Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses

Mole, Sara; Williams, Ruth; Goebel, Hans H.

doi:10.1007/s10048-005-0218-3

Cited by 274 publications

(269 citation statements)

References 158 publications

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“…Progressive accumulation of AFSM within cell bodies is pathognomic of the NCLs (1,9). This provides a useful diagnostic readout of the extent of pathology.…”

Section: Progressive Accumulation Of Autofluorescent Storage Materials Inmentioning

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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“…Progressive accumulation of AFSM within cell bodies is pathognomic of the NCLs (1,9). This provides a useful diagnostic readout of the extent of pathology.…”

Section: Progressive Accumulation Of Autofluorescent Storage Materials Inmentioning

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).…”

mentioning

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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“…Affected children progressively develop blindness, motor degeneration, epilepsy, and dementia, eventually reaching total dependency and premature death (Kousi, Lehesjoki, & Mole, 2012; Mole, Williams, & Goebel, 2005, 2011). There are no effective treatments.…”

Section: Introductionmentioning

confidence: 99%

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

et al. 2018

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IntroductionThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. Forms associated with mutations in two of these, CLN5 and CLN6, are being investigated in well‐established sheep models. Brain atrophy leading to psychomotor degeneration is among the defining features, as is regional progressive ossification of the inner cranium. Ongoing viral‐mediated gene therapy trials in these sheep are yielding encouraging results. In vivo assessment of brain atrophy is integral to the longitudinal monitoring of individual animals and provides robust data for translation to treatments for humans.MethodsComputed tomography (CT)‐based three‐dimensional reconstruction of the intracranial volume (ICV) over time reflects the progression of cortical brain atrophy, verifying the use of ICV measurements as a surrogate measure for brain size in ovine NCL.ResultsICVs of NCL‐affected sheep increase for the first few months, but then decline progressively between 5 and 13 months in CLN5−/− sheep and 11–15 months in CLN6−/−sheep. Cerebral ventricular volumes are also increased in affected animals. To facilitate ICV measures, the radiodensities of ovine brain tissue and cerebrospinal fluid were identified. Ovine brain tissue exhibited a Hounsfield unit (HU) range of (24; 56) and cerebrospinal fluid a HU range of (−12; 23).ConclusionsComputed tomography scanning and reconstruction verify that brain atrophy ovine CLN5 NCL originates in the occipital lobes with subsequent propagation throughout the whole cortex and these regional differences are reflected in the ICV loss.

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“…[1][2][3] Patients with JNCL experience retinal degeneration, seizures, severe motor and cognitive deterioration, and shortened life expectancy. 1 Clinically, this group of disorders is classified by age at disease onset, 2,4 with genetic heterogeneity with 14 causative genes identified to date (CLN1 through CLN14).…”

mentioning

confidence: 99%

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

Hull

Arno

et al. 2017

JAMA Ophthalmol

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IMPORTANCE Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported.OBJECTIVE To provide detailed clinical, electrophysiologic, structural, and molecular genetic findings in nonsyndromic inherited retinal degenerations associated with CLN3 mutations. DESIGN, SETTING, AND PARTICIPANTSA multi-institutional case series of 10 patients who presented with isolated nonsyndromic retinal disease and mutations in CLN3. Patient ages ranged from 16 to 70 years; duration of follow-up ranged from 3 to 29 years. MAIN OUTCOMES AND MEASURESLongitudinal clinical evaluation, including full ophthalmic examination, multimodal retinal imaging, perimetry, and electrophysiology. Molecular analyses were performed using whole-genome sequencing or whole-exome sequencing. Electron microscopy studies of peripheral lymphocytes and CLN3 transcript analysis with polymerase chain reaction amplification were performed in a subset of patients.RESULTS There were 7 females and 3 males in this case series, with a mean (range) age at last review of 37.1 (16-70) years. Of the 10 patients, 4 had a progressive late-onset rod-cone dystrophy, with a mean (range) age at onset of 29.7 (20-40) years, and 6 had an earlier onset rod-cone dystrophy, with a mean (range) age at onset of 12.1 (7-17) years. Ophthalmoscopic examination features included macular edema, mild intraretinal pigment migration, and widespread atrophy in advanced disease. Optical coherence tomography imaging demonstrated significant photoreceptor loss except in patients with late-onset disease who had a focal preservation of the ellipsoid zone and outer nuclear layer in the fovea. Electroretinography revealed a rod-cone pattern of dysfunction in 6 patients and were completely undetectable in 2 patients. Six novel CLN3 variants were identified in molecular analyses.CONCLUSIONS AND RELEVANCE This report describes detailed clinical, imaging, and genetic features of CLN3-associated nonsyndromic retinal degeneration. The age at onset and natural progression of retinal disease differs greatly between syndromic and nonsyndromic CLN3 disease, which may be associated with genotypic differences.

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Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses

Cited by 274 publications

References 158 publications

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

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

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses

Detailed Clinical Phenotype and Molecular Genetic Findings in CLN3-Associated Isolated Retinal Degeneration

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