Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic progressive myoclonus epilepsies (PMEs) are clinically characterized by the triad of stimulus sensitive myoclonus (segmental lightning like muscular jerks), epilepsy (grand mal and absences) and progressive neurologic deterioration (dementia, ataxia, and various neurologic signs depending on the cause). Etiologically heterogenous, PMEs are rare and mostly autosomal recessive disorders, with the exception of autosomal dominant dentatorubral-pallidoluysian atrophy and mitochondrial encephalomyopathy with ragged red fibers (MERRF). In the last five years, specific mutations have been defined in Lafora disease (gene for laforin or dual specificity phosphatase in 6q24), Unverricht-Lundborg disease (cystatin B in 21q22.3), Jansky-Bielschowsky ceroid lipofuscinoses (CLN2 gene for tripeptidyl peptidase 1 in 11q15), Finnish variant of late infantile ceroid lipofuscinoses (CLN5 gene in 13q21-32 encodes 407 amino acids with two transmembrane helices of unknown function), juvenile ceroid lipofuscinoses or Batten disease (CLN3 gene in 16p encodes 438 amino acid protein of unknown function), a subtype of Batten disease and infantile ceroid lipofuscinoses of the Haltia-Santavuori type (both are caused by mutations in palmitoyl-protein thiosterase gene at 1p32), dentadorubropallidoluysian atrophy (CAG repeats in a gene in 12p13.31) and the mitochondrial syndrome MERRF (tRNA Lys mutation in mitochondrial DNA). In this review, we cover mainly these rapid advances.
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PMID:Advances in the genetics of progressive myoclonus epilepsy. 1157 33

Clinical picture of neuronal ceroid lipofuscinosis with late infantile onset (LINCL) is characterized by myoclonic seizures and psychomotor regression. We present a case of classic LINCL and reduced cerebrospinal fluid (CSF) pterins in a girl of normal psychomotor development and born to non-consanguineous parents. She first presented with febrile seizures at the age of four. At that time, brain computed tomography finding was normal, but electroencephalogram showed hypsarrhythmia. At the age of five, tremor, generalized ataxia, and motor and mental regression appeared. Brain magnetic resonance imaging showed cerebellar atrophy. Electron microscopy examination showed storage of intracytoplasmic curvilinear inclusions in neurons, fibroblasts, and secretory cells of the skin and rectal mucosa. Tripeptidyl peptidase I (TPP-I) activity in leukocytes was very low (5.4 nmol/h/mg protein; range in homozygote cases of LINCL, 0.4-26.0). Molecular genetic studies showed a homozygous mutation, R208X, in exon 6 of CLN2 gene. CSF analysis revealed very low neopterin (7.3 nmol/L; normal range, 9-30) and biopterin (4.1 nmol/L; normal range, 10-30), reduced homovanillic acid (266 nmol/L; normal range, 211-871), and low homovanillic acid/5-hydroxyindoleacetic acid ratio (1.21; normal ratio, 1.5-3.5). Treatment with L-Dopa/Carbidopa (4 mg/kg) and antiepileptics was introduced, but without significant effect. It seems that low CSF pterins and impaired dopamine turnover are secondary manifestations of classical LINCL caused by homozygous inheritance of the R208X mutation in CLN2 gene.
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PMID:R208X mutation in CLN2 gene associated with reduced cerebrospinal fluid pterins in a girl with classic late infantile neuronal ceroid lipofuscinosis. 1295 Jan 56

Mutations in the CLN2 gene, which encodes a lysosomal serine protease, tripeptidyl-peptidase I (TPP I), result in an autosomal recessive neurodegenerative disease of children, classical late-infantile neuronal ceroid lipofuscinosis (cLINCL). cLINCL is inevitably fatal, and there currently exists no cure or effective treatment. In this report, we provide the characterization of the first CLN2-targeted mouse model for cLINCL. CLN2-targeted mice were fertile and apparently healthy at birth despite an absence of detectable TPP I activity. At approximately 7 weeks of age, neurological deficiencies became evident with the onset of a tremor that became progressively more severe and was eventually accompanied by ataxia. Lifespan of the affected mice was greatly reduced (median survival, 138 d), and extensive neuronal pathology was observed including a prominent accumulation of cytoplasmic storage material within the lysosomal-endosomal compartment, a loss of cerebellar Purkinje cells, and widespread axonal degeneration. The CLN2-targeted mouse therefore recapitulates much of the pathology and clinical features of cLINCL and represents an animal model that should provide clues to the normal cellular function of TPP I and the pathogenic processes that underlie neuronal death in its absence. In addition, the CLN2-targeted mouse also represents a valuable model for the evaluation of different therapeutic strategies.
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PMID:A mouse model of classical late-infantile neuronal ceroid lipofuscinosis based on targeted disruption of the CLN2 gene results in a loss of tripeptidyl-peptidase I activity and progressive neurodegeneration. 1548 30

The neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases characterized by progressive neuropathy and the accumulation of autofluorescent cytoplasmic granules. Clinical signs of a new canine NCL began in a 9-month-old male Dachshund with vomiting, mental dullness, and loss of previously learned commands and rapidly progressed to include disorientation, ataxia, visual deficits, generalized myoclonic seizures, and death at 12 months of age. Neurons throughout the CNS contained autofluorescent storage granules that stained with periodic acid-Schiff and Luxol fast blue stains. Electron microscopy revealed that the storage granule contents consisted of curvilinear-appearing material characteristic of human late infantile NCL caused by CLN2 mutations. Nucleotide sequence analysis of canine TPP1, the ortholog of human CLN2, revealed a single nucleotide deletion in exon 4 which predicted a frame shift with a premature stop codon. Brain tissue from the affected dog lacked detectable activity of the tripeptidyl-peptidase enzyme encoded by TPP1, whereas the specific activities of 15 other lysosomal enzymes were higher than those in the brains of three control dogs. The affected Dachshund was homozygous for the mutant c.325delC allele, his sire and dam were heterozygotes, and 181 unrelated dogs, including 77 Dachshunds, were all homozygous for the wild-type allele. A DNA assay that detects the mutant allele will help Dachshund breeders avoid producing affected puppies in future generations. Furthermore, this Dachshund NCL may prove to be a useful model for studying the pathogenesis of neurodegeneration in human late infantile NCL and for evaluating novel therapeutic interventions for this disease.
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PMID:A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis. 1662 47

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are recessively inherited neurodegenerative disorders that affect humans and other animals, characterised by brain atrophy and the accumulation of lysosome derived fluorescent storage bodies in neurons and most other cells. Common clinical signs include blindness, ataxia, dementia, seizures and premature death. The associated genes for six different human forms have been identified (CLN1, CLN2, CLN3, CLN5, CLN6 and CLN8), and three other human forms suggested (CLNs 4, 7 and 9). A form of NCL in Australian Devon cattle is caused by a single base duplication (c.662dupG) in bovine CLN5. This mutation causes a frame-shift and premature termination (p.Arg221GlyfsX6) which is predicted to result in a severely truncated protein, analogous to disease causing mutations in human Finnish late infantile variant NCL (CLN5), and a simple genetic diagnostic test has been developed. The symptoms and disease course in cattle also matches CLN5. Only one initiation site was found in the bovine gene, equivalent to the third of four possible initiation sites in the human gene. As cattle are anatomically and physiologically similar to humans with a human-like central nervous system and easy to maintain and breed, they provide a valuable alternative model for CLN5 studies.
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PMID:Neuronal ceroid lipofuscinosis in Devon cattle is caused by a single base duplication (c.662dupG) in the bovine CLN5 gene. 1693 76

The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are a group of fatal recessively inherited neurodegenerative diseases of humans and animals characterised by common clinical signs and pathology. These include blindness, ataxia, dementia, behavioural changes, seizures, brain and retinal atrophy and accumulation of fluorescent lysosome derived organelles in most cells. A number of different variants have been suggested and seven different causative genes identified in humans (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8 and CTSD). Animal models have played a central role in the investigation of this group of diseases and are extremely valuable for developing a better understanding of the disease mechanisms and possible therapeutic approaches. Ovine models include flocks of affected New Zealand South Hampshires and Borderdales and Australian Merinos. The ovine CLN6 gene has been sequenced in a representative selection of these sheep. These investigations unveiled the mutation responsible for the disease in Merino sheep (c.184C>T; p.Arg62Cys) and three common ovine allelic variants (c.56A>G, c.822G>A and c.933_934insCT). Linkage analysis established that CLN6 is the gene most likely to cause NCL in affected South Hampshire sheep, which do not have the c.184C>T mutation but show reduced expression of CLN6 mRNA in a range of tissues as determined by real-time PCR. Lack of linkage precludes CLN6 as a candidate for NCL in Borderdale sheep.
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PMID:A missense mutation (c.184C>T) in ovine CLN6 causes neuronal ceroid lipofuscinosis in Merino sheep whereas affected South Hampshire sheep have reduced levels of CLN6 mRNA. 1704 13

The neuronal ceroid lipofuscinoses are a group of dominant neurodegenerative, progressive, and fatal disorders characterized clinically by myoclonic epilepsy, in variable association with dementia, ataxia, and visual loss. Neuronal ceroid lipofuscinoses were classified into several phenotypes according to their age of onset: infantile, late infantile, juvenile, and adult. A specific phenotype was named "northern epilepsy," and its onset of signs occurs between ages 5-10 years. Deficiencies in the lysosomal activity of two specific enzymes were found in several types of neuronal ceroid lipofuscinosis: palmitoyl-protein thioesterase 1, encoded by the CLN1 gene, and tripeptidyl-peptidase 1, encoded by the CLN2 gene. Several mutations in CLN2 were described previously. We describe a novel mutation in two siblings of Israeli-Arab origin, with a clinical picture compatible with late infantile neuronal ceroid lipofuscinosis. Both siblings were found to be homozygous for a deletion of a C nucleotide at position 775 in exon 7 of the CLN2 gene. These findings have implications for the worldwide epidemiology of neuronal ceroid lipofuscinosis.
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PMID:Late infantile neuronal ceroid lipofuscinosis: a new mutation in Arabs. 1974 52

Clinical findings, pathological features and tripeptidyl peptidase 1 (TPP1) activity and genetic mutation analysis data of nine patients affected with the late-infantile form of neuronal ceroid lipofuscinoses (LINCL) in China are systematically reviewed with long-term follow-up. The patients were enrolled if curvilinear bodies were found on lymphocyte, skin or muscle specimens' examination, and/or reduction of tripeptidyl peptidase 1 (TPP1) activity were detected. CLN2 gene mutation were tested in five patients. The patients have onset age of 2-3.5 years, and most of them initially present partial seizure, and then progressed to deteriorated mental function, refractory myoclonic seizures, impaired vision, and ataxia with cerebellar atrophy. Discrete small vacuolated lymphocytes are found in 5-10% lymphocytes in 5 patients examined. Curvilinear bodies were found in vacuolated lymphocytes, in skin and muscle tissues. Tripeptidyl peptidase 1 (TPP1) activities are reduced in 5 patients with different CLN2 gene mutation. Detection of vacuolated lymphocytes may be a screen method for LINCL, ultrastructural examination of lymphocytes, combined with TPP1 activity assay, allowing for a definite and faster diagnosis and classification with minimal invasion.
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PMID:Clinical study in Chinese patients with late-infantile form neuronal ceroid lipofuscinoses. 2224 69

Late infantile neuronal ceroid lipofuscinosis (Jansky-Bielchowsky disease) is a rare disease caused by mutations in the CLN2 gene. The authors report the clinical outcome and correlate with genotype in 12 Spanish patients with this disease. Psychomotor regression, epilepsy, and other clinical symptoms/signs were assessed. Age at onset of clinical symptoms ranged from 18 months to 3.7 years, and they included delayed speech and simple febrile seizures followed by epilepsy. Partial seizures and myoclonic jerks occurred at an earlier age (median 3.4 and 3.7 years, respectively) than ataxia and cognitive decline (median 4 years). Clinical regression was initiated by loss of sentences (median 3.7 years) followed by loss of walking ability and absence of language (median 4.5 years). Patients showed blindness and lost sitting ability at similar age (median 5 years). The authors report 4 novel mutations in the CLN2 gene. This study provides detailed information about the natural history of this disease.
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PMID:Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. 2283 78

Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl-peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl-peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype-phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.
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PMID:Autosomal recessive spinocerebellar ataxia 7 (SCAR7) is caused by variants in TPP1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (CLN2 disease). 2341 7


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