspinal & Posterior thigh abnormal
  • RYR1 variant: Rhabdomyolysis/Exertional myalgia ¹⁰⁷
    • Genetics: RYR1 mutations
      • Heterozygous
      • Missense: Some previously associated with malignant hyperthermia
    • Clinical
      • Onset age: 3 to 45 years
      • Rhabdomyolysis (80%)
      • Exertional myalgia, isolated (20%)
      • Ptosis
      • Strength: Normal
      • Occasional features: Heat intolerance; Cold-induced muscle stiffness
    • Laboratory
      • Resting CK: Normal to 1100
      • Muscle biopsy
        • Fiber size: Varied
        • Internal nuclei
        • Internal architecture: Irregular or Cores
  • RYR1 variant: Congenital myopathy + Fatigable weakness ¹¹²
    • Epidemiology: 1 family, 2 patients
    • Genetics
      • Inheritance: Recessive
      • Mutations: Arg2241X nonsense, Leu2963Pro missense
    • Clinical
      • Onset
        • Age: Congenital
        • Hypotonia
        • Ptosis, Fatiguable
      • Myopathic facies Feeding difficulties
      • Weakness
        • Proximal
        • Respiratory
        • Walking: Delayed
        • Course: Progressive
      • Axial hypotonia
      • Eyes: Upgaze reduced, Ptosis
      • Skeletal
        • Scoliosis
        • Achilles tendon contractures, bilateral
    • Laboratory
      • Serum CK: Normal
      • Muscle ultrasound: Echogenicity increased
      • Muscle pathology
        • Internal nuclei
        • Fiber size: Atrophy
        • Type I fibers: Smaller
        • Core-like areas: Rare
      • EMG: Myopathic
      • Muscle (thigh) MRI
        • Symmetrical involvement
        • Muscles: Biceps, Semi-membranosus, Vasti & Adductors
  • RYR1 variant: Hypotonia + Benign course ¹⁷²
    • Epidemiology: 13 patients, 9 families
    • Genetics
      • Inheritance: Dominant or de novo
      • Mutation: c.12083C>T (p.Ser4028Leu)
    • Clinical
      • Onset age: Pre-natal to Childhood
      • Hypotonia
      • Weakness: Proximal & Trunk ± Diatal or Facial
      • Symptoms: Fatigability; Myalgia
      • Skeletal: Joint hyperlaxity; Scoliosis
      • Course: Early improvement
    • Laboratory
      • Muscle pathology: Type I predominance; Fiber sizes varied
      • Serum CK: Low
  • RYR1 variant: Centronuclear myopathy ¹⁴²
    • Epidemiology
      • > 35 patients
      • Common geographic region: South Africa, South America
    • Genetics
      • Inheritance: Recessive or Sporadic
      • Mutations: Compound heterozygote; Missense > Splice, Frameshift
    • Clinical
      • Onset age: Congenital or Pre-Natal
      • Early
        • Fetal movements: Reduced
        • Hypotonia
        • Feeding difficulties
      • External ophthalmoplegia
      • Weakness
        • Proximal ± Axial > Distal
          • Especially: Biceps; Quadriceps; Hip abductors
        • Bulbar: Dysphagia (75%)
        • Neck flexion (75%)
        • Face: Myopathic facies; Inverted V-shaped mouth
        • Maximal motor function: Sitting or Walking
        • Respiratory: Ventilator dependent; Frequent respiratory infections
      • Skeletal
        • Spine: Scoliosis (30%); Rigid spine (30%)
        • Contractures (35%)
      • Cardiac: Normal
      • Course: Slow improvement or Non-progressive
    • Muscle MRI
      • Involvement of: Vastus lateralis, Adductor magnus, Biceps brachii
    • Muscle pathology
      • Nuclei: Central (20% to 90% of fibers); Internal, often multiple
      • Type 1 muscle fibers
        • Predominance
        • Size: < Type 2
      • Cores & Mini-cores: May develop with increasing age
      • NADH
        • Central increase
        • Peripheral halos: Few patients
      • No necklace fibers or radial strands
      • Ultrastructure: Z-line streaming; Core-like irregularities
  • RYR1 variant: Periodic Paralysis (Episodic weakness) ± Myopathy
    • Epidemiology: 4 patients
    • Genetics
      • Mutation types: Misense & Stop; None with 2 stop mutations
      • Mutation number: 2 or 3 in 3 patients; Single (Heterozygous) in 1 patient (Arg1043His mutation)
      • Mutations: Asp708Asn, Arg2241X, Arg2939Lys; Gln70X, Arg109Trp, Met485Val; Arg1507Gln, Gly2446Ser
      • Inheritance: Recessive
    • Clinical
      • Onset ages: Neonatal to 23 years
      • Weakness, Fixed: 2 patients
        • Proximal & Trunk
      • Weakness, Episodic
        • Limbs ± Ophthalmoplegia & Face
        • Duration: Hours to Days
        • Associated features: Myalgias or Cramps
      • Morphology: Thin face
    • Laboratory
      • Serum CK: Normal
      • EMG: Myopathic or Normal
      • Muscle biopsy
        • Fiber size: Varied
        • Intermal nuclei
        • Core-like structures: 2 patients
        • Type 1 predominance: 1 patient
  • RYR1 variant: Congenital Hypotonia & Cardiac Disorders ¹⁷³
    • Epidemiology: 1 patient
    • Genetics
      • Inheritance: Recessive
      • Mutations: Intronic; c.6274+1G>A, c.10441-48G>A
    • Clinical
      • Onset: Neonatal
      • Hypotonia
      • Movements: Reduced
      • Tendon reflexes: Reduced
      • Ventilator dependent
      • Survival: < 1 week
    • Laboratory
      • NCV: Axon loss
      • Serum CK: Normal
      • Muscle MRI: Atrophy of thigh & abdominal muscles
      • Muscle pathology
        • Fiber sizes varied: Type 2 small
        • 2C fibers: Many
        • RYR1 staining: Reduced
        • Ultrastructure: Sarcomere organization: Abnormal
      • Brain MRI: CNS hemorrhages
      • Circulatory: Transposition of great arteries
  • Management
    • Avoid anesthesia-related malignant hyperthermia
    • Albuterol: May improve weakness
• Laboratory
  • CK
    • High in central core & MH patients
    • CK may be high in some asymptomatic carriers (G341R)
  • In vitro contracture test for malignant hyperthermia
    • Sensitivity: 97% to 99%
    • Specificity: 78% to 94%
• Muscle MRI ⁵²
  • Features of muscle involvement
    • Muscle signal: Increased T1
    • Clinical correlation: Similar patterns with different clinical syndromes & RYR1 mutations
  • Thigh
    • Involvement: Vasti, Sartorius, Adductor magnus
    • Spared: Rectus, Gracilis, Adductor longus
  • Lower leg
    • Involvement: Soleus, Gastrocnemius, Peronei
    • Spared: Tibialis anterior
• Central core: Muscle pathology
  • Myopathy
    • Muscle fiber size: Variable
    • Endomysial connective tissue: Increased
    • Internal nuclei: Especially in older patients
  • Cores: Internal zone, "core", in muscle fiber
    • Altered Z-disk morphology
    • Reduced or absent in core
      • Oxidative enzyme activity
      • Mitochondria
      • Some cores also have loss of central myofibrillar structure
    • Cores run whole length of muscle fiber: Especially with C-terminal RYR1 mutations
    • Most prominent on NADH & mitochondrial stains
    • More central location: More severe disease; Older age
    • Proteins in cores ³⁶
      • Myofibrillar proteins
        • αB-Crystallin; Desmin; Filamin C, Myotilin
        • Similar patterns of immunoreactivity seen in targets
      • Ca⁺⁺-related proteins
        • Depleted from the cores: TOM20
        • Present or Reduced: RYR1
        • Accumulate in, or around, lesions
          • Other sarcoplasmic reticulum proteins: Calsequestrin, SERCA1/2 & Triadin
          • T-tubule protein: Dihydropyridine receptor-α1-subunit (DHPR)
        • SelN mutation-related minicores: Normal distribution of Ca⁺⁺-related proteins
      • Other: Small heat-shock proteins
  • Fiber types: Single type in most
    • ATPase stain: Marked type I muscle fiber predominence
    • When both fiber types present: Cores tend to be in type I fibers
    • Myosin heavy chain: Often contain both type I (MYH7) & type IIX (MYH1)
  • Core patterns
    • Structured cores
      • Striated myofibrillar pattern
      • ATPase stain: Present
      • Dominant inheritance
    • Unstructured cores
      • ATPase stain: Reduced
      • Recessive inheritance
  • Core development
    • Fiber type predominance may precede core formation
    • Cores may start at ends of fibers & extend centrally
    • Increased age: More central cores
  • Clinical correlations
    • Well formed cores + Marked type 1 predominance
      • Morphology: Round; Single; Central
      • Myopathy syndrome: Often without MHS
      • RYR1 mutations: 90% with 60% in C-terminus
    • Variable cores + Less type 1 predominance + Internal nuclei
      • Morphology: Indistinct borders; Peripheral or Subsarcolemmal; Ovoid; Multiple
      • MHS syndrome: Usually normal strength
      • RYR1 mutations: 35%, Outside C-terminus
• RyR: Other
  • Antibodies vs RyR1
    • Granulomatous myopathy
    • Myasthenia gravis
  • RyR2 mutations
    • Catecholaminergic polymorphic ventricular tachycardia (CPVT)
    • R176Q mutation: Arrhythmogenic right ventricular dysplasia (ARVD)

Nemaline (Rod) Myopathies

Rods: General   Clinical features: General   Laboratory features: General   Pathology Rods: Hereditary   NEM1: α-tropomyosin 3 (TPM3); 1q21; Dom or Rec   NEM2: Nebulin (NEB); 2q23; Recessive   NEM3: α-Actin (ACTA1); 1q42     Dominant     Recessive   NEM4: β-tropomyosin(TPM2); 9p13; Dom or Rec   NEM5: Troponin T1 (TNNT1); 19q13; Recessive   NEM6: KBTBD13; 15q22; Dominant   NEM7: Cofilin-2 (CFL2); 14q13; Recessive   NEM8: KLHL40; 3p22; Recessive   NEM9: KLHL41; 2q31; Recessive   NEM10: LMOD3; 3p14; Recessive   NEM11: MYPN; 10q21; Recessive   NEM: Ryanodine receptor (Ryr1); 19q13     Rods + Cores: Dominant     Rods + Ophthalmoplegia: Recessive   NEM: RYR3; 15q13; Recessive   NEM + Cardiac: CAP2; 6p22; Recessive   Arthrogryposis (DA2B2): TNNT3; 11p15   MPD5: ADSSL1; 14q32   Also     Cap myopathy     CFTD     Filamin C     Klippel Feil 4: MYO18B     Myopathy with Myofibril Δ: PYROXD1     Pyruvate carboxylase deficiency     Rod myopathy, mild     Zebra body

Rods: Sporadic disorders   Infant onset myopathy   Adult onset myopathy (SLONM)   HIV rod myopathy Rod Myopathy   Distal Weakness & Contractures From: A Connolly

• Epidemiology
  • Incidence: 1 in 50,000
  • Most frequent causes
    • Recessive: Nebulin
    • Dominant: ACTA1
    • Japan: ADSSL
• Genetics
  • Inheritance: Dominant, Recessive & Sporadic
  • Common mutations: Skeletal muscle α-Actin (ACTA1); Nebulin
    • Similar phenotype
  • Variable features from single genes
    • Dominant or Recessive inheritance: α-Actin; α-tropomyosin 3 (TPM3)
    • Lethal congenital or Late onset: α-Actin; α-tropomyosin 3 (TPM3)
  • Mutant proteins
    • Associated with structure or regulation of Thin filaments
  • Mutations in same spectrum of genes also produce
    • Cap myopathy
    • Congenital fiber type disproportion
• Clinical features
  • Onset
    • Overall: Congenital (90%) to Adult
  • Severity: Varied
    • Severe
      • Common: ACTA1, Nebulin
      • Other: KLHL40, LMOD3, TNNT1, KLHL41, RYR1, TNNT3, TPM2, TPM3
    • Congenital (Typical): ACTA1, Nebulin, CFL2, TPM2, LMOD3
    • Mild: Childhood; ACTA1, Nebulin, TPM3, TPM2, MYPN, TNNT1
    • Adult onset: FILC, SLONM
  • Early onset cases: Respiratory failure & Feeding difficulties common
  • Motor
    • Early: Hypotonia
    • Weakness patterns
      • Degree: Varied
        • Severe in 40% to 50%
        • Most < 50% of normal strength
        • Other
          • Mild or Moderate severity
          • Distal Predominant
      • Bulbar dysfunction: Common
        • Dysphagia (60%): Especially ACTA1
      • Respiratory (60%)
      • Most severe: Neck flexors; Hip girdle
      • Distal: Nebulin, ACTA1, TNNT3, TPM2
      • Ophthalmoplegia: CFL-2; KLHL40
      • Paraspinous or Posterior neck: Adult onset
    • Slow movements: KBTBD13
  • Ophthalmoplegia: LMOD3
  • CNS: Cognitive involvement in younger onset patients
  • Cardiac
    • General: Rarely symptomatic after neonatal period
    • ACTA1: Reported with dominant de novo mutations
    • KFS4 (MYO18B): 1 patient
    • MYPN
  • GI: Acid reflux (50%)
  • Skeletal
    • Contractures
      • Arthrogryposis: Severe congenital cases
      • Mildly reduced joint motion: 75%; May be progressive
    • Scoliosis: 70%; Often progressive in late 1st decade
    • Bone fractures: 30%
    • Klippel-Feil: MYO18B
  • Course
    • Weakness
      • Often stable
      • Progressive: TNNT1, Recessive
    • Morbidity from respiratory infections & feeding problems less with increasing age
    • Walking
      • Rare in congenital rod myopathy
      • Childhood onset usually remain ambulant
  • Mortality
    • Deaths due to respiratory insufficiency
    • Early increased with
      • Respiratory insufficiency
      • Arthrogryposis
      • Failure to achieve early motor milestones
• Laboratory
  • CK: Normal (90%) or ± Elevated in adult-onset forms
  • EMG: Myopathic or Neuropathic (Especially severe cases)
• Muscle pathology: Thin filament disorders
  • Muscle fibers
    • Type I: Small; Predominant
    • Myonuclei: Abnormal shapes ¹⁵⁴
  • Rods
    • Histochemical appearance
      • Dark red-blue structures
      • Visible on: Gomori trichrome; Toluidine blue stained plastic sections
      • Subcellular location: Originate from Z-disks
        • Myopathy: Tend to cluster under sarcolemma & around nuclei
      • Differential diagnosis: Cytoplasmic bodies
    • Fiber type distribution
      • Type I more frequent than II: Milder disease; Increasing age
    • Size: 1 to 7 μm in length
    • Frequency: Often increase in number with age
    • Composition
      • α-actinin
      • Actin
      • Other Z-line proteins
    • Ultrastructure
      • Electron dense
      • Rod shaped
      • Emanate from Z-lines
        • Thickened Z-lines, or
        • Extend along long axis of thin filaments
    • Distinctive features
      • Rods in type I fibers: TPM3
      • Intranuclear rods: ACTA1; MYPN
      • Rectangular rods with fringes: KLHL40; LMOD3
      • Actin accumulation: ACTA1; CFL2
    • Underlying pathogenic process
      • Rod formation 2° to contractile dysfunction
      • Load-dependent processes may be involved
    • Rods: Differential diagnosis
      • Sarcoglycanopathies
      • Target fibers (Denervation): Usually cytoplasmic bodies, not rods
      • Tenotomy: Usually cytoplasmic bodies, not rods
      • Neostigmine myopathy ²³
      • HIV-associated myopathy ²⁴
      • Also see: Cytoplasmic bodies
  • Endomysial connective tissue
    • Usually normal
    • Increased: LMOD3; TNNT1; TNNT3

ROD MYOPATHIES: Specific syndromes

NEM1 Rod myopathy
  ● α-Tropomyosin 3 (TPM3)

• Epidemiology
  • Infrequent cause of nemaline rod myopathy
  • Frequency: < 3%
• TPM3 Genetics
  • Inheritance: May be Dominant or Recessive
  • Mutation hotspot: Arg168 (Arg168His, Arg168Cys, Arg168Gly)
  • TPM3 Clinical-Genetic correlations
    • Mildest syndromes: Missense mutation; Dominant inheritance
    • Severe syndromes: Stop codon; Recessive inheritance
    • Tropomyosin function
  • Allelic disorders
    • Congenital fiber Type Disproportion (CFTD)
    • Cap myopathy
    • Rod myopathy
    • Congenital hypercontractile syndrome
• TPM3 protein
  • Muscle: Expressed in type I muscle fibers
  • 11 different forms: Expressed in many tissues including brain
  • Actin-binding tropomyosin family
  • Component of sarcomeric thin filament troponin-tropomyosin complex
  • Predominantly expressed in type 1 (slow twitch) muscle fibers
  • Regulates: Muscle contraction; Binding of myosin head to actin filament
  • See: Muscle fiber proteins
• NEM 1 Rod myopathy: Dominant inheritance
  • TPM3 Mutations: Missense; Met9Arg, Arg167His ³⁸
  • Onset: 0 to 15 years
  • Clinical
    • Weakness
      • Development: Motor delay in some patients
      • Distribution
        • Symmetric
        • Distal Legs (Ankle dorsiflexors)
        • Arms
        • Respiratory failure
        • Proximal weakness: Later in disease course
      • Progression: Slow; Wheelchair often by 40 years
      • More severe than TPM2 mutations
    • Tendon reflexes: Reduced
    • Achalasia: Involvement of smooth muscle
    • Morphology
      • Kyphoscoliosis
      • Slender build
      • Long face
  • Laboratory
    • Serum CK: Normal
    • Pathology
      • Type I fibers: Atrophy; Predominance
      • Rods: In Type I fibers; May be infrequent
• NEM1 Rod myopathy: Recessive inheritance
  • Early onset, severe disease
    • TPM3 Mutation: Homozygous; Stop at codon 31
    • Onset: Birth
    • Motor development: Extremely delayed and impaired
    • Cognitive: Appropriate for age
    • Death: 21 months
    • Pathology
      • Rods: Only in type 1 fibers
      • Type 1 muscle fiber smallness
      • Loss of α-tropomyosin 3 from muscle
  • Intermediate syndrome³⁵
    • Family history: Sporadic
    • Genetics
      • Compound heterozygote
      • Mutations: X285Ser; Splice site at skeletal muscle-specific translational stop signal
    • Mutated protein: contains 57 additional amino acids
    • Clinical
      • Onset: Birth; Hypotonia
      • Motor
        • Walking: 18 months
        • Wheelchair: 6 years
        • Weakness: Proximal
      • Face: Long & narrow; High arched palate
    • Muscle pathology
      • Rods: In type I muscle fibers
      • Endomysial connective tissue: Increased
      • Type I fiber predominance
      • Internal nuclei
      • Small fibers both types
      • Reduced β-tropomyosin in muscle fibers
• Variant syndrome: Congenital fiber type disproportion with TPM3 mutations ⁷⁰
  ● Dominant or Sporadic
• General
  • Most common cause of CFTD: ~20% to 25%
  • Type 1 fibers: At least 50% smaller than type 2
  • Type 2 fibers: Normal or large sized
• Genetics
  • Mutations: Missense; Heterozygous
  • Locations: Leu100Met, Arg168Cys, Arg168Gly, Arg168His, Lys169Glu, Glu174Ala, Arg245Gly
  • Arg168Cys mutation: May be associated with CFTD & nemaline myopathy pathology in same family
• Clinical
  • Onset
    • Age
      • Usually < 1 year
      • Variable: Even within families
    • Hypotonia
    • Poor head control
  • Weakness
    • Proximal > Distal
    • Legs > Arms
    • Neck: Flexion & Extension
    • Ankle: Dorsiflexion
    • Trunk: Paraspinal; Abdominal
    • Facial: Mild; Myopathic face
    • Ptosis: Mild; Unilateral or Bilateral
    • Respiratory
      • Frequency: 90%
      • Nocturnal noninvasive ventilation: Onset 3 to 55 years
      • Even in some ambulatory patients
    • Scapular winging: Mild; 40%
    • Quadriceps: Relatively preserved
    • Course
      • Improvement in strength & function over time
      • Patients often eventually walk or run
  • Other muscle
    • Amyotrophy: Generalized
    • Body habitus: Thin
    • Gait: Waddling; Foot drop
  • Skeletal
    • Young children: Hypotonic stance; Exaggerated lumbar lordosis & thoracic kyphosis
    • Late childhood or adulthood: Mild-to-severe kyphoscoliosis with neck extensor contractures
    • Other contractures: Uncommon
  • Possible symptomatic treatments
    • Pyridostigmine
    • 3,4-Diaminopyridine
• Laboratory
  • EMG: Normal or Myopathic
  • Single fiber EMG: Abnormal jitter without blocking
  • NCV: Normal
  • Cardiac: Normal
  • Muscle MRI
    • No selective muscle involvement
    • Interstitial connective tissue: Mildly increased
  • Muscle pathology
    • Type 1 muscle fibers
      • Small size
        • 60% of normal; Range 30% to 80%
        • 23% to 50% of Type 2 size
      • Predominance: Minority of patients
    • Type 2 muscle fibers
      • Size: Large; 160% of normal; Range 110% to 220%
      • Type 2B: Absent
      • Type 2C: None or Few
      • Internal nuclei: In older patients; Up to 25% of type 2 fibers
    • Coexpression: Some muscle fibers express both fast & slow myosin
    • No rods: Even with ultrastructure evaluation
• Also see: Nemaline rod myopathy
• Variant syndrome: Cap myopathy 1 with TPM3 mutations
  ● Dominant or Sporadic
  • Epidemiology: 1 patient
  • TPM3 Mutation: Arg168Cys
  • Clinical
    • Delayed motor milestones
    • Kyphoscoliosis,
    • Muscle atrophy: Generalized
    • Weakness: Mild, Walking unsupported; Respiratory
    • Dysmorphic: Elongated face; High-arched palate
  • Laboratory
    • Muscle biopsy: Caps, NADH+
    • MRI: Masseter hypertrophy
• TPM3 variant syndrome: Congenital muscle stiffness, Hypercontractile ¹²³
  • Epidemiology: 2 patients (US & German)
  • Genetics
    • Mutations: Glutamic acid deletions; ΔE218, ΔE224
    • Inheritance: de novo; Dominant
    • Allelic disorders
  • TPM3 protein: Mutation effects
    • Muscle fibers: Maximal active tension reduced
    • Ca⁺⁺ sensitivity of troponin-tropomyosin complex: Increased
    • Cross-bridge cycling kinetics: Abnormal
    • Excitation-contraction coupling: Excessively sensitized
  • Clinical
    • Onset age: Congenital or Prenatal
    • Fetal movements: Reduced
    • Muscle
      • Stiffness: Gait & Passive movement; Increased with heat
      • Respiratory failure
    • Joints: Reduced range of movement; Thoracic kyphosis; Spine rigidity; Short stature
    • Muscle relaxants: No clear benefit
  • Laboratory
    • EMG: Myopathy + Denervation; No spontaneous activity
    • Muscle ultrasound: Increased echogenicity
    • Serum CK: 200 to 1,000
    • Muscle pathology
      • Fiber size: Moderately varied
      • Internal architectgure: Mildy irregular
      • Ultrastructure: Z-band streamning of mini-rods
  • Congenital stiffness: Differential diagnosis
    • CRYAB
    • ACTA1
    • TPM3

NEM2 Rod myopathy
  ● Nebulin (NEB)

• Epidemiology
  • Most common form of recessive "Typical" nemaline rod myopathy
• Genetics: Mutations
  • > 250 mutations
  • Point mutations: Most common
    • Missense variants: Common; Conserved actin- & tropomyosin-binding sites likely pathogenic
  • Common mutations
    • Ashkenazi Jews
      • 2,502-bp deletion in exon 55 & parts of introns 54 and 55
      • Carrier frequency: 1 in 108
      • Severity: "Typical" forms of nemaline myopathy
    • Chinese: c.21417+3A>G exon 144 splice
  • Small insertions, deletions or point mutations
  • Duplications (10% to 15%)
    • Location: Exons 82-105
    • Eight exons repeated 3 times in 32-kb triplicate
    • Normal copy #: 6
    • ≥ 2 extra: Nemaline myopathies
  • 3' end of gene: Exons 165 to 185; Z-disc part of nebulin
  • Mutations producing no nebulin protein
    • Severe disease
    • Death at 1 day to 9 months
  • Dominant mutation
    • ~100 kb in-frame deletion spanning NEB exons 14-89
    • Results in expression of smaller nebulin protein
    • Clinical: Distal NM in Finnish family
  • Allelic disorders: Severe congenital, or Intermediate (mild) forms of Rod myopathy
    • Rod myopathy
    • Distal Nebulin myopathy
    • Lethal multiple pterygium syndrome (Fetal akinesia; Arthrogryposis-6 (AMC6))
    • Core-Rod myopathy
    • Cap & Rod myopathy, Recessive
    • Cap & Rod Distal myopathy, Dominant
    • Nebulin mutations NOT identified in: Adult onset rod myopathy
• Nebulin (NEB) protein
  • Missense mutations: May cause myofilament structural changes ¹⁶⁵
• Clinical: Infantile onset; Mild to moderate severity ("Typical")
  • Onset: Birth; Some movement present
  • Weakness
    • Trunk
    • Distal legs: Ankle dorsiflexors
    • Knee flexors
    • Face
    • Nasal voice
    • Respiratory: More servere forms
  • Dysmorphic features
    • HEENT: High arched palate; Micrognathia
    • Contractures: Fingers
    • Chest deformaties
    • Joint hypermobility
  • Cardiac: Normal
  • Extraocular muscles: Normal
  • Progression
    • Slow or none
    • May improve after initial respirator dependance
  • Muscle pathology
    • Nebulin: Still present
    • Fiber size: Varied
    • Fiber types
      • Type 2 muscle fibers: Reduced numbers in milder disease
      • 2X myosin: Absent in younger patients with more severe disease
      • Co-expression of fast & slow myosin: Intermeditate disease severity
      • Neonatal myosin: More severe disease
    • Rods
      • Ultrastructure
        • Z disk aberrations
        • Myofibrillar dissociation & smallness: Severe disease
      • Contain: α-actinin; myotilin, telethonin, actin, tropomyosin & desmin
      • Present in normal-sized & small muscle fibers
      • Severe disease: Globular
      • Milder disease: Elongated; Subsarcolemmal & Cytoplasmic; More common
• Muscle MRI ⁵³
  • Mild phenotype
    • Involvement: Tibialis anterior, Soleus
    • Sparing: Thigh muscles
  • Moderate phenotype involvement
    • Rectus femoris, Vastus lateralis, Hamstring, Anterior leg, Soleus
• Nebulin Variant: Distal Nebulin myopathy
• Nebulin Variant: Core-Rod myopathy ⁸⁰
  • Epidemiology: 1 patient
  • Genetics
    • Recessive
    • Nebulin Mutations
      • Duplications
      • Truncation
      • g.195187_195188dupAC in exon 140: Loss of all nebulin isoforms
      • g.234878_234881dupTCAA in exon 171: Loss of some nebulin isoforms
  • Clinical
    • Onset
      • Age: Congenital
      • Hypotonia
      • Respiratory insufficiency
    • Weakness
      • Diffuse
      • Axial predominance
      • Mild facial
    • No independent walking
    • Skeletal: Scoliosis; Joint contractures
    • Cardiac: Normal
  • Laboratory
    • EMG: Myopathic
    • NCV: Normal
    • Muscle Pathology: Muscle fibers with rods & cores
    • MRI: Abnormal soleus & Anterior + Lateral compartments; Gastrocnemius spared
  • Other Core-Rod myopathy: RYR1 mutations
• Nebulin Variant: Cap & Rod Distal myopathy, Dominant ¹⁶⁴
  • Epidemiology: 1 Finnish family, 3 patients
  • Genetics
    • Inheritance: Dominant
    • Mutation: ~100 kb in-frame deletion involving NEB exons 14-89
  • Nebulin protein
    • Mutation results in expression of smaller nebulin
  • Clinical
    • Onset
      • Age: 3 years
      • Foot drop
    • Weakness
      • Neck
      • Elbow flexors
      • Hands: Wrists & Fingers (Extensors weaker than flexors)
      • Legs: Tibialis anterior & Toe extensors
    • Muscle atrophy: Distal; Arms & Legs
    • Dysmorphism: High-arched palate; Narrow face
  • Laboratory
    • Muscle pathology
      • Myopathic
      • Type 1 fiber predominance
      • Nemaline rods: Older patients
      • Cap-like structures
    • Serum CK: Normal
• Nebulin Variant: Cap & Rod myopathy, Recessive ¹¹⁴
  • Epidemiology: 1 patient
  • Genetics
    • Inheritance: Recessive
    • Nebulin mutations: c.1152+1G>A; c.1782+4_1782+5delAG
  • Clinical
    • Onset age: Infancy
    • Hypotonia
    • Weakness: Global; Fatigue; Wheelchair
    • Ptosis: Bilateral
    • Respiratory failure
    • Swallowing difficulty
    • Tendon reflexes: Reduced
    • Developmental disability
    • Morphology: Head
      • Dolichocephaly
      • Ears: Low-set; Attached lobes
      • Upper lip: Tented
      • Mouth: Downturned corners
      • Palate: High arched
    • Skeletal
      • Clinodactyly
      • Hyperconvex nails
      • Toes: 1st & 2nd overlapping
    • Cryptorchidism
  • Laboratory
    • NCV: Normal
    • EMG: Normal
    • Serum CK: Normal
    • Muscle biopsy: 7 months
      • Nemaline rods
      • Fiber-type disproportion: Type 1 Small & Predominant
    • Muscle biopsy: 6 years
      • Cap-like structures
        • Peripheral in muscle fibers
        • Contain rods
        • Toluidine blue positive
      • Nemaline rods
      • Ultrastructure: Z-disk & Myofibrillar abnormalities
    • Brain MRI: Normal
• Nebulin Variant: Fetal Akinesia syndrome (Lethal Multiple Pterygium ) ¹⁶³
  • Nosology: Arthrogryposis Multiplex Congenita-6 (AMC6)
  • Epidemiology: 28 families
  • Genetics
    • Nebulin Mutations
      • Types: Splice site, Deletion or Stop
    • Inheritance: Recessive
  • Clinical
    • Fetal akinesia
    • Growth retardation: Intrauterine
    • Limb contractures
    • Pterygia
    • Effusion: Pericardial; Hydrothorax
    • Face: Hypertelorism; Downslanting palpebral fissures, Long philtrum, Low set ears
  • Muscle
    • Nemaline rods
    • Fiber sizes: Varied

NEM3 Rod myopathy
  ● α-Actin (ACTA1; Skeletal muscle)

• Epidemiology: 23% of rod myopathies
• Genetics
  • Mutations
    • ~15 Missense mutations identified
    • Distributed in all 6 coding exons
    • Some involve known functional domains of actin
    • Recessive: Null alleles
  • Allelic syndromes
• Actin (ACTA1) protein
  • α-Skeletal muscle actin
    • Normal adults: Present in muscle but not heart
    • Development: Becomes predominant isoform in muscle at 3rd trimester of gestation
  • Dominant syndromes: Mutant ACTA1 exerts dominant negative effect
  • Aggregation may be caused by
    • Heat shock
    • Leptomycin B (a specific inhibitor of nuclear export mediated by leucine-rich nuclear export signals)
    • Mutation in leucine-rich nuclear export signals
• Clinical
  • Myopathies: Dominant inheritance
    • Clinical: Variable phenotypes
      • General
        • Onset age: Variable within families
        • Cardiac function: Normal
      • Mild
      • ACTA1 Mutations: Asn115Ser; Gly268Cys; Ile136Met
      • Clinical
        • Onset: Age 12
        • Weakness: Trunk & Proximal; Mild facial
        • Respiratory failure: 5th decade
        • Progression: Slow over decades
      • Laboratory
        • Serum CK: Normal
        • MRI: Gluteal & Anterolateral thigh involvement
        • Muscle morphology
          • Rods, especially in small fibers; Core-like structures
          • Muscle fiber hypertrophy: Ile136Met
      • Scapuloperoneal (SHPM) ¹²⁰
        • Genetics: Glu197Asp ACTA1 mutation
        • Clinical
          • Onset age: Infancy to 3rd decade
          • Weakness: Scapuloperoneal & Distal
            • Wrist extensor
            • Finger drop
            • Foot drop
            • Quadriceps (50%)
            • Scapular winging
            • Face: Mild
          • Contractures: Ankle; Elbow; Shoulder
          • Tendon reflexes: Reduced or Absent
        • Laboratory
          • Muscle pathology
            • Type I fiber atrophy
            • Internal architecure irregular
            • Internal nuclei
          • Serum CK: Normal to Slightly high
      • Severe ⁸⁵
      • ACTA1 genetics
        • New dominant mutations
        • N94K; L144F; Arg183Gly; G270R; Ile357Leu
      • Phenotypes
        • Lethal; Congenital
        • Congenital weakness
      • CNS involvement: Some patients
        • Developmental delay
        • Frontal lobe hypoplasia
        • Lateral ventricle dilation
      • Other organs: Few patients
        • Skeletal dysplasia
        • Hepatomegaly
        • Urinary tract stenosis
      • Muscle pathology
        • Fiber size: Varied; Small fibers in clusters
        • Nemaline rods: Cytoplasmic & Intranuclear
        • Cytoplasmic bodies (Asn94Lys mutation) ¹⁴⁰
        • Thin filament aggregates
        • Endomysial fibrosis
      • Asymmetric weakness
        • Genetics: Mosaic (de novo) mutations (Ala116Pro; Asp156His) ¹⁶⁷
        • Clinical
          • Onset: Neonatal or Infant
          • Weakness: Asymmetric; Proximal & Distal; Respiratory
          • Cardiomyopathy: 1 patient
      • Nemaline myopathy with intranuclear rods
      • Cap myopathy
      • Other mutations: Met132Val; Val163Met; Met269Arg
    • Pathology
      • Fiber types
        • Abnormal differentiation
        • Type I: Small
      • Glycogen accumulation
      • Rods
        • No relation between abundance & disease severity
        • More in small muscle fibers
        • Stain for α-actinin 2
        • Rods tend to be in type 1 muscle fibers
        • May be present in some muscles but not others
        • Some syndromes with no rods
      • Fiber morphology
        • Myofibrillar disruption
        • Whorling of actin thin filaments
  • Rod myopathy: Recessive inheritance ⁶⁶
    • ACTA1 Genetics
      • Truncation mutations identified; ? Missense
      • Truncation: Arg41X (French), Tyr364fsX (Spanish), Asp181fsX10 (British)
    • Clinical
      • Weakness
        • Severe in most: Diffuse; Hypotonia
        • Respiratory failure
        • Feeding difficulties
        • Death in 1st year: Most
        • Contractures (30%)
      • Course: Survival through childhood in some
    • Laboratory
      • Serum CK: Mildly elevated or normal
      • Muscle
        • Morphology: Nemaline rods & Zebra bodies
        • Actin: Skeletal α-actin absent; Cardiac α-actin increased
        • Lipid: Increased
  • ACTA1 variant: Congenital muscular dystrophy with Rigid spine ¹²⁸
    • Epidemiology: 1 Sri Lankan family, 2 brothers
    • Genetics
      • Mutations: Homozygous; Missense; c.460G>C, p.Val154Leu
      • Inheritance: Recessive
    • Clinical
      • Onset age: Infancy
      • Weakness
        • Neck
        • Falling
        • Distribution: Generalized
      • Muscle size: Small
      • Skeletal
        • Rigid spine
        • Kyphoscoliosis
    • Laboratory
      • Skeletal muscle
        • Fiber size: Varied
        • Internal nuclei
        • Fiber splitting
        • NADH: Central lucencies
        • Skeletal muscle α-actin: Present
        • Cardiac muscle α-actin: Increased
        • Ultrastructure: Smeared & accumulated Z-band material; Rare rods
      • Serum CK: 222 to 1900
      • NCV: Normal
      • Muscle MRI: Fatty repleacement
        • More severe: Posterior & Rectus femoris
        • Relative sparing: Vastus lateralis & medialis, Gracilis, Sartorius
      • EKG: Normal
  • Rod myopathy: Sporadic patients
    • Genetics: Often de novo, dominant mutations
  • ACTA1 variant: Nemaline myopathy with Intranuclear rods ⁶²
    • Genetics
      • Mutations: All involve ACTA1
      • Inheritance
        • Sporadic (Most) or Dominant
        • Marked phenotypic variation in family
    • Clinical
      • Onset age: Birth (Most) to 55 years
      • Narrow face
      • Thin musculature
      • Hypotonia
      • Weakness: Diffuse
    • Laboratory
      • Serum CK: Normal or Mildly elevated
      • EMG: Myopathic
      • Muscle: Intranuclear rods
        • Probably formed within nucleus
        • Larger than sarcoplasmic rods: Up to length of several sarcomeres
        • One or multiple per nucleus
        • Frequency: 2% to 80% of nuclei
        • Number of fibers with intranuclear rods correlates with disease severity
    • Course
      • Death in 1st year in 40% due to respiratory insufficiency
      • Similar to ACTA1 mutations without intranuclear rods
  • ACTA1 variant: Cap myopathy with ACTA1 mutation ⁸²
    • Epidemiology: 1 patient
    • Genetics
      • Mutation: Met47Val
      • Inheritance: Dominant
    • Clinical
      • Decreased fetal movements
      • Birth: Poor respiration
      • Motor
        • Hypotonia: Axial & Peripheral
        • Weakness: Severe
        • Minimal spontaneous movements
        • Generalized atrophy
      • Deep tendon reflexes: Absent
      • General
        • Low hairline
        • Micrognathia
        • High arched palate
        • Single palmar crease
        • Long fingers
        • Undescended testes
      • Death: 5 years
    • Laboratory
      • Serum CK: Normal
      • Head MRI: Normal
      • Muscle biopsies
        • 5 weeks: Type 1 smallness; No caps
        • 4 years
          • Caps: Contain thin filaments, α-Actinin, Actin & Desmin; NADH+
          • Internal nuclei
          • Expanded Z-bands
  • ACTA1 variant: Myofibrillar myopathy, Congenital ¹²¹
    • Epidemiology: 1 patient
    • Genetics
      • Inheritance: Sporadic, Dominant
      • Mutation: In-frame 2-amino-acid insertion; c.437_442dupCCTCCG; p.146_147dupAlaSer
    • Clinical
      • Onset age: Congenital
      • Hypotonia
      • Motor delay
      • Weakness
        • Arms > Legs
        • Face: Diplegia
      • Tendon reflexes: Reduced
      • Dysmorphic features
        • Ears: Low-set
        • Contractures: Metacarpophalangeal & proximal interphalangeal joints involving most fingers
        • High arched palate
      • Death: 3 years
    • Laboratory
      • Brain MRI: Normal
      • Serum CK: Normal
      • EMG: Fibrillations; Motor units small
      • Muscle biopsy
        • Fiber morphology: Varied size; Splitting; Internal nuclei
        • Fiber architecture: Vacuoles; Myofibrillar disorganization; Hyline structures
        • Fiber aggregates: Desmin; αB-crystallin, Myotilin, Dystrophin, NCAM
        • Fiber damage: Necrosis & Regeneration
        • Endomysial connective tissue: Increased
        • Perimysium: Widened
    • Differential diagnosis: Childhood-onset myofibrillar myopathies
      • BAG3
      • CRYAB, Recessive
      • ACTA1: Congenital; Child
      • PYROXD1
  • ACTA1 variant: Myofibrillar myopathy, Child onset ¹⁶⁶
    • Epidemiology: Italian family, 6 patients
    • Genetics
      • Inheritance: Dominant
      • Mutation: c.148G>A; p.Gly50Ser
    • Clinical
      • Onset: Infant or Childhood
      • Face: Weak; Temporal atrophy
      • Weakness
        • Neck
        • Diffuse: Proximal > Distal
      • Course: Slow progression
    • Laboratory
      • Serum CK: Usually normal
      • Muscle MRI
        • Abnormal: SCM, Rectus abdominis, Gluteus minimus, Vastus intermedius, Gastrocnemius
        • Symmetric
      • Muscle pathology
        • Fiber sizes: Varied
        • Internal nuclei
        • Nemaline rods
        • Cytoplasmic aggregates: Dark on gomori trichrome; Contain Desmin, Myotilin & α-B crystallin
  • ACTA1 variant: Cytoplasmic body myopathy, Congenital ¹⁴⁰
    • Epidemiology: 3 patients
    • Genetics
      • Inheritance: Sporadic; Dominant
      • Mutation: Asn94Lys; Heterozygous
    • ACTA1 protein
    • Clinical
      • Onset age: Congenital
      • Hypotonia
      • Weakness: Severe; Respiratory
    • Laboratory
      • Muscle: Cytoplasmic bodies
  • ACTA1 variant: Inclusion body & Rod myopathy ¹⁴⁹
    • Epidemiology: 1 family, 4 patients
    • Genetics
      • Inheritance: Dominant
      • Mutation: Gly50Asp
      • Allelic disorders
    • Clinical
      • Onset age: Childhood
      • Hypotonia: Axial
      • Weakness
        • Face
        • Trunk
          • Neck flexor
          • Abdominal
        • Distal
          • Fingers: Flexor ± Extensor
          • Toe dorsiflexors
        • Proximal
          • Legs: Quadriceps; Hip flexors
          • Arms: Shoulders; elbows
        • Slow running
      • Course: Slow progression
      • Other: Scoliosis & Scapular winging in 1 patient
    • Laboratory
      • Muscle
        • Vacuoles, rimmed
        • Rods: On ultrastructure
        • Type 1 fibers: Small
      • Serum CK: Mildly high
  • ACTA1 variant: Distal myopathy ¹⁵⁰
    • Epidemiology: 1 family, 3 patients
    • Genetics
      • Inheritance: Dominant
      • Mutation: Gly253Arg
    • Clinical
      • Onset age: Childhood to Teen-age
      • Weakness
        • Distal: Anterior distal leg; Finger extensor
        • Proximal: Hips; Later in life
        • Trunk (Older patient): Respiratory; Camptocormia
        • Course: Slow progression in adulthood
      • Other: Pes cavus; Joint hyperlaxity
    • Laboratory
      • Muscle
        • Atrophic muscle fibers
        • Rods
        • Myofibrillar pathology (Actin or Myotilin aggregates): 1 patient
      • Serum CK: Normal
      • EMG: Mixed neurogenic & myopathic
• Muscle MRI
  • Involved muscle signal: Increased T1
  • Involved muscles: Diffuse involvement of thigh and leg
  • Relative sparing: Gastrocnemius

NEM4 Rod myopathy
  ● β-Tropomyosin (TPM2)

• Epidemiology: Unusual cause of rod myopathy
• Genetics
  • TPM2 mutations: Lys7del; E117K; Glu139del; Q147P
  • TPM2 allelic disorders: Most dominant
    • Distal arthrogryposis 1A: Dominant or de novo
    • DA2B4: Dominant
    • Cap myopathy 2: Dominant
    • Escobar syndrome: Recessive
    • Congenital fiber type disproportion 5: Dominant
    • Nemaline rod myopathy (NEM4): Dominant or Recessive
• β-Tropomyosin protein
  • Mutation abnormalities
    • Altered interactions
      • Affinity for actin
      • Tropomyosin head-to-tail binding
    • Ca⁺⁺ activation of TPM contractility
      • Increased Ca⁺⁺ sensitivity: Hypercontractile molecular phenotype
        • More limb (93%) or jaw (30%) contractures
      • Non-hypercontractile mutations: Axial contractures more common (90%)
• Clinical
  • Onset: Infancy to Childhood
  • Weakness
    • Onset age: Adolescent or Adult
    • Proximal > Distal
    • Some with respiratory failure
    • Less severe than TPM3
    • Course: Slow progression; Some lose independent ambulation in adulthood
  • Contractures: Variable
    • Common: Distal & Proximal joints; Arms & Legs
    • Some patients: Few or None
  • Cardiac: Normal
• Laboratory
  • Serum CK: High
  • Muscle biopsy
    • Nemaline rods: Often subsarcolemmal
    • Fiber size: Varied
    • Type 1 fibers: Predominant; Small
    • Core-like regions: Some patients
• TPM2 Variant: Escobar syndrome ⁷⁴
  • Epidemiology: Consanguenous Algerian family
  • Genetics
    • Inheritance: Recessive
    • Mutation
      • Homozygous
      • Gln210Stop: Exon 6b, specific for skeletal muscle β-TM isoform 1
    • Allelic disorders
  • TPM2 protein: Absent skeletal muscle isoform of β-tropomyosin
  • Clinical
    • Onset: Congenital
    • Motor: Hypotonia; Delayed milestones
    • Respiratory distress
    • Joints: Pterygia; Arthrogryposis
    • Cardiac: Bifascicular ventricular block with right bundle block & left anterior hemiblock
  • Muscle
    • Connective tissue: Abundant
    • Rods: More common in type I muscle fibers (60%)
• TPM2 Variant: Congenital Fiber Type Disproportion 5 ⁹⁵
  • Genetics
    • Inheritance: Dominant
    • TPM2 Mutations: Missense; Ser61Pro, Ala155Val
    • Allelic disorders
  • Clinical: Variable severity
    • Neonatal; Well or Hypotonic
    • Motor milestones: Delayed
    • Weakness
      • Proximal
      • Face
      • Respiratory in more severe patient
      • Mild to Moderate
  • Laboratory
    • Muscle pathology
      • Type 1 fiber diameter: Small
      • Type 2 fiber diameter > Type 1: 50% to 60% difference
      • Ultrastructure: Small caps in 1 patient
    • Serum CK: Normal

• Epidemiology: 18 families
• Genetics
  • Mutations
    • Stop
      • Older Order Amish: Nonsense; E180X; Homozygous
      • Hispanic patient: c323C>G (S108X)
      • Palestinian: Complex truncating indel mutation
      • Other: Spice site; Exon 14 deletion
    • Missense
      • French-Canadian: c.287T>C (p.Leu96Pro)
  • Allelic disorders
    • Nemaline myopathy, Dominant
      • Mutation: E104V
    • Severe congenital weakness (SMA0-like) ¹⁷²
      • Mutation: c.129-1G > A; Splice; Homozygous
• TNNT1 protein
  • Link between troponin complex & tropomyosin (Tm)
  • Helps to regulate muscle contraction
• Clinical: Similar phenotype
  • Onset
    • 1st months of life
    • Tremors
      • Begin within few days of birth
      • Distribution: Jaw & Lower limbs
      • Resolve by 2 to 3 months
    • Hypotonia
    • Motor milestones: Delayed
    • Contractures: Shoulders, Hips & Knees; Mild
  • Progression
    • Proximal contractures: Increase
    • Weakness: Proximal > Distal; Respiratory
    • Rhabdomyolysis: French-Canadian; Infection trigger; Dantrolene treatment
    • Thoracic dystrophy: Pectus carinatum: Rigid chest wall; Develops with proximal contractures
    • Cardiac: No 1° involvement; Terminal right congestive failure
    • Feeding difficulties
    • Course
      • Many: Death from respiratory insufficiency < 2 years
      • French-Canadian: May live & remain ambulatory to adulthood
• Laboratory
  • Serum CK: Normal to 4x High
  • Leg MRI
    • Posterior thigh, Tibialis anterior & Deep posterior leg involvement
    • Symmetric
  • EMG: Mild myopathy or normal
  • Muscle Pathology
    • Type 1 fiber disproportion
    • Z-band streaming
    • Rods: Centrally placed
    • Myofibrillar disruption
    • Myofiber degeneration
    • French-Canadian: Multi-minicores in type 1 fibers

• Epidemiology: 32 European & Australian patients
• Genetics
  • Mutations: Missense; Arg248Ser, Lys390Asn, Arg408Cys
• KBTBD13 protein
  • Tissues: Skeletal & Cardiac muscle; Lung
  • Subcellular: Cytoplasm; Sarcomere
  • Interacts with: Cullin 3 ubiquitin ligase; Actin
  • Required for formation of functional Cul3 RING ubiquitin ligase complex
  • Involved in ubiquitination of proteins destined for degradation
  • Mutation
    • Actin binding: Altered
    • Thin filament stiffness: Increased
    • Ca⁺⁺ dynamics: Altered
    • Muscle contractile force: Reduced
    • Relaxation: Slow
  • Other BTB/Kelch protein disorders
• Clinical
  • Onset age: Childhood
  • Weakness
    • Mild to Moderate
    • Proximal & Neck flexors > Distal
    • No respiratory insufficiency
  • Muscle size: Atrophy in some patients
  • Movements: Slow; Unable to run; Poor rapid postural correction
  • Progression: Slow; Disability after 50 years
  • Skeletal (Some patients): High Palate; Thorax deformities
  • Cardiac: Normal
• Laboratory
  • Serum CK: Normal
  • EMG: Myopathic
  • Muscle CT: Fatty infiltration of proximal limb & truncal muscles
  • Muscle biopsy
    • Type 1: Predominance; Hypertrophy
    • Type 2: Atrophy
    • Internal nuclei
    • Rods: Granular; Diffusely distributed; All fibers
    • Core-like structures
      • Less sharply defined than typical cores
      • Ultrastructure: Large regions of rods with loss of muscle structure

• Epidemiology: 3 families
• Genetics
  • Mutations: Missense (Ala35Thr, Val7Met); 4 base pair deletion
  • Heterozygotes: Not affected
• Cofilin-2 protein
  • Member of AC (ADF/Cofilin) protein group
    • Regulate actin filament dynamics: Actin depolymerizing factors
    • Other group members: Cofilin-1 ; Destrin
  • Skeletal muscle specific isoform
  • Localized to thin filaments
  • Exerts effect on actin, in part, through interactions with tropomyosins
  • Binds G- and F-actin in 1:1 ratio
  • Major component of intranuclear & cytoplasmic actin rods
• Clinical
  • Onset: Hypotonia at birth
  • Early motor milestones: Delayed
  • Ambulation: Present for short distances; Frequent falls; Inability to run
  • No facial weakness or foot drop
• Muscle pathology
  • Nemaline rods: 1 of 2 patients
  • Minicores: Few fibers
  • Type I muscle fiber predominance
  • Fiber size variability
  • Concentric laminated bodies
  • Cofilin-2
    • Sarcomeric staining: Reduced
    • Phosphorylated forms: Absent
  • Phalloidin staining: 4% of myofibers contain actin filament accumulations

• Epidemiology: 28 kindreds
  • European & Asian
  • Most common severe nemaline myopathy in Japan (28%)
• Mutations
  • Loss of function
  • Homozygous or Compound heterozygous
  • Types: Frameshift; Missense; Nonsense; Splice site
  • Locations: All exons
  • Mutation associations
    • Arg500Cys: Mild phenotype
    • Thr506Pro: Hong Kong Ethnic Chinese; Severe phenotype
    • Glu528Lys mutation: Japanese & Kurdish; Slightly milder phenotype
  • Kelch repeat disorders
    • KLHL9: Distal weakness syndrome
    • KBTBD13: NEM6; Nemaline myopathy with cores
    • Gigaxonin: Giant axonal neuropathy
    • KLHL40: Nemaline rod myopathy
    • KLHL41: Nemaline rod myopathy
• KHLH40 protein
  • Localization: Sarcomeric A-band & I-band
  • Co-localized with RyR1
  • Binds & stabilizes in sarcomere: NEB; LMOD3
  • Other binding: CUL3
  • Maintenance of sarcomere structure & muscle contractility
  • Abundance very reduced in diseased muscle
• Clinical
  • Variation in severity
  • Onset: in utero
    • Fetal akinesia or Hypokinesia
    • Polyhydramnios
  • Skeletal
    • Arthrogryposis & Contractures (89%)
    • Fractures (53%)
    • Dysmorphic face, mild (100%)
    • Chest deformity
  • Motor: At birth
    • Respiratory failure (97%)
    • Swallowing difficulties (96%)
    • Face weakness (100%)
    • Ophthalmoplegia (17%)
    • Limbs: Severe; Some with no antigravity movement
  • Treatment ¹²⁵
    • Pyridostigmine (30 mg, 3x/day = 20 mg/kg/day)
    • Ephedrine
  • Death: Mean 5 months; Range 20 days to alive at 11 years
• Laboratory
  • Muscle
    • Rods are
      • Many
      • In most muscle fibers
      • Small: 200 to 500 nm in diameters
      • Shape: Cuboidal
      • Some only seen by EM
    • Muscle fiber size: Varied
    • Type 2 predominance: Some patients
    • Endomysial connective tissue: Normal or Increased
    • KLHL40 protein: Absent or Reduced
  • Hyponatremia
  • Serum CK: Normal after neonatal period

• Epidemiology: 4 families
• Genetics
• Mutations: Small deletions; Missense
• Frameshift: Severe phenotype with early death; Arthrogryposis
• Missense: Weakness; Survival to late childhood or Early adult
• KLHL41 protein in muscle
  • Perinuclear
  • Sarcomere: Near terminal cisternae over I-band
  • Endoplasmic reticulum
  • BTB-Kelch domain containing
  • Interacts with: Nebulin, N-RAP (Nebulin-related anchoring protein), Actin
  • Promotes assembly of myofibrils
  • Mutations: Reduced levels of KLHL41 in muscle
• Clinical: Severe phenotype
  • Fetal akinesia sequence
  • Hypotonia
  • Dislocation of hips & knees
  • Facial dysmorphism: Micrognathia; Cleft palate
  • Death: Cardiorespiratory arrest; Age 1 day
• Clinical: Intermediate phenotype
  • Weakness
    • Initial walking: 2 to 3 years
    • Respiratory insufficiency: 5 years
    • Dysarthria
    • Wheelchair: 16 years
  • Skeletal
    • Palate: High arched
    • Scoliosis
• Clinical: Mild phenotype
  • Weakness: Distal > Proximal
  • Contractures: Distal
• Muscle pathology
  • Nemaline rods: No correlation with disease severity

• Epidemiology: 18 families
• Genetics
  • Mutations: Mostly truncating; G326R; Gln335Arg; Leu550Phe
  • Missense mutations: Milder course
  • Germany & Austria founder mutation: Leu550Phe
• LMOD3 protein
  • Cytoskeleton
  • Tropomodulin family
  • Skeletal > Cardiac muscle
  • M line/thin filament pointed end region
  • Actin nucleator
  • Tropomyosin binding domain
  • Binding partners: Nebulin & KLHL40
• Clinical: Severe, often lethal
  • Onset age: Congenital (90%)
  • Antenatal
    • Polyhydramnios (62%)
    • Fetal movements: Reduced (48%)
    • Joint contractures, multiple (48%)
  • Birth
    • Premature delivery (35%)
    • Hypotonia
    • Weakness: General & Bulbar
    • Respiratory insufficiency
    • Feeding difficulties
  • Ophthalmoplegia (29%)
  • Face
    • Weak
    • Elongated
  • Bulbar
    • Dysphagia: May resolve with increasing age
    • Jaw: Chewing difficulty
    • Speech: Dysarthric
  • Limbs: Weak
  • Scoliosis: some surviving patients
  • Course
    • Severe type: Neonatal death in most
    • Milder course
      • Most ambulatory
      • Patients survive to adulthood
• Laboratory
  • Muscle MRI
    • Sparing: Vastus lateralis, Gracilis, Semimembranosus, Semitendinosus, Extensor digitorum longus
  • Muscle biopsy
    • Nemaline rods: Atypical
      • Present in smaller muscle fibers
      • Clustered
    • Endomysial connective tissue: Increased
    • Sarcomeres: Often reduced or absent
    • LMOD3 often absent
    • Ultrastructure
      • Nemaline bodies
        • Short thickened Z-discs in doublets interconnected by filaments
        • Surrounded by: Short, thin filament fringe
      • Z-band streaming
      • Myofilaments: Disorganized; Core-like structures

• Epidemiology: 5 patients
• Genetics
  • Mutations: Truncation & Splice site
  • Allelic disorders
    • Cardiomyopathies, Dominant
    • Cap myopathy
• MYPN protein
  • Sarcomere component
    • Location: Z- & I-bands
    • Tethers nebulin in skeletal muscle & nebulette in cardiac muscle to α-actinin (ACTN2 ) at Z lines
    • ACTN2 binding site: C-terminal & Central regions of MYPN
    • MYPN-α-Actinin-Nebulin
      • Can form a link tethering actin thin filaments & titin filaments in Z-line
      • Assembles I-Z-I bodies in striated muscle
    • N-terminal region: Binds to cardiac ankyrin repeat protein (CARP; ANKRD1] ; Attached to titin at I-band
  • Nucleus
    • In skeletal & cardiac muscle
    • MYPN colocalizes with CARP
  • Homologous protein: Palladin
• Clinical
  • Onset age: 4 to 25 years
  • Weakness
    • Legs ≥ Arms
    • Distal & Proximal
    • Neck
    • Respiratory
    • Progression: Slow
  • Cardiomyopathy (50%): Hypertrophy; Hypokinesia
  • Skeletal: Mild changes; Face Δ or High arched palate; No contractures
  • Intellect: Normal
• Laboratory
  • Serum CK: Normal
  • Muscle pathology
    • Rods: Granular shape; Intranuclear in 50%
    • Type 1 muscle fiber predominance (> 90%)
    • Fiber sizes: Moderate variation
    • Endomysial connective tissue: Increased in 1 patient
    • MYPN: Absent
  • Muscle CT (Thigh involvement): Sartorius, Gracilis, Biceps brevis femoris muscles
• Heterozygous carriers: No cardiac disease
• MYPN variant syndrome: Congenital myopathy with Caps ± Rods ¹³⁹
  • Epidemiology: French, Asian & African patients
  • Genetics
    • Mutations: Truncation & splice site
    • Allelic disorders
  • Clinical
    • Onset age: Congenital or Early childhood
    • Weakness
      • Diffuse: Axial; Limbs, Proximal & Distal
      • Face: May be asymmetric
      • Respiratory: Some patients
    • Cardiac: Normal
  • Laboratory
    • Serum CK: Normal or Mildly high
    • EMG: Myopathic
    • Muscle MRI: Diffuse smallness; Glutei, Posterior thigh, Anterior leg
    • Muscle biopsy
      • Caps: Stain for Trichrome, PAS, NADH-TR, Myopalladin, Desmin, α-Actinin
      • Rod-like structures: Atypical, Large, Rosette shape
      • Type 1 muscle fiber predominance

• Epidemiology: 1 Iranian-Caucasian patient
• Genetics
  • Mutations: Missense; Met2070Val (c.6208A>G), Arg2980Leu (c.939G>T)
• RYR3 protein
  • Location: Brain & Muscle
  • Muscle
    • Similar in both fiber types
    • Striated
    • Between double RYR1 rows
  • Functions
    • Mediates release of Ca⁺⁺: From sarcoplasmic reticulum → cytoplasm
    • Maintains Ca⁺⁺ release during prolonged periods of Ca⁺⁺ influx
    • Mediates Ca⁺⁺-induced Ca⁺⁺ release from endoplasmic reticulum in non-muscle cells
    • Activity regulated by calmodulin
• Clinical
  • Onset age: 5 years
  • Weakness
    • Face
    • Proximal
    • Symmetric
    • Legs & Arms
    • Vital capacity: 75%
  • Tongue: Small
  • Tendon reflexes: Reduced
  • Skeletal
    • Face: Long; Narrow
    • Micrognathia
    • Scapular winging
• Laboratory
  • NCV: Normal
  • RNS: Normal
  • EMG: Myopathic; No spontaneous activity
  • Serum CK: Normal
  • Muscle pathology
    • Fiber sizes: Varied; Type 1 small; Type 2 large
    • Fiber types: Type1 predominance
    • Rods: Perinuclear; Cytoplasmic; Subsarcolemmal
    • Core-like areas in regions with nemaline bodies

• Epidemiology: 1 patient
• Genetics
  • Mutation: Homozygous; c.1288 delT (C430fs)
  • Allelic disorders: Dilated cardiomyopathy; 6q22 microdeletion
• CAP2 protein
  • Regulates actin cytoskeleton
    • Bindings actin
    • Depolymerizes actin filaments
    • Balance actin monomers with filaments
    • Works with: Cofilin
• Clinical
  • Onset: Birth
  • Cardiomyopathy: Progressive; Dilated
  • Skin: Soft; Wound healing abnormal
  • Joints: Hyperlaxity
  • Hypotonia
  • Weakness: Face; Neck flexors; Ptosis (Lower lid)
  • Tendon reflexes: Reduced
  • Short stature
  • Course: Maintenance with cardiac treatments
• Laboratory
  • Pathology
    • Rods: In skeletal & cardiac muscle
    • Muscle: Fiber sizes varied; Type I predominance
  • Echocardiogram: Decreased biventricular systolioc function

• Epidemiology: Swiss family
• Onset
  • Age: Neonatal
  • Hypotonia
• Clinical: Mild Course
  • Walking: Onset 18 to 24 months
  • Weakness: Axial & Proximal
  • Difficulty running
  • Most with no limitation in normal ADLs
• Muscle biopsy
  • Type 1 muscle fiber predominance
  • Rods: 1% to 5% of muscle fibers; Increase with age

• Infantile onset types: Severe
  • Fetal akinesia sequence
    • Onset: 2nd trimester of pregnancy
    • Polyhydramnion; Joint contractures (Multiple); Lung hypoplasia
    • Not linked to α-actin, nebulin or α-tropomyosin 3
  • Birth
    • Diffuse Hypotonia, Weakness & Little spontaneous activity
    • Respiratory failure
    • Cardiomyopathy: Dilated
    • Arthrogryposis
    • Survival: Weeks to months
  • Pathology: Cytoplasmic & intranuclear rods
    • May need oil immersion lens to visualize
  
  
• Rod myopathy, Adult onset (SLONM): Heterogeneous ⁵⁹
  • Nosology: Sporadic, Late-Onset Nemaline Myopathy
  • Genetics
    • Family history: Often none
    • Gene testing: Usually negative
  • Clinical
    • Onset
      • Age: 3rd to 9th decade; Mean 52 years
      • Subacute: 4 to 8 weeks to nadir
    • Weakness
      • Limbs (85%)
        • Proximal > Distal
        • Arms & Legs
      • Axial
        • Posterior neck (50%)
        • Camptocormia
      • Cranial
        • Face (25% to 60%)
        • Dysphagia (50%)
      • Respiratory
        • Frequency: 50% to 100%; Reduced maximal respiratory pressure
        • Occasionally presenting feature
        • May be associated with M-protein
        • Failure: 30%
        • Common cause of death
      • Asymmetry (30% to 60%)
      • Face: Mild or None
    • Myalgia (60%)
    • Cardiomyopathy: Ventricular; Uncommon
    • Progression
      • High mortality in 5% to 40%: Death within 1 year
      • Slow progression over years in others
      • 10 year survival: 68%
    • Treatment
      • Prednisone
      • IvIg
      • Chemotherapy ± Autologous stem cell transplantation
      • Worse outcome
        • Long disease course before treatment
        • No reduction in M-protein levels
  • Laboratory
    • Muscle biopsy
      • Fiber size: Varied; Small fibers round or angular
      • Rods
        • Frequency: 4% to 40% of muscle fibers
        • Immunostain for: α-actinin; Myotilin; Desmin
        • May be best seen on trichrome in 3 μM sections
        • May only occur later in disease course
      • Rod bearing fibers also have
        • Large vesicular nuclei
        • Focal cytoplasmic basophilia
        • Small vacuoles
      • Cytoplasmic bodies
      • Mitochondrial pathology: COX- fibers common
      • Inflammation
        • Frequency (30%): Mild when present
        • Location: Endomysial or Perivascular
      • Necrotic muscle fibers: Occasional
      • Lobulated muscle fibers (50%)
      • Type I predominance (20%)
      • Ultrastructure: Rods < 1μM in length
    • M-protein
      • Frequency: 50%
      • Type: IgG κ or λ: 50% to 80%
      • Prognosis: No long term effect or ? Unfavorable outcome
    • Serum CK: Usually normal; 65 to 240
    • EMG
      • Irritable myopathy: Fibrillations in > 80%
      • Motor unit potentials: Mixed short & long duration
    • Muscle MRI
      • Trunk: Neck extensors; Paraspinous; Subscapularis
      • Legs: Gluteus, Hamstring (Semimembranosus & Biceps), Soleus
  • Rule out
    • Sarcoglycanopathies
    • HIV nemaline rod myopathy
    • Hereditary nemaline rod myopathy
    • IM-VAMP
  • Treatment: Uncertain; ? Prednisone
  
  
• Central core disease, Rods & Malignant Hyperthermia

Centronuclear (Myotubular) Myopathy ⁸⁹

Types   Dominant     CNM1: Dynamin 2; 19p13       CNM modifier: MTMR14     CNM3: MYF6; 12q21     CNM4: CCDC78; 16p13     CNM: BIN1: 2q14   Recessive     CNM2: BIN1: 2q14     CNM5 (+ DCM): SPEG; 2q35     CNM6: ZAK: 2q31     CNM: RYR1: 19q13     CNM: TTN; 2q31     CNM: GLDN; 15q21     Canine (Labrador): PTPLA   X-linked     CNMX: MTM1; Xq28       Carriers   Differential diagnosis     Myotonic dystrophy 1, Congenital Pathology

• Centronuclear myopathies: Differential features ¹¹⁹
  • Onset age
    • Adolescent or Adult: DNM2; MYF6; BIN1
    • Congenital/Infantile
      • Severe: MTM1 (Nonsense mutation)
      • Moderate: MTM1 > DNM2 > RYR1 > TTN
  • Clinical features
    • Ophthalmoparesis: Common, especially with younger onset
    • Respiratory insufficiency: Earlier onset
    • Distal predominant weakness: Later onset; DNM2; CCDC78
    • Contractures/Scoliosis/Rigid spine: DNM2; RYR1
    • Cardiomyopathy: TTN, SPEG; BIN1
    • No systemic features: MTM1
  • Pathology
  
  
• Centronuclear myopathy: X-linked (CNMX; MTM1; XLMTM)
    ● Myotubularin (MTM1) ; Chromosome Xq28; Recessive
  

  Genetics MTM1 protein Clinical Laboratory Female carriers PIP Phosphatase disorders

  • Epidemiology: 1 male in 50,000
  • Gene features
    • 15 exons: Translation start codon in exon 2
    • Gene expression
      • Ubiquitous
      • Smaller transcript selectively expressed in skeletal muscle & testis
    • Has characteristics of housekeeping function
      • High GC content of MTM1 promoter
      • No defined TATA-box or CAAT-box structure
  • Gene Mutations
    • General
      • > 500 different disease related mutations identified ¹⁰
      • Mutation Locations
        • Widely distributed throughout gene: All 15 exons involved
        • Spread unevenly across gene
        • Hotspots: 6 recurrent mutations
          • Codon 48 frameshift; P205L; R224X; R241C; 420insFIQ; R421X
          • Arg241 Cys: 2nd most frequent mutation; Causes mild (72%) or severe myopathy
      • Mutations in Males > Females
    • Mutation types
      • 60% null variants
      • Point mutations: Missense (55) & Nonsense (40); Most between exons 8 & 12
      • Small insertions or deletions (50)
      • Large deletions (15)
      • Splice site mutations (38)
        • IVS11, A-G, -10: Most common mutation; Causes severe myopathy
      • Germline mosaicism identified in some families
    • Mutation locations
      • Most frequent in exons: 4 > 12 > 3 > 8 > 9 > 11
      • Highly conserved regions
      • ? Reflects importance of mutated gene regions to functional domains
    • Genotype-Phenotype Correlations
      • Truncating & splice site mutations
        • Usually associated with severe phenotype
          • Frequent death or ventilator dependent
          • Muscle fiber size: Smaller
        • Some mild phenotypes with very distal mutations
      • Missense & single amino acid deletion mutations
        • Higher prevalence of mild phenotypes (33%)
        • All in phosphatase active site or SID domain have severe phenotype
      • Protein alteration
        • Predicted severe: 99% with severe phenotype
        • Normal level of myotubularin: Missense mutation or Small deletion or insertion
      • Large chromosomal deletions: Associated abnormal genital development
      • Some symptomatic female carriers
    • Many mutations can be explained by
      • Methylation-mediated DNA repair of modified CpG dinucleotides, or
      • DNA polymerase slippage with short tandem-repeated sequences
    • Allelic disorders
      • X-linked centronuclear myopathy (XLCNM)
      • Myotubular myopathy: Dogs
        • Labrador retriever (p.N155K)
        • Rottweiler (p.Q384P)
        • Boykin Spaniel (p.Arg512X)
      • Myotubular myopathy + Abnormal genital development
        • Contiguous gene syndrome
      • Xq27.3-q28 duplication syndrome
  • MTM1 protein
    • Type: PIP phosphatase
    • Tissue localization: Ubiquitously expressed
    • Cell localization
      • Sarcolemma
      • I band, including triads
      • Associated with endosomes
      • ? Nuclear
    • MTM1 structure
      • Contains active site of protein tyrosine phosphatases (PTP)
      • Similarity to: Dual-specificity serine/tyrosine phosphatases (dsPTPases)
    • MTM1 functions
      • Enzyme action: Dephosphorylates phosphatidylinositol 3-phosphate
      • Associates with SET (Suvar3-9, Enhancer-of-zeste, Trithorax) domains
        • SET domains: In proteins contributing to epigenetic mechanisms of gene regulation
      • Roles
        • Muscle fiber maturation
        • Plasma membrane homeostasis
        • Muscle: Formation & maintenance of "triad"
      • Overexpression
        • Induces the formation of filopodia-like projections
        • Affects protein trafficking from late endosome to lysosome
        • Muscle
          • Proliferation of membrane structures that contain myotubularin
          • Vacuoles labelled by markers of sarcolemma & T-tubules (caveolin-3, dystrophin, DHPR)
    • MTM1 interacts with: SPEG; Desmin
    • Myotubularin family & related disorders
      • Myotubularin-related protein-2: CMT 4B
      • SBF2 (MTMR13): CMT 4B2
      • Endosomal phosphoinositides: PIP5K3 ; François-Neetens Fleck Corneal Dystrophy
    • PIP phosphatase disorders
  • Clinical
    • Onset
      • Infancy
      • Respiratory failure
    • Pregnancy
      • Polyhydramnios: 50%
      • Fetal movement: Decreased
      • Premature delivery 31%
    • Skeletal: Large head (70%); Narrow face (80%); Long digits (60%)
    • Motor
      • Severe Hypotonia: At birth
      • Weakness: Proximal & Distal; Symmetric
      • Respiratory Insufficiency: 90% need external support
    • Ophthalmoplegia & Ptosis
      • Onset age: At birth (60%), or with disease progression
    • Prognosis
      • Early death: Mortality 44%
        • Mean = 5 to 10 months
        • 64% < 18 months
      • ? Improvement after neonatal period
      • Weakness course: Non-progressive
      • Survivors often
        • Respirator dependent (80%)
        • Feeding tube dependent
        • Require head support
        • Never ambulate
    • Systemic features in some survivors > 1 year
      • GI
        • Pyloric stenosis
        • Gallstones
        • Hepatic: Peliosis hepatis; Cholestasis
      • Hematologic
        • Spherocytosis
        • Bleeding diathesis: Vitamin K-responsive
      • Renal: Stones; Calcinosis
      • Skeletal: Rapid linear growth; Advanced bone age
      • Cognitive function: Reduced
    • Treatment: Some benefit from pyridostigmine or albuterol
  • Laboratory
    • CK: Normal or mildly elevated
    • EMG
      • Motor unit potentials: Small amplitude; Polyphasic
      • Spontaneous activity: Fibrillations; Positive sharp waves; Complex repetitive discharges
    • Neuromuscular Junction testing: May be abnormal ⁸⁶
      • Stimulated single fiber EMG: Abnormal in 1 patient
    • Muscle pathology ⁶⁷
      • Single central nucleus
        • In some muscle fibers: Range = 4% to 40%
        • Frequency may increase with age
        • Present in chains on longitudinal sections
        • May occur in both fiber types
        • Perinuclear: Vacuole-like areas
      • Type 1 muscle fiber predominance
      • Muscle fiber size
        • Average fiber size: Reduced
        • Increase in size with age: Reduced
        • Type 1 muscle fibers smaller than type 2: More prominent in older patients
        • Fiber size smaller in more severe disease
        • Fiber size smaller with truncation/deletion mutations than missense mutations
      • Central areas of fibers
        • Reduced myofibrillar ATPase reaction
        • Aggregations of organelles: Mitochondria, Lysosomes, SR
        • Increased oxidative enzyme activity & glycogen staining
      • Periphery of fibers
        • Oxidative enzyme activity: Pale halo
  • Myotubularin mutation: Carriers
    • Mild syndrome
      • Genetics: Missense mutations
      • Clinical
        • Weakness: Face, Mild
        • Skeletal: Asymmetry
    • More severe ⁵⁶
      • Genetics
        • Mutations: Stop; R253X; c.1354–1G>A (Splice site); Large deletion
        • Skewed X-inactivation
          • Several families
          • Minor relation to disease
        • Other mechanisms: Reduced expression of other allele
        • Incomplete penetrance
      • Clinical
        • Onset
          • 1st decade
          • Arm weakness
          • Gait disorder
          • Skeletal asymmetry
        • Weakness
          • Early: Arm
          • Proximal
          • Distal: With disease progression
          • Respiratory
            • Chest wall
            • Hemidiaphragm: Elevated
            • FVC: 23% to 100%
          • Asymmetry
          • Progressive
            • In 3rd to 5th decades
            • May lose ambulation
            • Respiratory
        • Skeletal
          • Asymmetry: Face; Smaller hand on side with more weakness
          • Kyphoscoliosis
          • Pes equinovarus (Bilateral)
      • Laboratory
        • Serum CK: Normal
        • Muscle pathology
          • Varied fiber size: Both fiber types
          • Internal nuclei
          • NADH: Normal internal architecture or Necklace fibers
        • Muscle MRI: Abnormal in weak muscles; Asymmetric
    • Neonatal onset ³⁹
      • Genetics
        • Mutation: 605delT
        • Non-familial case
      • Clinical
        • Hypotonia
        • Joint laxity
        • Waddling gait
        • Weakness: Limb-girdle; Facial
        • Tendon reflexes: Absent
  • Myotubularin knock-out mouse ³⁷
    • Progressive weakness
    • Muscle fiber development
      • Initially normal with peripheral nuclei
      • Later: Degenerative changes & central nuclei
    • Pathology of muscle fibers
      • Variable among muscles: Most in biceps
      • In type I & II muscle fibers
      • Atrophy
      • Mis-localized mitochondria & nuclei
    • Serum CK: Mildly elevated
    • Tissues other than muscle: Spared
  
  
• Centronuclear myopathy: Autosomal Recessive
  • General
    • Onset
      • Infancy, Childhood, Adult < 30 years: ~1/3 each
      • Possible subgroups ⁴⁹
        • Early onset with ophthalmoplegia
        • Early onset without ophthalmoplegia
        • Late onset without ophthalmoplegia
    • Clinical
      • Weakness: Proximal > Distal
      • Ophthalmoplegia: Early onset patients
      • Facial weakness
      • Usually survive past infancy
  
  
• Centronuclear myopathy 2 (CNM2)
    ● Bridging integrator 1 (BIN1; Amphiphysin 2) ; Chromosome 2q14.3; Recessive ⁶⁸ or Dominant
  • Epidemiology: 7 families
  • Genetics
    • Mutations
      • Types: Missense, Splice & Stop; K35N, D151N, K575X
      • Effect: Partial loss of function
      • Homozygous: Common
    • Allelic disorders
      • Centronuclear myopathy, Dominant, Mild, Adult-onset
      • Great Dane canine myopathy
  • BIN1 protein
    • Involved in membrane remodeling
    • Regulated by: Phosphoinositides
    • Role in organization of T tubules
    • Mutations
      • Loss of functional link to Dynamin 2
      • ? Disordered T tubule biogenesis
    • Malignant cells: Often reduced
  • Clinical: Severe CNM
    • Onset
      • Age: Birth to Childhood (8 yrs (D151N mutation))
      • Pregnancy: Reduced or normal fetal movements
    • Weakness
      • Proximal
      • Mild
      • Ophthalmoparesis & Ptosis: Some patients
      • Bulbar: Face; Dysarthria
      • No respiratory failure
    • Muscle atrophy: Diffuse
    • Skeletal
      • Facial dysmorphism, Mild
      • Contractures: Birth
    • Cardiac: Dilated in some patients
    • Course
      • Slowly progressive weakness
      • Survival through childhood: 60%
  • Laboratory
    • Serum CK: Variably high
    • Electrodiagnostic
      • Repetitive stimulation: Decrement
      • EMG: Myotonia & Pseudomyotonia; Myopathic units
  • Pathology
    • Fiber sizes: Less variability than other CNM types
    • Fiber types
      • Homogeneous population of rounded hypotrophic type I fibers
      • Type I predominance
    • Central nuclei
      • In many fibers
      • Clusters & Chains: Several nuclei in central part of fibers
      • Shapes: May be abnormal
    • NADH
      • Central nuclei (clear region) surrounded by rim of densely stained material
      • Radial organization of sarcoplasmic reticulum: Some patients
    • Endomysial connective tissue: Increased
    • Necrosis & Regeneration: Not present
    • Caveolin 3: Immunoreactivity in centrally located vacuoles in some fibers
    • T tubule marker dihydropyridine receptor-a (DHPRa): Immunoreactivity around centrally located nuclei
  • BIN1 variant syndrome: Centronuclear myopathy, Dominant, Adult onset ¹¹⁶
    • Epidemiology: 5 European families
    • Genetics
      • Inheritance: Dominant or Sporadic
      • Mutations
        • Types: Missense; Inframe deletions; Single base pair deletions in stop codon causing larger protein
        • c.1778delC, c.1779delA, c.1780delT, Arg24Cys, Lys21del
    • BIN1 protein
    • Clinical
      • Onset age: 22 to 50 years
      • Weakness
        • Proximal > Distal
        • Legs > Arms
        • Face & Respiration: Normal
        • Gait disorder or Wheelchair: Some patients
        • Progressive
      • Eyes: Ptosis (25%); Vertical gaze palsy (25%)
      • Cognitive: Normal
      • Cardiac: Normal
    • Laboratory
      • Muscle
        • Type I fibers: Predominant (65% to 92%) & Hypotrophy
        • Nuclei: Central & Clustered
        • Muscle fiber central staining: Dynamin 2, Caveolin-3, p62
        • Sarcoplasmic strands, Radial
      • Serum CK: Normal to High x10
      • MRI muscle
        • Distal leg: All muscles, especially posterior
        • Proximal: Patchy muscles; 1 patient with sartorius & adductor longus
      • EMG: Myopathic
  
  
• Centronuclear myopathy (CNM3): Autosomal Dominant
    ● MYF6 ; Chromosome 12q21.31; Dominant
  • Epidemiology: 1 patient
  • Genetics
    • MYF6 gene mutation: Ala112Ser
    • Ala112Ser: Also occurs at low frequency in random databases
    • MYF6 mutation in Becker dystrophy: Converts disease to more severe phenotype
  • MYF6 protein
    • Muscle determination factor
    • Helix--loop--helix domain: Common feature of myogenic factors
  • Clinical
    • Onset: Late Childhood - Adult
    • Weakness: Proximal > Distal
    • Leg cramps
    • ± Ophthalmoplegia, Facial, or Scapular weakness
  • Laboratory
    • CK: Normal or Mildly elevated
    • Muscle biopsy: Myopathic; Ring fibers; Central nuclei
  
  
• Centronuclear myopathy: Autosomal Dominant (CNM1) ⁶⁰
    ● Dynamin 2 (DNM2) ; Chromosome 19p13.2; Dominant or Sporadic
  • Epidemiology: Multiple centronuclear myopathy families
  • Genetics
    • Point mutations: R465W; R369Q; R369W; E368K
    • Locations
      • Exons 8 & 11
      • Middle domain
        • Involved in self assembly & centrosomal location of protein
        • Mild or intermediate phenotype
      • Pleckstrin homology domain: Severe phenotype
    • de novo mutations: Common
    • Allelic with
      • CMT, Dominant-intermediate Type B (CMTDIB): Mutations in plecstrin domain
      • CMT 2M
      • Centronuclear myopathy, Severe neonatal with good prognosis
      • Centronuclear myopathy with cataracts
      • Lethal congenital contracture syndrome 5 (LCCS5): Homozygous mutation
    • MTMR14 : Possible modifier gene
  • DNM2 protein
    • Ubiquitously expressed
    • Associated with microtubules
    • Family: Large GTPases
    • Binds to BIN1 & SNX9
    • Implicated in
      • Endocytosis & Cell motility
        • Regulates tubular invagination of plasma membrane
        • Part of cellular fusion-fission apparatus
      • Membrane: Remodeling & Trafficking processes
        • DNM2 oligomers form: Helical structure around neck of Nascent vesicle
        • GTP hydrolysis: Leads to vesicle release in cytoplasm
    • Dnm2^R465W/+ mouse ¹⁶⁸
      • Satellite cells (Pax7+): Reduced
      • Muscle regeneration: Impaired
  • Clinical
    • Onset
      • Age: Variable
        • Usual
          • Ages: Neonatal, Adolescence & Adult
          • Early milestones: Delayed motor or Normal
        • Earlier onset
          • Some severe, dominant or sporadic patients
      • Symptoms
        • Neonatal: Hypotonia; Respiratory insufficiency
        • Exercise-related muscle pain
        • Weakness
          • Difficulty walking & climbing stairs
          • Falls
          • Poor at sports
    • Weakness
      • Distal > Proximal: Upper extremity all distal
      • Axial: Neck flexors; Abdomen
      • Ocular: Ptosis; Ophthalmoplegia (50%); Strabismus (50%)
      • Face 40%
      • Respiratory: Common with neonatal onset; Restrictive
      • Dysphagia (40%)
      • Progression: Slow; Some patients in wheelchair in 6th decade
    • Fatigue: May respond to pyridostigmine
    • Muscle size
      • Atrophy: Distal (30%)
      • Hypertrophy: Paravertebral
    • Tendon reflexes: Often absent or reduced
    • Contractures
      • Ankles (90%)
      • Fingers
    • Skeletal
      • Palate: High arched
      • Spine (70%): Scoliosis or Hyperlordosis
      • Foot: Pes cavus
    • Other systemic changes in a few patients
      • Retinopathy
      • Neutropenia
      • Cardiomyopathy: In female carrier
  • Laboratory
    • Serum CK: Normal, usually; Mildly high, rarely
    • NCV: Reduced CMAP; NCV some mildly slow
    • EMG: Myopathic; Some with spontaneous activity or pseudomyotonia
    • Repetitive stimulation: Decrement or Normal
    • MRI: Early involvement of distal, posterior leg
      • Involved: Lateral soleus, Gastrocnemius; Posterior thigh; Adductor longus; Biceps; Semimembranosus
      • Spared: Sartorius, Gracilis & Rectus femoris
    • Muscle
      • Nuclei
        • Central: Some in chains
      • Type 1 muscle fibers: Predominant; Small
      • NADH: "Spoke-like" (radial) strands
      • Central region of fibers in regions without nuclei stains for: PAS, phosphorylase & Oxidative enzymes
      • Core-like lesions
        • In more preserved proximal muscles
        • Stain for: Desmin; DHPRα1s; RYR1
      • No multi-minicores or necklace fibers
      • Ultrastructure
        • Central nuclei are normal
        • Central spaces without nuclei have: Mitochondria, Sarcoplasmic reticulum, Golgi complex & Glycogen particles
        • Radial distribution of intermyofibrillar sarcoplasmic strands
  • Variant: Severe CNM, Neonatal onset with good prognosis ⁷¹
    • Family history: Sporadic or Dominant
    • Genetics: DNM2 mutations
      • De novo, Dominant
      • Heterozygous
      • Exon 16: Plekstrin Homology domain, N- & C-terminal regions
      • Types: Missense or In frame
      • Ala618Thr; A618D; Ser619Leu; Ser619Trp; V625del
    • Onset
      • Neonatal
      • Hypotonia
    • Clinical
      • Pregnancy: Normal
      • Motor
        • Hypotonia; Weak suck
        • Cranial nerve: Face weakness; Ptosis; Ophthalmoparesis; Strabismus
        • Weakness: Generalized; Distal > Proximal; Legs > Arms
        • Respiratory weakness: Restrictive syndrome common
        • Age at walking: Usually normal
      • Jaw contractures
      • Skeletal: Pes cavus
      • Cardiac function: Normal
      • Peripheral nerve: Normal
      • Prognosis
        • Good
        • Slow improvement to mid-childhood or adult
        • Some patients in wheelchair in 2nd to 6th decade
    • Laboratory
      • Serum CK: Normal to Slightly increased
      • EMG: Myopathic; Some with spontaneous activity or pseudomyotonia
      • NCV: Occasional axonal neuropathy
      • Muscle
        • Type I fibers: Predominance & Smallness
        • Nuclei
          • Central (3% to 50%): In both fiber types; Some in chains
          • Perinuclear clearing
        • Large fibers: May be both types
        • Radial sarcoplasmic strands: Some
        • Endomysial connective tissue: Variably increased
  • Variant: CNM with Cataracts
    • Genetics
      • DNM2 mutation: Leu621Pro
      • Allelic disorders
    • Clinical
      • Onset: Neonatal
      • Hypotonia
      • Respiratory insufficiency
      • Cataracts
      • External ophthalmoplegia
      • Course: Progressive; Death at 14 years
  • Lethal congenital contracture syndrome 5 (LCCS5), Recessive ⁹⁷
    • Epidemiology: 3 Pakistani infants in 1 family
    • Genetics
      • DNM2 mutation: Phe379Val; Homozygous
      • Allelic disorders
    • Clinical
      • Akinesia
      • Joint contractures
      • Hypotonia
      • Skeletal abnormalities
      • Hemorrhages: Brain & Retinal
    • Laboratory
      • Muscle: Central nuclei
  
  
• Centronuclear myopathy, Recessive ¹¹⁰
    ● Titin (TTN) ; Chromosome 2q31.2; Recessive
  • Epidemiology: 5 patients
  • Genetics
    • Mutations: Truncating or Splice; Compound Heterozygous
    • Allelic disorders
  • Clinical
    • Onset age: Congenital to 3 years
    • Weakness
      • Distribution: Diffuse; Proximal + Distal
      • Face
      • Respiratory
      • Ambulation: Present in 60%
      • Feeding difficulty: Occasional
      • Eye movements: Normal
    • Tendon reflexes: Usually absent
    • Scoliosis (80%)
    • Cardiac: Normal or Dilated cardiomyopathy
    • Cognition: Normal
  • Laboratory
    • Serum CK: Usually normal; May be up to 1,400
    • EMG: Often myopathic
    • Muscle biopsy
      • Nuclei
        • Central in 5% to 25% of muscle fibers
        • Internal, not central: 20% to 70% of muscle fibers
        • Multiple internal in single fiber: Often
      • NADH Internal architecture: Central clear (core-like) regions in some muscle fibers
      • Type 1 fibers: Predominance (60% to 80%); Smallness
      • Fiber size: Variation
      • Endomysial connective tissue: Increased in some patients
      • Titin C-terminal & Calpain-3 staining: Reduced in some patients
      • Ultrastructure: Myofibrillar & sarcomere disorganization in fibers with internal nuclei
  
  
• Centronuclear myopathy 5 (+ Dilated cardiomyopathy, Recessive) (CNM5) ¹¹³
    ● Striated muscle preferentially expressed protein kinase (SPEG; APEG1) ; Chromosome 2q35; Recessive
  • Epidemiology: 6 families, 7 patients
  • Genetics
    • Mutations: Stop (Gln2233*, Arg1426*, c.3709_3715þ29del36, c.3709_3715þ29del36); Missense (Gly2757Val; Thr2904Ala)
  • SPEG protein
    • Muscle cell location
      • Colocalizes with: DHPR; SERCA; Triadin (Junctional SR)
    • SPEGα & SPEGβ isoforms
      • Found in skeletal muscle
      • Disrupted by mutations
    • Interacts with: MTM1
  • Clinical
    • Onset age: Birth
    • Hypotonia
    • Weakness: Longer surviving patients
      • Motor milestones: Delayed
      • Proximal
      • Face
    • Feeding difficulty: G-tube needed
    • Respiratory insufficiency
    • Ophthalmoplegia
    • Tendon reflexes: Reduced
    • Skeletal
      • Palate: High arched
      • Contractures: Hip
      • Arthrogryposis
    • Circulatory
      • Cardiomyopathy, dilated
      • Pulmonary Arterial Hypertension
    • Course: Death at 3 weeks to Surviving at 6 years
  • Laboratory
    • Serum CK: 22 to 280
    • Muscle biopsy
      • Central nuclei
      • Fiber size: Small
      • Fiber type: I predominant
    • SPEG staining: Reduced
  
  
• Centronuclear myopathy: Autosomal Dominant
    ● Centronuclear myopathy: Genetically undefined phenotypes
  • Clinical subtype 1: Typical Dominant centronuclear myopathy ⁴⁹
    • Epidemiology: 2 families
    • Onset age: Childhood to Adult
    • Clinical
      • Weakness
        • Severity: Mild
        • Distribution: Diffuse; Proximal & Distal; Occasional distal predominant
        • Progression: Slow
        • Disability: Mild; Most ambulatory to at least 6th decade
      • Ptosis: Most
      • Contractures: Occasional patient
      • Tremor: Postural; Some patients
    • Laboratory
      • Serum CK: Normal
      • EKG: Normal
      • Pulmonary function: Normal or Reduced
      • EMG: Myogenic
  • Clinical subtype 2: Typical Dominant centronuclear myopathy with muscle hypertrophy ⁴⁹
    • Epidemiology: 1 family
    • Onset: Adolescence & Adult, Rare infant
    • Clinical
      • Muscle hypertrophy: Diffuse
      • Weakness
        • Slowly progressive
        • Distal arms
      • Ocular
        • Ptosis: Common
        • Ophthalmoplegia: Occasional patients
      • Skeletal
        • Rigid spine: Mild 40%
        • Ankle contractures: 30%
        • Finger contractures: 14%
    • Laboratory
      • Serum CK: High (2x to 4x) in some patients
      • EMG: Myopathic
      • FVC: May be reduced
  
  
  
• Centronuclear myopathy: Muscle Biopsy
  • Central nuclei
  • Central pallor on ATPase
    
  • Type 1 fibers predominant & small (50%)
  • NADH: Radial distribution of sarcoplasmic strands
  • 50% of carriers have central nuclei in muscle fibers
  • Endomysial fibrosis: More severe recessive cases
  
  
• Centronuclear myopathy: Canine ⁵⁰
    ● Protein tyrosine phosphatase-like (Proline instead of catalytic arginine), Member A; (PTPLA; HACD1)) ; 10p12.33 (Canine chromosome 2); Recessive
  
  • Epidemiology: Labrador retrievers
    • Carrier frequency: 15%
    • Common in many parts of world
  • Genetics
    • PTPLA mutation
      • Insertion: g.9459-9460ins238
      • Founder: Arose 50 years ago
    • Allelic with: Human CFTD
    • K64Q polymorphism: Found in arrhythmogenic right ventricular dysplasia but not likely pathogenic
  • PTPLA (HACD1) protein
    • Nosology: 3-hydroxyacyl-CoA dehydratase 1 (HACD1)
    • Mainly expressed in skeletal muscles & heart
    • Subcellular: Endoplasmic reticulum resident enzyme
    • Catalyzes 3rd reaction of elongation of very long chain fatty acids (VLCFA)
    • Role in myoblast growth & differentiation
  • Clinical
    • Onset
      • Age: 2 weeks
      • Weight loss
    • Muscle
      • Atrophy: Proximal legs; Cervical; Temporal
      • Hypotonia
      • Neck: Ventroflexion (Head drop)
      • Posture: Abnormal
      • Gait: "Bunny hopping"
      • Tendon reflexes: Absent
      • Mega-esophagus
      • Variable severity
      • Course
        • Progressive over 1st year
        • Then stable
        • Life span: Normal
  • Laboratory
    • Muscle pathology
      • Varied fiber size: Many small fibers
      • Central nuclei: In larger & some smaller muscle fibers
      • Type 1 muscle fibers: Predominance; Small
    • EMG: Fibrillations
    • Serum CK: Normal
    • CNS: Normal
  • Human HACD1 (PTPLA) disease: Congenital fiber size disproportion (Type 1 muscle fibers small & prodominant) ¹⁰⁹
    • Epidemiology: 5 patients
    • Genetics
      • Mutations
        • Type: Trp153Stop; Tyr248Stop; c.739_740delins1250; c.373_375+2delGAGGT; c.785-1G>T
        • Homozygous
      • Allelic with: Canine centronuclear myopathy
    • HACD1 (PTPLA) protein
    • Clinical
      • Onset: Congenital; Hypotonia
      • Weakness
        • Face: Drooling; Reduced suck
        • Head lag
        • Feeding problems
        • Weak cry
        • Apnea: Recurrent (40%)
        • Motor delay: Late walking
        • Hypotonia: Especially proximal
        • Proximal: Gowers sign; Waddling gait
        • Course: Gradual improvement
      • Tendon reflexes: Reduced
      • Cognition: Normal
      • Skeletal: Pes cavus; Pectus excavatum
    • Laboratory
      • Muscle biopsy
        • Type 1 muscle fibers: Small; Predominant (80%)
        • Type 2 muscle fibers: Occasional hypertrophy
        • Internal nuclei: Few fibers
        • No necrosis, cores or rods
        • Dystrophy proteins: Normal
      • Serum CK: Normal
      • EMG: Normal or Myopathic

• Nosology
  • Ventricular tachycardia, catecholaminergic polymorphic, 5 ± Muscle weakness (CPVT5)
  • Triadin knockout syndrome
• Epidemiology: > 20 patients
• Genetics
  • Mutations: Null, Splice, Missense
  • Allelic disorder: Long-QT Syndrome & Pediatric Sudden Cardiac Arrest
• Triadin protein
  • Expression: Cardiac & Skeletal muscle
  • More abundant in type 2 muscle fibers
  • Muscle: Terminal cisternae
  • Associated with
    • RYR1: Present in cores
  • Functions
    • Calcium release units
      • Location: Lateral cisterns of sarcoplasmic reticulum (SR) abut T-tubules
      • Molecules: DHPRs; RyRs; CASQ; Triadin; ATP2A1; STAC3; SPEG
    • Excitation-Contraction coupling
    • Interact with: Microtubules
• Clinical
  • Weakness
    • Onset age: Congenital or in utero
    • Early: Hypoactive or Hypomotile
    • General functions
      • Fatigue
      • Walk short distances
      • Strenuous activities: Reduced
    • Muscles
      • Upper extremities: Suprascapular, Pectoralis major, Deltoid, Finger extensors, Interossei
      • Trunk: Abdominals
      • Legs: Iliopsoas, Anterior tibial, Toe extensors
      • Face & Eyes: Normal
    • Tendon reflexes: Reduced
  • Cardiac
    • in utero: Bradycardia
    • Ventricular fibrillation
    • ? Long QT syndrome
    • Exercise-induced cardiac arrest in early childhood
• Laboratory
  • NCV, EMG & SF-EMG: Normal
  • RNS: Normal
  • Serum CK: Normal
  • EKG
    • T-wave inversion in precordial leads V1–V4
    • QT prolongation: Consistent or Transient
  • Muscle biopsy
    • Gomori trichrome: Abnormal spaces in muscle fibers with dot-like purple membranous material
    • Triadin staining: Reduced
    • Ultrastructure
      • Lateral cisterns of sarcoplasmic reticulum: Focal dilation
      • Triadin anchors from preserved lateral cisterns: Loss or Degeneration
• Triadin variant syndrome: Long-QT Syndrome & Pediatric Sudden Cardiac Arrest ²⁸
  
  • Epidemiology: 5 families
  • Genetics
    • Mutations: Frameshift; Homozygous or Compound heterozygous
    • Allelic disorders
  • Triadin protein
  • Clinical
    • Onset age: Childhood
    • Cardiac arrest: Exercise induced
  • Laboratory
    • Stress test: Ventricular ectopy
    • ECG: T-wave inversions in precordial leads V1 through V4

Congenital Muscular Dystrophy

Congenital Muscular Dystrophy: Typical Features

• Inheritance: Autosomal recessive (AR)
• Frequency: Common cause of AR neuromuscular disorders
• Clinical features
  • Onset age: Congenital or Infancy (< 1 year)
  • Weakness: Diffuse
  • Contractures
  • CNS
    • Common in severe forms of CMD
    • May be subclinical
    • Disorders of myelin or neuronal migration
• Muscle Pathology
  • Myopathic
    • Muscle fibers
      • Size: Varied; Small & Some large
      • Necrosis: Unusual after 4 years of age
    • Endomysial connective tissue: Increased in more severe disorders
  • Disorders of connective tissue molecules
    • Laminin α2: MDC1A
    • Collagen
      • Type VI: Ullrich; Bethlem (Later onset)
      • Type XII
    • Disorders of glycosylation ⁴⁸
      • Marker molecule: α-Dystroglycan
      • Common O-mannosyl glycan structure: NeuAcα2-3Galα1-4GlcNAcα1-2Man-Ser/Thr
      • Disorders: Defective O-mannosylation of α-dystroglycan
      • Specific disorders
        • α-Dystroglycan abnormalities
        • Carbohydrate deficient glycoproteins
      • Nosology
        • MDDGA: Brain, Eye & Muscle involvement (Walker-Warburg)
        • MDDGB: Congenital muscular dystrophy-dystroglycanopathy + Impaired intellectual development
        • MDDGC: Muscular dystrophy-like syndromes
  • Nuclear membranes: Lamin AC
  • Other

Fukuyama congenital muscular dystrophy (MDDGA4): Muscle-Eye-Brain

• Nosology: Muscular Dystrophy-Dystroglycanopathy (Congenital with brain and eye anomalies), Type A, 4
• Epidemiology
  • Japan: Common; Incidence is 40% of Duchenne MD
  • Western countries: Rare
• Genetics
  • Mutations
    • 80% of Japanese patients have similar haplotype
      • Retrotransposal insertion (3kb) of tandemly repeated sequences (Ancestral genotype)
        • Location: 3' untranslated end of fukutin gene
        • Effect of mutation: Reduced fukutin transcription
      • Up to 100% of Japanese patients at least heterozygous for tandem-repeat insertion (Ancestral genotype)
    • Other mutations
      • Japanese patients: Stop codons; Point mutations & small deletions
      • Turkish patient: Homozygous 1 bp Insertion (nt504(insT)) in exon 5
      • Ashkenazi Jews ⁷⁶
        • Mutation: c.1167insA; Homozygous
        • Carriers: 0.7% of American Ashkenazi Jews
        • Phenotype: Severe
  • Genetic-Clinical Correlations
    • Milder phenotype: Homozygous for retrotransposon
    • Severe phenotype: Heterozygous for retrotransposon & point mutation
      • More ocular involvement
    • Homozygosity for point mutations
      • WWS-like syndrome reported
      • May be lethal
  • Allelic disorders
    • Congenital muscular dystrophy (Muscle-Eye-Brain; MDDGA4)
    • Congenital muscular dystrophy (No mental retardation; MDDGB4)
    • LGMD 2M (MDDGC4)
    • Cardiomyopathy (CMD 1X)
• Fukutin protein ¹⁷
  • Brain mRNA
    • Expressed in similar levels in adult & fetal brain
    • Adult: Cortical neurons
    • Fetal: Neuronal precursor & Migrating cells
    • Cellular location: Neurons; Not astrocytes
  • Protein
    • ? More abundant in fetal brain
    • Possibly secreted
    • Skeletal muscle: Not detectable by immunocytochemistry
    • Catalyzes addition of ribitol in α-Dystroglycan glycosylation
• Clinical
  • General
    • Brain: Milder involvement than Walker-Warburg or Muscle-Eye-Brain
    • Eye: Only occasionally severely affected
    • Clinical heterogeneity: Some patients walk & have longer survival
  • Clinical features: Severe cases
    • Motor deficits
      • Onset: Months to 1 year
      • Hypotonia: Severe
      • Weakness & Wasting: Face & Limbs
      • Spasticity: Occasional
    • Face
      • Diplegia
      • Large cheeks
    • Skeletal
      • Contractures
      • Kyphoscoliosis
      • Skull: Microcephaly; Asymmetry
    • CNS
      • Seizures (50%)
      • Mental retardation: Severe; IQ 30 to 50
      • Hydrocephalus: Progressive
    • Ocular
      • Myopia
      • Retinal hypoplasia & detachment
      • Strabismus
      • Persistent primary vitreous body & hyaloid artery
      • Microphthalmos
      • Optic nerve atrophy
      • Blindness: From anterior & posterior chamber eye malformations
    • Course
      • Progressive disability
      • Death: Often < 11 years; Respiratory dysfunction
  • Clinical features: Milder or typical cases
    • Typical peak motor function: Unassisted sitting
    • Mildest cases: Walk unassisted
• Laboratory
  • CNS pathology
    • Cortex
      • Migrational defects
        • Altered radial & tangential neuronal migration
      • Micropolygyria (Type II lissencephaly), cobblestone
      • Absence of lamination in gray matter
      • Breaks in glia limitans & basal lamina
      • Fukutin mRNA in Fukuyama CMD brain
        • Absent in regions of overmigrated dysplasia
        • Moderate expression in more normal areas
    • White matter
      • Hypomyelination
      • Absent corpus callosum & septum pellucidum: Some patients
      • CT scan: Lucencies, especially Frontal, Occipital regions spared
    • Posterior fossa
      • Brainstem: Kinking
      • Pons: Flattening
      • Cerebellum: Hypoplasia
      • Posterior encephalocele
    • Older patients
      • Cerebellar efferent pathway: Dentate nucleus, Superior cerebellar peduncle & Red nucleus
      • Lateral thalamic nucleus
  • Serum CK: Moderately high
  • EMG: Myopathic
  • Muscle pathology: Myopathic
    • Connective tissue: Increased
    • Muscle fiber size: Variable
    • Internal nuclei
    • Differential involvement of muscle fascicles
    • Basal lamina: Disrupted
    • Muscle proteins
      • α-dystroglycan: Greatly reduced in surface membrane & NMJs
      • Laminin α2: Reduced
• Variant syndromes
  • Walker-Warburg (MDDG4A)
  • LGMD 2M
  • Cardiomyopathy (CMD 1X)

Congenital muscular dystrophy: Merosin (laminin α2-chain) deficient (MDC1A) ¹⁶⁹

Epidemiology: > 100 families Genetics Mutations in laminin α2-chain > 300 disease-associated variants Types Deletion (Frame-shift), Stop codon: Severe disease when biallelic Missense Milder disease: Often LGMD R23 Domain VI (N-terminal region) Late-onset LAMA2-MD Moderately reduced protein levels Cysteine residues: In one of 3 EGF-like repeats C-terminal region Splice site (Donor sites) Copy number variants: Often deletions Most common mutation (23%): 2 base pair deletion @ 2,096-2,097 Latino: c.1854_1861dup Mild disease: Mutations Internal in-frame deletion: Small protein (Missing N-terminal) Mutations in conserved donor splicing consensus sequence: Introns 37 & 63 Arg1549* Mutations uncommon: In globular or rod-like domain Offspring of carriers Heterozygotes more common than predicted by chance Allelic disorders Congenital Muscular Dystrophy (MDC1A) Mild weakness LGMD R23 Hypermyelinating neuropathy, Retardation, Epilepsy dy mouse CMD in cats 2° Laminin α2 loss Laminin-211 protein Heterotrimeric glycoprotein Heavy chain (400 kDa): α2-chain protein Light chains (200 kDa): β1 & γ1 Location Basement membrane Muscle, Skin, CNS & Peripheral nerve (Schwann cells) Binds to α-Dystroglycan in basal lamina α2-laminin: 400 kD protein Post-translationally cleaved into 300 kD & 80 kD subunits Subunits remain associated by disulfide bonds Globular domain attached to glycosylated residues of α-dystroglycan Laminin-211: Other Connects to: Collagen IV & Perlecan (Heparan sulfate proteoglycan) Link: Nidogens cross-linking Expression: Muscle; Nerve (Schwann cells); Brain Function: Link between muscle fiber sarcolemma & extracellular matrix α2-laminin expression: Disease relation Severe: 300 kDa & 80kDa subunits abnormal Mild or later onset: 300 kDa subunit often selectively reduced Laminin disorders: Other α4: CMD 1JJ β2: Congenital Myasthenic Syndrome Also see: Laminins Congenital muscular dystrophy: Clinical features Weakness Correlates with level of residual laminin α2 protein Absent laminin α2 protein Severe weakness Distribution: Symmetric; Proximal + Distal; Face Non-progressive Reduced laminin α2: See variant syndromes Muscle: Wasting & Hypotonia Walking Severe disease: Never Mild disease: At 2-3 years Skeletal Scoliosis Contractures Mild disease: Ankle tightness Severe disease Contractures at multiple joints Hips; Knees; Ankles; Elbows; Neck extensor Progressive with increasing age CNS Intelligence often normal Perceptual-motor dysfunction in some Seizures (20%) Neuropathy 171 Mild Occasional Axon loss: Large > Small ± Myelin Δ: Thin myelin; Tomaculae Course Progressively severe contractures Severe disease: Death 15 to 30 years 2° Respiratory failure Laboratory CK: Moderately high CNS MRI: White matter changes (Increased signal on T2); Cortex usually normal Muscle MRI Similar to Collagen VI Involvement of muscle periphery in anterior thigh Sparing: Gracilis & Sartorius Brain pathology patterns Cortical dysplasia Lissencephaly (Agyria or Pachygyria) Polymicrogyria Laminin-α2 disorders: Muscle pathology Laminin-α2 (Merosin) staining Usually absent 95% with absent merosin have Laminin-α2 gene mutation Also reduced in skin (Basal keratinocytes) Partial merosin loss: Milder disability or later onset Clinical: Milder disability or later onset; Late onset seizures Muscle pathology: Myopathy; Rimmed vacuoles & inflammation in some Especially reduced 300 kD subunit Correlates with reduction of laminin β2 chain Normal visual evoked potentials Occasional 2° loss: Other syndromes Pathology: Age-dependent Childhood Fiber size: Varied Endomysial connective tissue: Increased Immature muscle fibers (Type 2C): Many Laminin-α5: Increased Neonatal May be "predystrophic" Only a few degenerating & regenerating muscle fibers Inflammation: Rare, except in biopsies from very young patients Mild disease (Partial merosin loss) Varied fiber sizes Endomysial connective tissue: Increased Internal nuclei: Increased Fiber morphology: Split, Hypercontracted, Whorled Laminin α2 disorders: Variant syndromes Myopathy: Reduced laminin α2; Especially loss of 300 kD N-terminus (LGMD R23 ) Epidemiology: 10 patients; 2% of LGMD Genetics Inheritance: Recessive LAMA2 Mutations Missense Thr821Pro: Mild disease Pediatric CMD patients: More often loss of function Clinical Onset: 1 to 59 years Weakness Mild weakness Proximal ± Distal; Symmetric; Arms & Legs No loss of ambulation Calf hypertrophy: May occur Course: Progressive, slow CNS Epilepsy Impaired cognition Laboratory Brain MRI: Leukoencephalopathy, Most patients Serum CK: High; ~1,000 Muscle pathology Myopathy Rimmed vacuoles Inflammation in some Reduced laminin α2: Loss of 300 kD N-terminus NCV: May have demyelinating neuropathy Neuropathy, Hypermyelinating; Mental retardation; Epilepsy 31 Genetics: Probably allelic with Laminin α2 disorders Onset: Childhood; Developmental delay Clinical Weakness: Distal; Feet > Hands Mental retardation: Moderate Refractory epilepsy: Absences ± eyelid myoclonus; Tonic & complex partial seizures Tendon reflexes: Absent No muscle wasting or joint contractures Laboratory Serum CK: High; 530 Nerve conduction velocities: Reduced Brain MRI: Diffuse white matter involvement Muscle biopsy Myopathy Neurogenic features Laminin α2 mildly reduced Nerve biopsy Laminin α2 virtually absent ‘Globular’ hypermyelination: Located at paranodal regions Mild loss of myelinated axons No demyelination-remyelination changes Myopathies: 2° Laminin α2 loss LGMD 2I (Myopathy with abnormal merosin) Genetics: FKRP mutations with reduced Laminin α2 in muscle CDG: Myopathy with Epilepsy & Microcephaly DPM2 mutations with reduced Laminin α2 in muscle LGMD: ISPD mutations (MDDGC7) CMD syndromes: MEB; Muscle hypertrophy Mouse models dy/dy dy2J/dy2J: Milder phenotype; 300kD subunit selectively reduced

Pectoral folds (Arrow) with severe shoulder weakness

CMD: Normal merosin

Normal Merosin: "Pure" form of congenital MD

• Genes & Syndromes
  • CMD with Rigid spine: SEPN1
  • CMD + Respiratory failure & Muscle hypertrophy (CMD1B; MDC1B)
  • Ullrich: Collagen 6A2
  • CMD + Muscle hypertrophy: FKRP
  • Congenital MG: DOK7
• Clinical features
  • Mild to Moderate Weakness
  • Non-progressive course; mild disability
  • Contractures
  • Normal intelligence
  • Rigid spine
• Laboratory
  • CK: Normal to moderately high
  • MRI: Normal CNS
  • Muscle
    • Some patients have absent α actinin-3 in muscle
    • No gene defects in actinin identified

Congenital MD with integrin α-7 mutations

• Epidemiology: 3 Japanese patients
• Genetics
  • Mutation: 98 base pair deletion most common
• α7β1 Integrin protein
  • Subunit tissue specificity
    • α7: Muscle specific
    • β1: Expressed in many tissues
  • Abundance: α7β1 integrin is primary integrin in muscle
  • Functions
    • Laminin receptor
    • Transmembrane link: Cytoskeleton to Extracellular matrix
    • Myoblast migration
    • Formation of
      • Myotendinous junctions
      • Postsynaptic membrane
  • Changes in other myopathies
    • Increased in Duchenne & Becker MD
    • Reduced in Fukuyama & Laminin α2 deficient congenital MD
• Clinical
  • Motor
    • Hypotonia
    • Delayed milestones
    • Walk: Some patients; At 2 to 3 years
    • Proximal weakness
    • Respiratory involvement: With disease progression
  • Mental retardation in 1 patient
• Lab
  • CK mildly elevated
  • MRI: Normal brain
  • Pathology, Muscle
    • Fiber size variation
    • Reduced staining for integrin α-7

Congenital MD with Joint Hyperlaxity ⁶³

• Epidemiology: French-Canadian families from Southwestern Quebec
• Clinical: Similar to, but milder than, Ullrich CMD
  • Onset
    • Age: Birth
    • Hypotonia with Contractures
  • Weakness
    • Generalized
    • Walking (100%): 1 to 3 years
    • Progression
      • Slow
      • Wheelchair in 2nd to 4th decade
    • Respiratory
      • Vital capacity: Reduced; Mean 50%; Range 21% to 100%
      • No progression
      • No failure
  • Joints & Skeletal
    • Contractures: Ankle (71%), Knee (21%), Shoulder (21%)
    • Hyperlaxity
      • Distal + Other
      • Fingers (93%), Wrists (43%), Toes (43%), Elbows (43%), Cervical spine
    • Scoliosis: Variable; Mild to Severe
    • No protruding calcani
  • Intelligence: Normal
• Laboratory
  • Serum CK: Normal to 1000
  • Cardiac: Normal
• Muscle Pathology
  • Fiber size: Variation
    • Small fibers: Rounded or Angular
    • Hypertrophy
  • Central nuclei
  • Endomysial connective tissue: Increased
  • Type I muscle fiber predominance
  • Rimmed vacuoles: In scattered muscle fibers
  • Normal: α-dystroglycan; Collagen VI
• Heterozygotes: Joint hyperlaxity

Congenital MD with CNS atrophy & Absent large myelinated peripheral nerve axons

• Clinical
  • Onset: Neonatal
  • Arthrogryposis multiplex congenita
  • Psychomotor retardation: Severe and generalized
  • Motor
    • Hypotonia
    • Weakness: Face; Axial & limb
  • Dysmorphic features
  • Course: Respiratory failure & Death in 1st year in some
• Pathology
  • Ventriculomegaly
  • Atrophy: Severe of cerebrum and cerebellum

Congenital MD with cerebellar atrophy

• Clinical
  • Onset: Neonatal to 7 months
  • Hypotonia: Generalized; Delayed motor milestones
  • Weakness: Proximal > Distal
  • Cerebellar: Ataxia; Nystagmus; Dysarthria
  • Mental retardation
• Lab
  • CK: 900 to 5,000
  • Muscle
    • Fiber size variation
    • Connective tissue: Increased
    • Normal dystrophin & merosin
  • Cerebellum: Atrophy; Dandy-Walker variant
  • White matter: Normal
• Non-progressive

Muscle-Eye-Brain Disorders ¹⁹

• General CNS changes: "Cobblestone" cortex
  • Gyral absence or malformations
  • Disorganized cortex of variable thickness
  • Deficient neuronal migration
  
  
• Walker-Warburg Syndromes (WWS): General
  
  • Clinical: Systems with anomalies
    • Brain
    • Muscle
    • Eye
  • Gene disorders: Generally produce abnormal glycosylation of α-dystroglycan
    • MDDGA1: POMT1; 9q34
    • MDDGA2: POMT2; 14q24
    • MDDGA3: POMGnT1; 1p34
    • MDDGA4: Fukutin: 9q31
    • MDDGA5: FKRP; 19q13
    • MDDGA6: LARGE1; 22q12
    • MDDGA7: ISPD; 7p21
    • MDDGA8: GTDC2; 3p22
      
    • MDDGA9: DAG1; 3p21
      
    • MDDGA10: TMEM5; 12q14.2
    • MDDGA11: B3GALNT2; 1q42
    • MDDGA12: SGK196; 8p11
    • MDDGA13: B3GNT1; 11q13
    • MDDGA14: GMPPB; 3p21
    • MDDGA, Other: Many not identified
    • Also see: MDDGC15; DPM3
    • Note: MDDGB & MDDGC are
      • Alleic with MDDGA (Same genes)
      • Milder congenital muscular dystrophies (MDDGB)
      • Limb girdle muscular dystrophy syndromes (MDDGC)
      • MDDG: Biochemical types
      • Dystroglycanopathies
  • Other lissencephalies
    • Miller-Dieker
    • X-linked lissencephaly with agenesis of corpus callosum
    • Norman-Roberts
  • Muscle histology
    • Myopathy with increased connective tissue
    • α-dystroglycan: Hypoglycosylation
  
  
• Walker-Warburg Syndrome (MDDGA1)
  ● O-Mannosyltransferase 1 (POMT1) ; Chromosome 9q34.13; Recessive
  
  • Genetics: POMT1
    • Mutations
      • Misense: Gly76Arg
      • Stop & Frameshift: Gln303Stop; Gln385Stop; 2110InsG; 2167InsG
      • Transversion: 1283T to A,
    • Genetic heterogeneity
      • POMT1 mutations identified in 20% of Walker-Warburg families: Typical WW syndromes
    • Allelic with
      • LGMD with Mental retardation and reduced α-dystroglycan (MDDGB1)
      • Limb-girdle muscular dystrophy-dystroglycanopathy C1 (MDDGC1; LGMD 2K)
  • O-Mannosyltransferase 1 (POMT1) protein
    • O-mannosyl-transferase
    • Different isoforms due to alternative splicing
    • Ubiquitously expressed
    • Peak levels: Adult testis; Skeletal & cardiac muscle; Fetal brain
    • Functions
      • Synthesizes O-mannose linked core of oligosaccharide with POMgnT1
      • POMT1 catalyses first step in O-mannosyl glycan synthesis
  • O-Mannosylated proteins
    • O-Mannosylated proteins in mammals: α-dystroglycan, N-CAM, tenascin-J1
      • O-glycans attached to α-dystroglycan play a role in molecular recognition of laminin-α2
    • O-Mannosyl glycan sequences share
      • Galβ1-4GlcNAcβ1-2Man-OSer/Thr
      • Sialated variant in both brain & muscle: Neu5Acα2-3Galβ1-4GlcNAcβ1-2Man-O-Ser/Thr
    • O-Mannose–linked glycosylation locations: Brain, Peripheral-nerve, Muscle glycoproteins
    • 30% of all O-linked sugar chains in brain are O-mannose based
    • Other disorders of glycosylation: POMGnT1, Fukuyama CMD & FKRP, LARGE1
  • Epidemiology
    • World-wide distribution of WW syndrome
    • POMT1 mutations identified in Turkish & European families
  • Clinical
    • Most severe CMD with glycosylation disorder
    • Motor: Hypotonia
    • CNS
      • Seizures
      • Severe retardation
    • Eye: Multiple anterior & posterior anomalies; Congenital
      • Anterior
        • Cataract
        • Shallow anterior chamber
        • Microcornea & microphthalmia
        • Lens defects
      • Posterior
        • Retina: Detachment, Dysplasia & Undifferentiated neurons
        • Optic nerve & macula: Hypoplasia & atrophy
        • Coloboma
    • Other: Testicular defects in males
    • Course: Death in fetus or infancy
      • Usually < 1 year
      • Range 0.1 to 3 years
  • Laboratory
    • CK: Variable; POMT1 mutation patients > 1,500
    • Muscle pathology
      • Mild dystrophic changes
      • α-Dystroglycan in connective tissue: Reduced glycosylation
      • Normal merosin
  • CNS pathology
    • Cortex
      • Migrational defects
        • Pathology: Neuronal heterotopia
        • Pathophysiology
          • Defects in the pial glia limitans
          • Result in neural over-migration during neocortex lamination
      • Thin
      • Hydrocephalus: Dilated ventricles
      • Lissencephaly: Type 2; Not classic 4 layered cortex; Cobblestone
      • Occipital encephalocoele
    • White matter: Disorganized myelination; Absent or thin corpus callosum
    • Cerebellum: Afolia; Vermal or general hypoplasia
    • Brainstem: Small/Absent pyramids
    • Spinal cord: Small/Absent Lateral columns; Aberrant anterior root entry zones
  • Variant syndrome: Congenital muscular dystrophy with Muscle hypertrophy, Microcephaly & Mental retardation ¹⁵
    
    • Epidemiology: Italian children
    • Genetics: Recessive inheritance
    • Onset
      • Birth
      • Hypotonia
    • Clinical
      • Hypotonia
      • Joint contractures: Hips; Knees; Ankles: Elbows; Neck flexors
      • CNS: Psychomotor retardation; Absent speech
      • Motor: Inability to walk; Diffuse weakness
      • Muscle hypertrophy: Calf; Quadriceps; Tongue
      • Ocular: Normal
      • Course: Non-progressive
    • Laboratory
      • Serum CK: Very high
      • Muscle biopsy
        • Dystrophic changes
          • Small muscle fibers
          • Connective tissue increased
          • Little degeneration or regeneration
        • Laminins
          • α2: Partial reduction
          • α5: Increased
      • Brain MRI
        • Posterior fossa: Enlarged cisterna magna; Cerebellar vermis ± hemisphere hypoplasia
        • White matter: Patchy signal, especially periventricular
      • EKG: Normal
    • Also see: CMD with cerebellar cysts
  
  
• Walker-Warburg Syndrome (MDDGA2)
  ● O-Mannosyltransferase 2 (POMT2) ; Chromosome 14q24.3; Recessive
  
  • Nosology: Muscular dystrophy-Dystroglycanopathy (Congenital with brain and eye anomalies), Type A, 2
  • Epidemiology
    • 6 families linked to locus
    • 3 families with identified mutations
  • Genetic
    • Mutations: Homozygous R638X; c.1005+1G>A (splice site); T433X
    • Allelic with
      • Congenital muscular dystrophy-dystroglycanopathy with mental retardation B2 (MDDGB2)
      • Limb-girdle muscular dystrophy-dystroglycanopathy C2 (MDDGC2; LGMD 2N)
  • POMT2 protein
    • O-mannosyltransferase 2
      • Forms complex with protein O-mannosyl-transferase 1 (POMT1)
      • Catalyses 1st step in synthesis of O-mannosyl glycan (n α-dystroglycan)
    • Short transcript: Widely expressed
    • Long transcript: Expressed only in testes
    • Subcellular: Associated with endoplasmic reticulum
  • Clinical: Similar to other WWS syndromes
    • Onset
      • Age: Prenatal
      • Hydrocephalus
    • Hypotonia
    • Ophthalmic: Cataracts; Microphthalmia
  • Laboratory
    • Serum CK: High
    • MRI: Lissencephaly; Hydrocephalus; Hypoplasia of pons & cerebellum
    • Muscle biopsy
      • Fiber size: Varied
      • Endomysial connective tissue: Increased
      • Basophilic muscle fibers
      • α-dystroglycan staining: Reduced
  • POMT2 Variant syndrome: LGMD R14 ⁷⁹
    • Nosology: LGMD 2N
    • Epidemiology: 16 patients
    • Genetics: POMT2 mutation
      • Homozygous or Heterozygous
      • Missense: All patients with at least one
    • Clinical
      • Onset
        • Age: Birth to 55 years
        • Walking late
        • Serum: High CK
      • Motor
        • Weakness
          • Proximal > Distal
          • Legs > Arms
          • Legs: Hip exztensors & Knee flexors
          • Symmetric in most
        • Functional: Slow running
        • Calf hypertrophy
        • Scapular winging
        • Course: Slow progression
      • Skeletal: Lordosis, mild
      • Intellect: Cognitive impairment in many or Normal
      • Eye: Normal
      • Cardiac: Usually normal; Few with reduced LVEF
    • Laboratory
      • Serum CK: High; 300 to 5000
      • EMG: Myopathic
      • Muscle biopsy: Myopathic
        • Fiber sizes: Varied
        • Necrosis & Regeneration
        • Cellularity: Macrophages
        • α-dystroglycan: Reduced glycosylation
      • Muscle MRI: Involvement of hamstring, paraspinal & glutei
      • Brain MRI
        • Abnormal (30%): More severely involved patients
        • Ventricular enlargement, Periventricular changes
  
  
• Santavuori congenital muscular dystrophy (Finnish; Muscle-eye-brain disease (MEB)) (MDDGA3) ²⁹
  ● O-linked mannose β1,2-N-acetylglucosaminyltransferase (POMGnT1) ; Chromosome 1p34.1; Recessive
  • Epidemiology
    • Disease focus: Finnish (Founder effect)
    • Other: Turkish, French, Japanese, Chinese & Korean families
  • POMGnT1 gene
    • Mutations
      • Types: Missense, Nonsense & Frameshift
      • More severe phenotype with mutations toward 5’ end of gene
    • Allelic with
      • Congenital muscular dystrophy, milder (MDDGB3)
      • Limb girdle muscular dystrophy (MDDGC3; LGMD 2O)
  • POMGnT1 protein function
    • O-Mannosyl glycosylation
      • Transfers N-acetylglucosamine residue to an O-linked mannose
      • O-Mannosyl glycan required for binding between α-dystroglycan & laminin
      • Glycosylation stabilizes main O-glycosylation branch
    • ? Role in neuronal migration
    • Mutation effects: Reduced enzyme function
  • Clinical
    • Severity: Milder than Walker-Warburg
    • Motor
      • Hypotonia: Congenital
      • Development: Slow
    • CNS: Severe mental retardation
    • Eye
      • Coarse trabecular meshwork in anterior chamber: Myopia (>-6 diopters); Glaucoma
      • Retinal dysplasia
      • Juvenile cataracts
    • Death
      • Age: 6 to 42 years
      • Longer survival than Walker-Warburg
  • Laboratory
    • Serum CK: Mild elevation
    • Visual evoked potentials: Giant
  • Muscle pathology
    • Infancy: Muscle fiber degeneration & regeneration
    • Dystrophic: Childhood
      • Muscle fiber size: Varied
      • Muscle fiber regeneration
      • Endomysial connective tissue: Increased
    • Connective tissue components
      • α-Dystroglycan: Reduced
      • Merosin: Reduced (to 10% to 20%)
      • Laminin-β2: Increased
  • CNS pathology
    • Brainstem: Thin
    • Cerebellar: Hypoplasia with absent inferior vermis; Cysts
    • Cortex: Disorganization (cobblestone); Midline defects; Hydrocephalus
    • White matter: Abnormal, especially diffuse at young ages < 1.5 years
  • POMGNT1 variant syndrome: Muscular dystrophy (MDDGC3; LGMD R15)
    • Nosology: LGMD 2O
    • Epidemiology: Single Irish patient
    • POMGnT1 mutation: Homozygous; Asp556Asn
    • Clinical
      • Onset age: 12 years
      • Weakness
        • Proximal > Distal
        • Neck
        • Hip girdle,
        • Shoulder abductors
      • Muscle size
        • Hypertrophy: Calves; Quadriceps
        • Wasting: Hamstrings; Deltoid
      • Contractures: Posterior ankles
      • Intellect: Normal
      • Cardiac: Normal
      • Progression: Loss of ambulation < 20 years
    • Laboratory
      • Serum CK: Very high (> 5,000)
      • EMG: Myopathic
      • Muscle: Dystrophic; α-dystroglycan staining present with varied intensity
  
  
• Walker-Warburg Syndrome (MDDGA7; LGMD 2U) ⁹¹
  ● Isoprenoid synthase domain containing (ISPD) ; Chromosome 7p21.2; Recessive
  • Epidemiology: > 10 families; 2nd most common form of WWS (10%)
  • Genetics
    • Mutations
      • Types: Deletions; Missense (ISPD domain); Nonsense
      • Effects: Loss of function
    • Allelic with
      • Congenital Muscular Dystrophy (MDDGB7)
      • Limb-Girdle Muscular Dystrophy (MDDGC7)
  • ISPD protein
    • Mutations impair protein O-mannosylation: 1st step in synthesis of laminin binding glycan
  • Clinical syndromes
    • Walker-Warburg
      • Severe phenotype
      • Hypotonia
      • Eye: Microphthalmia; Cataracts; Glaucoma; Retinal pathology; Optic nerve hypoplasia
      • Death: 80% Neonatal to 24 months
    • Muscle-Eye-Brain
  • Laboratory
    • Serum CK: Very high; 1,900 to 100,000
    • MRI
      • Hydrocephalus
      • Cobblestone lissencephaly
      • Cerebellar hypoplasia
      • Kinked brainstem
      • Corpus callosum: Hypoplasia
    • Muscle
      • Dystrophic
      • α-Dystroglycan reduced or absent
  • Variant ISPD syndrome: Limb-Girdle Muscular Dystrophy (MDDGC7; LGMD R20) ⁹⁹
    • Nosology: LGMD 2U
    • Genetics
      • ISPD Mutations: Inframe deletion (Val372del); Missense & Stop
    • Clinical
      • Onset
        • Age: Early childhood
        • Hypotonia
        • Gait disorder
        • Gowers' sign
      • Weakness
        • Proximal > Distal
        • Course
          • Progressive
          • Loss of ambulation: Often ≤ 12 years
      • Muscle size: Hypertrophy
      • Brain: Normal
      • Cardiac: Mildly reduced LV function
    • Muscle
      • Fiber size: Varied
      • Endomysial connective tissue: Increased
      • Muscle fiber necrosis & Regeneration
      • α-dystroglycan: Absent or Severely reduced
      • Laminin-α2: Reduced
    • Laboratory
      • Serum CK: 700 to 9000
  • Variant ISPD syndrome: Limb-girdle dystrophy with Cerebellar involvement
    • Onset age: < 1 year
    • Weakness: Proximal
    • Eye
      • Myopia: Severe
      • Oculomotor apraxia
    • CNS: Cerebellar cysts & hypoplasia
  • Variant ISPD syndrome: Congential muscular dystrophy (MDDGB7) ⁷⁰
    • Genetics
      • Mutations: Missense (Ile153Thr) & Splice (c.535-3C>G, c.1251G>A)
    • Clinical
      • Weakness
        • Hypotonia
        • Proximal & Distal
        • Non-ambulant
        • Respiratory & Face: Normal
        • Course: Progressive over 1st year
      • Contractures: No
      • Cardiac, CNS & Eye: Normal
    • Laboratory
      • Serum CK: 2000 to 6000
      • Muscle
        • Fiber size: Varied
        • Endomysial connective tissue: Increased
        • α-dystroglycan: Reduced or Absent
      • Brain MRI: Normal
  
  
• Walker-Warburg Syndrome (MDDGA8) ⁹⁶
  ● Protein O-Mannose β-1,4-N-Acetylglucosaminyltransferase 2 (GTDC2; AGO61; c3orf39; POMGNT2) ; Chromosome 3p22.1; Recessive
  • Epidemiology: Consanguineous WWS families
  • Genetics
    • Mutations: Arg158His; Trp197X; Arg445X
    • Allelic disorders: LGMD syndrome
  • GTDC2 protein
    • Contains uncharacterized glycosyltransferase domain
    • High in brain, muscle, heart & kidneys
    • Pathway: α-Dystroglycan glycosylation
    • Disorders: α-Dystroglycan glycosylation
  • Clinical: Walker-Warburg Syndrome
    • Brain
      • Cobblestone lissencephaly
      • Hydrocephalus, severe
      • Cerebellar vermis: Hypoplasia
    • Eyes: Retinal hypoplasia; Microphthalmia; Macrophthalmia
    • Muscle: Hypotonia
    • Death: Few months of age
  • POMGNT2 variant syndrome: Limb-Girdle MD syndrome (MDDGC8) ¹²⁹
    • Nosology: LGMD 24
    • Epidemiology: 3 Japanese patients
    • Genetics
      • Inheritance: Recessive
      • Mutations: c.494T>C (Met165Thr) & c.785C>T (Pro253Leu), Heterozygous; c.785C>T (Pro253Leu), Homozygous
    • Clinical
      • Onset age: 11 mo to 13 years
      • Weakness: Proximal; 1 patient
      • Calf hypertrophy
      • Face: Normal
      • CNS: Intelligence reduced in 2 patients
    • Laboratory
      • Brain MRI: Normal
      • Muscle MRI: Diffuse atrophy
      • Serum CK: 300 to 4,000
      • Muscle biopsy
        • Muscle fiber necrosis & regeneration: Scattered
        • Internal nuclei
        • Endomysial connective tissue: Increased
        • Perimysium: Increased cells
        • α-Dystroglycan: Absent
  
  
• Walker-Warburg Syndrome & Cobblestone Lissencephaly (MDDGA10)
  ● Ribitol Xylosyltransferase 1 (RXYLT1; TMEM5) ; 12q14.2; Recessive
  • Epidemiology: 13 patients
  • Genetics
    • Mutations: Nonsense; Frame shift
    • Allelic disorder: Congenital MD + CNS
  • RXYLT1 protein
    • UDP-D-Xylose:Ribitol-5-phosphate β1-4 Xylosyltransferase
    • Linkage of 1st Xylose residue to ribitol-5-phosphate
    • Exostosin family domain
    • Membrane protein (Type 2)
    • Role: α-Dystroglycan glycosylation
    • RXYLT1 product: Acceptor substrate for B4GAT1 to add Glucuronate moiety
    • Mutation: Absent (-3GlcAβ1-3Xylα1-) repeat
  • Clinical
    • CNS syndromes
      • Walker-Warburg
      • Muscle-Eye-Brain (MEB)
    • Hypotonia
    • Retinal dysplasia
    • Gonadal dysgenesis
    • Course: Death in utero to 2 years
  • CNS pathology
    • Lissencephaly: Cobblestone
    • Occipital neural tube defects
    • Pachygyria
    • White matter pathology
    • Cerebellum: Dysplasia or Atrophy
    • Pons: Atrophy
  • Laboratory
    • Serum CK: Very High
    • Muscle
      • Myopathy
      • Muscle fiber necrosis
      • Endomysial connective tissue: Increased
      • α-Dystroglycan: Reduced
  • TMEM5 variant syndrome: Congenital Muscular Dystrophy + CNS ¹³²
    • Epidemiology: 1 Italian male
    • Genetics
      • Mutation: Homozygous c.139delG
    • Clinical
      • Onset
        • Age: Birth
        • Respiratory distress
      • CNS
        • Developmental milestones: Delayed
        • Intellectual disability: Moderate
      • Weakness: Mild limb-girdle muscle involvement
      • Fatigue
      • Cochlear dysplasia
      • Course: Stable
    • Laboratory
      • CNS MRI
        • Frontotemporal polymicrogyria
        • White matter: Abnormal signal
        • Cerebellar: Abnormal folia
        • Pons: Hypoplasia
      • EEG: slow waves
      • Serum CK: High; 2,000 to 3,200
      • Muscle pathology
        • Muscle fiber size: Variation
        • Necrosis
  
  
• Walker-Warburg Syndrome (MDDGA12) ¹⁰⁵
  ● Protein O-Mannose Kinase (SGK196; POMK) ; 8p11.21; Recessive
  • Epidemiology: 6 families
  • Genetics
    • Mutations: Heterozygous; Missense; Leu137Arg, V302D, Gln258Arg
    • Allelic with: MDDGC12
  • POMK (SGK196) protein
    • Ser/Thr protein kinase family: Kinase probably inactive
    • Membrane protein
    • ? ATP binding
    • α-Dystroglycan glycosylation
      • Phosphorylation at 6-position of O-mannose
  • Clinical
    • Eye: Hyperplastic primary vitreous; Myopia; Microphthalmia.
    • Hypotonia
    • Seizures
    • IQ: Very reduced
    • Meningoencephalocele
    • Death: 3 to 4 years
  • Laboratory
    • Head imaging
      • Hydrocephalus: Triventricular
      • Cortex: Thin; Agyria; Cobblestone lissencephaly
      • Cerebellar hemispheres & Brainstem: Compressed
      • Arnold Chiari malformation
    • Serum CK: 3,000 to 7,000
    • Muscle
      • Myopathy
      • Normal: Dystrophin; Sarcoglycans; Laminin-α2
  • SGK196 (POMK) variant syndrome: MDDGC12
    • Epidemiology: 2 Jordanian siblings
    • Genetics
      • Mutation: Truncating; Q109X
      • Allelic disorder
    • Clinical: MDDGC
      • Onset age: Infancy
      • Weakness
        • Infancy: Hypotonia; Delayed walking
        • Young adult: Proximal > Distal; Mild face; Independent ambulation
      • Calf: Pseudohypertrophy
      • Tendon reflexes: Reduced
      • CNS: IQ 80 to 85
      • Retina: Normal
    • Laboratory
      • Serum CK: High; 1000 to 1400
      • Muscle: Chronic myopathy
        • Necrosis & Regeneration
        • Dystrophin, dysferlin & sarcoglycans normal
      • Brain imaging: Normal or Unrelated focal changes
  
  
• Congenital Muscular Dystrophy & α-Dystroglycan Hypoglycosylation (MDDGA11) ¹⁰⁴
  ● β-1,3-N-acetylgalactosaminyltransferase 2 (B3GALNT2) ; Chromosome 1q42.3; Recessive
  • Epidemiology: US, Europe, Turkey, Saudi Arabia; 6 patients
  • Genetics
    • Mutations: Heterozygous or homozygous; Missense or Stop
  • B3GALNT2 protein
    • Location: Endoplasmic reticulum
    • Function
      • Protein Glycosylation
      • Completes trisaccharide GalNAc-β1,3-GlcNAc-β1,4-Man
  • Walker-Warburg phenotype
    • Clinical
      • Onset age: Birth
      • Hypotonia: No motor milestones
      • Cognitive development: Absent
      • Epilepsy
      • Eye: Optic nerve hypoplasia; Cataracts; Microphthalmia
    • Laboratory
      • MRI: Hydrocephalus; Lissencephaly, Cobblestone
      • Serum CK: 1,000 to 21,000
  • Muscle-Eye-Brain disease (Fukuyama congenital muscular dystrophy) phenotype
    • Clinical
      • Onset age: Birth to 17 months
      • Delay: Motor & Cognitive
      • Eye: Optic nerve hypoplasia or No changes
    • Laboratory
      • MRI: Polymicrogyria; Leukoencephalopathy; Cerebellar cysts or dysplasia
      • Serum CK: 800 to 2,000
  • Muscle pathology
    • Varied fiber size
    • Regeneration
    • Endomysial connective tissue: Increased
    • Internal nuclei
    • α-Dystroglycan: Glycosylation reduced (IIH6 binding variably reduced)
  
  
• Walker-Warburg (MDDGA13) ¹⁰⁶
  ● β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1; B4GAT1) ; Chromosome 11q13.2; Recessive
  • Epidemiology: East Indian & Saudi families
  • Genetics
    • Mutations
      • Homozygous
      • Both Asn390Asp & Ala406Val; c.821_822insTT (p.Glu274Aspfs*94)
  • B3GNT1 protein
    • Acceptor from RXYLT1: Adds Glucuronate moiety to α-dystroglycan
    • Xylose β1,4 glucuronyltransferase
    • Forms GlcAα1-4 linkage
    • Complex with LARGE1
  • Clinical
    • Onset age: Prenatal
    • Hydrocephalus: Intrauterine
    • Walker-Warburg syndrome
    • Motor & Cognitive impairment
    • Seizures
    • Spasticity
    • Optic nerve: Agenesis
    • GU: Undescended testes, Micropenis, Hydronephrosis
    • Death < 1 year
  • Laboratory
    • Serum CK: High, 3,180 to 15,000
    • MRI
      • Ventricular enlargement
      • Diffuse widening of gyri
      • Disorganization of cortical sulci: cobblestone lissencephaly along posterior occipital & temporal lobes
    • Muscle
      • Reduced laminin-α2 & α-sarcoglycan
      • α-dystroglycan: Reduced glycosylation; Reduced binding of to laminin
    • Brain pathology
      • Lissencephaly type II: Cortical dysplasia, Glio-neuroepithelial leptomeningeal heterotopia
      • Obliteration of subarachnoid space
      • Communicating hydrocephalus
      • Cerebellum: Cortical dysplasia/hypoplasia; Inferior vermian defect
      • Pyramids: Medulla hypoplasia
      • Inferior olives: C-shaped dysplasia
      • Hydromyelia
      • Retina: Focal disorganization; Dysplasia
  
  
• Congenital Muscular Dystrophy, Retardation ± Eye Disorders (MDDGB14; LGMD R19) ¹⁰⁸
  ● Mannose-1-phosphate guanyltransferase beta (GMPPB) ; Chromosome 3p21.31; Recessive
  • Nosology: LGMD 2T
  • Epidemiology: 8 families
  • Genetics
    • Mutations: Homozygous or Heterozygous; Missense (Most common)or Stop (Severe patient)
  • GMPPB protein
    • Location: Cytoplasm
    • Catalyzes: α-D-mannose-1-phosphate + GTP → GDP-α-D-mannose
    • GDP-mannose: Required in 4 glycosylation pathways
    • Inhibited by: GMPPA
  • Clinical
    • Allelic syndromes
      • Walker-Warburg (MDDGA14)
      • Congenital MD (MDDGB14)
      • LGMD 2T (MDDGC14)
      • Myasthenic syndrome
    • Onset age: Birth to 4 years
    • Weakness
      • Hypotonia
      • Poor head control
      • Delayed walking (80%)
      • Difficulty climbing stairs
      • Feeding difficulties (25%)
      • Exercise intolerance: Milder patient
    • CNS
      • Intellectual delay (80%)
      • Epilepsy (40%)
    • Eye: Cataracts (40%); Retinal disease (10%)
    • Cardiac: Cardiomyopathy (25%)
  • Laboratory
    • Serum CK: High; Range 630 to 7300
    • Brain MRI: Cerebellar hypoplasia (40%)
    • Muscle: α-dystroglycan has reduced glycosylation
  • GMPPB variant syndrome: Limb Girdle Muscular Dystrophy 2T (MDDGC14; LGMD 2T)
    • GMPPB genetics
      • Inheritance: Recessive
      • Mutations: Missense; Asp27His, Arg287Gln, Pro32Leu, Cys266Tyr
    • Clinical
      • Onset age: Birth to 4th decade
      • Weakness
        • Limbs, proximal
        • Course: Slow progression
      • Rhabdomyolysis & Cramps
      • Muscle size: Enlarged calves in some patients
      • CNS: Learning difficulties (50%)
      • Cardiomyopathy: 1 patient
    • Laboratory
      • Serum CK: High
      • Muscle
        • Fiber size: Varied
        • Internal nuclei
        • Muscle fiber necrosis
        • Endomysial connective tissue: Increased
        • α-dystroglycan: Reduced
        • Western blot: Laminin-α2 reduced
      • Muscle MRI: Involvement of Paraspinals, Hamstrings & Medial Gastrocnemius
  • GMPPB variant syndrome: Myasthenic syndrome ¹²²
    • Epidemiology: 7 patients in 5 families
    • Genetics
      • Inheritance: Recessive
      • Mutations: All through gene; Missense in at least 1 allele
    • Clinical
      • Onset age: 1.5 to 31 years
      • Weakness
        • Proximal limbs
        • External rotation: Arm & Thigh
        • Variable: Activity-dependent fatigue; Improve with rest
        • Face & Eyes: Spared
      • Treatment: Pyridostigmine ± Salbutamol
      • Cognition: Normal, or mildly delayed
    • Laboratory
      • EMG: Myopathic
      • RNS: Decrement in proximal muscles
      • SFEMG: Abnormal
      • Serum CK: High; 400 to 3000
      • Muscle pathology: Myopathic; α-Dystroglycan reduced
      • Muscle MRI: Proximal > Distal involvement

Congenital Muscular Dystrophy with Familial Junctional Epidermolysis Bullosa (EBSMD) ¹⁵⁷

• Genetics
  • Gene structure
    • 32 exons
    • Exons 2 to 32: Constant
    • First exons
      • 8 alternative
      • Variable length & sequence
      • Spliced into a common exon 2
  • Mutations
    • Types: Missense, Stop, Amall deletions & duplications
    • Location: Exon 31 (Rod domain) common
  • Allelic disorders
    • CMD + Epidermolysis Bullosa (EBS)
    • LGMD with no Skin changes (LGMD 2Q)
    • EBS-MD + Myasthenic syndrome (EBS-MD-MyS) ± Scapuloperoneal myopathy, Late-onset
    • EBS + Pyloric atresia
    • EBS-Ogna
• Plectin protein
  • Size: 500-kD
  • Structure: Contains intermediate filament & actin-binding domains
  • Family: Plakin
  • Tissue expression: Ubiquitous; Highest in stratified squamous epithelia, muscle & brain
  • Subcellular location: Concentrated at sites of stress
    • NMJ: Postsynaptic membrane
    • Muscle: Sarcolemma & Z-disks
    • Skin: Hemidesmosomes
    • Heart: Intercalated disks
  • Complexed with
    • Desmuslin : Associated with α-dystrobrevin
    • Desmin
    • Other: Microtubules, α-Spectrin, Nuclear lamin B, Integrin β4, Microtubule-associated proteins
  • Functions
    • Plectin types
      • 1: Connects Desmin intermediate filaments to Nucleus/ER
      • 1B
        • Links Desmin intermediate filaments to mitochondria
        • Reduction: Mitochondrial shape changes
      • 1D
        • Binds plectin to sarcomere
        • Muscle & Heart specific
      • 1F
        • Tethers Desmin intermediate filaments to sarcolemma
        • Location: Sarcolemma
        • Other associations: Dystrophin; β-Dystroglycan
    • Cytoskeletal linker: Connects
      • Intermediate filaments
      • Actin
      • Microtubules
      • Organelles
      • β4-Integrin
      • Type XVII collagen (BP180)
      • Nesprin-3a
      • Sarcolemmal proteins
    • Mechanical integrity of cells: Formation of intermyofibrillar desmin cytoskeleton
    • Substrate for caspase 8 during CD95- & tumor necrosis factor receptor-mediated apoptosis
  • Disease association: Partial, but reduced, expression associated with milder disease
• Clinical
  • Onset
    • Age: Congenital
    • Weakness or Hypotonia
    • Skin lesions: Blistering
  • Skin
    • Blistering: Due to Trauma & Heat
    • Alopecia
  • Muscle
    • Weakness: Myopathy & Myasthenic syndrome
      • Distribution
        • Proximal
        • Distal
        • Facial
        • Ocular
      • Course
        • Onset: Congenital or Childhood
        • Slow progression
        • Many in wheelchair by 10 years
      • Degree of weakness: May relate to level of plectin expression
    • Diffuse muscle hypotrophy
  • Systemic
    • Elbow contractures
    • Infantile respiratory complications
    • Alopecia
    • Decayed teeth
    • Laryngeal webs
    • Urethral strictures
    • Cardiomyopathy, Dilated, Biventricular
  • CNS: Brain atrophy; Enlarged ventricles
  • Treatment
    • 3,4-diaminopyridine: Some improvement
    • Pyridostigmine: No benefit
• Laboratory
  • Serum CK: High; > 1,000
  • Electrophysiology
    • Repetitive Nerve Stimulation: Decrement
    • EMG: Myopathic; Irritable
    • Endplate physiology
      • Quantal release by impulse: Normal
      • MEPPs: Small
      • AChRs: Fetal & Adult AChRs at NMJs
  • Muscle pathology
    • Myopathic
      • Necrosis & Regeneration
      • Muscle fiber size: Varied
      • Internal nuclei
      • Connective tissue: Increased
      • Abnormal internal architecture on NADH stain
    • Spike-like sarcolemmal projections with Integrin β1D stain
    • Endplates: Chains of small regions over fiber surface
    • Plectin
      • Absent or reduced staining in muscle Z-lines & skin
      • Abnormal related proteins: BP180; BP230
    • Hemidesmosomal protein HD1: Reduced staining
    • Desmin: Focal deposits in most muscle fibers
    • Some patients: Rods; Cytoplasmic bodies; Rimmed vacuoles
    • Mitochondria ³²
      • Increased number of COX- muscle fibers
      • Biochemistry: Reduced COX I (Complex I) & cytochrome c oxidase (Complex IV) activities
      • Morphology: Abnormal shape; Inclusions; Proliferation
      • Also see: Congenital muscular dystrophy with mitochondrial structural abnormalities
• Plectin Variant syndrome: Limb-Girdle Dystrophy R17 (LGMD R17) ⁸⁴
  • Nosology: LGMD 2Q
  • Epidemiology: Turkish & Russian families; 13 patients
  • Genetics
    • Inheritance: Recessive
    • Mutations
      • Homozygous
      • Location: Exon 1f (Isoform-specific sequence of plectin isoform 1f)
      • c.1_9del (Contains initiation codon); Glu20X
      • Other mutations with LGD phenotype: Q1022X; G3835S
  • Plectin protein: 1f isoform
    • Sarcolemma
    • More on type 2A muscle fibers
    • Costameres
    • Interacts with: Dystrophin; β-Dystroglycan
  • Clinical
    • Onset
      • Age: Early childhood
      • Delayed walking
    • Weakness
      • Generalized: Proximal > Distal
      • Face & Eyes: Ptosis in few patients
      • Course
        • Stable in childhood
        • Progressive in teens
        • Loss of ambulation: Adults
    • Muscle sizes
      • Atrophy: Axial
      • Hypertrophy: Gastrocnemius, Deltoid, Triceps
    • Skin: Normal
    • Joints: Contractures late
    • Pulmonary: Dyspnea; Bronchiolitis & Atelectasis
    • Course: Progression in adults
  • Laboratory
    • Serum CK: 3000 to 5500
    • EMG: Myopathic
    • RNS: Normal or Decrement
    • Muscle MRI
    • Chest CT: Reticulo-nodular pattern
  • Muscle pathology
    • Dystrophic
      • Fiber size: Varied
      • Myonuclei: Internal; Clustered
      • Necrosis & Regeneration
      • Endomysial connective tissue: Increased
      • Type 1 or 2 predominance
      • Desmin aggregates
      • Myf5-positive nuclei: Increased
      • COX- fibers: Some patients
    • Plectin
      • Reduced on sarcolemma (30%)
      • Isoform 1f: Reduced to 1%
      • Aggregates
    • Ultrastructure
      • Membrane duplications
      • Enlarged space between membrane & sarcomere
      • Misalignment of Z-disks
      • ? Disrupted connection between the sarcolemma and sarcomere