Myopathy + EOM

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EOM ± PERIOCULAR WEAKNESS in NEUROMUSCULAR DISORDERS

Neuromuscular junction
- Myasthenia Gravis
- Botulism
Muscle
Also see
- Ptosis
- Neuropathies

EOM in Myasthenia Gravis Pseudo-Internuclear Ophthalmoplegia

CONGENITAL & HEREDITARY OPHTHALMOPLEGIAS

Congenital

Familial static
Myopia
Congenital fibrosis
Duane's syndrome
Horizontal gaze
- HGPPS: 1; 2
Möbius Syndrome
Congenital ptosis
Blepharophimosis
- 1 ; 2 Short stature
IVIC Syndrome
Iris transillumination
Myopathy
Myasthenia gravis, Congenital

Later onset

Visceral myopathy
Mitochondrial (PEO)
Oculopharyngeal Muscular Dystrophy
Oculopharyngodistal myopathy (OPDM)
- 1: LRP12
- 2: GIPC1
- 3: NOTCH2NLC
- 4: RILPL1
OPML
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 (OPMD) ⁵

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

; Chromosome 14q11.2; Dominant or Recessive

Other locus
HNRNPA2B1
Differential diagnosis

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
- (GCN)11 allele: 0.05% frequency in the Thai population.
Genetics
- Common mutations
  - Expansions of GCG trinucleotide repeat in exon 1
  - Meiotically stable
  - Generational effects: Usually stable size; Rare mutation changes repeat size
  - Mutation mechanism: Unequal crossing over
- 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
- Dominant OPMD
  - 11 to 18 GCG repeats in PABPN1
    - Stretch of repeat alanines at N-terminus of PABPN1 increased to 11 to 18
    - GCA repeats: Included in repeat in some Cajun & Japanese families
  - Other mutation
    - Missense: Gly12Ala results in sequence of 13 contiguous alanine codons
  - 7 GCG repeats on other allele: More severe phenotype in dominant OPMD
  - Normal alleles
    - 9 repeats most common (69%), especially in French Canadians
    - 10 repeats more common in UK population ²
- Recessive or Semi-Dominant OPMD
  - Stretch of 10 repeat alanines at N-terminus of PABPN1 increased to 11
- Dosage effects
  - 11 repeats
    - Inheritance: Dominant with low penetrance
    - Later age at diagnosis: Mean: 72 years
    - Onset: Dysphagia ± Ptosis
  - Longer polyalanine repeat ((GCN)n) lengths: Especially ≥ 16
    - More: Proximal limb weakness early in disease; Dysphagia; Loss of ambulation
    - ? Cognitive decline
    - ? Earlier onset
    - Earlier diagnosis: 15 to 20 years
    - Serum CK: High
  - Homozygous 11 to 13 repeats: More severe than heterozygous
- 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
- 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
  - Age
    - Heterozygotes: 4th to 7th decade; Mean 64 years
    - Homozygotes: 2nd to 4th decade
  - Recessive: Latest onset
  - Ptosis: Most common
  - Limb weakness: With longer polyalanine 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
  - Severity: Usually Mild; Variable degrees
  - Proximal
  - Some distal weakness late in severe cases
  - Lower extremity (71%): Posterior thigh; Soleus (Not Gastrocnemius) ⁴
  - Upper extremity (38%)
  - Neck: "Astrologist's posture"
  - 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
Laboratory
- CK: Normal or mildly elevated
- EMG
  - Often myopathic with development of weakness
  - Denervation changes in some patients
Muscle pathology
- Rimmed cytoplasmic vacuoles: Not numerous
- Nuclei
  - Filaments
    - 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
      - Aggregated insoluble filamentous intranuclear inclusions in muscle
    - ? Specific marker for disease
    - More common in homozygotes
  - Myonuclear inclusions ¹¹
    - 11% of myonuclei
    - p62 stain
    - Colocalize with PABPN1 stain
    - Single inclusion in myonuclei: Differs from
      - IBM: Multiple small intranuclear inclusions
      - OPDM: Inclusions in nuclei in non-muscle fibers
- Cricopharyngeal & Lid muscles
  - Especially involved
  - Chronic myopathic changes
- Intramuscular nerve twigs: Ubiquitin labeling
OPMD Variants
- Homozygotes
  - Clinical
    - Onset
      - Age: 2nd to 4th decade
      - Ptosis
    - Ophthalmoplegia with Ptosis
    - Weakness
      - Proximal
      - More severe than heterozygotes
      - Posterior neck: 1 patient
      - Distal
      - Gait disorder: In 7th decade
    - Myalgias
    - Shortened life expectancy: Aspiration
    - Cognitive changes
    - Progression: Rapid
  - Laboratory
    - Serum CK: Mildly high
    - EMG: Myopathic
- Japanese
  - Distal weakness
  - Cardiac conduction block
OPMD families without increased GCG repeats
- Rule out
  - HNRNPA2B1 mutatations
  - Oculopharyngodistal myopathy
  - Inclusion body myopathy with joint contractures & ophthalmoplegia
  - Missense mutation in PABPN1

Oculopharyngodistal Myopathies (OPDM)

OPDM1: LRP12
OPDM2: GIPC1
OPDM3 + Neurological: NOTCH2NLC
OPDM4: RILPL1
OPDM5: LOC642361/NUTM2B-AS1
OPDM: ABCD3
Also see
OPMD
OPML1
DNA repeat disorders

Oculopharyngodistal Myopathy 1 (OPDM1) ⁶

● Low density lipoprotein receptor-related protein 12 (LRP12)

; Chromosome 8q22.3; Dominant or Sporadic

Epidemiology
- Japanese, English, Dutch, Turkish & French families + Sporadic (59%) ³
- Male > Female
Genetics
- Mutations
  - OPDM CGG DNA repeat expansion range: 100 to 200
  - OPDM patients: LRP12 CGG expansions in 38%
  - Location: 5' UTR of LRP12
  - Haplotype: Founder effect for expansions
- Normal LRP12: 12 to 45 repeat units
- Controls with expansions (55 to 200 units): 0.21%
- Allelic disorders
  - Motor neuron disease/Motor ± Sensory Neuropathy
LRP12 protein
- Location: Membrane
- Expression: Heart, Skeletal muscle, Brain, Lung, Placenta, Pancreas
- Endocytosis
- Signal transduction
Clinical
- General: Recessive vs Dominant forms
  - Recessive form more severe
  - Both forms with similar patterns of weakness
- Onset
  - Age: 6 to 50 years; Mean 22 years
  - Ptosis
- 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%)
- Muscle MRI
Pathology
- Myopathic changes: Chronic
- Vacuoles: Rimmed; Autophagic
- Filaments
  - 16 to 18 nm
  - Location: Cytoplasm & Nucleus
  - ? Contain phosphorylated tau
- Nuclear inclusions: Non-muscle cells ¹¹
LRP12 variant: ALS 28 / Motor neuron disease/Neuropathy, Motor-Sensory ¹²
- Epidemiology
  - >50 families
  - Common: Japan
- Genetics
  - Inheritance: Dominant or Sporadic
  - CGG repeat expansion range: 50 to 152; Most < 100; Mean 76
  - Mean CGG repeat number: Shorter than LRP12-oculopharyngodistal myopathy
  - Intergenerational change: Mild reduction in some families
- Clinical
  - Onset age: 4th to 6th decade
  - Weakness
    - Diffuse or Distal; Proximal predominant in some patients
    - Arms, Legs or Both
    - Asymmetric in 30%
  - Face: Usually normal; Dysarthria in some
  - Atrophy: Gastrocnemius muscle
  - Tendon reflexes: Normal or Reduced
  - Upper motor neuron: Not prominent
  - Sensory loss (19%)
  - Course: Slow progression; Wheelchair in 7th decade
- Laboratory
  - EMG: Denervation, active & chronic
  - NCV: CMAPs reduced amplitude in legs
  - Muscle
    - Denervation: Fiber type groups; Grouped atrophy
    - p62 aggregates
    - Vacuoles (18%): Rimmed
    - No Muscleblind-like 1 aggregates
  - Muscle MRI: Leg atrophy
  - Brain MRI: Normal
  - Serum CK: Mean 715

Oculopharyngodistal Myopathy 2 (OPDM2) ⁷

● GIPC PDZ Domain-containing family, member 1 (GIPC1)

; Chromosome 19p13.12; Dominant or Sporadic

Epidemiology: 46 families in Japan & China
Genetics
- Mutation: GGC (CGG) DNA repeat expansion in 5' UTR of GIPC1
  - Disease repeat size: 70 to 164
  - Normal repeat size: 13 to 32
  - Repeat methylation: Normal
- No anticipation
- Some contraction in repeat size between generations
- Penetrance: Incomplete
GIPC1 protein
- Scaffolding protein
- Regulates cell surface receptor expression & trafficking
Clinical
- Onset age: 14 to 70 years; Mean 43
- Weakness
  - Cranial: Ptosis; Face; Bulbar
  - Limbs
    - Distal: Wrist & Finger extensors; Ankle dorsiflexion
    - Proximal (60%)
    - Legs > Arms
- Ophthalmoparesis
- Joint contractures: Ankle
- Course: Slow progression
Laboratory
- EMG: Myopathic; Myotonia (33%)
- Serum CK: 174 to 2,524
- Muscle MRI: Thigh adductor magnus > Vastus intermedius & medialis & Biceps femoris, long head
- Muscle pathology
  - Fiber size: Varied; Pyknotic nuclear clumps
  - Endomysial connective tissue: Increased
  - Rimmed vacuoles
  - p62 inclusions in cytoplasm & nuclei
  - Ultrastructure
    - Cytoplasm: Myeloid bodies; Tubulofilamentous inclusions
    - Nuclei: Filamentous aggregates

Oculopharyngodistal Myopathy 4 (OPDM4) ⁹

● RAB-Interacting lysosomal protein-like 1 (RILPL1; Gospel)

; Chromosome 12q24.31; Dominant or Sporadic

Epidemiology: 17 patients, China founder
Genetics
- Mutation: CGG DNA repeat expansion in 5’ UTR of RILPL1
- Repeat #s: 135 to 197
- Penetrance: Incomplete
RILPL1 protein
- Role in regulation of cell shape & polarity
- Binds to: GAPDH; RAB10
- Mutation
  - CGG repeat translated into toxic poly-glycine protein
  - Poly-glycine: Co-localizes with p62 in intranuclear inclusions
Clinical
- Onset age: 2nd to 4th decade
- Eyes: Ptosis; Ophthalmoplegia
- Weakness: Face; Distal; Dysarthria; Onset 10 years after eye Δ
Laboratory
- Brain MRI: Normal
- Muscle MRI: Biceps femoris most involved in thigh
- Serum CK: Normal to 800
- Muscle
  - Fiber sizes: Varied; Grouped atrophy
  - Vacuoles: Rimmed; Autophagic
  - Nuclei: Filamentous inclusions
  - p62 aggregates

Oculopharyngeal Myopathy with Leukodystrophy (OPML1) ⁶

● LOC642361

/NUTM2B-AS1

; Chromosome 10q22.3; Dominant

Epidemiology: 1 Japanese family, 3 patients
Genetics
- Mutation: CGG repeat expansion
  - In bidirectionally transcribed long noncoding RNAs (LOC642361/NUTM2B-AS1)
  - Somatic instability
- Allelic disorder: Oculopharyngodistal myopathy
Clinical
- Myopathy
  - Weakness: Diffuse
  - Bulbar: Dysarthria; Dysphagia
  - Respiratory: 2 patients
- Eye
  - Ptosis
  - EOM: Limited range
- Systemic: 1 patient
  - GI dysmotility
  - Bladder dysfunction
  - Cardiomyopathy, dilated
- Leukoencephalopathy
  - Ataxia & Tremor: 1 patient
Laboratory
- Muscle: Non-specific myopathy
- Brain MRI: Increased DWI signal intensity in corticomedullary junction of cerebral white matter
NUTM2B-AS1 variant: Oculopharyngodistal myopathy ¹³
- Epidemiology: 6 Chinese & Thai patients
- Genetics
  - Mutation: CGG DNA repeat (Normal < 40; Patients > 70)
  - Inheritance: Dominant
- Clinical
  - Onset age: 3rd decade
  - Eye: Ptosis; Ophthalmoplegia
  - Bulbar: Dysphagia; Dysarthria
  - Weakness: Proximal ± Distal
- Laboratory
  - Serum CK: 869-1607
  - EMG: Myopathic
  - NCV Normal
  - Muscle pathology
    - Fiber sizes: Varied
    - Rimmed vacuoles
    - p62 aggregates
    - Internal nuclei
    - Endomysial connective tissue: Increased
  - Brain MRI: T2/FLAIR signal hyperintensities in corticospinal tracts

Oculopharyngodistal Myopathy ¹⁴

● ATP-Binding cassette, subfamily D, Member 3 (ABCD3)

; Chromosome 1p21.3; Dominant

Epidemiology: Non-Asian populations; 35 patients, 8 families
Genetics
- Mutations
  - CCG repeat expansions: 118 to 694 repeats
  - Mutation location: 5' UTR
  - Penetrance: Incomplete
  - Expanded allele usually not methylated (90%)
  - Shared ancestral haplotype
- Clinical-Genetic
  - Larger expansions: Earlier onset age
  - Females: Larger expansions
  - Maternal inheritance: More incomplete penetrance in offspring
- Allelic disorders
  - Zellweger syndrome
  - Bile acid synthesis defect, congenital, 5
ABCD3 protein
- Peroxisomal membrane transporter
  - Transport of branched-chain fatty acids & C27 bile acids into peroxisome
- Transcript: Upregulated in fibroblasts & muscle
Clinical
- Onset age: 10 to 52 years; Mean 27 years; Females mildly younger
- Ptosis (100%): Early feature
- Ophthalmoparesis (70%)
- Face weakness (77%)
- Bulbar: Dysarthria (65%); Dysphagia (77%)
- Limbs: Distal legs
Laboratory
- Muscle pathology
  - Rimmed vacuoles: AMP deaminase+
  - Internal nuclei
  - Myofiber splitting
  - Fibrous tissue: Increased
  - Internalized capillaries.
  - Ultrastructure: Autophagic vacuoles; Myeloid bodies
  - Intranuclear p62-positive inclusions: Few
- Muscle MRI: Distal leg, Soleus & Gastrocnemius
- EMG: Myopathic
- Serum CK: 142 - 377

Hereditary Inclusion Body Myopathy with Joint Contractures & Ophthalmoplegia ¹

● Myosin heavy chain IIa (MyHC IIa; MYH2)

; Chromosome 17p13.1; Dominant or Recessive

Nosology: Myopathy, Proximal & Ophthalmoplegia (MYPOP); CMYP6; CMYO6; IBM3
Epidemiology: Swedish family; Italian female
Genetics
- Point mutation: Glu706Lys
- Allelic disorders
  - Early-onset myopathy, Recessive
  - Distal arthrogryposis 5A
  - Myopathy with External ophthalmoplegia (No vacuoles)
    - Early onset
    - Juvenile
  - Myopathy, adult onset + Filamentous tangles & Nemaline rods
  - IBM3
    - Dominant
    - Recessive
MYH2 Protein
- Muscle fiber type: Fast myosin heavy chain, type IIa
- Present in skeletal muscle: 24 weeks gestation thtrough adult
Clinical
- Onset: Newborn with contractures (75%)
- Ophthalmoplegia
  - Children: Mild upgaze paresis
  - Adults: Complete
- 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%)
- Face: Dysmorphism
- Joint contractures
  - Distal arthrogryposis
  - 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 MRI involvement: Quadriceps, Adductors, Semitendinosus
- Muscle biopsy: Progressive changes with age
  - Childhood
    - Non-specific abnornmalities: Internal nuclei
    - Minicores (Myofilament disorganization): 2A fibers
  - 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
MYH2 variant: HIBM3, Recessive ⁸
- Epidemiology: 2 patients
- Genetics
  - Mutations: c.2377C>T (p.Arg793Ter in exon 21); c.4381G>T (p.Glu1461Ter in exon 32); c.737 G>A (p.Arg246His; Homozygous)
- Clinical
  - Onset ages: 1st & 2nd decades
  - Weakness
    - Proximal
    - Dysphagia
    - Respiratory
    - Face
  - Eyes: Ophthalmoplegia; Ptosis
  - Course: Slow progression
- Laboratory
  - Serum CK: 500 to 900
  - EMG: Small units; Fibrillations & Sharp waves; Neuromyotonia
  - Muscle
    - Vacuoles
    - Fiber types
      - No 2A fibers
      - Type II fibers may have both MyHCIIa & MyHCI
    - Fiber sizes: Varied
    - MyHCIIa: Small fibers; Larger fibers with abnormal internal architecture
MYH2 variant: Myopathy, adult onset + Filamentous tangles & Nemaline rods ¹⁰
- Epidemiology: 1 patient
- Genetics
  - Inheritance: Recessive
  - Mutations: Gln1111X; Phe516Val
- Clinical
  - Onset age: Teens
  - Eyes: Ptosis; Ophthalmoparesis
  - Weakness
    - Symmetric
    - Face
    - Neck flexors
    - Arms: Proximal + Finger extensors
    - Legs: Proximal
    - Axial
  - Course: Slow progression
- Laboratory
  - Serum CK: 450 to 630
  - EMG: Small & Large potentials
  - NCV: Normal
  - Muscle
    - Myofilamentous tangles: α-actinin +; In 2A fibers
    - Nemaline rods: Clusters; In 2A fibers; Some intranuclear
    - Ring fibers
    - Rimmed vacuoles
    - 2A fibers: Paucity & Atrophy
    - Hybrid (2B) fibers: Contain MYH2X & MYH2A
    - Ultrastructure: Disorganized myofibrils; Nemaline rods
Mouse model: Gene change causes myopathy with disruption of myofilaments

Return to Myopathy & NMJ Index

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. Neurology 2010;74 (9 Supp 2)
5. FEBS J 2013 Sep;280(17):4230-50, Neuromuscular Disorders 2015; Online August
6. Nat Genet 2019 Jul 22
7. Am J Hum Genet 2020 May 10, Brain 2020 Dec 29
8. Neuromuscul Disord 2018;28:675-679, Mol Genet Genomic Med 2020:e1320
9. Am J Hum Genet 2022 Feb 5, Ann Neurol 2022 Jun 14
10. Acta Neuropathol Commun 2021;9:79
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12. Am J Hum Genet 2023 Jun 9, J Neurol Neurosurg Psychiatry 2024 Jul 16
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14. Nat Commun 2024;15:6327

9/24/2024

EOM ± PERIOCULAR WEAKNESS in NEUROMUSCULAR DISORDERS

CONGENITAL & HEREDITARY OPHTHALMOPLEGIAS

Oculopharyngeal Muscular Dystrophy (OPMD) 5

Oculopharyngodistal Myopathies (OPDM)

Oculopharyngodistal Myopathy 1 (OPDM1) 6

Oculopharyngodistal Myopathy 2 (OPDM2) 7

Oculopharyngodistal Myopathy 4 (OPDM4) 9

Oculopharyngeal Myopathy with Leukodystrophy (OPML1) 6

Oculopharyngodistal Myopathy 14