Autosomal Dominant Optic Atrophy, Classic Form

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Retrieved

2021-01-23

Source

Orphanet

Trials

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Genes

OPA1, DNM1L, OPA3, MFN2, MFN1, DENR, DAPK2, OMA1, FIS1, UTRN, CRMP1, SIRT3, IMMT, MFF, MED12, YME1L1, SSBP1, PRKAB1, NFE2L2, PPARGC1A, PPARG, PRKAA1, KIF1B, OPA5, PRKAA2, GSTM1, FXN, WFS1, SLC14A1, LEP, TOMM70, TOMM40, SQSTM1, YAP1, OPTN, COX5A, MRPS30, MAD2L1BP, KEAP1, PAPOLA, ACO2, TPPP, PACC1, PGAM5, CCDC50, MCU, MAP1LC3B, MUL1, PINK1, TFB2M, OPA4, SEMA6A, ADCK1, MTPAP, TREH, APTX, TMED9, ASAP1, CD274, FGF21, GABARAPL1, TUSC2, CDK5R1, PDAP1, PHB2, ASAP2, TP53BP1, BECN1, CNR2, GABPA, ERG, EPHB2, ELAVL1, DGKG, CYP1B1, CYC1, CTRL, CPOX, COX8A, CDKN1A, AKAP1, CDH1, CAV1, CAST, CAPN1, BNIP3L, BNIP3, CEACAM1, BGLAP, BCL2, AFM, GSTT1, H2AX, HRES1, HES1, VEGFA, PHLDA2, ACP3, CLDN5, SPG7, SOD1, SLC5A1, SDHA, MAPK1, PRKCA, PLXNA2, PLIN1, PKLR, REG3A, NRF1, NOS3, NFE2L1, NDUFV2, MYC, LCN2, LAMP1, OPA8

Drugs

Alpha-tocotrienol quinone ( VINCERINONE )

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A rare neuro-ophthalmological disease which is one of the most common forms of hereditary optic neuropathy characterized by progressive bilateral visual loss with an onset during the first decade of life, associated with optic disc pallor, visual acuity loss, visual field deficits and color vision defects.

Epidemiology

The prevalence of Autosomal dominant optic atrophy (ADOA) is variable, commonly varying between 1/10,000 in Denmark (due to a founder effect) to 1/35,000 in the UK and probably worldwide.

Clinical description

ADOA is usually detected during the first decade of life, often by vision screening in school but later onset is possible. Visual impairment is usually moderate (visual acuity ranges from 20/80 to 20/120) but may range from mild to severe. Visual field defect is typically centrocecal, central, or paracentral. Color vision is often affected, usually but not always in the blue-yellow axis (tritanopia). Legal blindness is rare. Patients may also be asymptomatic, albeit bearing the mutation. In about 20% of cases, extra-ocular signs are present, such as sensorineural hearing loss or other severe neurological signs, that occur typically later in life, in young adults, such as myopathy, ataxia, peripheral neuropathy, chronic progressive external ophthalmoplegia (ADOA plus). Rare forms of the disease, similar to Behr syndrome have been reported with biallelic OPA1 mutations (Behr syndrome, OPA1).

Etiology

A majority, but not all ADOA patients harbor mutations in the gene OPA1 (3q29) which codes for an inner mitochondrial membrane protein intricately involved in mitochondrial biogenesis, mitochondrial DNA replication and mitochondrial dynamics. Visual impairment is highly variable both within and between families, even when considering the same mutation.

Diagnostic methods

ADOA is most often suspected in children with unexplained optic neuropathy, especially if associated with a similar family history (which may nevertheless be absent in 50% of cases). Fundus examination typically reveals bilateral and symmetrical pallor of the temporal side of the optic nerve head, pallor of the optic nerve rim and a temporal grey crescent, sometimes associated with abnormal optic disc cupping. Visual evoked potentials (VEP) are usually delayed and pattern electroretinogram shows an abnormal N95:P50 ratio, with reduction in the amplitude of the N95 waveform suggesting alterations of the retinal ganglion cells layer. Optical Coherence Tomography (OCT) discloses a global reduction of the peripapillary retinal nerve fiber layer thickness, mainly in the infero-temporal quadrant. The rest of the retinal is tipically normal. The diagnosis is confirmed by the genetic screening of OPA1.

Differential diagnosis

Differential diagnosis includes all the common causes of optic neuropathies: compressive, inflammatory, ischemic, toxic and metabolic causes. Other hereditary optic neuropathies such as Leber's hereditary optic neuropathy, Wolfram syndrome have different initial presentations (later onset, associated or not with other neurological or systemic signs), but the final clinical phenotype of optic neuropathy is not specific. Other genes involved in isolated or syndromic forms autosomal dominant optic atrophy are : ACO2, SPG7, AFG3L2, MFN2, OPA3, DRP1, and SSBP1.

Antenatal diagnosis

Prenatal identification of a mutation may be proposed in families with previously known mutations, with the understanding that not all the carriers will manifest the disease.

Genetic counseling

Transmission is autosomal dominant with a penetrance of 50%.

Management and treatment

There are currently no efficient treatments in ADOA. Low-vision aids may be recommended in patients with severely decreased visual acuity. Tobacco use, excessive alcohol intake and medications that may have mitochondrial toxicity should be avoided.

Prognosis

Visual impairment in ADOA is classically irreversible ; spontaneous recovery has been only exceptionally reported. Visual loss is usually mild, but can at times worsen later during lifetime. ADOA does not affect intellectual development or life span. Patients may have normal familial and social life although vocational integration may at times be problematic.