Myopathy + EOM

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EOM ± PERIOCULAR WEAKNESS in NEUROMUSCULAR DISORDERS

Neuromuscular junction
- Myasthenia Gravis
- Botulism
Muscle
- Thyroid
- Mitochondrial
- Congenital Myopathy
  - Centronuclear Myopathy: Infantile
  - Multicore
- Hereditary myopathies
  - Oculopharyngeal Muscular Dystrophy
  - Oculopharyngodistal myopathy
  - Inclusion body myopathy with joint contractures & ophthalmoplegia
  - Early-onset myopathy with external ophthalmoplegia: A; B
- Congenital & hereditary ophthalmoplegias
Also see
- Ptosis
- Neuropathies

EOM in Myasthenia Gravis Pseudo-Internuclear Ophthalmoplegia

CONGENITAL & HEREDITARY OPHTHALMOPLEGIAS

Congenital

Later onset

Visceral myopathy
Mitochondrial
Oculopharyngeal muscular dystrophy
Oculopharyngodistal myopathy
MYH2
Ataxia
- SCA 1, 2, 3, 7 & 8
- Ataxia telangectasia
- IOSCA
Motor neuron disease with dementia
Blau syndrome
Dystonic lipidosis
Niemann-Pick

Also see

Oculopharyngeal Muscular Dystrophy

l Polyadenylate-binding protein, Nuclear, 1 (PABPN1; PABN1; PABP2)

; Chromosome 14q11.2; Dominant

& Recessive

l Second locus in non-French-Canadian (Italian & Norman) families

Epidemiology
- OPMD is common in
  - French-Canadians (1:1,000)
  - Bukhara Jews in Israel (1:600)
  - OPMD is caused by two distinct founder GCG₉ mutations in these 2 populations
- New Mexico Hispanics: GCG₉ mutation
- Louisiana Cajun: GCA containing repeats
- Japan: GCA containing repeats
- Netherlands
- European prevalence: 1 in 100,000
- Recessive OPMD: 1 in 10,000 in Quebec; Rare elsewhere
Genetics
- Common mutations: Expansions of GCG repeat in exon 1
- Normal exon 1
  - GCG: Encodes alanine
  - 6 GCG Repeats: Present in 98% of controls
  - Background frequency of 7 repeats: 2% in French-Canadians; Rare in UK
  - GCG repeat location: Exon 1
- Mutation mechanism: Unequal crossing over
- Recessive OPMD
  - 7 repeats: Homozygous
- Dominant OPMD
  - 8 to 13 GCG repeats
    - 9 repeats most common (69%), especially in French Canadians
    - 10 repeats more common in UK population²
  - 7 GCG repeats on other allele: More severe phenotype
  - GCA repeats: Included in repeat in some Cajun & Japanese families
  - Other mutation
    - Missense: Gly12Ala results in sequence of 13 contiguous alanine codons
- Dosage effects
  - Homozygous more severe than heterozygous
  - Longer repeat lengths: More limb weakness early in disease; ? Earlier onset
- Other dominant neurologic disorders with homozygotes identified
  - Same clinical phenotype as heterozygote: Huntington's, Creutzfeldt-Jakob, Amyloid polyneuropathy
  - More severe clinical phenotype: CMT 1A, DRPLA, SCA 3, SCA 6, Welander distal myopathy
- Generational effects: Usually stable size; Rare mutation changes repeat size
- Locus is near Gowers distal myopathy
- Other polyalanine expansion diseases
  - Synpolydactyly, type 2 : HOXD13
  - Cleidocranial dysplasia : RUNX2
  - Familial holoprosencephaly (HPE5): ZIC2
  - Hand-Foot-Genital syndrome : HOXA13
  - Blepharophimosis/Ptosis/Epicanthus inversus syndrome type II : FOXL2
PABPN1 (PABP2; PABN1) protein
- Subcellular location: Nucleus
- Cellular location: PABP2 expressed in skeletal muscle
- Structure & Associations
  - Polyalanine repeats in N-terminus of PABN1
  - Binds poly (A) tail of mRNA
  - Usually present in dimer or oligomer form
  - Contains polyalanine tracts
- Function: Polyadenylation of mRNAs
- OPMD pathology
  - PABN1 structure: Lengthened N-terminal polyalanine domain
  - Mutated PABN1 protein metabolism
    - Resistant to chemical denaturation & enzymatic degradation
    - May be misfolded
    - May polymerize to form β-sheet structures
    - Longer mutated tracts may be more likely produce large aggregates of PABN1
    - Accumulates in nucleus
    - Forms polymers
    - Associates with: mRNA; Ubiquitin; Proteasome components
    - Aggregates may form toxic filaments & nuclear or cytoplasmic inclusions
  - PABN1 location: Nuclear inclusions
Clinical features
- Onset
  - Heterozygotes: 4th to 6th decade
  - Homozygotes: 2nd to 4th decade
  - Recessive: Latest onset
  - Ptosis: Most common
  - Limb weakness: With longer GCG repeats (13)
- Eyes
  - Ptosis
    - Often asymmetric
    - Surgical treatment: Frontalis sling
    - External link
  - EOM paresis: Incomplete
  - Superior field defect: Disappears with elevation of the upper lids; External link
- Dysphagia & Tongue weakness: Failure to swallow 80 cc cold water in 8 sec
- Myopathy: Weakness
  - Usually Mild: Variable degrees of severity
  - Proximal
  - Some distal weakness late in severe cases
  - Lower extremity (71%): Posterior thigh; Soleus (Not Gastrocnemius) ⁵
  - Upper extremity (38%)
  - Disability in severe cases (homozygotes) due to proximal leg weakness
  - Course: Slow progression
- Neuropathy: Reported in some patients; ? Association with OPMD
  - Sensory loss: Distal; Vibration
  - Tendon reflexes: Reduced
  - Fasciculations
  - Pathology: Axonal loss
- Variants
  - Homozygotes
    - Onset: 2nd to 4th decade
    - Ophthalmoplegia
    - Weakness: Proximal; More severe than heterozygotes
    - Shortened life expectancy: Aspiration
    - Cognitive changes
    - Progression: Rapid
  - Japanese: Distal weakness & Cardiac conduction block
Laboratory
- CK: Normal or mildly elevated
- EMG
  - Often myopathic
  - Denervation changes in some patients
Muscle pathology
- Rimmed cytoplasmic vacuoles: Not numerous
- Filaments in nuclei
  - Tubular; Form tangles & palisades
  - Size: 8.5 nm diameter; Up to 0.25 μm length
  - Contain: Mutant PABPN1 protein; Ubiquitin; Proteasome components; poly(A)-RNA; No DNA
  - ? Specific marker for disease
  - More common in homozygotes
- Cricopharyngeal & lid muscles especially involved: Chronic myopathic changes
- Ubiquitin labeling of intramuscular nerve twigs
OPMD families without increased GCG repeats
- Typical features
  - Ptosis
  - Dysphagia
  - Cytoplasmic inclusions on muscle biopsy
- Atypical features
  - Early age of onset
  - Severe ophthalmoplegia
  - High serum CK
- Rule out
  - Oculopharyngodistal myopathy
  - Inclusion body myopathy with joint contractures & ophthalmoplegia
  - Missense mutation in PABPN1

Oculopharyngodistal myopathy

l Autosomal Dominant or Recessive

Epidemiology
- Japanese, English, Dutch, Turkish & French families ³
- Male > Female
Onset
- Age: 6 to 50 years; Mean 22 years
- Ptosis
Clinical
- General: Recessive vs Dominant forms
  - Recessive form more severe
  - Both forms with similar patterns of weakness
- Eyes
  - Ptosis (80%): Often asymmetric
  - Ophthalmoplegia: Early in disease course
- Weakness
  - Masseter
  - Facial
    - Weakness may be severe
    - Wasting: Orbicularis oris, Malar & Zygomatic muscles
  - Bulbar
    - Dysphagia: Oropharyngeal
    - Dysarthria: Hoarse & Nasal voice
    - Tongue weakness
  - Limbs
    - Legs > Arms
    - Distal: Anterior tibial; Finger extensors
    - Onset: ~5 years after disease onset
    - Limb strength normal (20%)
  - Progression: To proximal muscles
  - Respiratory
    - Common
    - May develop while ambulant
    - Postural drop
  - Prognosis
    - Wheelchair after 15 to 30 years
    - Death: 29 to 75 years; Pulmonary
- Atrophy: Face & Distal limbs
- Hearing loss: Some patients
- Other: ? Associated cardiomyopathy
Laboratory
- Serum CK: High (Normal to 8x high)
- EMG: Myopathic; Myotonic discharges (50%)
Pathology
- Myopathic changes: Chronic
- Vacuoles: Rimmed; Autophagic
- Filaments
  - 16 to 18 nm
  - Location: Cytoplasm & Nucleus
  - ? Contain phosphorylated tau

Hereditary inclusion body myopathy with Joint Contractures & Ophthalmoplegia (IBM3)¹

l Myosin heavy chain IIa (MyHC IIa; MYH2)

; Chromosome 17p13.1; Dominant

Genetics
- Point mutation: Glu706Lys
- Allelic with: Early-onset myopathy, Recessive
Protein: Fast myosin heavy chain, type IIa
Epidemiology: Swedish family
Clinical
- Onset: Newborn with contractures (75%)
- Ophthalmoplegia: Mild upgaze paresis in children ® Complete in adults
- Muscle weakness
  - Proximal > Distal
  - Lower & Upper extremities
  - Quadriceps: May be prominently involved
  - Face: Mild
- Atrophy: Quadriceps & Pectorals
- Stiffness: ?After prolonged rest
- Fatigue
- Back pain
- Tremor (60%)
- Joint contractures: Normalize with development
Course
- Childhood: Non-progressive; Contractures resolve
- Adult (30 to 50 years): Progressive deterioration; Limitation of ambulation
Laboratory
- Serum CK: Normal in childhood; Increased 2x to 10x in adults
- EMG: Myopathic; Proximal > Distal
- Muscle biopsy: Progressive changes with age
  - Childhood
    - Non-specific abnornmalities: Internal nuclei
    - Minicores (Myofilament disorganization)
  - Adult
    - Rimmed vacuoles
      - Contain 15 to 21 nm cytoplasmic inclusions
      - All muscle fibers with rimmed vacuoles express MyHC IIa
    - Endomysial connective tissue: Increased
    - Muscle fiber degeneration & regeneration
    - Type IIa muscle fibers: Small; Infrequent
    - Ultrastructure: Focal disorganization of contractile filaments
Mouse model: Gene change causes myopathy with disruption of myofilaments

Early-onset Myopathy with External ophthalmoplegia⁴

l Chromosome 17p13.1-p12; Recessive

Epidemiology: Israeli-Arab inbred families
Genetics: ? Same as MYH2 mutations
Onset: Early childhood
Clinical
- Ocular: External ophthalmoplegia (100%)
  - Conjugate
  - Non-restrictive
  - Impairment greatest in upgaze
  - No ptosis or aberrant eye movements
- Weakness
  - Symmetric
  - Severity: 4/5
  - Face: Mild; Eyes > Mouth
  - Voice: Nasal
  - Neck: Flexors (100%)
  - Limbs
    - Proximal arms: Most common (75%)
    - Distal arms (50%)
    - Proximal legs (30%)
    - Distal legs: Normal
  - Associated with wasting
  - Progression: Slow
- Skeletal
  - Face: Dysmorphism
  - Scoliosis (73%)
Laboratory
- Orbital MRI: Fatty replacement of oculorotatory muscles
- EMG: Myopathic (50%)
- Serum CK: Usually normal; Occasional <2x normal in younger patients
Muscle biopsy
- Type 1 muscle fiber predominance
- Core-like changes

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References
1. Ann Neurol 1998;44:242-248; PNAS 2000;97:14614-14619
2. Brain 2001;124:522-526
3. JNNP 2004;75:1499-1501, Neurology 2011;76:227–235
4. Brain 2005;128:42-51
5. Neurology 2010;74 (9 Supp 2)

3/7/2012