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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 (Club foot) Bethlem myopathy   COL6A1: 21q22   COL6A2: 21q22   COL6A3: 2q37 Broad A band Cap: TPM2; 9p13 Carey-Fineman-Ziter Syndrome Central core: RYR1; 19q13 Centronuclear (Myotubular)   DNM2: 19p13   RYR1: 19q13   MYF6: 12q21   BIN1: 2q14   MTM1: Xq28   CCDC78: 16p13 CMH4: MYBPC3; 11p11 Congenital muscular dystrophies Cytoplasmic Body (Spheroid) Danon: LAMP2; Xq24 Diarrhea & Deafness DOPA-responsive dystonia Ehlers-Danlos: FKBP14; 7p14 EMARDD: MEGF10; 5q23 Excessive autophagy: VMA21; Xq28  Fiber Type Size Disproportion (CFTD)   CFTD 1: α-Actin: 1q42; Dominant   CFTD 2: Xq13; Recessive   CFTD 3: SEPN1: 1p36; Recessive   CFTD 4: TPM3; 1q21; Dominant   CFTD 5: TPM2; 9p13; Dominant   CFTD: MYL2; 12q24; Recessive 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 Mitochondrial Multicore (Minicore) Myasthenic Syndromes Myofibrillar Myosin storage: MYH7; 14q11 Myotonic dystrophy 1: DMPK; 19q13 Native American Myopathy: 12q13 Nemaline rod   α-Actin: 1q42   TPM3: 1q21   TPM2: 9p13   CFL2: 14q13   KBTBD13: 15q22   Nebulin: 2q23   RYR1: 19q13   TNNT1: 19q13   Slow movements: 15q21 Neuropathic syndromes Ophthalmoplegias Perifascicular myopathy, neonatal Reducing body: FHL1; Xq26 Sarcotubular (LGMD 2H): TRIM32; 9q31 Skeletal disorders + Weakness Spheroid body: MYOT; 5q31 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 DYSTROPHIES Adducted thumbs & Ophthalmoplegia Cerebellar atrophy CMD + Cardiomyopathy: Titin; 2q24 CNS atrophy & absent large myelinated PN axons Desmin inclusions: SEPN1; 1p36 Fukuyama: Fukutin; 9q31 Glycosylation disorders Integrin α-7: 12q13 Joint Hyperlaxity: 3p23 Junctional Epidermolysis Bullosa: Plectin; 8q24 Marinesco-Sjögren: SIL1; 5q31 Merosin (laminin α2-chain)   Deficient (MDC1A): 6q22   Normal: "Pure" form Mitochondrial structural (MDCMC): CHKB; 22q13 Muscle-Eye-Brain Disorders Muscle hypertrophy   Mental retardation   Respiratory failure (MDC1B): 1q42   Muscle hypertrophy (MDC1C): FKRP; 19q13   Severe retardation (MDC1D): LARGE; 22q12 Myasthenic syndrome: DOK7; 4p16 Rigid spine with CMD   SEPN1: 1p36   Lamin A/C: 1q21   SECISBP2: 9q22   Other rigid spine syndromes Santavuori (Finnish): POMGnT1; 1p34 Telethonin: 17q12 Ullrich   COL6A1; 21q22   COL6A2; 21q22   COL6A3; 2q37 Walker-Warburg (α-Dystroglycanopathies)   MDDGA1: POMT1: 9q34   MDDGA2: POMT2: 14q24   MDDGA3: POMGnT1; 1p32   MDDGA4: Fukutin: 9q31   MDDGA5: FKRP; 19q13   MDDGA6: LARGE: 22q12   MDDGA7: ISPD: 7p21   MDDGA8: GTDC2; 3p22   MDDGA10: TMEM5; 12q14.2   MDDGA11: B3GALNT2; 1q42   MDDGA: B3GNT1; 11q13   WWS: SGK196; 8p11 General features   α-Dystroglycan   Other congenital weakness

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

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
    • 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
• The best defined neuromuscular causes of congenital weakness include
  • Congenital Myopathies
    • Centronuclear (myotubular) myopathy
    • Nemaline rod myopathy
    • Central core disease
  • Congenital muscular dystrophies
  • Congenital presentations of adult dystrophies
    • Myotonic dystrophy
    • FSH dystrophy
  • Myasthenic syndromes
  • Neuropathic syndromes
• The 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
  • 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

Central Core Disease ± Malignant Hyperthermia

• Genetic features¹¹
  • > 250 mutations identified
  • Mutation types: Most missense; Few small deletions; Rare splice or insertion
  • Most central core families linked to Ryanodine receptor mutations
  • Some point mutations produce MH alone: 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
  • Some mutations with Central core disease & MH
    • 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
  • RYR1 Syndromes: Dominant mutations
    • Central core diseases
      • Congenital myopathy
      • Cores, Rods & Malignant Hyperthermia: Y4796C
      • Limb-Girdle Syndrome: Onset in teens
      • Minicores, Transient
      • Fetal akinesia
    • Malignant Hyperthermia: Onset in teens
    • King-Denborough Syndrome
    • High serum CK: Asymptomatic
    • Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1)
    • Axial myopathy, Adult onset
  • RYR1 Syndromes: Recessive mutations
    • Expressed along entire gene
    • Clinical syndromes
      • Central core diseases
        • Minicores, Transient: P3527S
        • Fetal akinesia: R614C & G215E; L4650P & K4724Q
        • Mild phenotype & Recessive inheritance
        • Samaritan myopathy: Tyr1088Cys
      • Nemaline (rod) myopathy with external ophthalmoplegia: Pro1573Leu & Asp2529Asn
      • Congenital myopathy with focal loss of cross-striations: Arg3539His & c.10627-2A>G splice site
  • 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
• Ryanodine receptor protein⁸¹
  • 560 kDa
  • Structure
    • Tetrameric
    • 6 to 8 transmembrane domains
    • C-terminal 20% of molecule forms transmembrane Ca⁺⁺ channel
    • N-terminal: Contains most ligand binding sites; Cytoplasmic domain
  • Regulatory molecules
    • Ca⁺⁺
    • Mg⁺⁺: Inhibitory
    • Adenine nucleotides & Cyclic ADPribose: Channel activation
    • Oxidation
    • Nitrosylation
    • Caffeine & 4-chloro-m-cresol (CmC)
      • Activate RyR channels
      • Facilitate channel opening: Increase 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
    • FK506 binding protein
    • Calmodulin (CaM): Participates in Ca++-dependent regulation of channel activity
      • Ca⁺⁺-free CaM: Activates RyR
      • Ca⁺⁺-bound CaM: Inhibits RyR channel function
    • Triadin
    • Calsequestrin
    • Kinases: PKA; CamK
    • Phosphatases: PP1, PP2A
    • Phosphodiesterase PDE4D3
    • Muscle A-kinase anchoring protein
  • Isoforms
    • RYR1: Skeletal muscle
    • RYR2 : Cardiac
    • RYR3 : CNS
  • Functions
    • Structural: Foot structure bridges gap between sarcoplasmic reticulum & t-tubule in skeletal muscle
    • 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 ryanodine receptors
      • Ca⁺⁺ released 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 following membrane depolarization (Physical interaction)
      • RyR2 activation in heart: Activation of L-type Ca⁺⁺ channels induces Ca⁺⁺-induced Ca⁺⁺ release (CICR)
  • 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
  • Onset: Childhood or congenital onset
  • Genetics
    • Mutation hotspot: C-terminal exons 101–102
  • Developmental
    • Reduced Fetal movements
    • Breech presentation
  • Motor
    • Hypotonia
    • Proximal Weakness: Legs > Arms
    • Face: Mild weakness
    • Extraocular movements: Normal
  • Cramps
  • Skeletal: Congenital hip dislocation; Scoliosis; Foot deformities
  • Course: Non- or Slowly Progressive
• Variants: Central core syndromes & Other RyR disorders
  • Malignant Hyperthermia: Onset in teens
  • King-Denborough Syndrome
  • Limb-Girdle Syndrome: Onset in teens
    • Weakness: Proximal; Symmetric
    • Malignant Hyperthermia
    • Course: Slowly progressive
  • High serum CK: Asymptomatic
  • 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
  • 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
  • Central core disease with transient minicores ³⁰
    • Nosology
      • Multicore syndrome: Mild phenotype
      • Multicore syndrome: "Central core-like"
    • Genetics
      • Inheritance: Recessive
      • RYR1 mutation: Homozygous; Missense; P3527S
      • Overlap with phenotype for central core syndrome: Missense V4849I
      • Epidemiology: Algerian, Turkish & German families
    • 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
  • Central core disease with fetal akinesia ⁴⁵
    • Inheritance: Dominant or Recessive
    • Mutations
      • Recessive
        • R614C (Often associated with MH) & G215E
        • L4650P & K4724Q
      • Dominant: G4899E (Mother less severely affected)
    • Clinical
      • Pregnancy
        • Fetal akinesia
          • Differential Dx in NM disorders: Nemaline & Myotubular myopathies; Pena-Shokeir
        • 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
      • Endomysial connective tissue: Increased
  • 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
  • Congenital neuromuscular disease with uniform type 1 fibers (CNMDU1) ⁶⁹
    • RYR1 genetics: Mutations
      • Heterozygous
      • Missense or Deletion
      • Location: C-terminal domain of RYR1; Pore forming segment
      • Mutations found in 40% of patients with CNMDU1
        • None in patients with mental retardation
    • Clinical: Congenital myopathy
      • Onset: Congenital or early childhood
      • Weakness: Mild; Proximal; Face normal
      • Tendon reflexes: Reduced or Absent
      • CNS: No mental retardation
    • Laboratory
      • Serum CK: Normal
      • EMG: Myopathic
      • Muscle biopsy
        • All muscle fibers type 1 (> 99%)
        • No cores
        • Endomysial connective tissue: Normal or Mild increase
  • Benign Samaritan congenital myopathy ⁹²
    • Epidemiology: Samaritan Israeli family, inbred
    • Genetics: 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
  • 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
  • Bent spine syndrome (Axial myopathy, Adult onset) ¹⁰¹
    • Genetics: RYR1 Mutations
      • Heterozygous
      • Missense
      • Varying regions in gene
    • 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
  • Antibodies vs RyR
    • Granulomatous myopathy
    • Myasthenia gravis
  • RyR2 mutations
    • Catecholaminergic polymorphic ventricular tachycardia (CPVT)
    • R176Q mutation: Arrhythmogenic right ventricular dysplasia (ARVD)
• 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 MRI⁵²
  • 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
    • Variable muscle fiber size
    • Increased endomysial connective tissue
    • 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
    • Most prominent on NADH & mitochondrial stains
    • Immunoreactivity in cores³⁶
      • Myofibrillar proteins
        • αB-Crystallin; Desmin; Filamin C
        • Similar patterns of immunoreactivity seen in targets
      • Ca⁺⁺-related proteins
        • Depleted from the cores: RyR1
        • Accumulate in, or around, lesions
          • Other sarcoplasmic reticulum proteins: Calsequestrin, SERCA1/2 & Triadin
          • T-tubule protein: Dihydropyridine receptor-α1-subunit
        • SelN mutation-related minicores: Normal distribution of Ca⁺⁺-related proteins
  • Marked type I muscle fiber predominence
  • Clinical correlation
    • Well formed cores + Marked type 1 predominance
      • Myopathy syndrome: Often without MHS
      • RYR1 mutations: 90% with 60% in C-terminus
    • Variable cores + Less type 1 predominance + Internal nuclei
      • MHS syndrome: Usually normal strength
      • RYR1 mutations: 35%, Outside C-terminus
• Management
  • Avoid anesthesia-related malignant hyperthermia
  • Albuterol: May improve weakness

Nemaline (Rod) Myopathies

Clinical features: General Laboratory features: General Pathology Hereditary Types   α-Actin (NEM3): 1q42   α-tropomyosin 3 (NEM1): 1q21   β-tropomyosin (NEM4): 9p13   Cofilin-2 (NEM7): 14q13   KBTBD13 (NEM6): 15q22   Nebulin (NEM2): 2q23   Ryanodine receptor: 19q13     Rods + Cores: Dominant     Rods + Ophthalmoplegia: Recessive   Troponin T1 (NEM5): 19q13   Also     Pyruvate carboxylase deficiency     Rod myopathy, mild Sporadic disorders with rods   Infant onset myopathy   Adult onset myopathy   HIV rod myopathy   Target fibers (Acute Denervation)

Rod myopathy: Distal weakness & contractures From A Connolly

• Onset
  • Overall: Congenital (90%) to Adult
  • Severe: Congenital; α-Actin, Nebulin & Troponin T1 mutations
  • Mild: Childhood; α-Actin, Nebulin, α-tropomyosin 3 (TPM3), β-tropomyosin (TPM2) mutations
  • Adult onset: Mutations not known
• Inheritance: Dominant, Recessive & Sporadic
• Common mutation: Skeletal muscle α-Actin
• Early onset cases: Respiratory failure & Feeding difficulties common
• Clinical features
  • Motor: Weakness & Hypotonia
  • CNS: Cognitive involvement in younger onset patients
  • Cardiac: Rarely symptomatic after neonatal period
  • Arthrogryposis: Severe congenital cases
  • Paraspinous or posterior neck weakness: Adult onset patients
• Course
  • 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
• 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: Usually structural member of thin filaments
• Muscle pathology: Thin filament disorders
  • Rods
    • Histochemical appearance: Dark red-blue structures only visible on Gomori trichrome stain
    • Fiber type distribution: Type I > II
    • Size: 1 to 7 μm in length
    • Composition: Contain 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
    • Subcellular location: Originate from Z-disks
      • Myopathy: Tend to cluster under sarcolemma & around nuclei
      • Target fibers: Center of target
    • Underlying pathogenic process
      • Rod formation 2° to contractile dysfunction
      • Load-dependent processes probably involved
    • Often increase in number with age
    • Differential diagnosis
      • Sarcoglycanopathies
      • Target fibers (Denervation)
      • Tenotomy
      • Neostigmine myopathy²³
      • HIV myopathy²⁴
  • Type I muscle fibers: Small; Predominant
• CK: Normal (90%) or ± Elevated in adult-onset forms
• EMG: Myopathic or Neuropathic (Especially severe cases)
• Most common mutations: Nebulin; ACTA1

ROD MYOPATHIES: Specific syndromes

NEM1 Rod myopathy
  l α-Tropomyosin 3 (TPM3)

Nemaline rod myopathy   Dominant   Recessive CFTD Cap myopathy



• TPM3 protein
  • Muscle: Expressed in type I muscle fibers
  • 11 different forms: Expressed in many tissues including brain
  • See: Muscle fiber proteins
• Clinical-Genetic correlations
  • Infrequent cause of nemaline rod myopathy
  • Frequency: < 3%
  • Mildest syndrome: Missense mutation; Dominant inheritance
  • Severe syndrome: Stop codon; Recessive inheritance
• Rod myopathy: Dominant inheritance
  • Mutations: Met9Arg; Arg167His³⁸
  • 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
    • 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
• Rod myopathy: Recessive inheritance
  • Early onset, severe disease
    • 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
  l 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 with TPM3 mutations
  l 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+

NEM2 Rod myopathy
  l Nebulin (NEB)

• Epidemiology
  • Most common form of recessive "Typical" nemaline rod myopathy
• Mutations
  • 64 mutations found in 55 families
  • Point mutations most common
  • Common mutation: Ashkenazi Jews
    • 2,502-bp deletion in exon 55 & parts of introns 54 and 55
    • Carrier frequency: 1 in 108
    • Severity: "Typical" form of nemaline myopathy
  • Small insertions, deletions or point mutations
  • 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
• Infantile onset: Mild to moderate ("Typical")
  • Onset: Birth; some movement present
  • Weakness
    • Trunk
    • Distal legs: Ankle dorsiflexors
    • Knee flexors
    • Face
    • Nasal voice
    • Respiratory
  • 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
    • Subsarcolemmal rods
      • Ultrastructure: Z disk aberrations
      • Contain: α-actinin; myotilin, telethonin, actin, tropomyosin & desmin
    • Type 2 muscle fibers: Reduced numbers
• Muscle MRI⁵³
  • Mild phenotype
    • Involvement: Tibialis anterior, Soleus
    • Sparing: Thigh muscles
  • Moderate phenotype involvement
    • Rectus femoris, Vastus lateralis, Hamstring, Anterior leg, Soleus
• Variant: Distal nebulin myopathy
• Variant: Core-Rod myopathy⁸⁰
  • 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
  • Onset
    • Age: Congenital
    • Hypotonia
    • Respiratory insufficiency
  • Clinical
    • 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
• Variants: Other
  • Rare cause of: Severe congenital, or Intermediate (mild) form of Rod myopathy
  • Nebulin mutations NOT identified in: Adult onset rod myopathy

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

• Genetics
  • Mutations
    • ~15 Missense mutations identified
    • Distributed in all 6 coding exons
    • Some involve known functional domains of actin
  • 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
  • Dominant inheritance
    • Onset: Variable within families
    • Clinical: Variable phenotypes
      • Mild
      • Mutations: Asn115Ser; Gly268Cys; Ile136Met
      • Onset: Age 12
      • Weakness: Trunk & Proximal; Mild facial
      • Respiratory failure: 5th decade
      • Progression: Slow over decades
      • Serum CK: Normal
      • MRI: Gluteal & Anterolateral thigh involvement
      • Muscle morphology
        • Rods, especially in small fibers; Core-like structures
        • Muscle fiber hypertrophy: Ile136Met
      • Severe ⁸⁵
      • 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
        • Thin filament aggregates
        • Endomysial fibrosis
      • Other mutations: Met132Val; Val163Met; Met269Arg
      • Cardiac function: Normal
    • Pathology
      • Abnormal fiber type differentiation
      • 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
      • Myofibrillar disruption
      • Whorling of actin thin filaments
  • Recessive inheritance⁶⁶
    • Genetics
      • Truncation mutations identified; ? Missense
      • Truncation: Arg41X (French), Tyr364fsX (Spanish), Asp181fsX10 (British)
    • Course
      • Weakness
        • Severe in most: Diffuse; Hypotonia
        • Respiratory failure
        • Feeding difficulties
        • Death in 1st year: Most
        • Contractures (30%)
      • Serum CK: Mildly elevated or normal
      • Muscle
        • Morphology: Nemaline rods & Zebra bodies
        • Actin: Skeletal α-actin absent; Cardiac α-actin increased
        • Lipid: Increased
      • Survival through childhood in some
  • Sporadic patients: Often de novo mutations
  • Variant: Nemaline myopathy with intranuclear rods ⁶²
    • All mutations involve ACTA1
    • Inheritance
      • Sporadic (Most) or Dominant
      • Marked phenotypic variation in family
    • Onset: Birth (Most) to 55 years
    • Clinical
      • 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
  • Variant: Cap myopathy with ACTA1 mutation⁸²
    • Epidemiology: 1 patient
    • Mutation: Met47Val, 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
• Muscle MRI
  • Involved muscle signal: Increased T1
  • Involved muscles: Diffuse involvement of thigh and leg
  • Relative sparing: Gastrocnemius

NEM4 Rod myopathy
  l β-Tropomyosin (TPM2)

• Genetics
  • Mutations: Missense Q147P & E117K
  • TPM2 allelic disorders
    • Distal arthrogryposis 1
    • DA2B
    • Cap myopathy
    • Escobar syndrome
    • Congenital fiber type disproportion 5
    • Nemaline rod myopathy (NEM4)
• β-Tropomyosin protein
  • Mutation abnormalities: Altered affinity for actin, or Defective Ca⁺⁺ activation of contractility
• Frequency: Rare
• Onset: Infancy to Childhood
• Clinical
  • Weakness: Proximal > Distal; Some with respiratory failure
  • Contractures: Few or None
  • Progression: Slow or None
• 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%)
• 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

NEM5 Rod myopathy ¹³
  l Troponin T1 (Skeletal, Slow; TNNT1)

• Mutation: Nonsense; E180X; Homozygous
• Epidemiology: Older Order Amish
• Clinical
  • Onset
    • 1st months of life
    • Tremors
      • Begin within few days of birth
      • Distribution: Jaw & Lower limbs
      • Resolve by 2 to 3 months
    • Hypotonia
    • Contractures: Shoulders & Hips; Mild
  • Progression
    • Proximal contractures: Increase
    • Weakness: Proximal > Distal
    • Pectus carinatum: Rigid chest wall; Develops with proximal contractures
    • Cardiac: No 1° involvement; Terminal right congestive failure
    • Death from respiratory insufficiency < 2 years
• Pathology
  • Type 1 fiber disproportion
  • Z-band streaming
  • Rods: Centrally placed
  • Myofibrillar disruption
  • Myofiber degeneration

• Epidemiology: 32 European & Australian patients
• Genetics
  • Mutations: Missense; Arg248Ser, Lys390Asn, Arg408Cys
• KBTBD13 protein
  • Tissues: Skeletal & Cardiac muscle; Lung
  • Subcellular: Cytoplasm
  • Other BTB/Kelch proteins
    • Gigaxonin: Giant axonal neuropathy
    • KLHL9: Distal myopathy
• 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: 1 Middle Eastern family, 2 siblings
• Genetics
  • Mutation: Missense, Ala35Thr; Homozygous
  • 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: 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
  
  
• Adult onset rod myopathy: Heterogeneous⁵⁹
  • Often no family history
  • Onset
    • 4th to 9th decade
    • Subacute
  • Clinical
    • Weakness
      • Proximal > Distal
      • Posterior neck weakness (50%)
      • Dysphagia (50%)
      • Respiratory failure (40%): Occasionally presenting feature
      • Asymmetry (30%)
      • No face weakness
    • Myalgia
    • Cardiomyopathy
    • Progression
      • High mortality in 40%: Death within 1 year
      • Slow progression over years in others
  • Laboratory
    • Muscle biopsy
      • Rods
        • Immunostain for α-actinin or myotilin
        • Rods may be best seen on trichrome in 3 μM sections
      • Rod bearing fibers also have
        • Large vesicular nuclei
        • Focal cytoplasmic basophilia
        • Small vacuoles
      • Inflammation (30%)
      • Necrotic muscle fibers: Occasional
      • Lobulated muscle fibers (50%)
      • Type I predominance (20%)
      • Ultrastructure: Rods < 1μM in length
    • M-protein (50%): ? Unfavorable outcome
    • Serum CK: Normal or Mildly elevated
    • EMG: Irritable myopathy
  • Rule out
    • Sarcoglycanopathies
    • HIV nemaline rod myopathy
    • Hereditary nemaline rod myopathy
  • Treatment: Uncertain; ? Prednisone
  
  
• Central core disease, Rods & Malignant Hyperthermia

Centronuclear (Myotubular) Myopathy ⁸⁹

Types   Dominant     CNM: Dynamin 2; 19p13       CNM modifier: MTMR14     CNM3: MYF6; 12q21     CNM4: CCDC78; 16p13   Recessive     CNM2: BIN1: 2q14     CNM: RYR1: 19q13     Canine (Labrador): PTPLA   X-linked     CNMX: MTM1; Xq28       Carriers   Differential diagnosis     Myotonic dystrophy 1, Congenital Pathology

• Centronuclear myopathy: X-linked (CNMX; MTM1)
    l Myotubularin (MTM1) ; Chromosome Xq28; Recessive
    
  • 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: Spread unevenly across whole gene
    • General
      • 151 different disease related mutations identified in 248 families¹⁰
      • Mutations widely distributed throughout the 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
      • 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
  • MTM1 protein features
    • Tisssue localization: Ubiquitously expressed
    • Cell localization
      • Sarcolemma
      • I band, including triads
      • Associated with endosomes
      • ? Nuclear
    • MTM1 structure
      • Contains active site of protein tyrosine phosphatases (PTP)
      • Displays 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
      • 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)
    • Myotubularin family & related disorders
      • Myotubularin-related protein-2: CMT 4B
      • SBF2 (MTMR13): CMT 4B2
      • Endosomal phosphoinositides: PIP5K3 ; François-Neetens Fleck Corneal Dystrophy
  • Clinical features
    • Onset: Infancy
    • Polyhydramnios: 50%
    • Skeletal: Large head (70%); Narrow face (80%); Long digits (60%)
    • Motor
      • Severe Hypotonia
      • Weakness: Proximal & Distal; Symmetric
      • Respiratory Insufficiency
    • Ophthalmoplegia & Ptosis
    • Prognosis
      • Early death: Mean = 5 months
      • ? Improvement after neonatal period
      • Weakness non-progressive
      • Survivors often
        • Respirator dependent (80%)
        • Feeding tube dependent
        • Require head support
    • Systemic features in some survivors > 1 year
      • Pyloric stenosis
      • Spherocytosis
      • Gallstones
      • Renal: Stones or calcinosis
      • Bleeding diathesis: Vitamin K-responsive
      • Skeletal: Rapid linear growth; Advanced bone age
      • Hepatic dysfunction
  • 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 pathology⁶⁷
      • Single central nucleus
        • In some muscle fibers: Range = 4% to 40%
        • Frequency may increase with age
        • Present in chains on longitudinal sections
      • 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
        • Increased oxidative enzyme activity & glycogen staining
      • Periphery of fibers
        • Oxidative enzyme activity: Pale halo
  • Treatment: Some benefit from pyridostigmine
  • Myotubularin mutation: Carriers
    • Occasional: Mild facial weakness
    • More severe⁵⁶
      • Genetics
        • Mutations: R253X; c.1354–1G>A (Splice site)
        • Skewed X-inactivation: 1 family
        • ? Other mechanisms
        • Incomplete penetrance
      • Onset
        • 1st decade
        • Arm weakness
        • Gait disorder
        • Skeletal asymmetry
      • Weakness
        • Early: Arm
        • Proximal & Distal: With disease progression
        • Elevated hemidiaphragm
        • Progressive in 3rd to 5th decades
      • Skeletal
        • Asymmetry
        • Kyphoscoliosis
        • Pes equinovarus (Bilateral)
      • Serum CK: Normal
      • Muscle pathology
        • Varied fiber size: Both fiber types
        • Internal nuclei
        • NADH: Normal internal architecture
    • Neonatal onset³⁹
      • Mutation: 605delT
      • Non-familial case
      • Clinical
        • Hypotonia
        • Joint laxity
        • Waddling gait
        • Weakness: Limb-girdle; Facial
        • Tendon reflexes: Absent
  • Myotubularin knock-out mouse³⁷
    • 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 subgroups⁴⁹
        • 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)
    l Bridging integrator 1 (BIN1; Amphiphysin 2) ; Chromosome 2q14.3; Recessive ⁶⁸
  • Epidemiology: 5 individuals; India, Iraq, Morocco
  • Genetics: Mutations
    • Types: Missense & Stop; K35N, D151N, K575X
    • Effect: All elicit only a partial loss of function
    • Homozygous
  • 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
    • 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 numerous fibers
      • Clusters & Chains: Several nuclei in central part of fibers
    • 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
  
  
• Centronuclear myopathy (CNM3): Autosomal Dominant
    l MYF6 ; Chromosome 12q21.31; Dominant
  • Epidemiology: 1 patient
  • MYF6 gene mutation: Ala112Ser
  • 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
    • MYF6 mutation in setting of Becker dystrophy: Converts disease to more severe phenotype
  • Laboratory
    • CK: Normal or Mildly elevated
    • Muscle biopsy: Myopathic; Ring fibers; Central nuclei
  
  
• Centronuclear myopathy: Autosomal Dominant ⁶⁰
    l 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
    • 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 syndrome: 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
  • 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
    • 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 described changes in occasional 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
    • 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
    • DNM2 mutation: Leu621Pro
    • Clinical
      • Onset: Neonatal
      • Hypotonia
      • Respiratory insufficiency
      • Cataracts
      • External ophthalmoplegia
      • Course: Progressive; Death at 14 years
  • Lethal congenital syndrome: Homozygous mutation ⁹⁷
    • Epidemiology: 3 infants in 1 family
    • DNM2 mutation Phe379Val; Homozygous
    • Clinical
      • Akinesia
      • Joint contractures
      • Hypotonia
      • Skeletal abnormalities
      • Hemorrhages: Brain & Retinal
    • Laboratory
      • Muscle: Central nuclei
  
  
• Centronuclear myopathy: Autosomal Dominant
    l Centronuclear myopathy: Genetically undefined phenotypes
  • Clinical subtype 1: Typical Dominant centronuclear myopathy⁴⁹
    • 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 hypertrophy⁴⁹
    • 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
    l Protein tyrosine phosphatase-like (Proline instead of catalytic arginine), Member A; (PTPLA) ; 10p12.33 (Canine chromosome 2); Recessive
  
  • Epidemiology: Labrador retrievers
    • Carrier frequency: 15%
    • Common in many parts of world
  • Mutation
    • Insertion: g.9459-9460ins238
    • Founder: Arose 50 years ago
  • PTPLA
    • 3-hydroxyacyl-CoA dehydratase (HACD)
    • Endoplasmic reticulum resident enzyme
    • Catalyzes 3rd reaction of elongation of very long chain fatty acids (VLCFA)
  • 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 fiber predominance
    • EMG: Fibrillationd
    • Serum CK: Normal
    • CNS: Normal

Congenital Muscular Dystrophies

CONGENITAL MUSCULAR DYSTROPHIES Adducted thumbs & Ophthalmoplegia Cerebellar atrophy CMD: 4p16 CMD + Cardiomyopathy: Titin; 2q24 CNS atrophy & absent large myelinated PN axons Desmin inclusions: SEPN1; 1p36 Fukuyama: Fukutin; 9q31 Integrin α-7: 12q13 Joint Hyperlaxity: 3p23 Junctional Epidermolysis Bullosa: Plectin; 8q24 Marinesco-Sjögren: SIL1; 5q31 Merosin (laminin α2-chain)   Deficient (MDC1A): 6q22   Normal: "Pure" form Mitochondrial structural (MDCMC): CHKB; 22q13 Muscle-Eye-Brain Disorders Muscle hypertrophy   Mental retardation   Respiratory failure (MDC1B): 1q42   Muscle hypertrophy (MDC1C): FKRP; 19q13   Severe retardation (MDC1D): LARGE; 22q12 Rigid spine with CMD   SEPN1: 1p36   Lamin A/C: 1q21   SECISBP2: 9q22   Other rigid spine syndromes Santavuori (Finnish): POMGnT1; 1p34 Telethonin: 17q12 Ullrich   COL6A1; 21q22   COL6A2; 21q22   COL6A3; 2q37 Walker-Warburg (α-Dystroglycanopathies)   MDDGA1: POMT1: 9q34   MDDGA2: POMT2: 14q24   MDDGA3: POMGnT1; 1p32   MDDGA4: Fukutin: 9q31   MDDGA5: FKRP; 19q13   MDDGA6: LARGE: 22q12

General features α-Dystroglycan disorders from A Kornberg MD

Congenital Muscular Dystrophy: Typical Features

• Inheritance: Autosomal recessive (AR)
• Frequency: Common cause of AR neuromuscular disorders
• Onset: Congenital or Infancy (< 1 year)
• Clinical features
  • Weakness: Diffuse
  • Contractures
  • CNS
    • Common in severe forms of CMD
    • May be subclinical
    • Disroders of myelin or neuronal migration
• Pathology of muscle
  • Myopathic
    • Varied fiber size
    • Increased endomysial connective tissue
    • Little muscle fiber degeneration after 4 years
  • Disorders of connective tissue molecules
    • Laminin α2: MDC1A
    • Collagen, type VI: Ullrich
    • Disorders of glycosylation⁴⁸
      • Marker molecule: α-Dystroglycan
      • Common O-mannosyl glycan structure: NeuAcα2-3Galα1-4GlcNAcα1-2Man-Ser/Thr
      • Disorders: Defective O-mannosylation of α-dystroglycan
      • Specific disorders
        • Walker–Warburg syndrome (WWS): POMT1
        • Walker-Warburg 2: POMT2
        • Muscle–eye–brain disease (MEB): POMGnT1
        • Fukuyama congenital muscular dystrophy (FCMD): Fukutin
        • MDC1C: FKRP
        • MDC1D: LARGE

Fukuyama congenital muscular dystrophy (MDDGA4)

• 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 Jews⁷⁶
        • 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 with
    • LGMD 2M (MDDGC4)
    • Congenital muscular dystrophy (MDDGB4)
    • Cardiomyopathy
• Fukutin protein¹⁷
  • 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
• 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

• Mutations in laminin α2-chain
  • Deletion, stop codon & occasional missense
  • Most common mutation (23%): 2 base pair deletion @ 2,096-2,097
  • Mild disease: Mutations
    • Internal in-frame deletion: Small protein (Missing N-terminal)
    • Mutations in conserved donor splicing consensus sequence of introns 37 and 63
  • Mutations uncommon: In globular or rod-like domain
  • Merosin expression
    • Severe: 300 kDa & 80kDa subunits abnormal
    • Mild or later onset: 300 kDa subunit often selectively reduced
  • Offspring of carriers: Heterozygotes more common than predicetd by chance
  • Defect in same gene in dy mouse
• Laminin α2 (Merosin) 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 α-dystroglycan

  Pectoral folds (Arrow) with severe shoulder weakness

• 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: Mild; Occasional; ± Demyelination
  • Course
    • Progressively severe contractures
    • Severe disease: Death 15 to 30 years 2° Respiratory failure
• Laboratory
  • CK: Moderately high
  • MRI of CNS: White matter changes (Increased signal on T2); Cortex usually normal
• Laminin α2 disorders: Muscle pathology
  • Merosin (Laminin α2) staining
    • Usually absent: 95% with absent merosin have gene mutation
    • 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: Variable fiber size; Increased endomysial connective tissue
    • Neonatal: May be "predystrophic" with only a few degenerating & regenerating muscle fibers
    • Inflammation: Rare, except in biopsies from very young patients
    • Mild disease (Partial merosin loss)
      • Dystrophic: Variation in fiber size Increased endomysialconnective tissue
      • Other: Increased internal nuclei; Occasional split, hypercontracted & Whorled fibers
• Laminin α2 disorders: Variant syndromes
  • Reduced laminin α2: Especially loss of 300 kD N-terminus
    • Genetics Probably allelic with Laminin α2 disorders
    • Clinical
      • Onset: Up to 59 years
      • Weakness
        • Mild weakness
        • Proximal ± Distal; Symmetric
      • Calf hypertrophy may occur
      • Course: Progressive, slowly
      • CNS
        • Epilepsy
        • Impaired cognition
    • Laboratory
      • Leukoencephalopathy: Many patients
      • Muscle pathology
        • Myopathy
        • Rimmed vacuoles
        • Inflammation in some
        • Reduced laminin α2: Loss of 300 kD N-terminus
  • Neuropathy, Hypermyelinating; Mental retardation; Epilepsy³¹
    • 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
    • dy^2J/dy^2J: Milder phenotype; 300kD subunit selectively reduced
• Laminin disorders: Other
  • α4: CMD 1JJ
  • β2: Congenital Myasthenic Syndrome

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
• 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
• Gene change: 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
  • Fiber size variation
  • Reduced staining for integrin α-7

Congenital MD with Joint Hyperlaxity⁶³

• 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: LARGE; 22q12
    • MDDGA7: ISPD; 7p21
    • MDDGA8: GTDC2; 3p22
      
    • MDDGA10: TMEM5; 12q14.2
    • MDDGA11: B3GALNT2; 1q42
    • MDDGA: B3GNT1; 11q13
    • WWS: SGK196; 8p11
    • Many not identified
  • Other lissencephalies
    • Miller-Dieker
    • X-linked lissencephaly with agenesis of corpus callosum
    • Norman-Roberts
  • Often allelic with
    • Milder congenital muscular dystrophies (MDDGB)
    • Limb girdle muscular dystrophy syndromes (MDDGC)
  • Muscle histology
    • Myopathy with increased connective tissue
    • α-dystroglycan: Hypoglycosylation
  
  
• Walker-Warburg Syndrome (MDDGA1)
  l 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, LARGE
  • 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)
  l 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
    • 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 2N⁷⁹
    • Epidemiology: Single patient
    • Genetics: POMT2 mutation
      • Homozygous
      • Missense
      • Thr184Met
    • Clinical
      • Onset: Walking at 18 months; HIgh CK
      • Functional: Slow running
      • Calf hypertrophy
      • Scapular winging
      • Skeletal: Lordosis, mild
      • Intellect: Normal
      • Eye: Normal
    • Laboratory
      • Serum CK: High; 1500 to 3300
      • EMG: Myopathic
      • Muscle biopsy: Myopathic
        • Fiber size variation
        • Necrosis & Regeneration
        • Cellularity: Macrophages
        • α-dystroglycan: Reduced
  
  
• Santavuori congenital muscular dystrophy (Finnish; Muscle-eye-brain disease (MEB)) (MDDGA3) ²⁹
  l O-linked mannose β1,2-N-acetylglucosaminyltransferase (POMGnT1) ; Chromosome 1p34.1; Recessive
  • 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
    • ? Role in neuronal migration
    • Mutation effects: Reduced enzyme function
  • Epidemiology
    • Disease focus: Finnish (Founder effect)
    • Other: Turkish, French, Japanese & Korean families
  • 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
    • Cortex: Disorganization (cobblestone); Midline defects; Hydrocephalus
    • White matter: Abnormal, especially diffuse at young ages < 1.5 years
  • Variant syndrome: Muscular dystrophy (MDDGC3; 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) ⁹¹
  l Isoprenoid synthase domain containing (ISPD) ; Chromosome 7p21.2; Recessive
  • Epidemiology: > 10 families; 2nd most common form of WWS (10%)
  • Mutations
    • Types: Deletions; Missense (ISPD domain); Nonsense
    • Effects: Loss of function
  • 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
    • Congenital Muscular Dystrophy
    • Limb-Girdle Muscular Dystrophy
  • 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) ⁹⁹
    • 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)
    • Non-ambulant
    • CNS & Eye: Normal
    • Weakness: Proximal
  
  
• Walker-Warburg Syndrome (MDDGA8) ⁹⁶
  l Glycosyltransferase-like domain-containing protein 2 (GTDC2; AGO61; c3orf39) ; Chromosome 3p22.1; Recessive
  • Epidemiology: Consanguineous WWS families
  • Genetics
    • Mutations: Arg158His; Trp197X; Arg445X
  • GTDC2 protein
    • Contains uncharacterized glycosyltransferase domain
    • High in brain, muscle, heart & kidneys
    • Possible role: 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
  
  
• Walker-Warburg Syndrome & Cobblestone Lissencephaly (MDDGA10)
  l Transmembrane protein 5 (TMEM5) ; 12q14.2; Recessive
  • Epidemiology: 3 families
  • Genetics
    • Mutations: Nonsense; Frame shift
  • TMEM5 protein
    • Exostosin family domain
    • Possible role: α-Dystroglycan glycosylation
  • 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
  
  
• Walker-Warburg Syndrome ¹⁰⁵
  l SGK196 ; 8p11.21; Recessive
  • Epidemiology: 1 family
  • Genetics
    • Mutations: Heterozygous; Missense; Leu137Arg, Gln258Arg
  • SGK196 protein
    • Ser/Thr protein kinase family: Kinase probably inactive
    • Membrane protein
    • ? ATP binding
    • ? α-Dystroglycan glycosylation
  • Clinical
    • Eye: Hyperplastic primary vitreous; Myopia; Microphthalmia.
    • Hypotonia
    • Death: 3 years
  • Laboratory
    • Head imaging
      • Hydrocephalus: Triventricular
      • Cortex: Thin; Agyria
      • Cerebellar hemispheres & Brainstem: Compressed
      • Arnold Chiari malformation
    • Serum CK: > 7000
    • Muscle
      • Myopathy
      • Normal: Dystrophin; Sarcoglycans; Laminin-α2
  
  
• Congenital Muscular Dystrophy & α-Dystroglycan Hypoglycosylation (MDDGA11) ¹⁰⁴
  l 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: Glycosylation; Completes trisaccharide GalNAc-b1,3-GlcNAc-b1,4-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 (MDDGA) ¹⁰⁶
  l β-1,3-N-acetylglucosaminyltransferase 1(B3GNT1) ; Chromosome 11q13.2; Recessive
  • Epidemiology: East Indian family
  • Genetics
    • Mutations: Homozygous for both Asn390Asp & Ala406Val
  • B3GNT1 protein
    • Forms complex with LARGE
  • Clinical
    • Intrauterine hydrocephalus
    • Walker-Warburg syndrome
  • Laboratory
    • Serum CK: High, 3,180
    • 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 with Familial Junctional Epidermolysis Bullosa

• Genetics
  • Gene structure
    • 32 exons
    • Exons 2 to 32: Constant
    • First exons
      • 8 alternative
      • Variable length & sequence
      • Spliced into a common exon 2
  • Mutations are missense, stop, small deletions & duplications
  • Variant syndrome: LGMD with no skin changes
• 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
    • 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
• Onset
  • Congenital
  • Weakness or Hypotonia
  • Skin lesions: Blistering
• Clinical
  • Skin: Blistering; Due to Trauma & Heat
  • Muscle
    • Weakness: Myopathy & Myasthenic syndrome
      • Distribution: Proximal, Distal, Facial & Ocular
      • Course: Slowly progressive; Many in wheelchair by 10 years
      • Degree of weakness may correlate with 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
    • Mitochondria³²
      • 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
• Variant syndrome: Limb-Girdle Dystrophy 2Q (LGMD 2Q) ⁸⁴
  • Epidemiology: Turkish families, consanguinous
  • Plectin Mutation
    • Homozygous
    • c.1_9del
    • Contains an initiation codon in exon 1f
    • Exon 1f: Isoform-specific sequence of plectin isoform 1f
  • 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: Normal
      • Course
        • Stable in childhood
        • Progressive in teens
        • Loss of ambulation: Adults
    • Muscle size: Atrophic
    • Skin: Normal
    • Joints: Contractures late
  • Muscle
    • Dystrophic
      • Fiber size: Varied
      • Internal nuclei
      • Necrosis & Regeneration
      • Endomysial connective tissue: Mildly increased
      • Type 2 predominance
    • Plectin
      • Reduced on sarcolemma (30%)
      • Isoform 1f: Reduced to 1%
    • Ultrastructure
      • Membrane duplications
      • Enlarged space between membrane & sarcomere
      • Misalignment of Z-disks
      • ? Disrupted connection between the sarcolemma and sarcomere
  • Laboratory
    • Serum CK: 3000 to 5500
    • EMG: Myopathic

Congenital muscular dystrophy with Mitochondrial Structural Abnormalities (Megaconial) (MDCMC) ²

• Epidemiology: Japanese, Turkish & British patients
• Genetics
  • Mutation types: Nonsense, Missense, Deletion, Splice site
• CHKB protein
  • Catalyzes
    • Phosphorylation of choline by ATP
    • 1st step in phosphatidylcholine biosynthesis
  • Mutations: Choline kinase activities absent; Phosphatidylcholine levels decreased
• Clinical
  • Onset
    • Age: Congenital
    • Hypotonia
  • Motor
    • Weakness: Proximal; Slowly progressive
    • Hypotonia
    • Late walking
  • Muscle wasting
  • Cardiomyopathy: Dilated
  • Mental retardation
  • Head circumference: May be small
• Laboratory
  • CK: Mildly elevated; 190 to 2700
  • Muscle pathology
    • Fiber size variation
    • Necrosis & Regeneration
    • Endomysial connective tissue: Increased
    • Mitochondria
      • SDH & COX staining
        • Increased at periphery of type 2 muscle fibers
        • Reduced in center of fibers (Normal SR in these regions)
      • EM: Enlarged mitochondria with abnormal structure
    • Lipid: Normal
    • Laminin-α2: Normal
• Mouse model: rmd
• Also see: Congenital muscular dystrophy with junctional epidermolysis bullosa

From D Cummings MD

Congenital MD + Rigid Spine

Congenital muscular dystrophy with early Spine Rigidity

• Genetics
  • Selenocysteine incorporated into proteins at UGA codon
  • UGA codon normally a stop codon
  • Recognition of UGA as Selenocysteine codon
    • Requires insertion sequence (SECIS) in 3'UTR of transcripts
    • Sec redefinition element (SRE) located adjacent to the UGA codon
  • SEPN1 mutations
    • Nonsense: Frameshift; Stop codon; Splicing
    • Missense locations
      • Conserved domain
      • Near UGA codon: SRE element⁷³
      • In SECIS sequence
  • Mutations also cause
    • Minicore congenital myopathy syndromes
    • Congenital myopathy with desmin inclusions
    • Congenital fiber type size disproportion (Small type I fibers)
• SEPN1 protein⁴⁰
  • Selenoprotein family: All are enzymes
  • Structure
    • Size: 70 kDa
    • Contains single selenocysteine residue
    • Glycoprotein
  • Subcellular localization: Endoplasmic reticulum; Membrane
  • Levels
    • High: Most human fetal tissues; Proliferating cells
    • Lower in adult tissues
    • Skeletal muscle: Progressive decrease as myoblasts fuse to become myotubes
  • Function: ? Early development in cell proliferation or regeneration
• Selenoproteins
  • Catalyze oxidation/reduction reactions
  • Contain Selenocysteine (Sec) residue(s) located at enzymatic active site
  • Selenium deficiency: Causes
    • Cardiomyopathy (Keshan disease)
    • Muscular dystrophy in livestock
  • Also see: Selenoprotein deficiency (SECISBP2)
• Epidemiology
  • Family origins: Moroccan, Turkish, Iranian, Scandinavian
• Clinical features: Overlap with Minicore congenital myopathy syndromes
  • Weakness⁸: Variable seveity
    • Onset: Variable
      • Early: Birth to 1 year
      • Later: 1st decade
    • Early onset: Hypotonia; Poor head control
    • Distribution
      • Neck; Face; Proximal; Distal
      • Symmetric
    • Respiratory
      • Vital capacity
        • Often reduced: Minimal to 55% by 1st decade
      • Nocturnal hypoventilation: Central apnea during paradoxical sleep
      • Progressive failure
    • Walking: Never to < 18 months
    • Muscle size: Small, especially inner thighs & calves
    • Course
      • Early improvement with development
      • Then Non-progressive or Slow decline
  • Skeletal
    • Spine
      • Rigid: Onset 3 to 7 years; Limited flexion of neck & spine
      • Scoliosis: Onset 4 to 12 years; Progressive
    • Other contractures (50%): Elbow flexors; Hip extensors; Ankles; Knees
  • Cardiac: Minor conduction defects, or Normal
  • CNS: Normal intelligence; No white matter changes
  • Endocrine: Insulin resistance
• Laboratory
  • Serum CK: Normal
  • MRI of muscle
    • Selective involvement of muscles
    • Volume loss & Increased signal on T1
    • Involved muscles: Vastus lateralis; Biceps femoris
    • Spared muscles: Vastus medialis; Semitendinous; Adductor magnus; Gracilis
• Muscle pathology: Choose muscle to biopsy by MRI
  • Anatomical pattern: Variable involvement of different muscles
  • Fiber size: Variable
  • Muscle fibers
    • Necrosis: Occasional
    • Minicores
      • Short-length areas
      • Ultrastructure: Sarcomere disorganization & mitochondria depletion
      • Immunostaining: Filamin C; αB-crystalline
    • Fiber types: Type I muscle fiber predominance or small; Both types present
  • Endomysial connective tissue: Minimal to mild increase
  • Merosin: Normal

• Weakness: Never walk
• Rigidity of the spine and scoliosis: Very early onset

Congenital muscular dystrophy with respiratory failure & muscle hypertrophy (CMD1B; MDC1B)⁷

• Epidemiology: Arab & German families
• Clinical
  • Severe diaphragm involvement: Respiratory failure
  • Weakness
    • Neck
    • Proximal > Distal
    • Arms & Legs
    • Face: Mild
    • Walking: Onset at 1.5 to 2.5 years
    • No clear progression of weakness
  • Muscle hypertrophy: Generalized
  • Contractures
    • Ankles
    • Spine rigidity (50%)
  • Intellect: Normal
• Laboratory
  • Serum CK: Very high; 1,700 to 7,600
  • Brain: Normal MRI
• Muscle
  • Dystrophic changes
  • Connective tissue proteins: Reduced on some fibers
    • Merosin: Reduced; No mutations in Merosin gene
    • Integrins α-7 & β1D: Reduced
    • Heparan sulfate proteoglycans: Normal

Early-onset Myopathy with Areflexia, Respiratory Distress & Dysphagia (EMARDD) ⁸⁷

• Epidemiology: 5 families
• Genetics:
  • Mutations: Often truncating; One missense Cys774Arg
  • Allelic with: Congenital myopathy with minicores
• MEGF10 protein
  • Transmembrane protein
  • Multiple epidermal growth factor family
  • Possible functions
    • Cell-cell adhesion
    • Engulfment receptor of apoptotic cells: Normal clearance of apoptotic neurons during neurogenesis
    • Regulation of muscle development & repair
      • Promotion of muscle precursor proliferati
      • Suppression of myoblast differentiation.
      • Likely mediated through Notch signaling pathway
  • Expression
    • CNS: Brain, Spinal cord (Interneurons & motor neurons in spinal gray matter)
    • Skeletal muscle & NMJ: Satellite cells
• Clinical
  • Onset age: Early or Prenatal with reduced fetal movements
  • Hypotonia: Motor milestones delayed
  • Weakness: Proximal & Distal
  • Skeletal
    • Contractures: Fingers & Equinovarus foot
    • Scoliosis
  • Areflexia
  • Respiratory
    • Distress & Failure: Paradoxical breathing
    • Diaphragm eventration or paralysis (Unilateral or Bilateral)
  • Dysphagia: Feeding often by gastrostomy
  • Cognition: Normal
  • Course: 50% die < 15 years
• Laboratory
  • Serum CK: Normal to 700
  • EMG: Myopathic; Normal RNS & NCV
  • Muscle
    • Muscle fiber size: Reduced; Mildly varied
    • Connective tissue: Reduced numbers of cells
    • MEGF10 protein: Absent in all muscle fibers
    • No detectable PAX7+ nuclei
  • Sural nerve: Normal
• Variant syndrome: Congenital myopathy with minicores
  • General: Less severe than EMARDD
  • Epidemiology: Single family
  • Genetics: Missense MEGF10 mutations; C326R, C774R
  • Clinical
    • Onset
      • Age: Infancy
      • Weakness: Hypotonia; Neck
    • Weakness
      • Proximal & Distal
      • Neck: Flexion
      • Ankles: Dorsiflexion > Plantarflexion
      • Difficulty walking & climbing stairs
      • Respiratory: Require BiPAP at night; Onset 10 years
      • Progression
        • To teens; Then static
        • Loss of ambulation: Some in teens
    • Tendon reflexes: Reduced or Absent
    • Scoliosis: Onset 1st decade
    • Contractures: Neck; Elbows; Knees; Heels
    • GI: Reflux; High arched palate
    • Cardiac: Normal
  • Laboratory
    • Serum CK: Normal or Mildly high
    • Muscle biopsy
      • Myopathic
        • Fiber size: Varied: Large & small
        • Emdomysial connective tissue: Increased;
        • Fatty replacement
        • Internal nuclei
        • Generally inactive
      • Internal architecture: Motheaten or Minicores
      • Ultrastructure: Focal Z-band disarray across few sarcomeres

Congenital Muscular Dystrophy with Muscle hypertrophy (MDC1C; MDDGB5) ^16,26

• Epidemiology: Mutations in 7 families
• Genetics
  • Allelic with
    • LGMD 2I (MDDGC5)
    • Myopathy with abnormal merosin (Laminin-2)
    • Walker-Warburg syndrome (MDDGA5) : Homozygous FKRP mutations; Met1Val & Cys318Tyr
  • Mutations: Missense
    • Ser221Arg, Ala455Asp, Pro448Leu, Tyr309Cys, Ser385Ter, Pro316Thr, Tyr465Ser
    • Tyr465Ser mutation adds potential new glycosylation site
  • No patients with 2 FKRP null alleles
  • Patients with L276I mutation usually have LGMD 2I
• FKRP protein
  • Ubiquitous
  • Highest levels in skeletal muscle, heart & placenta
  • Subcellular: Normal protein in Golgi
  • Function: ? Glycosyltransferase or phosphoryl-ligand transferase
  • More severe cases: Mutant protein⁵⁴
    • Location: Endoplasmic reticulum
    • Shorter half-life
    • Preferentially degraded by proteasome
• Clinical
  • Onset
    • First weeks of life
    • Hypotonia
    • Reduced movement & activity
  • Weakness
    • Diffuse: Limbs; Neck; Trunk; Face
    • Functional abilities
      • May sit unassisted
      • Inability to walk
  • Muscle size
    • Hypertrophy: Especially calf; Most patients
    • Wasting: Shoulder girdle; Other muscles
  • Contractures
    • Some patients
    • Knees; Ankles; Elbows; Spine
  • Skeletal: Small head; Scoliosis
  • CNS
    • Usually normal
    • Occasional patients with
      • Mild mental retardation: Psychomotor; Absent speech
      • Cerebellar cysts
• Laboratory
  • Serum CK
    • Very high: 3,000 to 8,000
    • May have lower levels with increasing age
  • EMG: Myopathic
  • Muscle biopsy
    • Varied fiber size
    • Connective tissue: Increased
    • Necrosis & Regeneration: Occasional fibers
    • Type I predominance: Mild
    • Laminins
      • α2: Partial reduction around muscle fibers; Normal in nerve
      • α5: Increase
    • Dystroglycans
      • α-dystroglycan
        • Muscle staining: Marked reduction: Similar to changes seen in Fukuyama CMD
        • Western blot: Abnormal molecular weight
      • β-dystroglycan: Normal
  • Brain MRI: Normal or Cerebellar cysts
  • EKG: Normal
• Also see: CMD with muscle hypertrophy, mental retardation & cerebellar hypoplasia

Scleroatonic muscular dystrophy (Ullrich) ²¹

• Genetics
  • Mutations
    • Recessive (COL6A1, COL6A2 & COL6A3)
      • Truncating or Missense
      • Reduced or absent Collagen VI in muscle
      • Commonly: Located in triple helical domain; Alter glycine residues
    • Dominant (COL6A1, COL6A2 & COL6A3)
      • Inframe deletion or mutation
      • Dominant negative effect⁴¹: Interferes with dimer formation & secretion of molecule
      • Often in N-terminal region: Proximal to cysteine in triple helical domain
      • Family history of disease uncommon
  • Allelic with
    • Bethlem myopathy
    • Myosclerosis: COL6A2 mutation
    • Ossification of posterior longitudinal ligament: Mutations in different part of COL6A1 gene
  • Some patients with similar syndrome: Not linked to these loci; Normal Collagen VI
• Collagen VI protein
  • Ubiquitious extracellular matrix protein
  • Concentrated outside basal lamina
  • Ullrich myopathy muscle & fibroblasts
    • Mislocalized, Low or Absent
• Clinical features
  • Variable
    • Some with severe weakness
    • Some families with COL6A3 mutations have milder disease
  • Onset
    • May be reduced fetal movements
    • Congenital contractures
    • Hypotonia
  • Joints
    • Early
      • Hyperlaxity of distal joints
      • Distal arthrogryposis: Some patients
    • Contractures
      • Proximal > Distal
      • Knee contractures may limit walking
      • Spine: Rigidity; Kyphoscoliosis
      • Torticollis
      • May improve with increasing age
  • Weakness
    

    From: A Connolly MD Hyperkeratosis pilari

    • Diffuse: Distal > Proximal; Neck flexors
    • Ambulation
      • May walk by age 1 to 2 years (30%)
      • Majority never walk
    • Respiratory insufficiency
      • Onset: Hypoventilation in 1st decade
      • Failure: Not correlated with degree of weakness
    • Muscle wasting: Distal predominant
    • Course
      • Slowly progressive
      • Walking
        • Some walk for a limited time: 3 to 6 years
      • Death
        • Age: 1st or 2nd decade
        • Associated with respiratory failure
  • Skin
    • Soft
    • Keratosis pilaris
    • Keloids
    • Atrophic scars
    • Striae
    • Petechiae
  • Skeletal
    • Prominent calcaneus of foot
    • Scoliosis
    • Rigid spine
  • Tendons: Similar to Ehlers-Danlos; Contractures
  • Cardiac: Normal
  • Intelligence: Normal
• Laboratory features
  • Serum CK: Normal to 10x elevated
  • EMG: Myopathic
• Muscle biopsy
  • Varied muscle fiber size: Some very small muscle fibers
  • Endomysial connective tissue: Progressive increase
  • Necrotic muscle fibers: Rare or Occasional
  • Lobulated fibers: Occasional
  • Collagen expression
    • Type VI
      • 2 patterns of pathology
        1. Absent from skeletal muscle & capillaries
        2. Absent on surface of muscle fibers but present in connective tissue
      • No correlation between pattern of pathology and clinical phenotype
    • Type IV: Upregulated
  • Ultrastructure
    • Muscle plasma membrane: Uneven, extension & folding
    • Basal lamina: Thickening & overproduction; Replication of capillary basement membrane
    • Capillary morphology⁴²: Small lumens; Increased pinocytotic vesicles in endothelial cells
    • Collagen: Disorganized fibrils
• Gene testing: Utah

Congenital Muscular Dystrophy with Mental Retardation & Abnormal Glycosylation (MDDGA6; MDC1D) ⁴³

• Epidemiology: Few patients
• Genetics
  • 5th largest human gene
  • Mutations
    • Missense: Glu509Lys
    • Insertion (1bp): 1999insT
    • Deletion: Intron 8 to Intron 10
  • Allelic with
    • Congenital Muscular Dystrophy (MDDGB6)
  • Other mutations in: myd mouse
• LARGE protein
  • Ubiquitously expressed
  • Highest levels in heart, brain & skeletal muscle
  • Two putative catalytic domains with homology to
    • α-glycosyltransferase (bacterial WaaIJ family)
      • Synthesis of outer membrane lipopolysaccaride
    • β-1,3-N-acetylglucosaminyltransferase (iGnT)
      • Synthesis of poly-N-acetyllactosamine backbone of erythrocyte i antigen
  • May play role in glycosylation of α-dystroglycan⁴⁷
• Onset
  • Age: 5 months
  • Global developmental delay
• Clinical
  • Congenital muscular dystrophy
    • Hypotonia
    • Slow improvement over 1st decade
    • Muscle hypertrophy
      • Moderate
      • Quadriceps; Calf; Arm muscle
      • Tongue: Normal
    • Muscle atrophy: None
    • Weakness
      • Proximal > Distal
      • Legs > Arms
      • Face: Mild weakness
      • EOM: Normal
  • CNS
    • Mental retardation: Profound
    • Mirror movements
    • Nystagmus: Lateral
    • Spasticity: Tone increased; Tendon reflexes increased; Extensor plantar
  • Contractures
    • Mild
    • Ankle & Elbow
• Laboratory
  • Serum CK: High; 400 to 4500
  • NCV: Normal Motor & Sensory
  • EMG: Myopathic
  • Electroretinogram: Small evoked response
  • CNS imaging
    • White matter changes: Periventricular to arcuate fibers; Anterior & Temporal
    • Structural abnormalities: Abnormal neuronal migration; Small brainstem
  • Pathology: Muscle
    • α-dystroglycan
      • Immunolabelling: Reduced
      • Immunoblotting with to glycosylated epitope: Reduced molecular weight of α-dystroglycan
      • Retains some laminin binding activity
    • Laminin α2: Normal
    • Dysferlin: Upregulated in myd mouse
  • Mouse model: myd mouse muscle

Congenital Muscular Dystrophy with Adducted Thumbs, Ophthalmoplegia & Mental retardation ³⁴

• Epidemiology: Consanguinous Sicilian siblings
• Onset: Congenital
• Clinical
  • Joints: Adducted thumbs ; Toe contractures; Hyperlordosis
  • Motor: Hypotonia; Delayed walking
  • Weakness: Diffuse; Facial; Severe
  • Ocular: Ophthalmoplegia; Ptosis
  • Cognitive: Mental retardation, IQ 65 to 70
• Laboratory
  • Serum CK: High, 130 to 750
  • NCV: Normal
  • MRI: Cerebellar hypoplasia, Mild
  • Muscle
    • Dystrophic: Varied fiber size; Increased endomysial connective tissue
    • Normal laminins & α-dystroglycan

Congenital muscular dystrophy & myasthenic syndrome ⁵⁵

• Epidemiology: Palestinian family, consanguinous
• Genetics
  • DOK7 mutation: c.957delC Homozygous
  • Allelic with: Limb-Girdle Myasthenia
• Onset
  • Age: Neonatal or in utero
  • Reduced fetal movements
  • Hypotonia
• Clinical
  • Motor
    • Early: Hypotonia; Reduced anti-gravity movements
    • Weakness
      • Proximal > Distal
      • Most severe: Trunk & Shoulder girdle muscles
      • Mild to moderate involvement: Face, Neck, Proximal limb
      • None: Extra-ocular, Bulbar
      • Course: Slow progression
      • Episodic exacerbations: No precipitating factors
  • Muscle size: Small, No hypertrophy
  • Course
    • Some death in childhood or adult: 50% with respiratory infections
    • Motor: Static
    • Most survivors able to walk as children & adults
  • Joints
    • No contractures
    • Mild laxity in adults
  • Intelligence: Normal
• Laboratory
  • Serum CK: Normal or Minimally elevated
  • Brain CT: Normal
  • Echocardiogram: Normal
• Muscle pathology
  • Morphology: "Dystrophic"
  • Normal staining: Laminins (α2, α5, β1, β2), Dystrophin, Sarcoglycans (α, β, γ), α & β-Dystroglycan

OTHER CONGENITAL WEAKNESS

• Largest # of triplet repeats of any MD syndrome (> 1,000)
• Examine parents (esp mother) for evidence of disease

• Congenital FSH often presents with no clearly affected parent

• Acid Maltase
• Debranching Enzyme
• Branching Enzyme
• Carnitine Deficiency
• Mitochondrial (Cytochrome Oxidase Deficiency)

• Spinal Muscular Atrophy: 5q & X-linked
• Congenital Neuropathies: Hypomyelinating; CIDP

Broad A band disease

• Epidemiology: 2 sporadic cases
• Clinical
  • Onset: Neonatal
  • Hypotonia
  • Developmental delay: Motor; Speech
  • Progressive improvement in function
  • Retinal dystrophy: One patient
• Laboratory
  • Serum CK: Mildly high
  • EMG: Normal
• Muscle pathology
  • Broad A bands visible on plastic sections
  • Misalignment of myosin thick filaments

Trilaminar myopathy

• Epidemiology: 1 sporadic case
• Clinical
  • Onset: Birth
  • Tone: Increased resistance to passive movement
  • Contractures
  • Course: Increasing spontaneous movements
  • Cognition: Normal
• Laboratory
  • Serum CK: High (6x to 40x)
  • EMG: Normal
• Muscle pathology
  • Fiber size: Varied
  • Large fibers: Trilaminar appearance
    • NADH: Dark inner & outer zones
    • ATPase: Pale inner & outer zones
  • Ultrastructure
    • Central zone lacks organized myofibrils
    • AChRs: Extrajunctional, between intermediate & outer zones

Zebra body myopathy

• Epidemiology: 2 sporadic cases; ? clinical entity
• Mutations: Null alleles
• Clinical
  • Onset: Birth
  • Hypotonia
  • Weakness
    • Symmetric or Asymmetric
    • May be greater in arms
  • Muscle size: Small
  • Tendon reflexes: Normal
  • Course: static or slow improvement
• Laboratory
  • Serum CK: Normal or Mildly high
  • EMG: Myopathic
• Muscle pathology
  • Fiber size: Varied
  • Zebra bodies
    • Visible by ultrastructure
    • Z-line material in stacks separated by thin filaments (striped)
    • May occur in: Morphologically normal muscle; Same muscle fibers as rods
  • Nemaline rods

Weakness with early skeletal disorders

• Tel Hashomer camptodactyly syndrome
    l Autosomal Recessive
  • Clinical features
    • Skeletal: Camptodactyly (flexed fingers); Club feet; Spina bifida - Cervical
    • Skin: absent interphalangeal creases; Whorls 7 or more fingers; Palmar creases
    • Abnormal sweat pores
    • Cardiac: Mitral valve prolapse
    • Myopathy: Wasting; Variable fiber size; High serum CK
    • Heterozygotes: Partial skeletal (5th finger camptodactyly) & skin manifestations
  
  
• Camera-Marugo-Cohen Syndrome
  • Clinical features
    • Obesity
    • Mental retardation
    • Skeletal: Body asymmetry; Camptodactyly; Clinodactyly
    • Muscle weakness: Proximal, Legs > Arms 50%; Congenital hypotonia 50%

Williams-Beuren syndrome

• Genetics
  • Microdeletion in region of highly repetitive DNA
  • 2° to recombination between misaligned repeat sequences flanking WBS region
• Clinical
  • Vascular stenoses: Supravalvular aortic; Coronary; Pulmonary; Renal
  • GU: Urethral stenosis; Small or solitary kidney
  • ENT: Elfin faces; Hoarse voice; Vocal cord paralysis
  • Gastrointestinal: Inguinal hernia; Constipation; Diverticulosis
  • Metabolic: Episodic dehydration; Hypertension; Hypercalcemia
  • Mental retardation: 65 IQ average
    • Deficient visuo-spatial ability
    • Relatively preserved verbal function
    • "Cocktail party" personality
    • Attention defecit
    • Hypersensitivity to sound
  • Joint contractures
  • Motor
    • Infants: Hypotonia; Delayed walking; Fatigue
    • Adults: Cramps; Myalgia; Fatigue
• Muscle pathology
  • Myopathy: Variable fiber size
  • Some with lipid storage & Carnitine deficiency

Neonatal perifascicular myopathy¹

• Onset
  • Age: Neonatal
  • Motor: Hypotonia & Weakness
• Clinical
  • Motor
    • Hypotonia
    • Weakness: Diffuse
  • CNS
    • Cognitive delay
    • Mental retardation: Mild
  • Course
    • Non-progressive
    • Improvement in motor skills with increasing age
• Muscle pathology
  • Muscle fibers: Perifascicular pattern of pathology
    • Atrophy
    • Immature, type 2C muscle fibers
  • Connective tissue
    • Alkaline phosphatase staining of perimysium
    • Cells: Macrophages or dendritic
  • Inflammation: Perivascular, near & around intermediate sized vessels

Immunoneurologic Disorder (Woods-Black-Norbury Syndrome)

• Males: Neonatal hypotonia; Early death
• Females: Spastic paraparesis
  • Weakness: Progressive
  • Tendon reflexes: Brisk
  • Bladder dysfunction
  • Night vision: reduced
  • IgG2 dficiency

Congenital absence, weakness, or hypoplasia of muscles

Extraocular muscles

• Congenital fibrosis of extraocular muscles (CFEOM)
  
  
  • Congenital fibrosis of extraocular muscles 1 (CFEOM1)
    l Kinesin family member 21A (KIF21A) ; Chromosome 12q12; Dominant & Sporadic
    • Mutations⁴⁶
      • Heterozygous
      • Missense: R954W; R954Q; Other
      • Stalk region of protein: Most common
      • Some de novo: More in sporadic cases
      • May also produce CFEOM3 phentype
    • KIF21A protein
      • Transport: Motor protein
      • Kinesin class: Same as KIF21B & KIF4
      • Other kinesin mutations
        • CMT 2A: KIF1Bβ
        • SPG 10: KIF5A
    • Clinical
      • Ptosis: Congenital; Bilateral
      • EOM
        • Common defect: Inability to elevate eye
        • Other: Little horizontal movement
      • Eyes fixed 20° to 30° below horizontal
      • Head tilt: Posterior
      • Blepharophimosis
    • Pathology
      • Developmental absence of the superior division of oculomotor nerve
      • Reduced # of midbrain α oculomotor neurons
      • Anomalous extraocular muscle insertion
      • Muscle changes: Superior rectus & Levator palpebrae superioris
    • Also see clinical variant: FEOM 3A
    
    
  • Congenital fibrosis of extraocular muscles 2 (CFEOM2)
    l Aristaless homeobox, drosophila, homolog of (ARIX; PHOX2A) ; Chromosome 11q13.4; Recessive
    • Mutations: Splice sites & Missense
    • ARIX protein
      • Homeodomain transcription factor
      • Required for cranial nerve III & IV development
    • Epidemiology: Saudi Arabia (Ala72Val); Turkey
    • Clinical
      • Limited extraocular movements
        • Eyes fixed in abduction
        • Deficient function of muscles innerved by the third or fourth cranial nerves
        • Can raise eyes above horizontal or have unilateral involvement
      • Ptosis
      • Visual acuity
        • Poor
        • Severe amblyopia: In eyes with pupil covered by ptotic lid
      • Pupils
        • Miotic
        • Fixed or sluggishly reactive to light or pupillary dilators
    
    
  • Congenital fibrosis of extraocular muscles 3 (CFEOM3)
    l Tubulin, Beta-3 (TUBB3) ; Chromosome 16q24.3; Dominant
    • Genetics
      • TUBB3 mutations
        • Missense
        • R62Q; Arg262Cys (Common); R262H; Ala302Thr; R380C; Glu410Lys; Asp417His; Asp417Asn
      • Locations: Regions of β-tubulin regulating microtubule dynamics, motor protein trafficking & interactions with MAPs
      • E410, D417 & R262: Loss of Kinesin Localization on Microtubule Plus Ends
      • A302T, R62Q & R380C: Microtubules more stable & longer lifetimes
      • R262C, R262H & E410K: Duration of individual growth events prolonged; Increased rate of depolymerization
      • Similar CFEOM3 syndrome seen with: Some KIF21A mutations
    • TUBB3 protein
      • May play role in axon growth guidance & maintenance
      • Mutations may impair tubulin heterodimer formation
      • May interact with KIF21A
      • See: Axonal transport
    • Clinical
      • Variable expression
      • Often asymmetric
      • Ptosis
      • Extraocular movements: Limited
        • Deficient function of muscles innerved by the third or fourth cranial nerves
        • Can raise eyes above horizontal or have unilateral involvement
        • Mild: Limited vertical gaze
        • Severe: 1° gaze fixed in hypo- & exotropic position; Marked restriction of EOM
        • Marcus-Gunn: Ptotic eyelid elevation associated with synkinetic jaw movements
      • Other features: Some mutations
        • Aberrant innervation of cranial musculature by trigeminal nerve
        • Intellectual & behavioral impairments: A302T, E410K, R262H & R380C
        • Facial paralysis
        • Axonal sensorimotor polyneuropathy: Later-onset; E410K D417H or R262H mutations
          • Onset age: 1st to 3rd decade
          • Leg weakness
          • Sensory loss
          • EMG: Chronic, generalized sensorimotor polyneuropathy
          • May occur without CFEOM in some patients: CMT 2-like syndrome
        • Wrist & finger contractures: D417H or R262H mutations
      • Course: Non-progressive
    • MRI
      • Hypoplasia: Oculomotor nerve
      • Hypoplasia: muscles innervated by III nerve
      • No polymicrogyria
        • Superior division: Levator palpebrae superioris; Superior rectus
        • Inferior division: Medial rectus
      • Oculomotor nerve aberrant innervation: Lateral rectus muscle
      • Dysgenesis of corpus callosum, anterior commissure (AC) & internal capsule
        • More severe: A302T, E410K, R262H & R380C
        • Less severe: R62Q, R262C, or D417N
      • White matter: Generalized loss
      • Basal ganglia: Dysmorphisms correlating with specific mutations
      • Cortex: Normal
    • Variant syndrome: TUBB3 E410K mutation
      • Clinical
        • Moebius syndrome
          • Congenital fibrosis of extraocular muscles
          • Facial weakness
        • Polyneuropathy: Sensory-Motor; Progressive
        • Kallmann syndrome (Hypogonadotropic hypogonadism & Anosmia)
        • Midface hypoplasia
        • Intellectual disabilities
        • Some patients: Vocal cord paralysis, Tracheomalacia, Cyclic vomiting
      • MRI
        • Thin corpus callosum & anterior commissure
        • Olfactory sulci & bulbs: Absent
        • Oculomotor & Facial nerves: Absent
    
    
  • Congenital fibrosis of extraocular muscles (CFEOM) + Polymicrogyria ¹⁰³
    l Tubulin, Beta-2B (TUBB2B) ; Chromosome 6p25.2; Dominant
    • Epidemiology
      • Australian-based Caucasian family
      • Rare cause of CF-EOM
    • Genetics
      • TUBB2B mutation: E421K; Heterozygous
        • Alters microtubule dynamics: Increased polymer stability; Reduced TUBB2B αβ-heterodimer production
        • Can reduce kinesin localization
      • Other TUBB2B mutations: Polymicrogyria, symmetric or asymmetric
    • TUBB2B protein
      • Forms α/β tubulin heterodimers
      • Required for neuronal migration
    • Clinical
      • Congenital fibrosis of extraocular muscles (CFEOM)
        • Ptosis: Bilateral
        • Vertical eye movements
          • Severely limited
          • Jerky convergent movements on attempted elevation
        • Horizontal movements: Variably restricted
        • Eyes fixed in downgaze: Bilateral
        • Chin-up head position: Compensatory
        • Pupils: Normal
      • Intellectual disability
      • Head circumference: < 2nd percentile
    • Laboratory
      • MRI
        • Polymicrogyria
        • Commissural projection neurons: Aberrant trajectories
        • Caudate: Small
        • Extra-ocular muscles: Small
      • Nerve conduction studies: Normal
    • Mother: Mild polymicrogyria
    
    
  • CFEOM with ulnar hand anomalies ⁵⁸
    l Chromosome 21qter; Recessive
    
    • Epidemiology: 1 Turkish family
    • Clinical
      • Ocular
        • Ophthalmoplegia
          • Muscles
            • Especially inferior oblique & superior rectus
            • Limited upgaze: Most common
            • Levator palpebrae: Some patients
            • Severe cases: Complete ophthalmoplegia
          • Non-progressive
          • Forced ductions: Normal
        • Blepharoptosis: Right eye
        • Head posture: Chin elevation
        • EOM pathology: Fibrosis
      • Hands
        • Postaxial oligodactyly/oligosyndactyly
          • Especially absent 5th finger
        • More severe on right side
  
  
• Duane syndromes
  
  

  General DURS1: 8q13 DURS2: CHN1; 2q31 DRRS (Okihiro): SALL4; 20q13 BSAS: HOXA1; 7p15 Other DURS-like syndromes

  
  

  Click image for movie

  Duane syndrome

  • Clinical features, Duane syndromes: General
    • Restriction of abduction, adduction, or both
    • Eye adduction causes
      • Globe retraction
      • Palpebral fissue narrowing
    • Strabismus: Esotropia most common
    • Usually unilateral & sporadic
    • Bilateral syndromes
      • Amblyopia & Strabismus: More common
      • Especially familial cases
    • Associated congenital malformations common
      • Skeletal
      • Ear
      • Ocular
      • Neural
    • Pathology
      • Absent abducens nuclei + nerve
      • Lateral rectus muscle
        • Denervated
        • Aberrant innervation by inferior division of oculomotor nerve
              (Also innervates ipsilateral medial rectus muscle)
  
  
  • DURS1
    l Chromosome 8q13; ? Sporadic
    

    Duane-like phenomenon in patient diagnosed as chronic ocular myasthenia gravis. Mild ptosis in R eye on center gaze. (Top) Increased ptosis & retraction in R eye     with adduction (L gaze). (Bottom)

    • Genetic: Deletion in 8q rearranged region
    • Clinical: Multisystem disorder
      • Weakness of abduction
      • Retraction of eye & ptosis with adduction
      • Associated C2-C3 vertebral fusion (Klippel-Feil)
      • Thenar hypoplasia
      • Deafness
    
    
  • DURS2 ⁷²
    l α2-Chimerin (CHN1) ; Chromosome 2q31; Dominant
    • Genetics: Mutations
      • Missense: Heterozygous
      • Gain-of-function: Increase α2-chimaerin RacGAP activity
      • Some mutations enhance
        • α2-chimaerin translocation to cell membrane
        • Ability of α2-chimaerin to self-associate
      • Functional effect: Axonal disorder
        • Aberrant branching and/or defasciculation of nerve
    • CHN1 protein
      • Rac-specific GTPase-activating: Down-regulates Rac activity
      • Binds to diacylglycerol (DAG), a membrane associated phorbol ester signaling lipid
      • Strongest expression during development in midbrain & hindbrain
    • Congenital ophthalmoplegia
      • Abduction: Absent or reduced
      • Adduction: Reduced in some patients
      • Eye retraction & ptosis on adduction
      • Higher incidence of
        • Bilateral involvement
        • Vertical movement abnormalities
    • Pathology
      • Absent abducens nerve & nucleus in pons
      • Hypoplastic oculomotor nerves: Small oculomotor-innervated muscles
    • Mice with loss of α2-chimaerin
      • Disrupted ephrin/EphA4 signaling
      • Elevated RacGTP levels
      • Phenotype: Hopping rabbit-like gait resulting from
      • Pathology: Excessive & aberrant midline crossing of corticospinal tract axons & spinal interneuron projections
    
    
  • Duane anomaly + Radial ray abnormalities & Deafness (DRRS; Okihiro syndrome)
    l Sal-like 4 (SALL4) ; Chromosome 20q13.2; Dominant
    • Allelic with: IVIC syndrome
    • Clinical
      • Upper limb: Hypoplasia of thenar muscles; Absence of thumb & first metacarpal
      • Ocular: Duane syndrome; Coloboma
      • Renal: Malrotation; Absence
      • Ear: Deafness; Narrow external auditory meatus
    • Differential diagnosis: Holt-Oram syndrome
    
    
  • Bosley-Salih-Alorainey Syndrome (BSAS)
    l Homeobox A1 (HOXA1) ; Chromosome 7p15.2; Recessive
    
    • Epidemiology: Saudi-Arabian, Turkish & Native American (Navajo) families
    • Genetics
      • Mutations
        • Stop: 175-176insG, R26X, Y28X
        • Homozygous
      • Mutations in other HOX genes: Cause malformed distal extremities
    • Clinical
      • Duane syndrome: Bilateral
        • Horizontal gaze: Abduction & Adduction limited
        • Up & down gaze: Preserved
        • Convergence: Normal; Associated globe retraction
      • Deafness & Mutism (89%)
      • Motor development (66%): Delayed; Walking > 3 years
      • Other CNS (22%)
        • Mental retardation
        • Autism spectrum disorder
    • Malformations
      • Carotid
        • Hypoplasia or absence of skull canals & arteries: Internal carotid often absent
        • Compensatory enlargement of basilar & posterior communicating arteries
      • Ear: Absent cochlea, semicircular canals & vestibule
      • VI nerve: Absent
      • Normal: Cerebellum, Brainstem, Cerebrum
    • Allelic disorder: Athabascan (Navajo) brainstem dysgenesis syndrome (ABDS)
      • Mutation: R26X
      • Onset: Congenital
      • Clinical: BSAS +
        • Face weakness
        • Central hypoventilation
        • Vocal cord paralysis: 20%
        • CNS
          • Hypoventilation
          • Developmental delay: Global
          • Seizures: 50%
        • Heart
          • Congenital defects: 50%
          • Outflow tract anomalies in some
        • BAERs & Caloric testing: No response
      • Similar syndrome to HOXA1-/- mice
    
    
  • Duane syndromes: Other multisystem or sporadic
    • Karyotypic change on Chromosomes 4 or 22
    • Wildervanck syndrome
      • Duane anomaly
      • Klippel-Feil anomaly (fused cervical vertebrae)
      • Congenital perceptive deafness
      • Mostly seen in females
    • Bosley-Salih-Alorainey Syndrome (BSAS)
    
    
  
  
• Möbius Syndrome
  
  
• PEO (Horizontal gaze palsy) & Scoliosis
  l ROBO3 ; Chromosome 11q24.2; Recessive
  • Epidemiology: 10 families, Turkish, Indian, Pakistan, Greek, Arab
  • Onset: 1st decade or Congenital
  • Mutations: Missense; 1 bp insertion; Splice site
  • ROBO3 protein
    • Expressed by commissural axons in brainstem
    • ? Allows axons to cross the midline
  • Clinical
    • Gaze paresis
      • Horizontal: No conjugate horizontal smooth pursuit, saccades, or vestibuloocular reflex
      • Vertical: Spared
      • ? Supranuclear
      • Esotropia: 30%
    • Nystagmus: Pendular
    • Facial myokymia (1 patient)
    • Scoliosis: Mild to Moderate
    • Mental retardation: 30%
    • No weakness
  • MRI
    • Brainstem: Dysplastic in some patients
  
  
• Superior rectus muscle
  • External link: DJO
  
  
• Axenfeld-Rieger anomaly
  l Dominant
  • Eyes
    • Hypoplastic anterior iris
    • Absent eye muscles, partial
    • Proptosis
    • Hypertelorism
  • Ears: Sensorineural deafness, mild
  • CNS
    • Communicating hydrocephalus
    • Psychomotor retardation
  • Short stature
  
  
• Congenital ptosis, Hereditary
  l Type 1 ; Chromosome 1p32-p34.1; Dominant
  • Ptosis: Symmetric or Asymmetric
  • Normal eye movements
  • Penetrance: Incomplete
  
  l Type 2 ; Chromosome Xq24-q27.1; Dominant
  • Male = Female
  • Penetrance: High
  • Onset: Congenital
  • Bilateral: Symmetric
  • Normal eye movements
  
  
• ROCA syndrome
  
  Retardation of growth & development
  Ocular ptosis
  Cardiac defect
  Anal atresia
  
  • Clinical
    • Retardation: Growth; Mental
    • Face: Ptosis, Epicanthus, Broad nasal bridge, Low-set & abnormal ears
    • Congenital heart defect
    • Anal atresia
  
  
• Blepharophimosis: Palpebral fissure is reduced in horizontal dimension
  • Blepharophimosis 1 : + Ptosis & Epicanthus inversus
    l FOXL2 ; Chromosome 3q22.3; Dominant
    • Genetics
      • Polyalanine repeat expansions (30%): May cause blepharophimosis syndrome without ovarian failure
    • Clinical
      • Ptosis
      • Telecanthus
      • Lid phimosis
      • Epicanthus inversus: Small skin fold arising from lower lid running inwards and upwards toward nose
      • ± Ovarian failure
    
    
  • Saethre-Chotzen Syndrome (SCS; Blepharophimosis 2)
    l TWIST Chromosome 7p21.1; Dominant
    
    
  • Blepharophimosis with short stature
    l Autosomal recessive
    • Family: Yeminite-Jewish
    • Clinical
      • Eyes: Blepharophimosis; Ptosis; Ophthalmoplegia
      • Face: Prognathism; Synophrys; Thick eyebrows; Weak frontalis
      • Skeletal: Short stature; Syndactyty toes 2 & 3
      • CNS: Borderline mental retardation; Anosmia
    
    
  • Ohdo syndromes
    
    • Genetics: Several sub-types
      • Deletions of chromosome 3 short arm
      • Ohdo type: Typical clinical features, No hypotonia
      • Verloes type: Brain malformation & Epilepsy
      • Say/Barber/Biesecker/Young/Simpson (SBBYS) type : KAT6B mutations ; Hypotonia, Hyperextensible joints
      • Maat-Kievit-Brunner (MKB) type : MED12 mutations ; Thick alae nasi, Triangular face
    • Clinical: General features
      • Mental retardation
      • Congenital heart disease
      • Eyes: Blepharophimosis; Blepharoptosis
      • Teeth: Hypoplastic
    
    
  • Schwartz-Jampel syndrome
    
    
  • Dubowitz syndrome
    • Ptosis
    • Blepharophimosis
    • Lateral telecanthus
    • Skeletal
      • Microcephaly
      • Short stature
    • Mental retardation (50%)
  
  
  • Marden-Walker syndrome
  
  

Face

• Nosology: Cayler syndrome; Di George syndrome
• Genetics: Often paternally derived chromosome
• Facial weakness: Variable severity
  • Congenital
  • Mild: Unilateral lower lip
  • Severe: Complete facial paresis
• Cardiac
  • Atrial septal defect
  • Ventricular septal defect
• Myopathy²⁰
  • Strength: Normal
  • Serum CK: May be high
  • Muscle biopsy: Variation in fiber size; Increased glycogen
• Skeletal
  • Cervical vertebral fusion
  • Adducted thumbs
  • Facial dysmorphism
• Bifid uvula
• Immune
  • T-cell abnormalities
  • Thymic hypoplasia
• CNS (10%)
  • Microcephaly: Variable
  • Mental retardation

• Double knockout of MyoR (Musculin) and capsulin (TCF21)
• Phenotype
  • Absent muscles in 1st branchial arch: Masseter; Pterygoids, Medial & Lateral; Temporalis
  • Cleft palate
  • Diaphragmatic hernia: Posterior

Diaphragm Weakness ⁷⁸

• Phrenic nerve: General
  • Chief muscle of inspiration
  • Motor innervation
    • Roots: C3, C4, C5
    • Phrenic nerve
  • Sensory innervation
    • Phrenic nerve
    • Intercostal nerves
  • Lesions
    • Infants: More severely clinically affected
    • Clinical: Unilateral
      • 50% Asymptomatic
      • 25% Exertional dyspnea, mild
      • Vital capacity: 75% of predicted
    • Clinical: Bilateral
      • Exertional dyspnea: Severe
      • Orthopnea
      • Nocturnal hypoxemia & hypercapnia
      • Vital capacity: 45% of predicted; Supine < 75% of upright
    • Radiology: Elevated diaphragm on afffected side
• Hereditary & Congenital & X-linked
  • General
    • Bilateral & left side reported
    • Usually recessive
  • General types of congenital diaphragmatic hernia (CDH)
    • Bochdalek
      • 70 to 90% of CDH cases
      • Left sided
      • Posterolateral
    • Morgagni: Anterior retrosternal
    • Central CDH
      • Midline of septum transversum
      • 1 to 2% of CDH
  • Specific syndromes
    • Fryns
    • Simpson-Golabi-Behmel
    • Tetrasomy 12p
    • Brachmann-de Lange syndrome
    • Lethal multiple pterygium
    • SMARD1 (HMN 6; DSMA1)
    • EMARDD (Early onset myopathy, areflexia, respiratory distress & dysphagia)
    • MDC1B
    • Myotubularin female carriers: Elevated hemidiaphragm
    • Acid maltase deficiency
  • Diaphragmatic hernia
    • DIH1 : Chromosome 15q26.1
    • DIH2 : Chromosome 8p23.1
      • Frequently unilateral
      • Associations: Hypoplasia of left lung; Atrial septal defect
    • DIH3 : Zinc finger protein, multitype 2 (ZFPM2) ; Chromosome 8q23.1
    • Diaphragmatic defects with skull ossification & limb deficiencies : ? Autosomal recessive
    • Congenital Anterior Diaphragmatic Hernia
      • ? X-linked vs. multifactorial with high male:female sex ratio
      • Frequent neonatal death
        
• Acquired
  • Traumatic
    • Etiologies
      • Surgery
        • Open-heart surgery
        • Lung transplantation
        • Esophageal surgery
        • Mediastinal procedures
      • Neck or thorax trauma
    • Associated with brachial plexus injury
    • Course: Biphasic worsening
      • 1st hours: Tachypnea & O₂ requirement
      • Days to weeks: Atelectasis or infection
    • Diagnosis: Chest fluoroscopy
    • Prognosis
      • Recovery: 50%; Onset in 1st 2 weeks
      • Mortality: 10% for unilateral & 50% for bilateral
    • Treatment: Plication of affected diaphragm
  • Phrenic nerve lesions: Other
    • Neoplasm
    • Herpes zoster⁷⁷
      • Unilateral
    • ALS
  • Muscle disorders
    • Chronic obstructive pulmonary disease (COPD)
      • Muscle fiber atrophy
      • Fiber changes: More type I; Myosin loss; Sarcomere disruption
    • Amyloid
  • Also see: Respiratory failure

Hands

• Cardiac: ASD; VSD; AV block
• Skeletal: Bilateral; Left > Right in 70%
  • Thumb (85%): Absence; Hypoplasia; Triphalangeal
  • Radius (64%): Absence or hypoplasia
  • Contractures: Elbow; Wrist
  • Severe cases: Phocomelia
• Absent or hypoplastic muscles
  • Thenar (100%): Non-opposing thumb
  • Trapezius: Scapular winging; Sloping shoulders
  • Other: Deltoid; Biceps; Triceps; Wrist Extensor; Ulnar abductors; Supinator
  • Lower limbs: Normal

• More frequent: Females; Left side
  
  

• Unilateral finger extensor hypoplasia
• Flexion contracture
• Polyneuropathy: Sensory with hypohydrosis
• Also see: Holt-Oram
  

From: P Bailey
Dextrocardia
Poland Syndrome

Trunk

• General
  • Male: Female = 2.4:1
  • Right: Left = 1.7:1
  • Prevalence: 1 in 30,000
  • Onset: ? 6th week of gestation
• Clinical manifestations: Variable
• Muscle Aplasia
  • Sternal head of pectoral
  • Other: Serratus anterior; Latissimus dorsi; Glutei;
      Infraspinatus & Supraspinatus
  • Unilateral: Most
• Hand anomalies: Ipsilateral, Hypoplastic
  • Simple syndactyly
  • Short fingers
  • More severe anomalies²⁸
  • External link: Radiology
• Craniofacial anomalies
  • Möbius syndrome
  • Ptosis
  • Craniofacial mandibular prognathism
  • Craniofrontonasal dysplasia
  • Romberg syndrome
  • External ear anomalies
• Skeletal anomalies
  • Spinal
    • Scoliosis
    • Hemivertebrae
    • Rib agenesis
    • Klippel–Feil syndrome : External link
  • Thoracic
    • Ribs, clavicle & sternum
    • Sprengel’s deformity
    • Pectus excavatum & carinatum
  • Lower limbs: Popliteal webs; Club foot; Toe syndactyly
• GI: GI hernia; Ulcerative colitis; Pyloric stenosis; Liver herniation
• GU: Renal agenesis; Ureteral reflux; Undescended testes
• Systemic features: Other
  • Axillary hair: Patchy absence
  • Breast & nipple aplasia
  • Cardiovascular
    • Dextrocardia
    • Atrial septal defect
    • Vascular malformations
  • Neoplasms: Occasional
    • Thoracic teratoma
    • Pleural fibroma
    • Hematopoetic: Leukaemia; Lymphoma
• Also see
  • Holt-Oram
  • Carey-Fineman-Ziter

• Contiguous gene syndrome with
  • Hydrocephalus
  • Duane's
• Also see: Holt-Oram
  
  

• Entrapment of suprascapular nerve: Adult onset
• Also see: Erb's palsy

• Nosology: Prune belly; Eagle-Barrett syndrome
• Epidemiology: 1 Turkish family
• Genetics
  • Mutations
    • Type: Deletion/Insertion; Frameshift; p.Pro392Alafs*43
    • Homozygous
  • Similar syndrome in CHRM3 null mice
• CHRM3
  • Major receptor mediating urinary bladder contraction with micturition
• Clinical
  • General: Full syndrome more common in males
  • Onset age: Congenital
  • Absent abdominal muscles: Abdominal distension
  • Autonomic
    • Pupil constriction to light: Impaired
    • Dry mouth
  • GU
    • Urinary obstruction: Bladder outflow obstruction (BOO)
    • Cryptorchidism
  • Imperforate anus
  • Skeletal: Pectus excavatum; Club foot; Hip dislocation
  • Cardiac: Patent ductus arteriosus
• Laboratory
  • Cystogram: Massive & irregular-walled bladder with diverticulae
• Variant: Similar syndrome with no CHRM3 mutation in Adult ⁸⁸
  • Clinical
    • Onset age: Childhood
    • Micturition failure: Dilated urinary bladder; Since childhood
    • Pupils: Mydriasis; No constriction with light, near vision or muscarinic stimulation
    • Hypohidrosis
  • Laboratory
    • No M3 protein in bladder tissue
  • Differential diagnosis
    • Sjögren
    • Immune autonomic neuropathy

Legs

• Peroneus tertius muscle
  • Present in man & horses
  • Innervation: Deep peroneal nerve
  • Action: Dorsiflexion & eversion of foot during swing phase of gait
    • Levels foot & helps toes to clear ground
    • Improves economy of bipedal walking
• Absence of muscle
  • Frequency: 4.4% to 15% of limbs
  • More frequent on right side (14:9)

• Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects
• Hypoplasia
  • Systemic: Lung; Thyroid
  • Psoas muscle
  • Cranial nerves V, VII, VIII, IX & X
  • CNS: Pons; Medulla; Cerebellum; Spinal cord

Multicore (Minicore) Disease ¹²

ACADS: 12q24 CCDC78: 16p13 MEGF10: 5q23 MYH7: 14q11 RYR1: 19q13 SECISBP2: 9q22 SEPN1: 1p36 Titin: 2q31 General Arthrogryposis Ophthalmoplegia

Multicores

• Genetics
  • Inheritance: Recessive or Sporadic; ? Dominant families
  • 50% of multicore disease not linked to RYR1 or SEPN1
• Onset: Varied
  • Age: Anti-natal to Childhood
  • Delayed motor milestones
• Four general presentations
  • Classic
    • Weakness: Axial predominance
    • Scoliosis: Severe
    • Respiratory insufficiency
  • Mild
    • Weakness: Generalized; Especially pelvic girdle
    • Hands: Weakness; Amyotrophy; Hyperlaxity
  • Ophthalmoplegia
  • Antenatal: Arthrogryposis
• Features usually normal
  • Serum creatine kinase levels
  • Intellect
  • Cardiac
  • No malignant hyperthermia

• General
  • Common form: 30% of Mini-Multicore families
  • More severe
• Clinical
  • Genetics
    • SEPN1 mutations
    • Allelic with: Congenital MD with rigid spine
  • Early onset features
    • Fetal movements: Reduced
    • Hypotonia
  • Weakness
    • Early
      • Motor delay
      • All eventually ambulant
    • Distribution
      • Axial > Proximal > Distal
      • Upper & Lower extremities
    • Facial: Common; Mild
    • Ocular
      • Ptosis
      • Ophthalmoplegia
        • Some patients
        • Partial to complete (10%) paresis
    • Respiratory: More common with
      • Age > 10 years
      • Scolosis > 60°
      • Nocturnal hypoventilation
    • Course: Non- or Slowly progressive
  • Muscle bulk: Amyotrophy
  • Skeletal
    • Contractures: Mild or absent
    • Ligamentous laxity
      • Feet: Flat or everted feet; Genu valgus
      • Knees: Hyperextended
      • Lumbar lourdosis
    • Rigid spine
    • Scoliosis: > 10 years
  • Cardiac (Occasional): Septal defects; Conduction block; Cardiomyopathy
  • Intelligence: Normal
  • No malignant hyperthermia
• Laboratory
  • CK: Normal or slightly elevated (20%)
  • EMG: Myopathic, especially > 4 years & Proximal muscles
  • Muscle MRI: Involvement of vasti; Sparing of rectus femoris
  • Pathology: Muscle
    • Muscle fiber size: Variable
    • Dystrophic features: Some patients
      • Regenerating muscle fibers
      • Endomysial connective tissue: Increased
    • Multiple small cores in individual muscle fibers
      • Histochemistry: Reduced activity on NADH & Mitochonrial stains
      • Short: Do not extend whole length of muscle fiber
      • Frequency: Present in 60% to 90% of muscle fibers
      • Occur in both type I & II muscle fibers
      • More prominent with greater age
      • Ultrastructure: Unstructured central regions; Disordered sarcomere
    • Type I muscle fibers
      • Predominance
      • Occasional smallness
    • Internal nuclei
    • Cores smaller than with RYR1 mutations

• Genetics: Several associated genes
  • RYR1: Dominant or Recessive
  • SEPN1
  • Short-chain acyl–CoA dehydrogenase deficiency (ACADS)
• Clinical
  • Onset: Congenital or 1st year
  • Motor
    • Hypotonia
    • Feeding difficulties
    • Axial & shoulder girdle involvement
    • Respiratory function: Reduced; Occasional failure
    • Muscle MRI: More involvement of sartorius & soleus
  • Weight: Low
  • Scoliosis

• Arthrogryposis, generalized
• Head
  • Dolichocephaly
  • Prominent nasal root
  • Oblique palpebral fissures
  • High arched palate
  • Low-set ears
  • Short neck: With mild pterygium colli
• Spine: Kyphosis or kyphoscoliosis, Early & severe
• Other features
  • Thorax, bell-shaped
  • Clinodactyly,
  • Cryptorchidism, bilateral
  • Single palmar crease
• Weaknes
  • Proximal
  • Mild
  • Vital capacity reduced

• Epidemiology: Moroccan & Sudanese families
• Genetics
  • Titin mutations
    • Homozygous deletions
    • Out of frame
  • Inheritance: Recessive
  • Allelic disorders
• Titin protein
• Clinical
  • Delayed motor milestones
  • Hypotonia at birth: Some patients
  • Weakness
    • Onset: < 1 year
    • Symmetric
    • Generalized: Proximal + Distal + Face
    • Legs > Arms
    • Ptosis: Some asymmetric
    • Course: Slowly progressive; Ambulation present in 2nd decade
  • Muscle size
    • Upper limbs: Atrophy
    • Legs: Pseudohypertrophy, especially thighs & calves
  • Contractures
    • Spinal rigidity
    • Joint & Neck
  • Cardiomyopathy
    • Progressive
    • Dilated
    • Onset ages: 5 to 12 years
    • Rhythm disturbances: Ventricular
    • Interstitial fibrosis
    • Sudden death
• Laboratory
  • Serum CK: Mildly high
  • Muscle
    • Disruption of sarcomeric M-line protein complex: Truncated titins lacking C-terminal incorporated into sarcomeres
    • Minicores: Irregular borders
    • Central nuclei
    • Myopathy: Increased endomysial connective tissue; Later in childhood
    • Calpain-3 reduced
• Mutation carriers: Normal

• Epidemiology: 1 family
• Genetics
  • Mutation: Splice-acceptor variant; Causes 222 bp inframe insertion
• CCDC78 protein
  • Expressed in skeletal muscle
  • Enriched in perinuclear regions & triad
  • May co-localize with DHPR1α
• Clinical
  • Onset
    • Age: Congenital
    • Hypotonia
  • Weakness
    • Distal > Proximal, or Diffuse
    • Ambulation preserved
    • Respiratory, Face & EOM: Normal
    • Progression: Mild or none
  • Fatigue
  • Myalgias
  • CNS: Mild cognitive impairment
• Laboratory
  • Muscle pathology
    • Internal nuclei: Single; Often central; 10% to 25% of fibers
    • Type I fiber predominance
    • SDH: Cores, atypical & small clear regions; Irregular dark regions
    • Muscle fiber aggregates: Contain CCDC78; Desmin; Actin (around clear center)
  • Serum CK: Normal or Slightly high
  • EMG: Normal

Congenital myopathy with excess of thin filaments ⁵

• Genetics
  • Actin (ACTA1) gene mutations
    • Gly15Arg: Surface exposed residue
    • Val163Leu: Hydrophobic core
  • Allelic syndromes
• Clinical
  • Hypotonia
  • Respiratory insufficiency
  • Cardiomyopathy
  • Course: Variable with same actin mutation
    • Death in 1st months: 2 patients
    • Survival to childhood: 1 patient
• Serum CK: Normal
• Muscle
  • Masses of thin filaments (Actin)
  • Nuclear ± cytoplasmic rods
  • Fiber size variation

Carey-Fineman-Ziter Syndrome

• Nosology: Myopathy, congenital nonprogressive, with Möbius sequence & Robin sequence
• Onset: Congenital
• Clinical
  • Myopathy
    • Non-progressive
    • Hypotonia
    • Muscle hypoplasia
      • Pectoral & Humeral muscles (Poland)
      • Often bilateral
  • Mobius syndrome
    • Ocular
      • Ophthalmoplegia
      • Ptosis
      • Palpebral fissures: Down slanted
    • VII nerve: Facial weakness, bilateral
    • X nerve
      • Dysphagia
      • Feeding disorders (100%)
  • Craniofacial
    • Macrocephaly
    • Triangular nose
    • Robin sequence
      • Micrognathia
      • Glossoptosis: Tongue displaced backward; May obstruct airway
      • Cleft palate (50%)
  • Skeletal
    • Scoliosis (40%)
    • Talipes (40%)
    • Equinovarus
    • Brachydactyly (70%)
  • Developmental delay
• CNS: Usually normal intelligence
• Laboratory
  • Electrophysiology
    • NCV: Normal
    • EMG: Small motor units; Fasciculations
  • Serum CK: Normal
  • Muscle biopsy
    • Fiber size variation
    • Degeneration
    • Regeneration (Desmin + fibers)
    • Fiber types: Type II predominance; Small type I

Reducing Body Myopathies^3,4

• Genetics
  • Mutations: Missense; H123Y, H123Q, C132F, C153R, C153Y
  • General location: Zinc coordinating residues in second LIM domain
  • Histidine 123 mutations: Often de novo
  • Zinc coordinating residue cysteine 153: Milder phenotype
  • Allelic with
    • Scapuloperoneal (Hyaline body) myopathy, Type I
    • Myofibrillar myopathy
    • Rigid spine syndrome
    • X-linked myopathy with postural muscle atrophy (XMPMA)
• FHL1 protein
  • Cellular location
    • Myoblasts: Nuclear
    • Differentiated myotubes: Cytosolic
  • Mutation effects
    • Induces formation of aggresome-like inclusions
    • Inclusions incorporate both mutant & wild-type FHL1
    • Other proteins trapped in a dominant-negative manner
• Clinical syndromes⁷⁵
  • Severe: Infantile & Childhood
    • Family history: Often sporadic
    • Onset
      • 1st 4 years
      • Most severe: Motor delay in 1st year
      • Not congenital
    • Weakness
      • Proximal > Distal
      • Progression: Rapid; My occur after stable phase
      • Respiratory
    • Skeletal
      • Rigid spine: Some patients
      • Scoliosis
      • Contractures: Variable
    • Later in disease course
      • Dysphagia
      • Face: Ptosis
      • Fatal outcome: < 10 years in some patients
  • Late onset: Adult ⁶
    
    • Onset age: Up to 4th decade
    • Clinical
      • Early development: Normal
      • Weakness
        • Proximal > Distal
        • Scapuloperoneal
        • Asymmetric
        • Respiratory failure
        • Paraspinal muscles: May be involved
        • Progressive to diffuse involvement
        • More prominent than in parents
      • Skeletal: Less than with childhood onset
        • Rigid spine: Some patients
        • Scoliosis
      • Cardiomyopathy: Dilated; Some patients
      • Carrier females
        • May be symptomatic
        • More signs with skewed X-inactivation
    • Laboratory
      • Serum CK: Increased to 3x normal
      • EMG
        • Mixed neurogenic & myogenic patterns
        • May show spontaneous activity
  • Scapuloperoneal (Hyaline body) myopathy, Type I
  • Congenital myopathic: Uncommon
    • Delayed developmental milestones
    • Benign course
    • ? Different disorder
• Muscle biopsy
  • Muscle fiber size: Variable
  • Increased Acid phosphatase activity
  • Reducing bodies
    • Location: Cytoplasmic; Often near nucleus
    • Histochemistry staining
      • Trichrome
        • Dark green inclusions
        • ± Associated with eosinophilic cytoplasmic bodies
      • Menadione-NBT (without α-glycerophosphate): Positive
        • Mechanism: Reduce nitro-blue tetrazolium (NBT)
    • Contain aggresome-like proteins
      • Desmin
      • Ubiquitin
      • Luminal endoplasmic reticulum chaperone GRP78
      • γ-tubulin
      • FHL1
      • MYBPC1
      • Pericentrin
    • May be more common in type I muscle fibers
    • Rimmed vacuoles in some patients
    • Ultrastructure
      • Reducing bodies
        • Structure: Granular tubulo-filamentous material (17 nm in diameter)
        • Location: Periphery of sarcoplasm & Around nucleus
      • Cytoplasmic bodies: Common
    • Immunocytochemistry: Reducing bodies
      • Contain proteins normally associated with nucleoli
      • Also stain for dystrophin, α-sarcoglycan, vimentin & ubiquitin
• Other disorders with reducing bodies
  • Acid maltase deficiency
  • Distal myopathies with rimmed vacuoles

Fingerprint Body Myopathy

• Epidemiology: Few sporadic cases
• Inheritance: Sporadic or Recessive
• Onset: Congenital
• Clinical
  • Weakness
    • Proximal > Distal: Limbs & Trunk
    • Symmetric
    • Sparing of cranial nerves
  • Hypotonia
  • Intellectual impairment: Occasional
  • Course: Nonprogressive or Slowly progressive
• Laboratory
  • Serum CK: High in some patients
  • EMG: Myopathic
• Muscle biopsy: Inclusions
  • Histochemistry: Ovoid; 1 to 10 μM; Red on H& E; Green on GT
  • Ultrastructure: Arrays of parallel osmiophilic lamellae resembling fingerprints
  • Fingerprint bodies also seen with
    • Myotonic dystrophy
    • OPD
    • Inflammatory myopathies
    • Malignant hyperthermia & Central cores²⁵

Congenital myopathy with apoptotic changes⁹

• Epidemiology: 1 Sporadic Japanese patient identified
• Clinical
  • Onset: Congenital hypotonia
  • Psychomotor development: Markedly delayed
  • Motor
    • Hypotonia
    • Muscle atrophy: Generalized
    • Myopathic face
  • Tendon reflexes: Normal
  • Contractures: Ankles
• Laboratory
  • Serum CK: Normal
  • Serum Lactate: Normal
• Muscle pathology
  • Muscle fibers
    • Small
    • Basophilic: Scattered
    • Acid phosphatase positive: Many
    • Immature (Type 2C): 40%
    • Vacuoles: 20% of fibers
  • Endomysial fibrosis: Mild
  • Nuclei: Condensation of chromatin; Fragmentation
  • Apoptosis related changes
    • Bax-positive (Pro-apoptotic) muscle fibers: 80%
    • No Bcl-2 positive (Anti-apoptotic) muscle fibers
    • Activated caspase-3 in fibers: 6%
    • TUNEL positive nuclei: 2%

Hyaline Body Myopathies

• Nosology: Also called
  • Myopathy with lysis of type I myofibrils
  • Myosin storage myopathy
• Genetics
  • Mutation
    • Missense
      • Arg1845Trp; His1904Leu
      • Location
        • Rod region of slow/β-cardiac MyHC
        • Exons 37 to 39
    • Heterozygous
  • MYH7 mutations cause
    • Cardiomyopathy: Mutations commonly in globular head domain
      • Hypertrophic cardiomyopathy (CMH1)
      • Hypertrophic cardiomyopathy with cores
      • Dilated cardiomyopathy (CMD 1S)
      • Left ventricular non-compaction 5 (LVNCS5)
        • Mutation locations: Globular head, ATP binding pocket, Exons 8–9
    • Myopathy: Mutations in rod & tail domains (Exons 32 to 39)
      • Distal myopathy (MPD1; Gowers-Laing)
      • Scapuloperoneal myopathy: Arg1845Trp
      • Multicore/Minicore myopathy
      • Hyaline body myopathy (Myosin storage)
      • Cytoplasmic bodies
      • Neonatal hypotonia
• MYH7 protein
• Clinical features
  • Variable penetrance
  • Onset: Infancy or early childhood
  • Motor
    • Early
      • Hypotonia
      • Delayed motor milestones
    • Weakness
      • Proximal ± Distal
      • Scapuloperoneal
      • Arms & Legs
      • Symmetric
      • May be severe & disabling
  • Course: Slowly or Non-progressive
  • Systemic: Occasional cardiac arrhythmias
• Laboratory
  • Serum CK: Normal or Mildly elevated
  • EMG: Myopathic
  • Muscle biopsy
    • Hyaline bodies
      • Subsarcolemmal
      • Eosinophilic
      • Mostly in Type I fibers
      • Lack oxidative or glycogen activity
      • May stain for myosin ATPase (Acid pH 4.3)
      • Ultrastructure
        • Matrix of granular & filamentous material
        • May be subsarcolemmal
        • Not membrane bound
        • Some intranuclear inclusions
    • Type I muscle fiber predominance
  • Hyaline bodies also noted in an adult onset scapuloperoneal myopathy
• MYH7 variant: Multi-minicore Disease (MmD) with variable cardiac involvement ⁹⁴
    l Dominant
  • Epidemiology: 2 families
  • Genetics: Missense mutations (Exons 32 & 34); Leu1467Val, Arg1588Pro
  • Clinical
    • Onset age: Childhood
    • Weakness
      • Proximal or Distal predominant
      • Arms & Legs
      • Respiratory: With disease progression
      • Face: Mild
      • Scapular winging
      • Asymmetry: Mild
      • Course: Slow progression
    • Wasting: forearms
    • Myalgias
    • Cardiac
      • Cardiomyopathy: Dilated
      • Sudden death in 1 family
    • Tremor
    • Spinal rigidity
    • Contractures: Elbows; Long finger flexors
  • Laboratory
    • Muscle biopsy
      • Type 1 predominance
      • Internal nuclei
      • Multicores
      • Ring fibers
      • Ultrastructure: Myofibrillar changes
    • MRI leg: Distal > Proximal; Posterior > Anterior
    • NCV & EMG: Non-diagnostic
    • Serum CK: May be mildly high