Recognizing differentiating clinical signs of CLN3 disease (Batten disease) at presentation

Abstract

Purpose: To help differentiate CLN3 (Batten) disease, a devastating childhood metabolic disorder, from the similarly presenting early-onset Stargardt disease (STGD1). Early clinical identification of children with CLN3 disease is essential for adequate referral, counselling and rehabilitation.

Methods: Medical chart review of 38 children who were referred to a specialized ophthalmological centre because of rapid vision loss. The patients were subsequently diagnosed with either CLN3 disease (18 patients) or early-onset STGD1 (20 patients).

Results: Both children who were later diagnosed with CLN3 disease, as children who were later diagnosed with early-onset STGD1, initially presented with visual acuity (VA) loss due to macular dystrophy at 5-10 years of age. VA in CLN3 disease decreased significantly faster than in STGD1 (p = 0.01). Colour vision was often already severely affected in CLN3 disease while unaffected or only mildly affected in STGD1. Optic disc pallor on fundoscopy and an abnormal nerve fibre layer on optical coherence tomography were common in CLN3 disease compared to generally unaffected in STGD1. In CLN3 disease, dark-adapted (DA) full-field electroretinogram (ERG) responses were either absent or electronegative. In early-onset STGD1, DA ERG responses were generally unaffected. None of the STGD1 patients had an electronegative ERG.

Conclusion: Already upon presentation at the ophthalmologist, the retina in CLN3 disease is more extensively and more severely affected compared to the retina in early-onset STGD1. This results in more rapid VA loss, severe colour vision abnormalities and abnormal DA ERG responses as the main differentiating early clinical features of CLN3 disease.

Keywords: Batten disease; CLN3 disease; childhood retinal dystrophy; deep phenotyping; early recognition; early-onset STGD1.

Fig. 1

Vision loss course in CLN3 disease and early‐onset STGD1. Visual acuity measurements in CLN3 disease compared to early‐onset Stargardt disease (STGD1). Velocity coefficient calculations confirm similar VODS around presentation but subsequently a significantly faster decrease of visual acuity in CLN3 disease (VODSoverall = 0.347–0.151*years since onset) compared to early‐onset STGD1 (VODSoverall = 0.347–0.151*years since onset; p = 0.02) for the complete follow‐up period as shown in figure). In both disease cohorts, VOD = VOS.

Fig. 2

Severity of colour vision deficiency around diagnosis in CLN3 disease and early‐onset STGD1. Red‐green and tritan colour vision deficiency in n = 7 CLN3 disease patients and n = 14* early‐onset STGD1 patients tested with (at least) the HRR around diagnosis. *Excluded from this figure is one (male) early‐onset STGD1 patient with a suspected co‐occurring congenital colour vision deficiency (see also Table S1 and S2).

Fig. 3

Fundoscopy, and optical coherence tomography (OCT) around diagnosis in CLN3 disease and early‐onset STGD1. Representative fundoscopy (A), fundus autofluorescence (FAF) (B) and OCT (C), from n = 1 CLN3 disease patient (CLN3‐5) and n = 1 early‐onset STGD1 patient (STGD1‐18) (see Table S2) around presentation compared to n = 1 age‐matched healthy control. Of note, due to eccentric fixation in both the CLN3 disease and early‐onset STGD1 patients, line scans often did not capture the macula and while (one of the radial) MM6 image(s) did, often the retina was not centered so clearly as seen in the early‐onset STGD1 patient.

Fig. 4

Light adapted and dark adapted ERG responses around diagnosis in CLN3 disease and early‐onset STGD1. Dark adapted (DA 0.01, 3.0) and light adapted (LA 3.0 and 30 Hz flicker) full‐field ERG responses in n = 7 CLN3 disease patients and n = 11 early‐onset STGD1 patients examined around presentation compared to n = 1 age‐matched healthy control. In the lower row, the composite DA 3.0 responses are shown.

Fig. 5

Multidimensional analysis of retinal involvement in CLN3 disease compared to early‐onset STGD1. CLN3 disease and early‐onset STGD1 present seemingly similar (A), but in‐depth analysis of ophthalmological test results performed around diagnosis reveals that the retinal disease is in CLN3 disease already more extensive (B). In CLN3, more ocular components are involved compared to STGD1: not only photoreceptors (cones and rods) but also inner retina and optic nerve. In addition, the different components are more severely affected, for example a severe cone involvement resulting in a severely impaired VA and severe colour vision deficiency around diagnosis. VA, visual acuity; def, deficiency; RG, red‐green.