Juvenile Batten Disease (CLN3): Detailed Ocular Phenotype, Novel Observations, Delayed Diagnosis, Masquerades, and Prospects for Therapy

Abstract

Purpose To characterize the retinal phenotype of juvenile neuronal ceroid lipofuscinosis (JNCL), highlight delayed and mistaken diagnosis, and propose an algorithm for early identification. Design Retrospective case series. Participants Eight children (5 female) with JNCL. Methods Review of clinical notes, retinal imaging including fundus autofluorescence and OCT, electroretinography (ERG), and both microscopy and molecular genetic testing. Main Outcome Measurements Demographic data, signs and symptoms, visual acuity (VA), fundus autofluorescence and OCT findings, ERG phenotype, and microscopy/molecular genetics. Results Participants presented with rapid bilateral vision loss over 1 to 18 months, with mean VA deteriorating from 0.44 logarithm of the minimum angle of resolution (logMAR) (range, 0.20–1.78 logMAR) at baseline to 1.34 logMAR (0.30 logMAR - light perception) at last follow-up. Age of onset ranged from 3 to 7 years (mean, 5.3 years). The age at diagnosis of JNCL ranged from 7 to 10 years (mean, 8.3 years). Six children displayed eccentric fixation, and 6 children had cognitive or neurologic signs at the time of diagnosis (75%). Seven patients had bilateral bull’s-eye maculopathy at presentation. Coats-like exudative vasculopathy, not previously reported in JNCL, was observed in 1 patient. OCT imaging revealed near complete loss of outer retinal layers and marked atrophy of the nerve fiber and ganglion cell layers at the central macula. An electronegative ERG was present in 4 patients (50%), but with additional a-wave reduction, there was an undetectable ERG in the remaining 4 patients. Blood film microscopy revealed vacuolated lymphocytes, and electron microscopy showed lysosomal (fingerprint) inclusions in all 8 patients. Conclusions In a young child with bilateral rapidly progressive vision loss and macular disturbance, blood film microscopy to detect vacuolated lymphocytes is a rapid, readily accessible, and sensitive screening test for JNCL. Early suspicion of JNCL can be aided by detailed directed history and high-resolution retinal imaging, with subsequent targeted microscopy/genetic testing. Early diagnosis is critical to ensure appropriate management, counseling, support, and social care for children and their families. Furthermore, although potential therapies for this group of disorders are in early-phase clinical trial, realistic expectations are that successful intervention will be most effective when initiated at the earliest stage of disease.

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

“…While very useful to identify retinal dystrophy with macular atrophy, these images are less useful for an in‐depth and quantitative analysis of retinal layers in these children. This may explain why we did not corroborate a CLN3 disease‐specific macular striation pattern (Dulz et al 2016 ; Wright et al 2019 ). Although there were some differences between the three assessors in this study, they did point towards an apparent CLN3 disease‐specific early inner retina/NFL involvement (Preising et al 2017 ).…”

“…To the best of our knowledge, we provide the most extensive overview of the ophthalmological characteristics early in CLN3 disease described so far. Previous reports on ocular abnormalities in CLN3 disease generally discussed either relatively old patients years after diagnosis or small patient numbers, without or with only few control patients with an isolated retinal disease (Eksandh et al 2000 ; Hainsworth et al 2009 ; Dulz et al 2016 ; Hansen et al 2016 ; Preising et al 2017 ; Wright et al 2019 ).…”

The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

“…Moreover, CLN3 -associated Batten disease, first diagnosed by ophthalmologists, is another example where early diagnosis is critical to direct management, counseling, and support for young patients and their families. The systemic therapeutic options for this disease in early-phase clinical trial benefit from a start at the earliest stage of disease [ 28 , 29 ].…”

Negative electroretinograms: genetic and acquired causes, diagnostic approaches and physiological insights

“…Negative ERGs have been reported in a number of systemic conditions. Many of these are neurological or neurodegenerative conditions, some of which have a metabolic basis: these include disease associated with bi-allelic variants in CLN3 (juvenile Batten disease) [63,64], GNB5-associated disease [65], WDR73 (Galloway-Mowat syndrome) [66], Spinocerebellar ataxia-1 [67] (dominantly inherited, associated with an expanded trinucleotide repeat in the gene ATXN1) and others. In the commonest cause of congenital disorder of glyclosylation, phosphomannomutase-2 deficiency (due to bi-allelic variants in PMM2), negative ERGs have been reported [68,69].…”