Infantile type of so-called neuronal ceroid-lipofuscinosis

Santavuori, Pirkko; Haltia, Matti; Rapola, Juhani; Raitta, Christina

doi:10.1016/0022-510x(73)90075-0

Cited by 186 publications

(99 citation statements)

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“…The brain has always been considered the main locus of pathology in CLN1 disease (4,34,38). However, compared with promising data obtained for another form of NCL, CLN2 disease (32,33,39), previous attempts to treat Ppt1 −/− mice by targeting the known sites of pathology in the forebrain and cerebellum have had relatively limited success (3,28).…”

Section: Discussionmentioning

confidence: 99%

“…To better understand the early sensorimotor changes that occur in Ppt1 −/− mice (18), we focused our analysis on the spinal cord, a structure that has not been seriously considered as a site of pathology in any major form of NCL (38) but in which we had previously seen pathology in end-stage PPT1-deficient mice (31). We have expanded upon the original brief description of the cellular pathology in the human CLN1 spinal cord (4,34), and revealed that pathology in this region is not only more profound than initially anticipated but also occurs surprisingly early in disease progression in Ppt1 −/− mice. Indeed, the regional atrophy, loss of different neuron populations, profound glial response, and accumulation of autofluorescent storage material that occur in the brains of these mice (11,13,14) all occur to a similar extent in the spinal cord, but at an earlier stage of disease progression.…”

Section: Discussionmentioning

confidence: 99%

“…Because no effective treatments are currently available, all forms of NCL are fatal (2,3). Classic CLN1 disease or infantile NCL (INCL) is caused by autosomal-recessive mutations in the PPT1 gene (4,5). This encodes palmitoyl protein thioesterase 1 (PPT1), a lysosomal enzyme that catalyzes the cleavage of thioester bonds linking long-chain fatty acids to proteins (6,7).…”

mentioning

confidence: 99%

“…CLN1 disease is a very severe and rapidly progressing form of NCL, presenting as early as 6 to 24 mo of age. Affected children display a rapid loss of motor function, visual acuity, and cognitive abilities and a greatly reduced life expectancy of between 9 and 13 y (8,9).…”

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confidence: 99%

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Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1 −/− ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 −/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 −/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.infantile Batten disease | adeno-associated virus | spinal cord | brain | combination therapy

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

101

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“…The cortical neuronal loss is accompanied by gliosis and macrophage accumulation. The cells in the brain, retina, skin, rectum, and the peripheral blood lymphocytes show GRODs on ultrastructual examination [39,[65][66][67][68][69][70][71][72]. CLN1 (the traditional Infantile Neuronal Ceroid-Lipofuscinosis, INCL, Santavuori-Haltia disease), caused by a deficiency of the soluble lysosomal enzyme, palmitoyl-protein thioesterase 1 (PPT1), that cleaves the palmitate moiety from cysteine residues of S-palmitolyated proteins, classically presents in this manner [4,5].…”

Section: Rakheja and Mj Bennett / Neuronal Ceroid-lipofuscinosesmentioning

confidence: 99%

Neuronal ceroid-lipofuscinoses

Rakheja

Bennett

2018

TRD

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Abstract. The neuronal ceroid-lipofuscinoses (NCLs) are a group of recessively inherited diseases characterized by progressive neuronal loss, accumulation of intracellular lipofuscin-like autofluorescent storage material with distinctive ultrastructural features, and clinical signs and symptoms of progressive neurodegeneration. Initially classified by the age of onset of clinical signs and symptoms as well as the ultrastructural morphology of the storage material, the growing family of NCLs can now also be biologically classified by their underlying genetic defects. For a few NCLs, we now understand the functions of the proteins encoded by the NCL genes, which has enabled refining of the diagnostic algorithms and ignited hopes for finding effective treatments in the future. Ongoing research into understanding the functions of the remainder of the NCL proteins as well as continuing advancements in technology (such as massively-parallel gene sequencing) has and will continue to inform the clinical approach, diagnostic algorithms, and treatment strategies.

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