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HEREDITARY OPTIC NEUROPATHIES

HEREDITARY OPTIC NEUROPATHIES. GEORGE PAPANIKOLAOU SINGLETON HOSPITAL SWANSEA. CLASSIFICATION. MONOSYMPTOMATIC FAMILIAL NEUROLOGIC SYNDROMES MULTISYSTEM DISEASE 1:10,000-1:50,000. PATTERN OF INHERITENCE. AD AR X-linked Mitochondrial. Difficulties:

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HEREDITARY OPTIC NEUROPATHIES

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  1. HEREDITARY OPTIC NEUROPATHIES GEORGE PAPANIKOLAOU SINGLETON HOSPITAL SWANSEA

  2. CLASSIFICATION • MONOSYMPTOMATIC • FAMILIAL NEUROLOGIC SYNDROMES • MULTISYSTEM DISEASE • 1:10,000-1:50,000

  3. PATTERN OF INHERITENCE • AD • AR • X-linked • Mitochondrial • Difficulties: • Different genotype same phenotype • Same genotype  different phenotype • Single cases Molecular diagnosis

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

  5. 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!!)

  6. MONOSYMPTOMATIC OPTIC NEUROPATHIES LEBER’S 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

  7. FUNDUS EXAMINATION (maternal relatives) Consider diagnosis in any case of unexplained bilat. Opt. Neuropathy regardless of AGE, GENDER, FAMILY HISTORY, FUNDOSCOPIC APPEARENCE

  8. ASSOCIATIONS • Minor neurologic (MS-like) • Leber’s plus • Heart block (WPW, LGL) ECG

  9. 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

  10. PROGNOSIS • Mutation • 11778: 5% improve (3460) • 14484: 60% improve • Age (<20y) AVOID: Tobacco/ Alcohol CN Environmental toxins

  11. DOMINANT OPTIC ATROPHY (DOA) Prevalence:1:10000- 1:50000 (COMMONEST) Age: within first 2 decades (4-6y)- UNAWARE Inheritence: AD (3q- OPA1, 18q) Penetrence:98% Intra, interfamilial variability No associated syndromes Progress: insidious slow, stable OPA1: NTG /Dynamin related GTP-ase/ inner mit. membrane

  12. 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

  13. AUTOSOMAL RECESSIVE OPTIC NEUROPATHY • ISOLATED (very rare, ?DOA with incomplete penetrence) • WOLFRAM’S SYNDROME (DIDMOAD • WFS-1 gene Chr. 4 • Birth- 4y • BEHR’S DISEASE • Infancy • METHYLGLUTACONIC ACIDURIA (MGA) • OPA-3

  14. X -LINKED HEREDITARY OPTIC NEUROPATHY • Very rare • Dutch pedigree • Slowly progressive • other neurologic findings • Deafness • Retinopathy • OPA-2

  15. FAMILIAL NEUROLOGIC SYNDROMES+ OA SPINOCEREBELLAR ATAXIA • ADCA+OA • 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.

  16. FRIEDRIECH ATAXIAS AR/ 9q Onset: 8-15y Spinal degeneration+ peripheral neuropathy OA (50%, not severe loss) Ataxia Loss of vibratory sensation Extensor plantars

  17. POLYNEUROPATHIES • CHARCOT- MARIE-TOOTH • Onset: first two decades/ motor>sensory • 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)

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

  19. MULTISYSTEM DISEASE >100 Usually AR but can be X-linked • Storage diseases and cerebral degenerations of childhood • Mucopolysaccharidoses • Lipidoses • Krabbe’s • Metachromatic leucodystrophy (MLD)(22, 50% OA) • Adrenoleucodystrophy (X) • Pelizaeus- Merzbacher(X)

  20. Cockayne (AR) • Smith- Lemli- Opitz (AR) • Zellweger (AR) • Menkes (X) • Canavan’s (AR) • Hallerroden-Spatz (AR) Quantitative chromosomal abnormalities Cerebral palsy (10% OA)

  21. Mitochondrial diseases of childhood • Subacute necrotising encephalomyelopathy of Leigh • MERRL • MELAS • CPEO • OA+other neurologic abnormalities in infant: • Very long chain fatty acids (ALD) • Aryl- sulfatase A levels (MLD) • Urine amino acids

  22. Thanks

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