The absence of fundus abnormalities in Stargardt disease

Abstract

Purpose To raise awareness of Stargardt disease (STGD1) patients without fundus abnormalities. Methods Medical records were evaluated for age at onset, initial symptoms and diagnosis, reason for delay of diagnosis, age at STGD1 diagnosis, best-corrected visual acuity (BCVA), ophthalmoscopy, fundus photography, fundus autofluorescence (FAF), fluorescein angiography (FA), spectral-domain optical coherence tomography (SD-OCT), full-field electroretinography (ffERG), color vision test, and the presence of ABCA4 variants. Results In 11.1% of our STGD1 cohort of 280 patients, no fundus abnormalities were observed at first ophthalmic consultation. The median age at onset was 8 years (range, 1-18). There was a median delay in diagnosis of 3 years (range, 0-19) in 27 out of 31 patients, which resulted in a median age at diagnosis of 12 years (range, 7-26). Patients were misdiagnosed with amblyopia, myopia, optic disk pathology, mental health problems, tension headache, neuritis bulbaris, and uveitis. Subtle abnormalities, such as lipofuscin accumulation, were seen on FAF at an earlier disease stage than in ophthalmoscopy. On SD-OCT, this included a thickened external limiting membrane. Color vision tests showed red-green insufficiency in 79% of patients. Reduced ERG amplitudes were only present in 26% (N = 8) and a dark choroid sign in 65% of the patients. Visual acuity considerably fluctuated in the first 5 years after onset. The majority of the patients (65%) carried a least one variant with a severe effect on ABCA4 function. Conclusions Childhood-onset STGD1 patients were diagnosed with a delay of median 3 years. The presence of accurate competence, equipment, and the possibility for genetic screening is required; therefore, we recommend to refer children with visual complaints without initial fundus abnormalities to a specialized ophthalmologic center. In particular, to diagnose patients at an early stage of disease is of increased importance with the advent of new therapeutic possibilities.

Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations

“…At the time of examination, the girl had mildly decreased visual acuities and no fundus changes except a prominent thickening of the external limiting membrane (ELM) on OCT ( Burke et al, 2013 ). A subsequent study ( Lee et al, 2014 ) and several others thereafter ( Bax et al, 2019a ; Melillo et al, 2016 ; Pang et al, 2015 ; Park et al, 2015 ) corroborated the observation of ELM thickening to be a prominent feature of early stage ABCA4 -associated retinopathy while more recently, this thickening has been attributed to the adjacent outer nuclear layer (ONL) ( Khan et al., 2018 ). It is possible that structural changes occur prior to functional loss in patients.…”

“…In a cohort of 50 young ABCA4 -associated retinopathy patients (age ≤ 10 years), Lambertus and colleagues identified 10 individuals with visual function loss in the absence of discernible fundus abnormalities at the time of examination and reported the onset of visual acuity decline from as early as 3 years of age ( Lambertus et al, 2015 ). Defects in color vision have also been reported in patients with early to no detectable fundus changes ( Bax et al, 2019a ; Vandenbroucke et al, 2015 ). The youngest documented case of ABCA 4-associated retinopathy was an asymptomatic 5-year-old girl in a pseudodominant family harboring the c.5018 + 2T>C, p.(?)…”

Stargardt disease: Multimodal imaging: A review

“…Conversely, Bax et al 13 only reported a thickened ELM in two patients with normal fundi at 6 and 12 months after disease onset where all children showed disorganisation and loss of the RPE on OCT scans. Sequential OCT images have illustrated focal collapse of the inner retinal layers, secondary to loss of the outer retinal structures 13 . These changes appear to preferentially affect perifoveal areas.…”

“…Without multimodal imaging, these children can be easily misdiagnosed as functional visual loss, amblyopia and other forms of IRDs given pattern electroretinography (ERG) may be normal and full‐field ERG may show electronegative waveform in the early stages 11,12 . The lack of signs on fundoscopy may lead to unnecessary neuroimaging, lumbar punctures and even psychiatric evaluation and years of inappropriate occlusion therapy 13 . Similarly, without multimodal imaging late‐onset STGD1 can often be misdiagnosed as age‐related macular degeneration (AMD) due to the similar appearance of flecks and drusen on fundus examination, and the similar sight‐threatening complications of geographic atrophy and subretinal neovascular membranes 8,14 .…”

Hereditäre Netzhautdystrophien: Kombination ophthalmologischer Methoden zur Optimierung des Readout

“…Aufgrund der hohen klinischen Variabilität, der uneinheitlichen Terminologie und der meist unspezifischen Symptomatik bei Krankheitsbeginn stellt die Diagnose einer IRD insbesondere in Frühstadien hohe Anforderungen an den Augenarzt [5 -7]. Hereditäre Netzhautdystrophien werden nicht selten ohne ophthalmoskopisch erkennbare Fundusveränderungen symptomatisch: Bei Kindern mit Morbus Stargardt kann dies zu einer Verzögerung der Diagnose um 3 Jahre führen [8]. Für die betroffenen Patienten ist eine frühzeitige Diagnosestellung von hoher Bedeutung, weil sich negative soziale Auswirkungen durch eine verminderte Leistungsfähigkeit in Ausbildung und Beruf infolge von Visusminderung und Gesichtsfeldausfällen durch frühzeitige rehabilitative Maßnahmen begrenzen lassen.…”