Autofluorescence and Infrared Retinal Imaging in patients and obligate carriers with Neuronal Ceroid Lipofuscinosis

Kelly, John P.; Weiss, Avery H.; Rowell, Gus; Seigel, Gail M.

doi:10.3109/13816810903258829

Cited by 17 publications

(8 citation statements)

References 25 publications

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“…The optic nerve pallor, vascular attenuation, macular atrophy and pigmentary changes reported by Kelly and colleagues [22] in their cohort of 27 NCL patients are also consistent with our description of ocular findings in LINCL. In addition to color fundus photography, in this cohort, 9 NCL patients underwent standardized fundus autofluorescence (FAF) imaging.…”

Section: Discussionsupporting

confidence: 92%

“…In addition to color fundus photography, in this cohort, 9 NCL patients underwent standardized fundus autofluorescence (FAF) imaging. Kelly and colleagues [22] report an increased FAF early in the disease course and decreased FAF with more extensive retinal atrophy. The exact subset of LINCL patients who were imaged is not specified in the report, nor is the extent of disease progression noted in any of the NCL patients examined.…”

Section: Discussionmentioning

confidence: 99%

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Spectrum of Ocular Manifestations in CLN2-Associated Batten (Jansky-Bielschowsky) Disease Correlate with Advancing Age and Deteriorating Neurological Function

et al. 2013

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BackgroundLate infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten’s disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described.MethodsPatients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed.ResultsFifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations.ConclusionsOphthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Spectrum of Ocular Manifestations in CLN2-Associated Batten (Jansky-Bielschowsky) Disease Correlate with Advancing Age and Deteriorating Neurological Function

et al. 2013

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“…Under these ‘low light’ conditions, the genetically modified CLN3-deficient mice displayed a strong thinning of retinal layers and showed typical hallmarks for microgliosis. In vivo imaging and stainings also detected increased amounts of autofluorescent material in ‘low light’-exposed Cln3 Δex7/8 animals, potentially reflecting increased autofluorescence observed in the fundus of early-stage jNCL patients ( Kelly et al, 2009 ).…”

Section: Discussionmentioning

confidence: 91%

Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage

Dannhausen

Möhle

Langmann

2018

Disease Models &Amp; Mechanisms

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Juvenile neuronal ceroid lipofuscinosis (jNCL) is a rare but fatal inherited lysosomal storage disorder mainly affecting children. The disease is caused by mutations in the CLN3 gene that lead to the accumulation of storage material in many tissues, prominent immune responses and neuronal degeneration. One of the first symptoms is vision loss followed by motor dysfunction and mental decline. The established Cln3Δex7/8 mouse model mimics many pathological features of the human disease except the retinal phenotype, which is very mild and occurs only very late in these mice. Here, we first carefully analyzed the retinal structure and microglia responses in these animals. While prominent autofluorescent spots were present in the fundus, only a moderate reduction of retinal thickness and no prominent microgliosis was seen in young CLN3-deficient mice. We next genetically introduced a light-sensitive RPE65 variant and established a light-damage paradigm that showed a high susceptibility of young Cln3Δex7/8 mice after exposure to 10,000 lux bright light for 30 min. Under these ‘low light’ conditions, CLN3-deficient mice showed a strong retinal degeneration, microglial activation, deposition of autofluorescent material and transcriptomic changes compared to wild-type animals. Finally, we treated the light-exposed Cln3Δex7/8 animals with the immunomodulatory compound minocycline, and thereby rescued the retinal phenotype and diminished microgliosis. Our findings indicate that exposure to specific light conditions accelerates CLN3-dependent retinal degeneration, and that immunomodulation by minocycline could be a possible treatment option to delay vision loss in jNCL patients..

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“…It has been reported that ASM could be detected as a yellow pigment under brightfield illumination; this material also exhibits autofluorescence, which is excited at 320–480 nm (Seehafer and Pearce, 2006; Kelly et al, 2009; Jung et al, 2010). These characteristics were used to identify the ASM in the present experiments.…”

Section: Methodsmentioning

confidence: 99%

Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene‐deficient mice

Ohtaki

Ohara

Song

et al. 2012

J of Neuroscience Research

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Autofluorescent storage material (ASM) is an aging pigment that accumulates during the normal course of senescence. Although the role of ASM has yet to be fully elucidated, ASM has been implicated in age-related neurodegeneration. In this study, we determined the level of ASM in chloride channel 3 (ClC-3) gene-deficient (KO) mice both in response to aging and following mild global ischemia. To understand the mechanism of action of the ASM, mice subjected to ischemia were treated with the cyclooxygenase (COX) inhibitor indomethacin or with the noncompetitive glutamate receptor antagonist MK-801. ClC-3 KO mice displayed age-related neurodegeneration of the neocortex as well as the hippocampus. The cortical layers in particular granular layers became thinner with aging. ASM accumulated in the brains of ClC-3 KO mice was increased seven- to 50-fold over that observed in the corresponding regions of their wild-type littermates. Young wild-type mice survived longer than age-matched ClC-3 KO mice after permanent global ischemia. However, in the case of older animals, the survival curves were similar. The ASM also increased four- to fivefold 10 days after mild global ischemia, an effect that was suppressed by treatment with indomethacin and MK-801. These results suggest that temporary ischemia might trigger a process similar to aging in the brain, mimicking the effect of age-related neurodegenerative diseases.

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Autofluorescence and Infrared Retinal Imaging in patients and obligate carriers with Neuronal Ceroid Lipofuscinosis

Abstract: Patients with NCL show increases in retinal fluorophores in early stages and decreases in FAF in late stages of the disease. Obligate carriers of NCL have mildly elevated FAF but this finding is not a specific measure of the carrier state.

Cited by 17 publications

References 25 publications

Spectrum of Ocular Manifestations in CLN2-Associated Batten (Jansky-Bielschowsky) Disease Correlate with Advancing Age and Deteriorating Neurological Function

Spectrum of Ocular Manifestations in CLN2-Associated Batten (Jansky-Bielschowsky) Disease Correlate with Advancing Age and Deteriorating Neurological Function

Immunomodulation with minocycline rescues retinal degeneration in juvenile neuronal ceroid lipofuscinosis mice highly susceptible to light damage

Accumulation of autofluorescent storage material in brain is accelerated by ischemia in chloride channel 3 gene‐deficient mice

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