Progressive conduction defects and cardiac death in late infantile neuronal ceroid lipofuscinosis

Fukumura, Shinobu; Saito, Yoshiaki; Saito, Takashi; Komaki, Hirofumi; Nakagawa, Eiji; Sugai, Kenji; Sasaki, Masayuki; Oka, Akira; Takamisawa, Itaru

doi:10.1111/j.1469-8749.2011.04170.x

Cited by 24 publications

(14 citation statements)

References 12 publications

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“…This suggests that retention of magnesium in CLN6 animals may be a compensatory mechanism to counteract the abnormalities in heart function. It is also noteworthy that lipopigment is consistently reported to accumulate in heart tissue, and cardiac abnormalities have been described in various NCL models and patients (Michielsen et al, 1984; Galvin et al, 2008; Ostergaard et al, 2011; Fukumura et al, 2012). However, this is the first study to implicate the heart as an important region in CLN6 disease and the first to provide presymptomatic evidence of significant cardiac changes in a model of NCL disease.…”

Section: Discussionmentioning

confidence: 97%

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

et al. 2013

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SummaryNeuronal ceroid lipofuscinoses, the most common fatal childhood neurodegenerative illnesses, share many features with more prevalent neurodegenerative diseases. Neuronal ceroid lipofuscinoses are caused by mutations in CLN genes. CLN6 encodes a transmembrane endoplasmic reticulum protein with no known function. We characterized the behavioural phenotype of spontaneous mutant mice modeling CLN6 disease, and demonstrate progressive motor and visual decline and reduced lifespan in these mice, consistent with symptoms observed in neuronal ceroid lipofuscinosis patients. Alterations to biometal homeostasis are known to play a critical role in pathology in Alzheimer's, Parkinson's, Huntington's and motor neuron diseases. We have previously shown accumulation of the biometals, zinc, copper, manganese and cobalt, in CLN6 Merino and South Hampshire sheep at the age of symptom onset. Here we determine the physiological and disease-associated expression of CLN6, demonstrating regional CLN6 transcript loss, and concurrent accumulation of the same biometals in the CNS and the heart of presymptomatic CLN6 mice. Furthermore, increased expression of the ER/Golgi-localized cation transporter protein, Zip7, was detected in cerebellar Purkinje cells and whole brain fractions. Purkinje cells not only control motor function, an early symptomatic change in the CLN6 mice, but also display prominent neuropathological changes in mouse models and patients with different forms of neuronal ceroid lipofuscinoses. Whole brain fractionation analysis revealed biometal accumulation in fractions expressing markers for ER, Golgi, endosomes and lysosomes of CLN6 brains. These data are consistent with a link between CLN6 expression and biometal homeostasis in CLN6 disease, and provide further support for altered cation transporter regulation as a key factor in neurodegeneration.

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Section: Discussionmentioning

confidence: 97%

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

et al. 2013

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“…There is a growing body of evidence for cardiac dysfunction (47)(48)(49) as well as systemic metabolic defects (50,51) in CLN1 disease and other models of NCL. Targeting such additional sites of pathology and secondary disease mechanisms using other therapeutic modalities such as small-molecule drugs or recombinant PPT1 may further extend the life span and improve the quality of life for CLN1 disease patients.…”

Section: Discussionmentioning

confidence: 99%

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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“…Based on our data affected children should routinely be monitored for signs of extra-neural pathology, particularly in heart, liver and skeletal muscle. This will be especially important for children currently enrolled in clinical trials in which only the CNS is being targeted for treatment, particularly since cardiac failure has been documented as the proximate cause of death in at least one CLN2 disease patient 20 . Elevated blood levels of cTn1, ALT activity and CK activity in these children will indicate a need to complement the CNS treatment with systemic treatment that would prevent pathology outside of the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it seems likely that current efforts to treat the disease by exclusively targeting delivery of TPP1 to the CNS will not only fail to prevent disease-related blindness, but will also likely result in the appearance of clinically evident functional impairment of non-neuronal organs, particularly the heart, when lifespan is prolonged due to the delay in neurological sign progression. Indeed, even in a human CLN2 disease patient that had not received any therapeutic intervention, cardiac functional impairment severe enough to be deemed the proximate cause of death has been reported 20 . Cardiac functional impairment and histopathology have also been reported in other forms of NCL in both humans and dogs 19, 21, 28, 29 .…”

Section: Discussionmentioning

confidence: 99%

Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression

et al. 2017

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CLN2 neuronal ceroid lipofuscinosis is a hereditary lysosomal storage disease with primarily neurological signs that results from mutations in TPP1 which encodes the lysosomal enzyme tripeptidyl peptidase-1 (TPP1). Studies using a canine model for this disorder demonstrated that delivery of TPP1 enzyme to the cerebrospinal fluid (CSF) by intracerebroventricular administration of an AAV-TPP1 vector resulted in substantial delays in the onset and progression of neurological signs and prolongation of lifespan. We hypothesized that the treatment may not deliver therapeutic levels of this protein to tissues outside the central nervous system that also require TPP1 for normal lysosomal function. To test this hypothesis, dogs treated with CSF administration of AAV-TPP1 were evaluated for development of non-neuronal pathology. Affected treated dogs exhibited progressive cardiac pathology reflected by elevated plasma cardiac troponin-1, impaired cardiac function, and development of histopathological myocardial lesions. Progressive increases in plasma activity levels of alanine aminotransferase and creatine kinase indicated development of pathology in the liver and muscles. The treatment also did not prevent disease-related accumulation of lysosomal storage bodies in heart or liver. These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system.

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Progressive conduction defects and cardiac death in late infantile neuronal ceroid lipofuscinosis

Cited by 24 publications

References 12 publications

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

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

Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression

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