Atypical presentation of neuronal ceroid lipofuscinosis type 8 in a sibling pair and review of the eye findings and neurological features

Abstract

PurposeTo report atypical presentation of neuronal ceroid lipofuscinoses type 8 (CLN8) to the eye clinic and review clinical features of CLN8.ObservationsDetailed eye exam by slit lamp exam, indirect ophthalmoscopy, fundus photography, optical coherence tomography, visual fields and electroretinogram (ERG). Molecular genetic testing using Next Generation Sequencing panel (NGS) and array Comparative Genomic Hybridization (aCGH).The siblings in this study presented to the eye clinic with retinitis pigmentosa and cystoid macular edema, and a history of seizures but no severe neurocognitive deficits or regression. Genetic testing identified a c.200C > T (p.A67V) variant in the CLN8 gene and a deletion encompassing the entire gene. Electron microscopy of lymphocytes revealed fingerprint inclusions in both siblings.Conclusionsand Importance: Pathogenic variants in CLN8 account for the retinitis pigmentosa and seizures in our patients however, currently, they do not have regression or neurocognitive decline. The presentation of NCL can be very diverse and it is important for ophthalmologists to consider this in the differential diagnosis of retinal disorders with seizures or other neurological features. Molecular genetic testing of multiple genes causing isolated and syndromic eye disorders using NGS panels and aCGH along with additional complementary testing may often be required to arrive at a definitive diagnosis.

Retinal degeneration in mice and humans with neuronal ceroid lipofuscinosis type 8

“…Additionally, attenuated rod and cone photoreceptor function was noted in numerous reports of CLN8 in humans, similar to that noted in the current study (10,(47)(48)(49).…”

“…Variation in phenotypic presentation of retinopathy has been noted in humans with mutations in CLN8, with main ocular lesions ranging from cystoid macular edema, diffuse macular schisis, optic disk atrophy, peripheral bone spicules, and retinal atrophy (10,47,48). Significant similarities are noted between the limited descriptive reports available of retinopathy in humans with CLN8 and Cln8 −/− mice of this study, including attenuated retinal vasculature and diffuse retinal pigment epithelial mottling (10).…”

“…Ocular symptoms such as retinal degeneration can be the first sign of NCL disease and facilitate an early diagnosis (7). Ocular manifestations of NCL are most commonly noted with CLN3 (8,9), though retinopathy and visual deficits associated with CLN8 have also been reported (10).…”

CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report

“…Subsequent cases were reported in Turkey [ 18 , 22 ], Italy [ 28 ], Germany [ 29 ], Israel [ 30 ], Ireland [ 31 ], Pakistan [ 22 ], Japan [ 32 ], China [ 33 ], and Saudi Arabia [ 34 ], some showing a milder phenotype. A few highly atypical presentations reported thus far include a congenital NCL in an Argentinian female [ 35 ] and a seizure disorder with retinitis pigmentosa but normal cognition in Hispanic siblings [ 36 ]. Table 2 summarizes these reports.…”

“…Our patient used to ride a bicycle until the age of 11, remains ambulatory and capable of comprehensible speech. Cognitive deterioration accompanies other symptoms of NCL in all but one reported family [ 36 ], but the rate and severity of impairment vary greatly. Overall, it appears to parallel the general course of the disease, with the more rapidly progressive cases developing more profound deficits.…”