Retinal phenotype of patients with hereditary defects in lipid metabolism

Age-related macular degeneration (AMD) is the leading cause of blindness in
adults over 50 years old, which will affect an estimated 14.9-21.5 million
people in Europe alone by 2040. One of the earliest signs of AMD is the
formation of drusen, which are deposits of extracellular debris, photoreceptor
remnants and lipids, between the retinal pigment epithelium (RPE) and Bruch*s
membrane beneath the retina. The pathological role of drusen remains poorly
understood, as do the consequences of their formation for the course of the
disease. Although the formation of Drusen typically begins after the age of 55,
a clinical subtype of AMD termed Early Onset Drusen (EOD) is known to begin at
an earlier age, often unbeknownst to the patient.

Genome-wide association studies on AMD identified significant correlations with
several genes, of which complement C3 (C3) is the best known. Several genes
related to lipid metabolism were also identified in these studies including:
Apolipoprotein E (APOE), ATP binding cassette subfamily A member 1 (ABCA1) and
LDL receptor (LDLR). Since lipid accumulation has been described in drusen, we
hypothesize a role for these genes in the formation of drusen and thus the
early stages of AMD. This is supported by research suggesting that the number
of drusen is increased in retinas of mice with mutations in lipid-related
proteins. Research into this mechanism has been limited to mouse studies mainly
and human studies are rare.

Our aim is to study the role of lipid metabolism-related genes in the formation
of drusen and AMD by investigating whether individuals with specific mutations
develop drusen at an early age and are thus at greater risk of developing AMD.
This will lead to increased knowledge of the role of these genes in the
disease. Furthermore, this study could lead to a recommendation to perform
early screening for retinal abnormalities in this rare group of patients.

To investigate whether mutations in genes associated with lipid metabolism are
a risk factor for retinal pathology such as the early formation of drusen

Patients will be invited for a single visit to the ophthalmology outpatient
clinic to undergo a non-invasive ophthalmological screening which will include
assessment of visual acuity, slit-lamp examination, retinal photography
(autofluorescence imaging, color fundus photographs) and optical coherence
tomography (OCT) imaging of the macula.

Burdens for the patients are limited to a single visit to the ophthalmology
department in the AMC, lasting around 60 minutes. This visit will include a
non-invasive ophthalmological screening which will include the use of mydriatic
drops to enlarge the pupils, which is required for the photographs. These drops
may cause a temporary reduction of visual acuity lasting around 3 hours during
which the patient is not allowed to drive a car. This effect is fully
reversible and there is only a minimal risk of adverse allergic reactions.
There are no other physical risks associated with the investigations performed.
If the patient gives consent to being contacted again should any pathology of
the eyes be discovered (for example glaucomatous cupping of the optic disc) we
will do so and, depending on the nature of the pathology, recommend referral to
an ophthalmological clinic for further diagnostics/treatment.
Benefits for individuals include a unique contribution to the knowledge of AMD,
as well as a thorough screening for ocular pathology with the possibility of
having early diagnosis of pathological changes and treatment thereof.
The results of the study will further elucidate the pathophysiological
mechanisms of drusen-formation, and correspondingly increase knowledge of AMD.
Identification of a causal role of these genes in AMD could lead additional
therapeutic options for its treatment.