A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571 + 1G >>> A) leading to excision of exon 3
Tony FrugierNadia L. MitchellImke TammenPeter J. HouwelingD.G. ArthurGraham W. KayOtto P. van DiggelenR.D. JollyDavid N. Palmer
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Neuronal ceroid lipofuscinosis
Substitution (logic)
splice
Batten disease
An inherited neurological disease of sheep was characterized by the intracellular accumulation of autofluorescent lipopigments in neurones and a wide variety of other cells within the body. The staining, fluorescent, ultrastructural and physical characteristics of the storage material were similar to those found in a heterogeneous group of storage diseases of children known as Batten's disease or the ceroid-lipofuscinoses. The ovine disease did not exactly fit any of the main human entities, but had features in common with both the late infantile and juvenile forms. It was concluded that this was a useful model for studying the pathogenesis of this type of storage disease and for therapeutic trials. A flock of sheep is maintained for this purpose.
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To report a case of Batten disease due to a previously unreported mutation in PPT1.A 9-year-old girl presented with classic clinical findings of Batten Disease.Genetic testing for the mutations in the most common Batten disease gene, CLN3, was negative. Evaluation of a panel of genes known to be implicated in neuronal ceroid lipofuscinoses revealed disease causing mutations in PPT1, one of which was novel.Mutations in PPT1 typically cause the infantile form of neuronal ceroid lipofuscinosis. Clinical diagnosis of the juvenile form of neuronal ceroid lipofuscinosis, Batten disease, should still be considered in cases with negative CLN3 genetic testing. Batten disease can occur due to genetic heterogeneity. Testing of other members of the neuronal ceroid lipofuscinosis gene family can lead to confirmation of the correct diagnosis.
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Neuronal ceroid lipofuscinosis (NCL) is a hereditary lysosomal storage disease with progressive brain neurodegeneration. Mutations in ceroid lipofuscinosis neuronal protein 5 (CLN5) cause CLN5 disease, a severe condition characterized by seizures, visual failure, motor decline, and progressive cognitive deterioration. This study aimed to identify causative gene variants in Pakistani consanguineous families diagnosed with NCL.
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The neuronal ceroid-lipofuscinoses are a group of diseases that are characterized by progressive neuroretinal symptomatology, progressive accumulation of autofluorescing waxy lipopigments (ceroid-lipofuscin) within the brain and other tissues, and cerebral atrophy. Juvenile neuronal ceroid-lipofuscinosis, or Batten disease, is a form of neuronal ceroid-lipofuscinosis that is characterized by onset of neuroretinal symptoms between 4 and 10 years. Juvenile neuronal ceroid-lipofuscinosis is the most common type of neuronal ceroid-lipofuscinosis in the United States and Europe and is inherited as an autosomal recessive genetic disorder. Research in the last decade has led to the identification of the responsible gene for juvenile neuronal ceroid-lipofuscinosis, which is designated as CLN3. CLN3 is located on chromosome 16p11.2-12.1. The major mutation is a 1.02 kb deletion, which removes exons 7 and 8. Both homozygotic and heterozygotic deletions at the CLN3 gene site have been associated with the clinical syndromes of juvenile neuronal ceroid-lipofuscinosis. We report a possible atypical case of neuronal ceroid-lipofuscinosis, an infant, who presented at 5 months of age with a lack of developmental milestones, poor vision, severe retinopathy, intractable seizures, and progressive cerebral atrophy. Extensive laboratory investigations, including thorough metabolic evaluations, were unremarkable except for neuroimaging studies, electroencephalography, and electroretinography, all of which showed abnormalities confirming both cerebral and retinal degeneration. Although skin and conjunctival biopsies did not show classic fingerprint cytosomes by electron microscopic study, which characterize juvenile neuronal ceroid-lipofuscinosis, a diagnosis of an atypical form of juvenile neuronal ceroid-lipofuscinosis was suspected on the basis of the clinical picture. The retinal abnormalities, surprisingly, were those believed to be diagnostic of juvenile-onset neuronal ceroid-lipofuscinosis, or Batten disease. Subsequently, a heterozygous mutation for the common 1.02 kb deletion characteristic of juvenile neuronal ceroid-lipofuscinosis was established. ( J Child Neurol 2004;19:42—46).
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The infantile form of neuronal ceroid lipofuscinosis (ie, infantile Batten disease) is the most rapidly progressing type and is caused by an inherited deficiency in the lysosomal enzyme palmitoyl protein thioesterase 1. The absence of enzyme activity leads to progressive accumulation of autofluorescent material in many cell types, particularly neurons of the central nervous system. Clinical signs of infantile neuronal ceroid lipofuscinosis appear between 6 months and 1 year of age and include vision loss, cognitive decline, motor deficits, seizures, and premature death, typically by 3 to 5 years of age. There is currently no effective treatment. However, preclinical experiments in the murine model of infantile neuronal ceroid lipofuscinosis have shown that gene therapy, enzyme replacement, stem cell transplantation, and small-molecule drugs, alone or in combination, can significantly slow disease progression. A more thorough understanding of the underlying pathogenesis of infantile neuronal ceroid lipofuscinosis will identify new therapeutic targets.
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The human hereditary ceroid-lipofuscinoses are a group of autosomal recessively inherited diseases characterized by massive accumulations of autofluorescent lysosomal storage bodies in the cells of many tissues and by neuronal degeneration throughout the central nervous system. There are a number of clinically and genetically distinct forms of ceroid-lipofuscinosis, the most common of which is the juvenile type, also known as Batten disease and CLN3. To study the mechanisms that lead to pathology in CLN3 and to evaluate potential therapies, a mouse model has been generated by targeted disruption of the mouse ortholog of the CLN3 gene (Cln3). As in affected humans, mice homozygous for the disrupted Cln3 allele show accumulation of autofluorescent storage material in neurons and other cell types. The storage material consists of membrane-bounded intracellular inclusions with ultrastructural features typical of the ceroid-lipofuscinoses. The accumulation of this storage material validates the Cln3 knockout mice as a model for the human disorder.
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The word Batten which it seems very rare and recessivene urder active disease which mainy found in children .Generally it grws with childhood which is the most common form of a group of diseasorder called as neuronal ceroid lipofuscinoses. In the field of medicine it is also called as Neuronal Ceroid Lipofuscinosis (NCL).The major difference between Batten and NCL are: Progressivness, age of onset, side effect, pathogenic response, mode of action to receptor etc.It is a genetic diseasorder which generay deveped during childhood The maximum risk factor is in between the age 5 to10.At eary stage the major symptoms are seizure and eye prbelms The earliest symptoms range from being fairly obvious, with a child experiencing seizures or vision problems, through to subtle signs such as mild personality changes or clumsiness. Now a day by through the development of many animal model and by the help of new technology gradually we controll over the disease.
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