HEREDITARY OPTIC NEUROPATHIES

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HEREDITARY OPTIC NEUROPATHIES
GEORGE PAPANIKOLAOU SINGLETON HOSPITAL SWANSEA
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CLASSIFICATION

• MONOSYMPTOMATIC
• FAMILIAL NEUROLOGIC SYNDROMES
• MULTISYSTEM DISEASE
• 110,000-150,000

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PATTERN OF INHERITENCE

• AD
• AR
• X-linked
• Mitochondrial

• Difficulties
• Different genotype? same phenotype
• Same genotype ? different phenotype
• Single cases

Molecular diagnosis
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DIFFERENTIAL DIAGNOSIS

• Primary retinal degenerations (CONE dystrophy)
• Toxins
• Infiltration/ compression
• MS
• Atrophic papilloedema
• Paraeoplastic

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COMMON FEATURES Primary loss of ganglion cells? OA

• Bilat./ Symmetrical/ irreversible/ painless ?
  VA
• No RAPD
• Optic nerve pallor
• Colour vision defect
• VF
• ERG, VEP, PERG
• Onset insidious (except LHON)/ congenital-late
• Intra-, inter- familial variability (EXAMINE
  family!!)

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MONOSYMPTOMATIC OPTIC NEUROPATHIES
LEBERS HEREDITARY OPTIC NEUROPATHY
Prevalence 3.22/100.000 Age of onset 15-35y BUT
ANY AGE Gender male 80-90 Visual loss
acute-subacute/ severe/ sequential 75
(2/12) Pupillary light reaction relatively
spared MRI (STIR) ? signal mid/post,
intraorbital ON, noCSF visible, CNS NAD Blood
test available
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FUNDUS EXAMINATION (maternal relatives)
Circumpapillary telangiectasia 30-60 Normal OA, all after 6/12
Pseudoedema
Absence of leakage in FFA
Consider diagnosis in any case of unexplained
bilat. Opt. Neuropathy regardless of AGE, GENDER,
FAMILY HISTORY, FUNDOSCOPIC APPEARENCE
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ASSOCIATIONS

• Minor neurologic (MS-like)
• Lebers plus
• Heart block (WPW, LGL) ECG

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HEREDITY
Mitochondrial (maternal) Complex I respiratory
chain Retina/ ON/ EOM highly ATP dependent

• Primary mutations (90-95)
• 11778 40-90
• 14484 10-15
• 3460 8-15
• Secondary mutations

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PROGNOSIS

• Mutation
• 11778 5 improve (3460)
• 14484 60 improve
• Age (lt20y)

AVOID Tobacco/ Alcohol CN Environmental toxins
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DOMINANT OPTIC ATROPHY (DOA)
Prevalence110000- 150000 (COMMONEST) Age
within first 2 decades (4-6y)- UNAWARE Inheritence
AD (3q- OPA1, 18q) Penetrence98 Intra,
interfamilial variability No associated
syndromes Progress insidious slow, stable OPA1
NTG /Dynamin related GTP-ase/ inner mit. membrane
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Clinical Features
VA 6/6-PL (6/36) Colour vision tritan/
generalised dyschromatopsia VF
pseudobitemporal, peripheral inversion of
red-blue isopters OA subtle, temporal, entire
disc triangular excavation of temporal
optic disc MRI ? signal visible CSF
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AUTOSOMAL RECESSIVE OPTIC NEUROPATHY

• ISOLATED (very rare, ?DOA with incomplete
  penetrence)
• WOLFRAMS SYNDROME (DIDMOAD
• WFS-1 gene Chr. 4
• Birth- 4y
• BEHRS DISEASE
• Infancy
• METHYLGLUTACONIC ACIDURIA (MGA)
• OPA-3

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X -LINKED HEREDITARY OPTIC NEUROPATHY

• Very rare
• Dutch pedigree
• Slowly progressive
• other neurologic findings
• Deafness
• Retinopathy
• OPA-2

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FAMILIAL NEUROLOGIC SYNDROMES OA
SPINOCEREBELLAR ATAXIA

• ADCAOA
• Type I brainstem signs
• Type II retinopathy (secondary OA)
• Type III cerebellum
• SCA1, SCA2, SCA3, SCA6, SCA7
• Later onset (2nd deacade), mild visual loss,
  ophthalmoplegia, ataxia, basal ganglia sympt.

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• FRIEDRIECH ATAXIAS

AR/ 9q Onset 8-15y Spinal degeneration
peripheral neuropathy OA (50, not severe
loss) Ataxia Loss of vibratory sensation Extensor
plantars
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POLYNEUROPATHIES

• CHARCOT- MARIE-TOOTH
• Onset first two decades/ motorgtsensory
• AD visual loss early childhood
• AR peripheral neuropathy in childhood
• X-linked hearing loss in infancy
• Pes cavus
• Foot deformities
• Scoliosis
• Wasting of distal extremities
• Hearing loss/ OA (mild, subclinical)

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• FAMILIAL DYSAUTONOMIA (RILEY-DAY)
• AR/ Ashkenazi Jews
• 2nd decade
• Polyneuropathyautonomic dysfunction
• Indiference to pain
• Reduced lacrimation
• Corneal scarring
• OA (very common)

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MULTISYSTEM DISEASE gt100 Usually AR but can be
X-linked

• Storage diseases and cerebral degenerations of
  childhood
• Mucopolysaccharidoses
• Lipidoses
• Krabbes
• Metachromatic leucodystrophy (MLD)(22, 50 OA)
• Adrenoleucodystrophy (X)
• Pelizaeus- Merzbacher(X)

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• Cockayne (AR)
• Smith- Lemli- Opitz (AR)
• Zellweger (AR)
• Menkes (X)
• Canavans (AR)
• Hallerroden-Spatz (AR)

Quantitative chromosomal abnormalities
Cerebral palsy (10 OA)
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Mitochondrial diseases of childhood

• Subacute necrotising encephalomyelopathy of
  Leigh
• MERRL
• MELAS
• CPEO

• OAother neurologic abnormalities in infant
• Very long chain fatty acids (ALD)
• Aryl- sulfatase A levels (MLD)
• Urine amino acids

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Thanks
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