Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence

Artur V Cideciyan; Tomas S Aleman; Malgorzata Swider; Sharon B Schwartz; Janet D Steinberg; Alexander J Brucker; Albert M Maguire; Jean Bennett; Edwin M Stone; Samuel G Jacobson

doi:10.1093/hmg/ddh048

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Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence

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Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence

Artur V Cideciyan, Tomas S Aleman, Malgorzata Swider, Sharon B Schwartz, Janet D Steinberg, Alexander J Brucker, Albert M Maguire, Jean Bennett, Edwin M Stone and Samuel G Jacobson

Human molecular genetics, Vol.13(5), pp.525-534

03/01/2004

DOI: 10.1093/hmg/ddh048

PMID: 14709597

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Abstract

Mutations in ABCA4, which encodes a photoreceptor specific ATP-binding cassette transporter (ABCR), cause autosomal recessive forms of human blindness due to retinal degeneration (RD) including Stargardt disease. The exact disease sequence leading to photoreceptor and vision loss in ABCA4-RD is not known. Extrapolation from murine and in vitro studies predicts that two of the earliest pathophysiological features resulting from disturbed ABCR function in man would be slowed kinetics of the retinoid cycle and accelerated deposition of lipofuscin in the retinal pigment epithelium (RPE). To determine the human pathogenetic sequence, we studied surrogate measures of retinoid cycle kinetics, lipofuscin accumulation, and rod and cone photoreceptor and RPE loss in ABCA4-RD patients with a wide spectrum of disease severities. There were different extents of photoreceptor/RPE loss and lipofuscin accumulation in different regions of the retina. Slowing of retinoid cycle kinetics was not present in all patients; when present, it was not homogeneous across the retina; and the extent of slowing correlated well with the degree of degeneration. The orderly relationship between these phenotypic features permitted the development of a model of disease sequence in ABCA4-RD. The model predicted lipofuscin accumulation as a key and early component of the disease expression in man, as in mice. In man, however, abnormal slowing of the rod and cone retinoid cycle occurs at later stages of the disease sequence. Knowledge of the human ABCA4 disease sequence will be critical for defining rates of progression, selecting appropriate patients and retinal locations for future therapy, and choosing appropriate treatment outcomes.

Humans

Middle Aged

Dark Adaptation - physiology

Fluorescence

Retinal Degeneration - physiopathology

Mutation - genetics

Genes, Recessive

Retinal Degeneration - metabolism

Disease Progression

Pigment Epithelium of Eye - metabolism

Phenotype

ATP-Binding Cassette Transporters - genetics

Models, Biological

Adult

Kinetics

Photoreceptor Cells, Vertebrate - metabolism

Photic Stimulation

Lipofuscin - metabolism

Details

Title: Subtitle: Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence
Creators: Artur V Cideciyan - Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA. cideciya@mail.med.upenn.edu
Tomas S Aleman
Malgorzata Swider
Sharon B Schwartz
Janet D Steinberg
Alexander J Brucker
Albert M Maguire
Jean Bennett
Edwin M Stone
Samuel G Jacobson
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.13(5), pp.525-534
DOI: 10.1093/hmg/ddh048
PMID: 14709597
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: EY-13729 / NEI NIH HHS EY-13385 / NEI NIH HHS EY-13203 / NEI NIH HHS EY-10820 / NEI NIH HHS EY-12156 / NEI NIH HHS
Language: English
Date published: 03/01/2004
Academic Unit: Iowa Neuroscience Institute; Ophthalmology and Visual Sciences
Record Identifier: 9983979911102771

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