Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fragile X mental retardation and Friedreich's ataxia were among the first pathogenic trinucleotide repeat disorders to be described in which noncoding repeat expansions interfere with gene expression and cause a loss of protein production. Invoking a similar loss-of-function hypothesis for the CTG expansion causing myotonic dystrophy type 1 (DM1) located in the 3' noncoding portion of a kinase gene was more difficult because DM is a dominantly inherited multisystemic disorder in which the second copy of the gene is unaffected. However, the discovery that a transcribed but untranslated CCTG expansion causes myotonic dystrophy type 2 (DM2), along with other discoveries on DM1 and DM2 pathogenesis, indicate that the CTG and CCTG expansions are pathogenic at the RNA level. This review will detail recent developments on the molecular mechanisms of RNA pathogenesis in DM, and the growing number of expansion disorders that might involve similar pathogenic RNA mechanisms.
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PMID:Pathogenic RNA repeats: an expanding role in genetic disease. 1536 5

Myotonic dystrophy (DM) is the most common adult muscular dystrophy, characterized by autosomal dominant progressive myopathy, myotonia and multiorgan involvement. To date two distinct forms caused by similar mutations have been identified. Myotonic dystrophy type 1 (DM1, Steinert's disease) was described more than 100 years ago and is caused by a (CTG)n expansion in DMPK, while myotonic dystrophy type 2 (DM2) was identified only 18 years ago and is caused by a (CCTG)n expansion in ZNF9/CNBP. When transcribed into CUG/CCUG-containing RNA, mutant transcripts aggregate as nuclear foci that sequester RNA-binding proteins, resulting in spliceopathy of downstream effector genes. Despite clinical and genetic similarities, DM1 and DM2 are distinct disorders requiring different diagnostic and management strategies. DM1 may present in four different forms: congenital, early childhood, adult onset and late-onset oligosymptomatic DM1. Congenital DM1 is the most severe form of DM characterized by extreme muscle weakness and mental retardation. In DM2 the clinical phenotype is extremely variable and there are no distinct clinical subgroups. Congenital and childhood-onset forms are not present in DM2 and, in contrast to DM1, myotonia may be absent even on EMG. Due to the lack of awareness of the disease among clinicians, DM2 remains largely underdiagnosed. The delay in receiving the correct diagnosis after onset of first symptoms is very long in DM: on average more than 5 years for DM1 and more than 14 years for DM2 patients. The long delay in the diagnosis of DM causes unnecessary problems for the patients to manage their lives and anguish with uncertainty of prognosis and treatment.
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PMID:Clinical aspects, molecular pathomechanisms and management of myotonic dystrophies. 2480 43

More than 40 diseases, most of which primarily affect the nervous system, are caused by expansions of simple sequence repeats dispersed throughout the human genome. Expanded trinucleotide repeat diseases were discovered first and remain the most frequent. More recently tetra-, penta-, hexa-, and even dodeca-nucleotide repeat expansions have been identified as the cause of human disease, including some of the most common genetic disorders seen by neurologists. Repeat expansion diseases include both causes of myotonic dystrophy (DM1 and DM2), the most common genetic cause of amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72), Huntington disease, and eight other polyglutamine disorders, including the most common forms of dominantly inherited ataxia, the most common recessive ataxia (Friedreich ataxia), and the most common heritable mental retardation (fragile X syndrome). Here I review distinctive features of this group of diseases that stem from the unusual, dynamic nature of the underlying mutations. These features include marked clinical heterogeneity and the phenomenon of clinical anticipation. I then discuss the diverse molecular mechanisms driving disease pathogenesis, which vary depending on the repeat sequence, size, and location within the disease gene, and whether the repeat is translated into protein. I conclude with a brief clinical and genetic description of individual repeat expansion diseases that are most relevant to neurologists.
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PMID:Repeat expansion diseases. 2932 6