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HEREDITARY OPTIC NEUROPATHIES

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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: - PowerPoint PPT Presentation
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HEREDITARY OPTIC NEUROPATHIES GEORGE PAPANIKOLAOU SINGLETON HOSPITAL SWANSEA
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Page 1: HEREDITARY OPTIC NEUROPATHIES

HEREDITARY OPTIC NEUROPATHIES

GEORGE PAPANIKOLAOU

SINGLETON HOSPITAL

SWANSEA

Page 2: HEREDITARY OPTIC NEUROPATHIES

CLASSIFICATION

• MONOSYMPTOMATIC

• FAMILIAL NEUROLOGIC SYNDROMES

• MULTISYSTEM DISEASE

1:10,000-1:50,000

Page 3: HEREDITARY OPTIC NEUROPATHIES

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!!)

Page 6: HEREDITARY OPTIC NEUROPATHIES

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

Page 7: HEREDITARY OPTIC NEUROPATHIES

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)

• Leber’s plus

• Heart block (WPW, LGL) ECG

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HEREDITY

• Primary mutations (90-95%)

11778: 40-90%

14484: 10-15%

3460: 8-15%

• Secondary mutations

Mitochondrial (maternal)

Complex I respiratory chain

Retina/ ON/ EOM: highly ATP dependent

Page 14: HEREDITARY OPTIC NEUROPATHIES

PROGNOSIS

• Mutation

11778: 5% improve (3460)

14484: 60% improve

• Age (<20y)

AVOID:

Tobacco/ Alcohol

CN

Environmental toxins

Page 15: HEREDITARY OPTIC NEUROPATHIES

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

Page 16: HEREDITARY OPTIC NEUROPATHIES

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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Page 18: HEREDITARY OPTIC NEUROPATHIES

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

Page 19: HEREDITARY OPTIC NEUROPATHIES

X -LINKED HEREDITARY OPTIC NEUROPATHY

Very rare

Dutch pedigree

Slowly progressive

• other neurologic findings

• Deafness

• Retinopathy

OPA-2

Page 20: HEREDITARY OPTIC NEUROPATHIES

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.

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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

Page 22: HEREDITARY OPTIC NEUROPATHIES

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)

Page 23: HEREDITARY OPTIC NEUROPATHIES

• FAMILIAL DYSAUTONOMIA (RILEY-DAY)

AR/ Ashkenazi Jews

2nd decade

Polyneuropathy+autonomic dysfunction

Indiference to pain

Reduced lacrimation

Corneal scarring

OA (very common)

Page 24: HEREDITARY OPTIC NEUROPATHIES

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)

Page 25: HEREDITARY OPTIC NEUROPATHIES

• Cockayne (AR)

• Smith- Lemli- Opitz (AR)

• Zellweger (AR)

• Menkes (X)

• Canavan’s (AR)

• Hallerroden-Spatz (AR)

Quantitative chromosomal abnormalities

Cerebral palsy (10% OA)

Page 26: HEREDITARY OPTIC NEUROPATHIES

Mitochondrial diseases of childhood

• Subacute necrotising encephalomyelopathy of Leigh

• MERRL

• MELAS

• CPEO

OA+other neurologic abnormalities in infant:

1. Very long chain fatty acids (ALD)

2. Aryl- sulfatase A levels (MLD)

3. Urine amino acids

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