The Genetics of Hereditary Retinopathies and Optic Neuropathies

Alessandro Iannaccone, MD, MS


Compr Ophthalmol Update. 2005;6(1):39-62. 

In This Article

Hereditary Optic Neuropathies

In addition to Leber hereditary optic neuropathy, which is due to mitochondrial DNA mutations that will be not be reviewed here,[8,82] hereditary optic neuropathies can be inherited as autosomal dominant, autosomal recessive, and X-linked traits, and are estimated to affect one in every 10,000 to one in every 50,000 individuals.[82,83,84] Of these, the most common is the autosomal dominant Kjer type ( . Accessed October 4, 2004; . Accessed October 4, 2004). The gene responsible for autosomal dominant optic atrophy of the Kjer type is OPA1 , a nuclear gene on the long arm of chromosome 3 (3q29) that, however, appears to be indispensable for proper function of mitochondria,[85] thereby emphasizing the pathophysiological link between autosomal dominant optic atrophy and Leber hereditary optic neuropathy. The diagnosis of autosomal dominant optic atrophy is rather challenging, because the expression of the disease varies greatly between and within families. Many patients can be unaware of being affected, having had, at times, visual acuities that could not be corrected beyond 20/30 as their only symptom and a tritan defect to color vision testing with little change, if any, in vision for a long period of time.[84] No single visual function test is capable of discriminating consistently affecteds from unaffecteds, but a combination of tests can be used successfully in this endeavor.[86] The possible role of the OPA1 gene in normal-tension glaucoma has also been recently reviewed elsewhere.[1] Another autosomal dominant optic neuropathy gene has been mapped to the long arm of chromosome 18 (18q12.2-q12.3, OPA4 locus) and so have the genes for X-linked (short arm of the X chromosome, OPA2 locus at Xp11.4-p11.2) and autosomal recessive forms (loci on chromosome 8q21-q22, ROA1, and 19q13.32, OPA3 ) ( . Accessed October 4, 2004; . Accessed October 4, 2004). Mutations in the OPA3 gene are usually associated with the rare autosomal recessive early onset hereditary optic neuropathy syndrome known as Costeff (or optic atrophy plus) syndrome, which is more common among Iraqi Jews ( . Accessed October 4, 2004). However, very recently, heterozygous mutations in OPA3 have also been identified in patients with a novel autosomal dominant hereditary optic neuropathy cataract ocular syndrome,[87] the actual prevalence of which is presently undetermined. When autosomal recessive inheritance is suspected or known, though, the more common Wolfram syndrome must be strongly considered in the differential diagnostic process (see section on Wolfram syndrome).


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