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Query: UMLS:C0025362 (mental retardation)
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Herein we describe the molecular and clinical findings in a North American Caucasian family with dentatorubral-pallidoluysian atrophy (DRPLA). These patients all presented with an autosomal dominant neurodegenerative disorder characterized by a variable combination of clinical symptoms including seizures, ataxia, dementia, choreiform movements, mental retardation, and psychiatric disease. Neuroradiologic findings in the index case revealed deep subcortical white matter changes on magnetic resonance imaging. Prior to referral, the family carried a diagnosis of Huntington's disease (HD). Subsequent direct molecular testing for HD failed to identify the HD expansion mutation in affected individuals. Molecular testing for DRPLA, however, demonstrated the presence of the recently characterized DRPLA expansion mutation in all affected individuals. The size of the expansion correlated with the age of onset of clinical symptoms. As DRPLA has rarely been reported in North American and European populations, the molecular confirmation of DRPLA in this family provides support for the hypothesis that DRPLA may not be as geographically restricted as once thought.
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PMID:Molecular and clinical findings in a family with dentatorubral-pallidoluysian atrophy. 784 69

Expansion of trinucleotide repeats is now recognized as a major cause of neurological disease. At least seven disorders result from trinucleotide repeat expansion: X-linked spinal and bulbar muscular atrophy (SBMA), two fragile X syndromes of mental retardation (FRAXA and FRAXE), myotonic dystrophy, Huntington's disease, spinocerebellar ataxia type 1 (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). The expanded trinucleotide repeats are unstable, and the phenomenon of anticipation, i.e., worsening of disease phenotype over successive generations, correlates with increasing expansion size. In this review, we compare the clinical and molecular features of the trinucleotide repeat diseases, which may be classified into two types. Fragile X and myotonic dystrophy are multisystem disorders usually associated with large expansions of untranslated repeats, while the four neurodegenerative disorders, SBMA, Huntington's disease, SCA1, and DRPLA, are caused by smaller expansions of CAG repeats within the protein coding portion of the gene. CAG repeats encode polyglutamine tracts. Polyglutamine tract expansion thus appears to be a common mechanism of inherited neurodegenerative disease. Although polyglutamine tract lengthening presumably has a toxic gain of function effect in the CAG trinucleotide repeat disorders, the basis of this neuronal toxicity remains unknown.
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PMID:Trinucleotide repeat expansion in neurological disease. 799 66

Anticipation refers to the progressively earlier onset and increase in disease severity in successive generations. We studied four families with hereditary dentatorubral-pallidoluysian atrophy (DRPLA), a neurodegenerative disease, and anticipation was present in the mode of inheritance. In subsequent generations DRPLA shows an earlier onset and more severe as well as additional symptoms. Older onset patients suffer from cerebellar ataxia with or without dementia, whereas younger onset patients present as progressive myoclonus epilepsy syndrome, which consists of mental retardation, dementia, and cerebellar ataxia as well as epilepsy and myoclonus. Anticipation with paternal transmission was significantly greater than with maternal transmission.
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PMID:Anticipation in hereditary dentatorubral-pallidoluysian atrophy. 800 97

Two sisters were presented, 16 years old and 12 years old, who showed similar clinical courses. They had had mental retardation since early childhood, and then ataxia began. They suffered from astatic and tonic seizures from early school age, which gradually evolved to intractable epilepsies. Spasticity progressed, and they deteriorated both physically and mentally. They revealed photo-sensitivity; convulsions were induced by the flickering of light. They were attacked by myoclonic seizures as well as choreoathetosis, and became bedridden by the latter part of the elementary school age. There were no fruitful results of any kind from the laboratory examinations for metabolic disorders. EEG showed that the epileptic seizure discharges were induced by photic stimulation; there were frequent 3-4 Hz diffuse spike-and-wave short bursts during waking and sleep periods. MRI findings of the elder sister at the age of 16 revealed remarkable diffuse brain atrophy. Gene analysis showed abnormally enlarged DNA fragments localized on the short arm of chromosome 12. This meant expanded CAG trinucleotide repeats. The younger sister died at the age of 12 years. Autopsy findings revealed degeneration of both dentatorubral and pallidoluysian pathways. There were especially remarkable gliosis and neuronal cell loss in the outer segment of globus pallidus, and moderate neuronal cell loss and typical grumose degeneration in the dentate nucleus. The diagnosis of juvenile-type hereditary dentatorubral-pallidoluysian atrophy was compatible with the pathologic findings. This diagnosis will be made possible before death through the understanding of the clinical symptoms and molecular genetics.
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PMID:[Sisters with early onset hereditary dentatorubral-pallidoluysian atrophy of childhood--DNA analysis and clinicopathological findings]. 853 13

The clinical, genetic, and neuroradiologic characteristics of dentatorubral-pallidoluysian atrophy (DRPLA) are delineated in six patients from three generations of a Japanese family. The clinical characteristics of the disease varied, the age at onset depending on patients with juvenile-onset were characterized by myoclonus, epilepsy, and mental retardation whereas cerebellar ataxia, choreoathetosis, and dementia were typical of adult- and senile-onset patients. All affected individuals showed one expanded allele with the repeat number of CAG at the DRPLA locus, ranging from 58 to 82, and a normal allele, ranging from 10 to 21. The most severely affected patient, a case of maternal transmission and with the largest allele, became bedridden in a vegetative state by age 12. On the CT and MRI, varying degrees of brain atrophy were present in all patients. T2-weighted MRI in patients with senile-onset showed symmetric high-signal lesions in the cerebral white matter, globus pallidus, thalamus, midbrain, and pons. However, MRI in younger patients revealed no such lesions and CT failed to demonstrate lesions in the globus pallidus and brain stem. Thus, intrafamilial heterogeneity of DRPLA was also evident on MRI. High-signal lesions involving both, subcortical white matter and thalamus may be characteristics of senile-onset patients and may correlate with their dementia.
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PMID:Dentatorubral-pallidoluysian atrophy (DRPLA): clinical, genetic, and neuroradiologic studies in a family. 858 78

Trinucleotide repeat expansion is increasingly recognized as a cause of neurogenetic diseases. To date, seven diseases have been identified as expanded repeat disorders: the fragile X syndrome of mental retardation both FRAXA and FRAXE loci), myotonic dystrophy, X-linked spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type I, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. All are neurologic disorders, affecting one or more regions of the neuraxis. Moreover, five of the seven (the last five above) are progressive neurodegenerative disorders whose strikingly similar mutations suggest a common mechanism of neuronal degeneration. In this article we discuss specific characteristics of each trinucleotide repeat disease, review their shared clinical and genetic features, and address possible molecular mechanisms underlying the neuropathology in each disease. Particular attention is paid to the neurodegenerative diseases, all of which are caused by CAG repeats encoding polyglutamine tracts in the disease gene protein.
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PMID:Trinucleotide repeats in neurogenetic disorders. 883 37

The catalog of genetic diseases whose mutational mechanisms are based on the expansion of nucleotide triplets includes 8 disorders classified in terms of type of triplet sequence and the mechanism by which the mutation manifests clinically. To date there are 3 groups. The first is made up of several mental retardation syndromes linked to fragility in the X chromosome (FRAXA, FRAXE, FRAXF, FRA16), with CGG type triplets and large growth expansions located close to a CpG island whose methylation determines degree of chromosome fragility as well as the size of expansion. The second group encompasses diseases arising from CAG triplets. Examples are spinal bulbar atrophy, Huntington's chorea (HC), type 1 dominant cerebellar ataxia (DCA1), dentatorubral-pallidoluysian atrophy (DRPLA) and Machado-Joseph's disease. In this group the expansion codes a polyglutamate residue that gives rise to clinical manifestations by way of functional gain. Myotonic dystrophy (MD) remains in a separate group, with large-size expansion but no chromosomal fragility, and clinical manifestations in multiple systems. All entities encompass phenotypic variation or tendency to inter-generational growth of the expanded fragment that triggers the anticipation phenomenon to varying degrees--greater for some diseases (MD) in cases of maternal transmission and for others (DCA1, HC and DRPLA) when transmission is paternal. The mechanisms by which expansions occur is unknown but the decisive element in some entities may be failure to correct errors in DNA duplication and errors in the integrity of the repeated sequence. We review the difficulties inherent in establishing correlations between genotype and phenotype and in providing genetic counseling.
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PMID:[Diseases due to instability of DNA]. 883 55

We described a family of dentatorubral-pallidoluysian atrophy (DRPLA). The mother presented with cerebellar ataxia at 35 years of age and thereafter her neurological symptoms became exacerbated. Her daughter had mental retardation during the preschool period and epilepsy at 10 years. Her son presented with epilepsy at 14 years. Their clinical phenotypes demonstrated maternal anticipation in this family. Genetical analysis of their DNA revealed CAG repeat expansion of the DRPLA gene, the number of which was 51 (mother), 65 (her daughter), and 53 (her son). MR imaging showed disappearance of T, shortening of the red nucleus in the mother and her daughter in contrast to the normal appearance in her son. MR imaging was effective in evaluating neuropathological changes in the DRPLA patients.
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PMID:[A family of dentatorubral-pallidoluysian atrophy: clinical and neuroradiologic studies]. 924 89

The human genome has many nucleotide repeat sequences. These range from a single repeating base to entire duplicated genes. Expansion of repeating triplets of nucleotides in the genome has recently been associated with nine degenerative and developmental neuropsychiatric diseases: fragile X syndrome, fragile X-linked mental retardation, myotonic dystrophy, Friedreich's ataxia, spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. These diseases are all conditions of the central nervous system; in all of them, the inheritance pattern usually exhibits the phenomenon of anticipation (defined as progressively earlier age of onset or a worsening disease severity over successive generations), and the severity of the phenotypic expression and penetrance appears to be related to the extent of the triplet expansion. Identification of this pathological genetic phenomenon solves several of the mysteries that surrounded these conditions but raises many important questions regarding pathogenic mechanisms that may be shared. There is some indication that triplet expansions may also underlie other neuropsychiatric conditions such as schizophrenia or bipolar disorder.
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PMID:Triplet repeat gene sequences in neuropsychiatric diseases. 938 23

Pathology and associated clinical symptoms of hereditary dentatorubral-pallidoluysian atrophy (H-DRPLA) which was established as a new inherited neurodegenerative disease in 1982 are described. Obligatory lesions in the central nervous system combine with degeneration of the dentatorubral and pallidoluysian pathway, and occasional degenerative lesions are found in the cerebral white matter, putamen, Goll's nucleus of the medulla oblongata, and lateral corticospinal and Goll's tract of the spinal cord. The main clinical symptoms are myoclonus, epilepsy, dementia or mental retardation, cerebellar ataxia and choreoathetosis. Furthermore, newly developing aspects in the pathology of H-DRPLA following the discovery of the gene locus of H-DRPLA in 1994 are briefly described.
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PMID:Hereditary dentatorubral-pallidoluysian atrophy. 1103 86


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