Case#:two cases from two additional families (case 3, 11 years and case 4, 11 years).
DiseaseAssertion: Stargardt’s Disease
FamilyInfo: NR
ParentalTesting: NR
CasePresentingHPOs: HP:0030500, HP:0011507
CasePhenotypeFreeText: LogMAR visual acuity for the right and left eye of cases 1–4 was 0.3 and 0.2, 0.1 and 0.1, 0.5 and 0.4, and 0.3 and 0.4, respectively. Gross disruption of the outer retinal layers at the macula in all cases; in two (cases 2 and 4), the presumed external limiting membrane (ELM) peak was broadened with the inner segment ellipsoid band (ISe) missing. Subtle white-yellowish fine dots at the macula and numerous white-yellowish flecks extending anterior to the arcade are shown in the colour fundus photograph of case 1. Autofluorescence (AF) imaging of case 1 detected well-defined dots with high signal at the central macula surrounded by a ring of increased signal and numerous foci with high or low signal extending to the peripheral retina. Case 2 also had subtle white-yellowish fine dots at the central macula and numerous white-yellowish flecks extending anterior to the arcade, both associated with high signal on AF imaging. In addition, case 3 had white-yellowish fine dots at the macula and numerous white-yellowish flecks extending to the periphery, both of which had high or low signal on AF imaging. Case 4 showed subtle fine macular dots mainly in a para-foveal location, which are well-defined on AF imaging.
CaseNotHPOs: HP:0007401, HP:0000505
CaseNotPhenotypeFreeText: Most cases with STGD have central macular atrophy with numerous more peripheral flecks (Michaelides et al. 2003). Given their relatively good visual acuity, it is likely that the central macular dots observed in our cases may be an early sign of macular dysfunction before the development of macular atrophy. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases
CasePreviousTesting: The age of disease onset in cases 1–4, defined as either the age at which visual loss was first noted by the subject or in the asymptomatic subjects when abnormal retinal appearance was first detected, was 5, 7, 8, and 6 years old, respectively.
GenotypingMethod: After informed consent was obtained, blood samples were taken from probands of 2/3 families for ABCA4 screening. A full medical history was obtained, and a full ophthalmologic examination was performed in all cases. Mutation screening of ABCA4 was performed in two probands of the three families, and two likely disease-causing variants were identified in each case; c.768G > T, p.V256V (a previously reported splicing-altering synonymous variant) and c.4363T > C, p.C1455R (a missense variant) in case 1, and c.1906C > T, p.Q636* (a non-sense variant) and c.5461-10 T > C (a disease-associated intronic variant with uncertain effect) in case 3. A blood sample was not available in one proband (case 4).
Variant: NM_000350.3(ABCA4):c.1906C>T (p.Gln636Ter) and NM_000350.3:c.5461-10T>C
LegacyVariant: c.1906C>T (p.Gln636Ter) and c.5461-10T>C
ClinVar: 265012 and 92870
CAID: CA10588302 and CA220687
gnomeAD: 1:94528164 G / A and 1:94476951 A / G
MultipleGeneVariants:No
PreviouslyPublished: No
AdditionalInfo:
Most symptoms/diagnoses are consistent with Stargardt’s Disease 3, however the probands in the study were younger in age, so many of the symptoms hadn’t progressed much. Also, all of the cases had decent visual acuity, which contradicts a symptom of Stargardt’s Disease 3. Similar fine macular dots or a ‘mottled macula’ have also been reported in other inherited retinal diseases, for example, in those caused by mutations in RDH5 or RPE65, both of which encode proteins with known function in the visual cycle. The thickening of the ELM may be an OCT abnormality that precedes atrophy in the early stages of STGD