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CONGENITAL MYOPATHIES & WEAKNESS

CONGENITAL WEAKNESS
Absent muscles
Actin aggregate: ACTA1; 1q42
Apoptosis
Arthrogryposis
Autophagy, high: VMA21; Xq28 
Broad A band
Cap
CARDAR: TRDN; 6q22
Carey-Fineman-Ziter: TMEM8C; 9q34
Central core: RYR1; 19q13
Centronuclear (Myotubular)
CMH4: MYBPC3; 11p11
CMND: SPTBN4; 19q13
Collagens
  Bethlem
  COL12A1: 6q13
  MED: COL9A2 & COL9A3
  P4HA1
  Ullrich
Core
Cylindrical spirals
Cytoplasmic Body (Spheroid)
Danon: LAMP2; Xq24
Diarrhea & Deafness
DOPA-responsive dystonia
Ehlers-Danlos: FKBP14; 7p14
EMARDD: MEGF10; 5q23
Fiber Type
  Size Δ (CFTD)
  Type I predominance
    ZAK: 2q31
  Type 2 atrophy: MYL1; 2q34
Fingerprint body
Focal
FSH dystrophy: 4q35
Hyaline body: MYH7; 14q11
 
IBM3: MYH2; 17p13
Lethal congenital: CNTN1; 12q11
Mallory body: SEPN1; 1p36
Mental retardation: CUL4B; Xq24
Metabolic disorders
MFM11: UNC45B; 17q12
Mitochondrial
Multicore (Minicore)
Muscular Dystrophy (CMD)
  α-Dystroglycan
  CDG
Myasthenic Syndromes
Myofibrillar
Myopathy: CACNA1S; 1q32
Myosin storage: MYH7; 14q11
Myotonic dystrophy 1: DMPK; 19q13
Native American: Stac3; 12q13
Nemaline rod
Neuropathic syndromes
NMOAS: DHX16; 6p21
Ophthalmoplegias
Perifascicular myopathy, neonatal
Reducing body: FHL1; Xq26
Sarcotubular (LGD 2H): TRIM32; 9q31
Shwachman–Diamond: SBDS; 7q11
Skeletal disorders + Weakness
Spheroid body: MYOT; 5q31
Spindle excess: HRAS; 11p15
Tel Hashomer camptodactyly
Thin filaments, Excess: α-Actin; 1q42
Trilaminar myopathy
Type 1 fiber smallness
Williams-Beuren syndrome
Woods-Black-Norbury syndrome
Zebra body: α-Actin; 1q42
CONGENITAL MUSCULAR DYSTROPHY
Adducted thumbs & Ophthalmoplegia
Axon loss, Large myelinated & CNS Δ
α-Dystroglycan disorders (MDDG)
Cataracts & ID: INPP5K; 17p13
Cerebellar atrophy
CMD + Cardiomyopathy: Titin; 2q24
CMS10: DOK7; 4p16
Desmin inclusions: SEPN1; 1p36
Dysferlin: 2p13
EBSMD: Plec1; 8q24
Fukuyama: Fukutin; 9q31
Glycosylation disorders
  Muscle (MDDGA)
Integrin α-7: 12q13
Integrin α-9: 3p23
Laminin-α2 (Merosin)
  Deficient (MDC1A): 6q22
  Normal: "Pure" form
Marinesco-Sjögren: SIL1; 5q31
MDCDC: TRIP4; 15q22
MDDGA3: POMGnT1; 1p34
Mitochondrial structure: CHKB; 22q13
Multisystem: PIGY; 4q22
Muscle-Eye-Brain (MEB)
Muscle hypertrophy
  MDDGA6 (MDC1D): LARGE1; 22q12
  MDDGB5 (MDC1C): FKRP; 19q13
  Mental retardation
  Respiratory failure (MDC1B): 1q42
Nuclear membrane
  LMNA; 1q22
  SYNE1; 6q25
Rigid spine with CMD
  SEPN1: 1p36
  Lamin A/C: 1q21
  SECISBP2: 9q22
Telethonin: 17q12
Ullrich
  1: COL6A
    6A1; 21q22
    6A2; 21q22
    6A3; 2q37
  2: COL12A1; 6q13
Walker-Warburg (MDDGA)

Batten
ABSENT or WEAK
MUSCLES

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



Congenital Weakness: General




from A Kornberg MD

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

Central Core Disorders ± Malignant Hyperthermia 170

  Ryanodine Receptor 1 (RYR1; RyR) ; Chromosome 19q13.2; Dominant or Recessive

RYR1
Genetics
RyR protein
Clinical
Laboratory
Pathology
Variants
  RyR clinical syndromes
    Dominant
      Central core diseases
        Congenital myopathy
        Cores, Rods & Malignant Hyperthermia
        Limb-Girdle Syndrome: Onset in teens
        Minicores, Transient
        Fetal akinesia
      Malignant Hyperthermia: Onset in teens
      King-Denborough Syndrome
      Type 1 fiber predominance
        Congenital (CNMDU1)
        Hypotonia, Benign
      Axial myopathy, Adult onset
      Serum CK high: Asymptomatic
    Recessive
      Dusty Core
      Central core diseases
        Minicores, Transient
        Fetal akinesia
        Mild phenotype & Recessive inheritance
        Samaritan myopathy
      Nemaline rods + External ophthalmoplegia
      Congenital myopathy
        Centronuclear myopathy
        Fatigable weakness
        Focal lost striations
        Hypotonia & Cardiac
      Periodic Paralysis
Multicore/Minicore
  RYR1
  SEPN1
  ACTN2
  CCDC78
  FXR1
  MYH2
  MEGF10

Core-Rod
  NEB
  ACTA1
  KBTBD13 (NEM6)
  CFL2 (NEM7)
  TRIP4
  TNNT1

Cores: Other
  MYH7
  Myopathy +
    Myofibril Δ: PYROXD1
    Eccentric core: UNC45B

NADH Stain

Nemaline (Rod) Myopathies

Rods: General
  Clinical features: General
  Laboratory features: General
  Pathology

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


Rod Myopathy
  Distal Weakness & Contractures



From: A Connolly


Rod myopathies: General features 22

ROD MYOPATHIES: Specific syndromes



NEM1 Rod myopathy
  α-Tropomyosin 3 (TPM3)
; Chromosome 1q21.3; Dominant or Recessive

NEM2 Rod myopathy
  Nebulin (NEB)
; Chromosome 2q23.3; Recessive >> Dominant


NEM3 Rod myopathy
  α-Actin (ACTA1; Skeletal muscle)
; Chromosome 1q42.13; Dominant or Sporadic, > Recessive
NEM4 Rod myopathy
  β-Tropomyosin (TPM2)
; Chromosome 9p13.3; Dominant or Recessive

NEM5 Rod myopathy 13
  Troponin T1 (Skeletal, Slow; TNNT1) ; Chromosome 19q13.42; Recessive
NEM6 Rod myopathy with Slow movements 27
  Kelch-repeat and BTB (POZ) domain containing 13 (KBTBD13) ; Chromosome 15q22.31; Dominant
NEM7 Rod myopathy 65
  Cofilin-2 (CFL2) ; Chromosome 14q13.1; Recessive
NEM8 Nemaline Rod myopathy, severe 107
  Kelch-like family member 40 (KLHL40; KBTBD5; Sarcosynapsin; SYRP) ; Chromosome 3p22.1; Recessive

NEM9: Nemaline Rod myopathy 9 111
  Kelch-like family member 41 (KLHL41; KBTBD10) ; Chromosome 2q31.1; Recessive
NEM: Nemaline Rod myopathy 10 (NEM10) 115
  Leiomodin-3 (LMOD3) ; Chromosome 3p14.1; Recessive
NEM 11: Rod myopathy 136
  Myopalladin (MYPN) ; Chromosome 10q21.3; Recessive
NEM: Nemaline Rod myopathy 144
  Ryanodine Receptor 3 (RYR3) ; Chromosome 15q13-q14; Recessive
NEM: Cardiomyopathy + Rods, Infantile 174
  Cyclase-associated actin cytoskeleton regulatory protein 2 (CAP2) ; Chromosome 6p22.3; Recessive
Rod myopathy: Mild 64
  Dominant
Rod myopathy: Other forms

Centronuclear (Myotubular) Myopathy 89

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

Congenital Myopathy: Cardiac Arrhythmia ± Muscle weakness (CARDAR) 138
  Triadin (TRDN) ; Chromosome 6q22.31; Recessive

Congenital Muscular Dystrophy

Congenital Muscular Dystrophy: Typical Features


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

  Fukutin (FKTN) ; Chromosome 9q31.2; Recessive


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

  Laminin α2 (LAMA2) ; Chromosome 6q22.33; Recessive
  • Epidemiology: > 100 families
  • Genetics
    • Mutations in laminin α2-chain
      • > 300 disease-associated variants
      • Types
        • Deletion (Frame-shift), Stop codon: Severe disease when biallelic
        • Missense
          • Milder disease: Often LGMD R23
          • Domain VI (N-terminal region)
            • Late-onset LAMA2-MD
            • Moderately reduced protein levels
          • Cysteine residues: In one of 3 EGF-like repeats
          • C-terminal region
        • Splice site (Donor sites)
        • Copy number variants: Often deletions
      • Most common mutation (23%): 2 base pair deletion @ 2,096-2,097
      • Latino: c.1854_1861dup
      • Mild disease: Mutations
        • Internal in-frame deletion: Small protein (Missing N-terminal)
        • Mutations in conserved donor splicing consensus sequence: Introns 37 & 63
        • Arg1549*
      • Mutations uncommon: In globular or rod-like domain
    • Offspring of carriers
      • Heterozygotes more common than predicted by chance
    • Allelic disorders
    • 2° Laminin α2 loss
  • Laminin-211 protein
    • Heterotrimeric glycoprotein
      • Heavy chain (400 kDa): α2-chain protein
      • Light chains (200 kDa): β1 & γ1
    • Location
      • Basement membrane
      • Muscle, Skin, CNS & Peripheral nerve (Schwann cells)
    • Binds to α-Dystroglycan in basal lamina
    • α2-laminin: 400 kD protein
      • Post-translationally cleaved into 300 kD & 80 kD subunits
      • Subunits remain associated by disulfide bonds
      • Globular domain attached to glycosylated residues of α-dystroglycan
    • Laminin-211: Other
      • Connects to: Collagen IV & Perlecan (Heparan sulfate proteoglycan)
      • Link: Nidogens cross-linking
    • Expression: Muscle; Nerve (Schwann cells); Brain
    • Function: Link between muscle fiber sarcolemma & extracellular matrix
    • α2-laminin expression: Disease relation
      • Severe: 300 kDa & 80kDa subunits abnormal
      • Mild or later onset: 300 kDa subunit often selectively reduced
    • Laminin disorders: Other
      • α4: CMD 1JJ
      • β2: Congenital Myasthenic Syndrome
    • Also see: Laminins
  • Congenital muscular dystrophy: Clinical features
    • Weakness
      • Correlates with level of residual laminin α2 protein
      • Absent laminin α2 protein
        • Severe weakness
        • Distribution: Symmetric; Proximal + Distal; Face
        • Non-progressive
      • Reduced laminin α2: See variant syndromes
    • Muscle: Wasting & Hypotonia
    • Walking
      • Severe disease: Never
      • Mild disease: At 2-3 years
    • Skeletal
      • Scoliosis
      • Contractures
        • Mild disease: Ankle tightness
        • Severe disease
          • Contractures at multiple joints
          • Hips; Knees; Ankles; Elbows; Neck extensor
          • Progressive with increasing age
    • CNS
      • Intelligence often normal
      • Perceptual-motor dysfunction in some
      • Seizures (20%)
    • Neuropathy 171
      • Mild
      • Occasional
      • Axon loss: Large > Small
      • ± Myelin Δ: Thin myelin; Tomaculae
    • Course
      • Progressively severe contractures
      • Severe disease: Death 15 to 30 years 2° Respiratory failure
  • Laboratory
    • CK: Moderately high
    • CNS MRI: White matter changes (Increased signal on T2); Cortex usually normal
    • Muscle MRI
      • Similar to Collagen VI
      • Involvement of muscle periphery in anterior thigh
      • Sparing: Gracilis & Sartorius
    • Brain pathology patterns
      • Cortical dysplasia
      • Lissencephaly (Agyria or Pachygyria)
      • Polymicrogyria
  • Laminin-α2 disorders: Muscle pathology
    • Laminin-α2 (Merosin) staining
      • Usually absent
        • 95% with absent merosin have Laminin-α2 gene mutation
        • Also reduced in skin (Basal keratinocytes)
      • Partial merosin loss: Milder disability or later onset
        • Clinical: Milder disability or later onset; Late onset seizures
        • Muscle pathology: Myopathy; Rimmed vacuoles & inflammation in some
        • Especially reduced 300 kD subunit
        • Correlates with reduction of laminin β2 chain
        • Normal visual evoked potentials
        • Occasional 2° loss: Other syndromes
    • Pathology: Age-dependent
      • Childhood
        • Fiber size: Varied
        • Endomysial connective tissue: Increased
        • Immature muscle fibers (Type 2C): Many
        • Laminin-α5: Increased
      • Neonatal
        • May be "predystrophic"
        • Only a few degenerating & regenerating muscle fibers
      • Inflammation: Rare, except in biopsies from very young patients
      • Mild disease (Partial merosin loss)
        • Varied fiber sizes
        • Endomysial connective tissue: Increased
        • Internal nuclei: Increased
        • Fiber morphology: Split, Hypercontracted, Whorled
  • Laminin α2 disorders: Variant syndromes
    • Myopathy: Reduced laminin α2; Especially loss of 300 kD N-terminus (LGMD R23 )
      • Epidemiology: 10 patients; 2% of LGMD
      • Genetics
      • Clinical
        • Onset: 1 to 59 years
        • Weakness
          • Mild weakness
          • Proximal ± Distal; Symmetric; Arms & Legs
          • No loss of ambulation
        • Calf hypertrophy: May occur
        • Course: Progressive, slow
        • CNS
          • Epilepsy
          • Impaired cognition
      • Laboratory
        • Brain MRI: Leukoencephalopathy, Most patients
        • Serum CK: High; ~1,000
        • Muscle pathology
          • Myopathy
          • Rimmed vacuoles
          • Inflammation in some
          • Reduced laminin α2: Loss of 300 kD N-terminus
        • NCV: May have demyelinating neuropathy
    • Neuropathy, Hypermyelinating; Mental retardation; Epilepsy 31
      • Genetics: Probably allelic with Laminin α2 disorders
      • Onset: Childhood; Developmental delay
      • Clinical
        • Weakness: Distal; Feet > Hands
        • Mental retardation: Moderate
        • Refractory epilepsy: Absences ± eyelid myoclonus; Tonic & complex partial seizures
        • Tendon reflexes: Absent
        • No muscle wasting or joint contractures
      • Laboratory
        • Serum CK: High; 530
        • Nerve conduction velocities: Reduced
        • Brain MRI: Diffuse white matter involvement
        • Muscle biopsy
          • Myopathy
          • Neurogenic features
          • Laminin α2 mildly reduced
        • Nerve biopsy
          • Laminin α2 virtually absent
          • ‘Globular’ hypermyelination: Located at paranodal regions
          • Mild loss of myelinated axons
          • No demyelination-remyelination changes
    • Myopathies: 2° Laminin α2 loss
    • Mouse models
      • dy/dy
      • dy2J/dy2J: Milder phenotype; 300kD subunit selectively reduced

Pectoral folds (Arrow) with
severe shoulder weakness



CMD: Normal merosin

Normal Merosin: "Pure" form of congenital MD

  Recessive

Congenital MD with integrin α-7 mutations

  Integrin α-7 (ITGA7) ; Chromosome 12q13.2; Recessive

Congenital MD with Joint Hyperlaxity 63

  ? Integrin-α9 (ITGA9) ; Chromosome 3p22.2; Recessive

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

  Recessive

Congenital MD with cerebellar atrophy

  ? Autosomal recessive

Muscle-Eye-Brain Disorders 19

Fukuyama
Muscle-eye-brain disease (Santavuori)
Walker-Warburg

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

  Plectin (Plec) ; Chromosome 8q24.3; Recessive

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

  Choline kinase beta (CHKB) ; Chromosome 22q13.33; Recessive

Congenital Muscular Dystrophy with early Spine Rigidity (RSMD1) 160

  Selenoprotein N, 1 (SEPN1; SELENON) ; Chromosome 1p36.11; Recessive
  • Epidemiology
    • > 140 patients
    • Family origins: Moroccan, Turkish, Iranian, Scandinavian
  • Genetics
    • Selenocysteine incorporated into proteins at UGA codon
      • UGA codon normally a stop codon
      • Recognition of UGA as Selenocysteine codon instead of stop codon
        • Requires insertion sequence (SECIS)
          • Untranslated cis element
          • Location: 3'UTR of transcripts
          • Needed for selenocysteine integration
        • Sec redefinition element (SRE): Adjacent to UGA codon
        • Associated with SBP2 binding
    • SEPN1 mutations
      • > 70 described
      • Hotspots: Exon 1; Also exons 6, 7 & 11
      • Common mutation: c.1A>G
      • Founder effects
        • c.817G>A: Iran & Turkey
        • c.943G>A: Northern Europe
        • c.713dupA: Western Europe
      • Nonsense
        • Types: Frameshift; Stop codon; Splicing
        • Biallelic: More severe disease
      • Missense locations
        • Conserved domain
        • Near UGA codon: SRE element 73
        • In SECIS sequence
      • Severe phenotype
        • c.1A>G, c.13_22dup, c.-19_73del92nt, c.818G>A
    • Allelic disorders
  • SEPN1 protein 40
    • Selenoprotein family: All are enzymes
    • Structure
      • Size: 70 kDa
      • Contains single selenocysteine residue
      • Glycoprotein
    • Subcellular localization
      • Membrane
      • Endoplasmic/sarcoplasmicreticulum (ER/SR) protein
      • Ubiquitous
    • Levels
      • High: Most human fetal tissues; Proliferating cells
      • Lower in adult tissues
      • Skeletal muscle
        • Progressive decrease: Myoblasts fuse → Myotubes
    • Selenium
    • Functions
      • ? Early development in cell proliferation or regeneration
      • Protects cells against oxidative or ER stress
      • Defends Ca++ homeostasis 162
        • Counteracts ERO1-mediated oxidation of SERCA1 (ATP-dependent Ca++ pump)
        • ER Ca++ sensor
        • Links ER luminal calcium levels to redox activity
        • Acting as reductase to refill ER calcium stores
      • Mitochondria: Bioenergetics 161
        • Enriched at mitochondria-associated membranes (MAM)
          • MAM: Contact sites; ER communicates with mitochondria
        • Needed for calcium transients between ER & mitochondria
        • Integrity of ER-mitochondria contacts
    • Selenoproteins
      • Catalyze oxidation/reduction reactions
      • Contain Selenocysteine (Sec) residue(s) at enzymatic active site
      • Selenium deficiency: Causes
        • Cardiomyopathy (Keshan disease)
        • Muscular dystrophy in livestock
      • Also see: Selenoprotein deficiency (SECISBP2)
  • Clinical features
    • Overlap with Minicore congenital myopathy syndromes
    • Weakness 8: Variable seveity
      • Onset: Variable
        • Early: Birth to 1 year
        • Later: 1st decade
      • Early onset: Hypotonia; Poor head control
      • Distribution of weakness & atrophy
        • Axial: Neck flexors; SCM; Abdominal
        • Face
        • Proximal: Inner thigh
        • Distal: Forearm & Leg
        • Dysphagia (20%)
        • Symmetric
      • Respiratory
        • Most or All patients
        • Vital capacity
          • Often reduced: Minimal to 55% by 1st decade
        • Nocturnal hypoventilation
          • Central apnea during paradoxical sleep
        • Progressive failure
      • Walking: Never to < 18 months
      • Ophthalmoparesis: Severe disease
      • Muscle size: Small, especially inner thighs & calves
    • Tendon reflexes: Reduced or Absent
    • Skeletal
      • Spine
        • Rigid (88%)
          • 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; Mouth open
      • Scapula: Pseudo-winging due to dorsal hyperlordosis
      • Joint hyperlaxity: Distal
      • Neck: Long & Slender
      • Palate: High arched
    • Systemic
      • Body weight: Decreased around puberty; Cachexia
      • Cardiac: Minor conduction defects, or Normal
      • Endocrine: Insulin resistance
      • Fatty tissue: Altered distribution
    • CNS: Normal intelligence; No white matter changes
    • Course
      • Early improvement: With development
      • Decline: From end of 3rd decade
      • Loss of ambulation: 10%
      • Lifespan: Reduced
      • Prognosis determinants: Correlate with disease severity
        • Scoliosis/respiratory management
        • SEPN1 mutations
        • Body mass abnormality
  • Laboratory
  • Muscle pathology: Choose muscle to biopsy by MRI
    • Anatomical pattern: Variable involvement of different muscles
    • Muscle fibers
      • Minicores
        • Short-length areas
        • Multiple
        • Ultrastructure: Sarcomere disorganization & mitochondria depletion
        • Immunostaining: Filamin C; αB-crystalline
      • Fiber types: Type I muscle fiber predominance or small; Both types present
      • Size: Varied
      • Eosinophilic inclusions (Mallory bodies): Some patients
      • Necrosis: Few
    • Endomysial connective tissue: Minimal to mild increase
    • Merosin: Normal



From D Cummings MD
Congenital MD + Rigid Spine

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

  Chromosome 1q42; Recessive

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

  Multiple epidermal growth factor-like domains 10 (MEGF10) ; Chromosome 5q23.2; Recessive

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

  Fukutin-related protein (FKRP) ; Chromosome 19q13.32; Recessive

Ullrich congenital muscular dystrophy 1 (UCMD1; Scleroatonic) 21

  Collagen, type VI, subunit α1 (COL6A1) ; Chromosome 21q22.3; Recessive or Dominant
  Collagen, type VI, subunit α2 (COL6A2) ; Chromosome 21q22.3; Recessive or Dominant
  Collagen, type VI, subunit α3 (COL6A3) ; Chromosome 2q37.3; Recessive or Dominant

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

  LARGE1 (Acetylglucosaminyltransferase-like protein) ; Chromosome 22q12.3; Recessive

Congenital Muscular Dystrophy + Cataracts & Intellectual Disability (MDCCAID) 137

  Inositol polyphosphate-5-phosphatase K (INPP5K; SKIP) ; Chromosome 17p13.3; Recessive

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

  Autosomal Recessive

CDG: Multisystem Disorder 131

  Phosphatidylinositol glycan anchor biosynthesis Class Y protein (PIGY) ; Chromosome 4q22.1; Recessive

Congenital muscular dystrophy & myasthenic syndrome 55

  DOK7 ; Chromosome 4p16.3; Recessive

Congenital disorder of Tendons, Bone, Muscle & Eyes 141

  Procollagen-proline, 2-oxoglutarate-4-dioxygenase, alpha subunit, isoform 1 (P4HA1) ; Chromosome 10q22.1; Recessive

Intellectual Disability, Hypotonia, Motor Neuropathy & Deafness (CMND)

  β-IV-Spectrin, Nonerythrocytic (SPTBN4) ; Chromosome 19q13.2; Recessive

Neuromuscular disease & Ocular or Auditory anomalies ± Seizures (NMOAS)

  DEAH Box polypeptide 16 (DHX16) ; Chromosome 6p21.33; Dominant de novo

OTHER CONGENITAL WEAKNESS

Congenital Myotonic Dystrophy
  Myotonin protein kinase; Chromosome 19; Dominant Congenital Facioscapulohumeral (FSH) Dystrophy
  Chromosome 4q35; Dominant Metabolic Myopathies Congenital Myasthenic Syndromes

Congenital Neuropathic Syndromes Rule out CNS hypotonia


Broad A band disease


Trilaminar myopathy


Zebra body myopathy 118

  α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Sporadic, ? Dominant

Weakness with early skeletal disorders


Williams-Beuren syndrome

  Autosomal dominant contiguous gene syndrome; Chromosome 7q11.23
  Deleted genes: Elastin ; RFC2 ; LIM-kinase ; GTF3 muscle transcription factor (MusTRD1); GTF2I

Neonatal perifascicular myopathy 1


Immunoneurologic Disorder (Woods-Black-Norbury Syndrome)

  Dominant; Chromosome Xq26-qter

Congenital absence, weakness, or hypoplasia of muscles

Congenital Cranial Dysinnervation (CCDD)
Extraocular muscles
  Axenfeld-Rieger
  Blepharophimosis
  CCDD: ECEL1; 2q37
  CCDD: COLA25A1; 4q25
  Congenital fibrosis
  Duane retraction syndromes (DRS)
  Holt-Oram: TBX5
  Möbius syndrome (MBS)
  Ptosis + Scoliosis
    HGPPS1: ROBO3; 11q24
    HGPPS2: DCC; 18q21
Face
  Cardiofacial syndrome
  Depressor anguli oris
  Mastication
  Möbius syndrome
Hands
  Finger extensors
  Holt-Oram
  Palmaris longis
  Thenar eminence
Legs
  Peroneus tertius
  Psoas (CHILD)
Trunk
  Abdominal
  Brachial plexus
  Diaphragm
  Pectoral
  Poland syndrome
  Prune belly
  Trapezius

Extraocular muscles


Face

Depressor anguli oris: Cardiofacial syndrome
  Chromosome 22q11.2 (deletion) Dominant; Also Multifactorial

Also see: Congenital facial paresis



Absent Muscles of Mastication: Mouse model

Diaphragm Weakness & Defects 78


Congenital Myopathy with Diaphragmatic defects, Respiratory Insufficiency, dysmorphic Facies (MYODRIF) 177
  Myogenic differentiation antigen 1 (MYOD1; MYF3)) ; Chromosome 11p15.1; Recessive

Hands

Holt-Oram Syndrome
  Human transcription factor TBX5 ; Chromosome 12q24.21; Dominant
Palmaris longus muscle
  Autosomal dominant with incomplete penetrance Finger & thumb extensors
  Autosomal Recessive

Trunk

Pectoral (Poland syndrome)

  Usually sporadic
  • 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 anomalies 28
    • 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


From: P Bailey

Dextrocardia
Poland Syndrome

Trapezius
  Chromosome 8q12.2-q21.2; Dominant
Hypoplasia of Shoulder & Neck muscles 126
  Chromodomain helicase DNA-binding protein 7 (CHD7) ; Chromosome 8q12.2; Dominant (de novo) Superior transverse scapular ligament: Calcification
  Autosomal Dominant
Abdominal musculature: Prune belly syndrome
  Cholinergic receptor, muscarinic, 3 (CHRM3) ; Chromosome 1q43; Recessive & Sporadic

Osler 1901


Legs

Peroneus tertius muscle
  Autosomal recessive

Psoas (CHILD Syndrome)
  NAD(P)H Steroid dehydrogenase-like protein ; Chromosome Xq28; Dominant
  Emopamil-binding protein ; Chromosome Xq28; Dominant



Multicore (Minicore) Myopathy 12

General

ACADS: 12q24
ACTN2
Arthrogryposis
CCDC78: 16p13
Hypogonadism
MEGF10: 5q23
MYH7: 14q11
Ophthalmoplegia
RYR1: 19q13
SECISBP2: 9q22
SEPN1: 1p36
Titin: 2q31

Cores

Multicores


Multicore myopathy: General Clinical Features
Multicore (Minicore) Disease
  Selenoprotein N, 1 (SEPN1) ; Chromosome 1p36.11; Recessive or Sporadic

Minicore myopathy with Ophthalmoplegia
Minicore myopathy: Antenatal onset with Arthrogryposis 33
Multicore myopathy: Mental retardation, Short stature & Hypogonadotropic hypogonadism (Chudley syndrome)
Multicore disease: Congenital myopathy + Fatal dilated cardiomyopathy (EOMFC)
  Titin ; Chromosome 2q31.2; Recessive

Congenital myopathy with Internal nuclei & Atypical Cores (Centronuclear myopathy 4 (CNM4) 93
  Coiled-coil domain-containing protein 78 (CCDC78) ; Chromosome 16p13.3; Dominant

Multiple structured Cores & Z-line Abnormalities (MsCD; MYOCOZ) 151
  Actinin, α-2 (ACTN2) ; Chromosome 1q43; Dominant, de novo, Recessive

Congenital Multi-Minicore Myopathy 155

FMR1 autosomal homolog 1 (FXR1) ; Chromosome 3q26.33; Recessive

Congenital myopathy with excess of thin filaments 5

α-Actin (ACTA1; Skeletal muscle) ; Chromosome 1q42.13; Sporadic

Carey-Fineman-Ziter Syndrome 1 (CFZS 1) 143

  Transmembrane protein 8C (TMEM8C; Myomaker; MYMK) ; Chromosome 9q34.2; Recessive

Carey-Fineman-Ziter Syndrome 2 (CFZS2)

  Myomixer (MYMX) ; Chromosome 6p21.1; Recessive

Reducing Body Myopathies 3, 4

  Four-and-a-half-LIM protein 1 (FHL1) ; Chromosome Xq26.3; Dominant or Semi-Dominant

Fingerprint Body Myopathy


Congenital myopathy with apoptotic changes 9


Hyaline Body Myopathies

MYH7: 14q11.2
  MSMA: Dominant
  MSMB (Scapuloperoneal 3): Recessive
  Scapuloperoneal 2: Dominant
Scapuloperoneal 1: FHL1; Xq26; Dominant


Hyaline Body Myopathy (Myosin Storage; MSMA) 44
  Myosin - Cardiac β heavy chain (MYH7) ; Chromosome 14q11.2; Sporadic or Dominant

Congenital Myopathy with Muscle Spindle Excess (CMEMS) 18

  V-HA-RAS Harvey rat sarcoma viral oncogene homolog (HRAS) ; Chromosome 11p15.5; Dominant, de novo or Recessive

Congenital Myopathy with Caps 57

Genetics: General
  Mutations in some of same genes
    that produce Rod myopathies & CFTD
Dominant
  1: γ-Tropomyosin 3 (TPM3): 1q22
  2: β-Tropomyosin 2 (TPM2): 9p13
  α-Actin 1, Skeletal muscle (ACTA1): 1q42
Recessive
  Nebulin: 2q23
  Myopalladin: 10q21
Muscle Pathology

Also see
  Myofibrillar (Desmin storage) myopathy
  Cap pathology


Cap Myopathy 2 (CAPM2) : TPM2 mutations
  β-Tropomyosin 2 (TPM2) ; Chromosome 9p13.3; Dominant

Myofibrillar myopathy 11 (MFM11): Myopathy with Eccentric cores 156

  UNC45 myosin chaperone B (UNC45B) ; Chromosome 17q12; Recessive

Myofibrillar Myopathy 8 (MFM8): Early-Onset with Internal Nuclei, & Myofibrillar Disorganization 133

  Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 1 (PYROXD1; PYRD1) ; Chromosome 12p12.1; Recessive

X-linked Mental retardation syndrome (Cabezas) 14

  Cullin 4B (CUL4B) ; Chromosome Xq24; Recessive

Congenital Weakness with Diarrhea & Deafness

  Recessive

Congenital Fiber Type Size Disproportion (Type I fibers small) 51

Differential diagnosis
General
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
CFTD: HACD1 (PTPLA); 10p12; Recessive
CFTD: MYH7; 14q11; Dominant
CFTD: MYL2; 12q24; Recessive
Myopathy
  SCN4A: 17q23; Recessive
  Titin: 2q31; Recessive
Pathology

Multisystem Selenoprotein Deficiency 83

  Selenocysteine insertion sequence–binding protein 2 (SECISBP2; SBP2) ; Chromosome 9q22.2; Recessive

Ehlers-Danlos, Variant with progressive Kyphoscoliosis, Myopathy & Hearing loss (EDSKMH) 90

  Peptidyl-prolyl cis-trans isomerase 14 (FK506-binding protein 14; FKBP14) ; Chromosome 7p14.3; Recessive

Shwachman–Diamond Syndrome, Neonatal with Myopathy 127

  SBDS gene ; Chromosome 7q11.21; Recessive

Congenital Myopathy with Type I fiber predominance 134

  Leucine zipper- & Sterile alpha motif-containing kinase (ZAK) ; Chromosome 2q31.1; Recessive

Congenital Myopathy with Smallness or Absence of Type 2 Muscle Fibers (MYOFTA) 146

  Myosin, light polypeptide 1, alkali, skeletal, fast (MYL1) ; Chromosome 2q34; Recessive
Return to Myopathy & NMJ Index
Return to Neuromuscular Home Page

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