Clinical and Molecular Characteristics of Childhood-Onset Stargardt Disease

Abstract

PurposeTo describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD).DesignRetrospective case series.ParticipantsForty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012.MethodsA detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients.Main Outcome MeasuresClinical, imaging, electrophysiologic, and molecular genetic findings.ResultsThe median ages of onset and the median age at baseline examination were 8.5 (range, 3–16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD.ConclusionsChildhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.

A Report on Molecular Diagnostic Testing for Inherited Retinal Dystrophies by Targeted Genetic Analyses

“…Whereas, molecular diagnostic testing for ABCA4-associated diseases was requested for a majority (113 of 150) of patients. The rate of detection of causative mutations in these patients varies between 50% to 80%, depending on testing methods and patient ethnicity (Braun et al, 2013;Fujinami et al, 2015). In a previous study, we observed causative mutations in 48% of patients diagnosed with ABCA4-associated disease, whereas mutations were found in 59% of the probands in the current study by screening the coding region of the ABCA4 gene (Downs et al, 2007).…”

Macular function measured by binocular mfERG and compared with macular structure in healthy children

“…Function and structure of the central macula are affected in various diseases in childhood such as Stargardt disease, achromatopsia and x-linked juvenile retinoschisis [33][34][35]. Although not always in agreement, a combination of mfERG and OCT provides important and complementary information about the central retina [36].…”

The CommonABCA4Variant p.Asn1868Ile Shows Nonpenetrance and Variable Expression of Stargardt Disease When Present intransWith Severe Variants

“…[5][6][7][8][9][10] A combination of disease-causing ABCA4 alleles may, therefore, result in a severe, early-onset STGD1 phenotype (i.e., onset 10 years of age), 11,12 which is often observed as rapidly progressive cone-rod dystrophy, 5,13 in classical STGD1, 10 or in late-onset STGD1. [14][15][16] In about half of the patients with late-onset STGD1 (onset >44 years of age), only one disease-causing allele was identified, despite the sequence analysis of all coding variants.…”