History of Ophthalmology: Theodor Leber, MD

By C. Nathaniel Robal, MD, PhD

Jules Stein Eye Institute

Historical Background: Theodor Leber was born in Karlsruth, Germany on February, 29th 1840. His father was a respected professor of romantic languages. Leber had a very early interest in the natural sciences and attended medical school in Heidelberg, Germany. Leber’s initial contribution to ophthalmology came in September 1864, when he presented his findings on the subject of “blood circulation of the eye.” In 1891, Leber published his work on “the origin and mediators of inflammation” and was the first to describe chemotaxis. As a result he is credited as one of the founding forefathers of ophthalmic research. Leber was the Director of the Eye Clinic in Gottingen, then the Chair and Director of the Eye Clinic at Heidelberg until his retirement in 1910 [1]. Modern Ophthalmologists remember Leber by the diseases that still bear his name.

Important eponyms:
· Leber’s congenital amaurosis (LCA): In 1869, Leber described LCA in affected children of the same sibship born to healthy parents. The disease was characterized by abolished photomotor reflex, wandering nystagmus, and a normal fundus at birth progressing to a typical appearance of retinitis pigmentosa.
· Also known for: Leber’s hereditary optic neuropathy, Leber’s miliary aneurysm and Leber’s Stellate Neuroretinitis.

Disease process: LCA is autosomal recessive and has a worldwide prevalence of 3 in 100,000 newborn babies. LCA accounts for >5% of inherited retinopathies. Approximately 20% of children attending schools for the blind have this disease. Seven genes have been linked to the disease [2].

Key findings include:
· Absent or diminished papillary light reflexes;
· Initially, normal fundi despite very poor vision which progresses to mild to severe macular pigmentation with arteriolar attenuation;
· ERG is non recordable;
· Systemically associated with mental handicap, deafness, epilepsy, CNS and renal abnormalities and skeletal malformations.

150 years later: LCA continues to shape our understanding of ophthalmic diseases. In 2008, two groups published proof of concept studies where adenovirus type 2 was subretinally injected to correct the RPE65-/- gene deficiency in LCA patients [3, 4]. Initial results do suggest an increase in vision. The results are very promising for potentially curative treatments and underscore the strong union between science and ophthalmology.

References

1. Blum, M., et al., Theodor Leber: a founder of ophthalmic research. Surv Ophthalmol, 1992. 37(1): p. 63-8.

2. Kaplan, J., Leber congenital amaurosis: from darkness to spotlight. Ophthalmic Genet, 2008. 29(3): p. 92-8.

3. Maguire, A.M., et al., Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med, 2008. 358(21): p. 2240-8.

4. Hauswirth, W., et al., Phase I Trial of Leber Congenital Amaurosis due to RPE65 Mutations by Ocular Subretinal Injection of Adeno-Associated Virus Gene Vector: Short-Term Results. Hum Gene Ther, 2008.