Histopathologic and immunocytochemical analysis of the retina and ocular tissues in batten disease

Bensaoula, T.; Shibuya, Hisashi; Katz, Martin L.; Smith, J. Russell; Johnson, Gary S.; John, Sinoj K.; Milam, Ann H.

doi:10.1016/s0161-6420(00)00264-5

Cited by 55 publications

(14 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The microscopic findings noted in this report are comparable to that seen on the high-resolution spectral-domain OCT images in our patients. The outer retinal (photoreceptor and RPE) atrophy is also similar to that noted in two reports of JNCL eyes evaluated at autopsy [17,19]. …”

Section: Discussionsupporting

confidence: 84%

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

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 84%

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

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The remaining retinal pigment epithelium (RPE) contains fewer lipofuscin granules than controls and is devoid of melanin granules. 11, 33, 93 RPE also contains PAS-positive material, confirmed by electron microscopy (EM) to be typical curvilinear inclusions.…”

Section: Pathogenesismentioning

confidence: 90%

“…No granules are seen in remaining photoreceptor cells. 11 In areas there is retinal pigment epithelial atrophy as well as hypertrophy. The remaining retinal pigment epithelium (RPE) contains fewer lipofuscin granules than controls and is devoid of melanin granules.…”

Section: Pathogenesismentioning

confidence: 99%

See 1 more Smart Citation

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and the Eye

Bozorg

Ramirez-Montealegre

Chung

et al. 2009

Survey of Ophthalmology

View full text Add to dashboard Cite

Juvenile neuronal ceroid lipofuscinoses (JNCL) or Batten disease is the most common type of NCL in the United States and Europe. This devastating disorder presents with vision failure and progresses to include seizures, motor dysfunction, and dementia. Death usually occurs in the third decade, but some patients die before age twenty. Though the mechanism of visual failure remains poorly understood, recent advances in molecular genetics have improved diagnostic testing and suggested possible therapeutic strategies. The ophthalmologist plays a crucial role in both early diagnosis and documentation of progression of JNCL. We update Batten disease research, particularly as it relates to the eye, and present various theories on the pathophysiology of retinal degeneration.

show abstract

“…Retinal disease progresses along a similar degenerative course to retinitis pigmentosa. There is a loss of photoreceptors and retinal pigment epithelium (RPE), culminating in widespread atrophy and severe loss of neurons from all retinal layers accompanied by severe gliosis at end stage ( 16 , 18 ). The decline to blindness is typically rapid (1–2 years) compared with other retinal degenerations ( 14 , 15 , 17 ), but affected individuals can often remain blind-only for a prolonged period (1–9 years) before other signs of deterioration ( 11 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium ofCln3^Δex1-6mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)

Wavre‐Shapton

Calvi

Turmaine³

et al. 2015

Hum. Mol. Genet.

View full text Add to dashboard Cite

Retinal degeneration and visual impairment are the first signs of juvenile neuronal ceroid lipofuscinosis caused by CLN3 mutations, followed by inevitable progression to blindness. We investigated retinal degeneration in Cln3Δex1-6 null mice, revealing classic ‘fingerprint’ lysosomal storage in the retinal pigment epithelium (RPE), replicating the human disease. The lysosomes contain mitochondrial F0-ATP synthase subunit c along with undigested membranes, indicating a reduced degradative capacity. Mature autophagosomes and basal phagolysosomes, the terminal degradative compartments of autophagy and phagocytosis, are also increased in Cln3Δex1-6 RPE, reflecting disruption to these key pathways that underpin the daily phagocytic turnover of photoreceptor outer segments (POS) required for maintenance of vision. The accumulated autophagosomes have post-lysosome fusion morphology, with undigested internal contents visible, while accumulated phagosomes are frequently docked to cathepsin D-positive lysosomes, without mixing of phagosomal and lysosomal contents. This suggests lysosome-processing defects affect both autophagy and phagocytosis, supported by evidence that phagosomes induced in Cln3Δex1-6-derived mouse embryonic fibroblasts have visibly disorganized membranes, unprocessed internal vesicles and membrane contents, in addition to reduced LAMP1 membrane recruitment. We propose that defective lysosomes in Cln3Δex1-6 RPE have a reduced degradative capacity that impairs the final steps of the intimately connected autophagic and phagocytic pathways that are responsible for degradation of POS. A build-up of degradative organellar by-products and decreased recycling of cellular materials is likely to disrupt processes vital to maintenance of vision by the RPE.

show abstract

Histopathologic and immunocytochemical analysis of the retina and ocular tissues in batten disease

Cited by 55 publications

References 22 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

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and the Eye

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium ofCln3^Δex1-6mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)

Contact Info

Product

Resources

About

Histopathologic and immunocytochemical analysis of the retina and ocular tissues in batten disease

Cited by 55 publications

References 22 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

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) and the Eye

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium ofCln3Δex1-6mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)

Contact Info

Product

Resources

About

Photoreceptor phagosome processing defects and disturbed autophagy in retinal pigment epithelium ofCln3^Δex1-6mice modelling juvenile neuronal ceroid lipofuscinosis (Batten disease)