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. 2023 Jun;146(3):241-256.
doi: 10.1007/s10633-023-09930-1. Epub 2023 Mar 25.

Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging

Dhimas H Sakti  1   2 , Elisa E Cornish  1   3 , Clare L Fraser  1 , Benjamin M Nash  3   4 , Trent M Sandercoe  5 , Michael M Jones  5 , Neil A Rowe  5 , Robyn V Jamieson  1   3 , Alexandra M Johnson  6 , John R Grigg  7   8   9
Affiliations

Early recognition of CLN3 disease facilitated by visual electrophysiology and multimodal imaging

Dhimas H Sakti et al. Doc Ophthalmol. 2023 Jun.

Abstract

Background: Neuronal ceroid lipofuscinosis is a group of neurodegenerative disorders with varying visual dysfunction. CLN3 is a subtype which commonly presents with visual decline. Visual symptomatology can be indistinct making early diagnosis difficult. This study reports ocular biomarkers of CLN3 patients to assist clinicians in early diagnosis, disease monitoring, and future therapy.

Methods: Retrospective review of 5 confirmed CLN3 patients in our eye clinic. Best corrected visual acuity (BCVA), electroretinogram (ERG), ultra-widefield (UWF) fundus photography and fundus autofluorescence (FAF), and optical coherence tomography (OCT) studies were undertaken.

Results: Five unrelated children, 4 females and 1 male, with median age of 6.2 years (4.6-11.7) at first assessment were investigated at the clinic from 2016 to 2021. Four homozygous and one heterozygous pathogenic CLN3 variants were found. Best corrected visual acuities (BCVAs) ranged from 0.18 to 0.88 logMAR at first presentation. Electronegative ERGs were identified in all patients. Bull's eye maculopathies found in all patients. Hyper-autofluorescence ring surrounding hypo-autofluorescence fovea on FAF was found. Foveal ellipsoid zone (EZ) disruptions were found in all patients with additional inner and outer retinal microcystic changes in one patient. Neurological problems noted included autism, anxiety, motor dyspraxia, behavioural issue, and psychomotor regression.

Conclusions: CLN3 patients presented at median age 6.2 years with visual decline. Early onset maculopathy with an electronegative ERG and variable cognitive and motor decline should prompt further investigations including neuropaediatric evaluation and genetic assessment for CLN3 disease. The structural parameters such as EZ and FAF will facilitate ocular monitoring.

Keywords: Batten; CLN3; Lysosomal storage disorders; Neuronal ceroid lipofuscinoses.

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Conflict of interest statement

DH Sakti, None; EE Cornish, None; CL Fraser, None; BM Nash, None; TM Sandercoe, None; MM Jones, None; NA Rowe; AM Johnson, None; J R Grigg; and RV Jamieson are consultant to Novartis.

Figures

Fig. 1
Fig. 1
BCVA relationship with age. BCVA was plotted against age for patients P1 & P2. The BCVA trend deteriorated with increasing age. P1 eyes are shown in circle. P2 eyes are shown in square. Right eyes are presented in black colour, while left eyes in blue colour. BCVA Best corrected visual acuity
Fig. 2
Fig. 2
Multimodal retinal imaging for all patients. Right eye UWF-fundus pseudocolour photograph, UWF-FAF, and macular SD-OCT for P1-P5. Double black arrows indicate the margin of bull’s eye maculopathy (BEM). (P1-A) BEM and macular yellow-orange appearance found in P1. (P1-B) HyperAF ring surrounding hypoAF fovea. (P1-C) EZ loss on fovea. (P2-A) BEM was found in P2. (P2-B) HyperAF ring surrounding hypoAF fovea. (P2-C) EZ loss on fovea. (P3-A) BEM, macular yellow-orange appearance, vessel rarefication, retinal atrophy outside vascular arcade found in P3. (P3-B) HyperAF ring surrounding hypoAF fovea, hypoAF corresponding to retinal atrophy. (P3-C) EZ loss on fovea. (P4-A) BEM and vessel rarefication found in P4. Insert image of enlarged macula shows BEM. (P4-B) HyperAF ring surrounding hypoAF fovea. (P4-C) EZ loss on fovea. (P5-A) BEM, macular striae, macular yellow-orange appearance, vessel rarefication found in P5. Insert image shows clearer macular striae. (P5-B) HyperAF ring surrounding hypoAF fovea. (P5-C) Schitic changes on macula and EZ loss on fovea. (N-A,B,C) Normal control showed normal fundus pseudocolour photograph, normal UWF-FAF with foveal reduction of AF, and normal SD-OCT with normal thickness and distinct lamination. AF Autofluorescence, BEM Bull’s eye maculopathy, EZ ellipsoid zone, FAF fundus autofluorescence, SD-OCT spectral domain-optical coherence tomography, UWF ultra-wide field
Fig. 3
Fig. 3
Multimodal retinal imaging follow-up for selected patients. The left eye multimodal retinal imaging was selected to illustrate change over time. UWF-fundus pseudocolour photography, UWF-FAF, and SD-OCT follow-up of P1 and P2 are shown. (P1-A) Bull’s eye maculopathy (BEM) and macular yellow-orange appearance were found in P1 at 4.6 yrs. (P1-D) Macular yellow-orange appearance became more apparent at 5.3yrs. (P1-F) Macular yellow-orange appearance covering macula and retinal atrophy outside vascular arcade at 6.8 yrs. (P1-B) HyperAF ring surrounding hypoAF fovea at 4.6 yrs. (P1-E) More apparent perifoveal hyperAF ring at 5.3 yrs. (P1-G) Perifoveal hyperAF ring disappearance, hypoAF outside vascular arcade corresponding to retinal atrophy at 6.8 yrs. (P2-A) BEM was found in P2 at 5.9 yrs. (P2-D) Macular yellow-orange appearance started to bed found at 7 yrs. (P2-F) BEM, macular yellow-orange appearance, vessel rarefication, retinal atrophy on inferonasal area at 9.4 yrs. (P2-B) HyperAF ring surrounding hypoAF fovea at 5.9 yrs. (P2-E) More apparent perifoveal hyperAF ring at 7 yrs. (P2-G) Perifoveal hyperAF ring disappearance, replaced by hypoAF ring. HypoAF on inferonasal area corresponding to retinal atrophy at 9.4 yrs BL SD-OCT was taken using Heidelberg, while FU SD-OCT was taken using Cirrus device. (P1-C)(P2-C) BL SD-OCT of P1 and P2 showed disruption of foveal EZ. (P1-H)(P2-H) FU SD-OCT of P1 and P2 showed progressed disappearance of EZ. Signal hypertransmission into choroid (yellow arrow) was present in both FU SD-OCT. AF Autofluorescence, BEM Bull’s eye maculopathy, BL baseline, EZ ellipsoid zone, FAF fundus autofluorescence, FU follow-up, SD-OCT spectral domain-optical coherence tomography, UWF ultra-wide field
Fig. 4
Fig. 4
Full-field ERGs and pattern ERG recordings. The full-field ERGs were recorded according to ISCEV protocols for paediatric ERG and in one case the non-standard abbreviated ERG protocol was used. P1 and P2 were examined using skin electrodes, P3 used DTL electrodes, P4 underwent a paediatric non-standard abbreviated ERG protocol using skin electrode, and P5 used gold foil electrodes. P4 ERG was performed using a modified Great Ormond Street Hospital (GOSH) protocol as described in the methods. All patients showed severely reduced or undetectable DA 0.01 response. All patients excluding P4 showed a reduced b:a wave ratio (electronegative) for DA 3.0 and DA 12.0. P4 had a very noisy recordings, and there is a suggestion of a reduced b wave. The LA 30 Hz and LA 3.0 were significantly reduced for P1-P2. P4’s responses were noisy but also appeared reduced. Patients P3 and P5 were at the lower of the normal range. In patients P1 to P4, the pERG 30 deg p50 amplitude was almost undetectable. Patient P5 showed an identifiable waveform, but the p50 amplitude was reduced. Despite P4 having poor compliance and cooperation during the testing which resulted in noisy recordings, the combination of the potential electronegative scotopic ERG and a significantly reduced LA 30 Hz and LA 3.0 raised the possibility of Batten disease as a potential diagnosis. DA Dark adapted, DTL Dawson, Trick, and Litzkow electrodes, ERG electroretinogram, ffERG full-field ERG, LA light adapted, pERG pattern ERG
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