The neuronal ceroid‐lipofuscinoses

Abstract

The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy. Ten genes have been identified so far that result in an NCL (CLN1-10). The most common forms are CLN1, CLN2, and CLN3, which were previously known as Infantile, Late-Infantile, and Juvenile NCL's, respectively. CLN1 and CLN2 result from mutations in soluble lysosomal enzymes palmitoyl-protein thioesterase (PPT) and tripeptidyl peptidase 1 (TPP1), which can be measured in white blood cells for clinical diagnosis. Molecular diagnostic testing is routinely available for CLN1, CLN2, and CLN3. Sequencing of other NCL genes may be required to establish a diagnosis when the common forms are ruled out. The pathogenesis of NCL neuronal loss resulting from loss of function of any of the NCL gene products remains unknown and no treatment options are presently available.

Possible involvement of the cerebellum in motor-function impairment in progranulin-deficient mice

“…However, two NCL cases, each involving homozygous mutations in GRN, have been reported recently [11]. The major phenotypes of NCL include visual loss, seizures, early death, and loss of motor and cognitive function [25]. In the present study, HZ mice did not show evident impairment in motor function on the rotarod test, whereas homozygous KO mice failed to have normal motor function.…”

Systemic Diseases Associated with Retinal Dystrophies

“…They result from the accumulation of autofluorescent lipofuscinlike material in lysosomes, which can be found in multiple tissues; however, tissue destruction is almost entirely confined to the central nervous system. 49 Conventionally, four types of NCL have been described based on the age of onset. In the juvenile type (JNCL), rapid progressive visual loss to complete blindness is most prominent and often the presenting feature.…”

“…ANCL is relatively rare, with an onset of symptoms in the fourth decade or later, with dementia and progressive motor dysfunction. 49 Currently, there is no treatment available for NCLs. Early diagnosis may improve anticipatory care and remedial management of signs and symptoms, including seizures.…”

“…Early diagnosis may improve anticipatory care and remedial management of signs and symptoms, including seizures. 49 This phenotypic classification of NCLs was derived around 1969, 50 more than 25 years before the first NCL genes were identified. NCLs are autosomal recessive conditions and are now known to be genetically heterogeneous.…”

Detection of mis-folded protein aggregates from a clinical perspective

“…While the exact nature and relevance of protein misfolding is sometimes debated, for instance the relevance and nature of Huntingtin (Htt) aggregation in HD [8,9], there is agreement that misfolded, mis-aggregated or wrongly processed proteins are the unifying feature of these conditions Learning and memory impairment, anterograde amnesia, executive dysfunction, depression, apathy, irritability, suicidality, loss of impulse control, dementia, PD, dysarthria [151] Atrophy of frontal and temporal cortices and medial temporal lobe, atrophy of the thalamus, hypothalamus and mammillary bodies. Thinning of the corpus callosum, pallor of the substantia nigra and locus coeruleus, cavum septum pellucidum [151] Lytico-Bodig disease Tau [153] Acquired Global dementia, progressive aphasia, gaze palsy, parkinsonism, progressive supranuclear palsy [153] Poorly understood, neurofibrillary tangles are found in the brain [153] Continued on the next page [155] Focal lesion of the leptomeninges and underlying cerebral cortex [155] Neuronal Ceroid Lipofuscinosis ATP synthase subunit c, saposin A, saposin D [156] Congenital, monogenic, subtypes exists [157] Hypotonia, myoclonic jerks, generalized epileptic seizures, developmental regression, optic atrophy, macular degeneration, spastic tetraplegia, blindness, severe and constant microcephaly, and pharmaco-resistant epileptic seizures, myoclonia, ataxia, extrapyramidal signs [156] Cerebellar and cortical atrophy, loss of pyramidal neurons and Purkinje cells, reactive astrogliosis [156] Argyrophilic grain disease Tau [158] Acquired; old age [158] Cognitive decline, dementia, mood imbalance, personality changes, behavioural abnormalities [158] Argyrophilic grains in trans entorhinal cortex, entorhinal cortex, hippocampus, presubiculum, temporal cortex, orbitofrontal cortex, insular cortex, and amygdala [158] [10]. Full recovery has not yet been observed in any patient after damage to nerve tissue has begun.…”