PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “trinucleotide repeat disorders”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 91 records · Page 5Linked to original sources
PubMed2006

A biologic model to study the genetics of psychotic, mood, and anxiety disorders: the velocardiofacial syndrome.

Recent advances in molecular genetics have led to new insights on the velocardiofacial syndrome (VCFS). Most patients have a large deletion on one copy of chromosome 22 (encompassing up to 30 genes), which can be confirmed with genetic testing. A wide spectrum of psychiatric symptoms has been reported in patients with VCFS, including schizophrenia and bipolar disorder. Preliminary studies of candidate genes from the deletion region suggest that allelic differences may increase susceptibility to psychiatric disorders, but these studies await replication. Mouse models with genetically engineered deletions have the potential to isolate the genes associated with VCFS neuropsychiatric symptoms. VCFS is likely to represent the deficiency of several genes with complex interactions. Further psychiatric research is warranted to delineate more comprehensively the neuro-psychiatric phenotype associated with VCFS. Accurate psychiatric diagnosis will better inform and advance ongoing genetic research.

Alleles↗
PubMed2026

Loss of interruption in the HTT CAG repeat is associated with somatic expansion and loss of medium spiny neurons in Huntington's disease.

Synonymous loss-of-interruption variants in the expanded CAG repeat sequence of Huntingtin (HTT) accelerate the clinical onset and progression of Huntington's disease (HD). Medium spiny neurons (MSNs) are gradually lost in HD and undergo selective somatic CAG expansion, but it is unclear how somatic expansion relates to MSN pathology. Here, we show that MSNs with large (111-150 CAG) and very large (>150 CAG) somatic expansions are rare in early manifest HD but accumulate in proportion with duration of disease. In patients with the deleterious CAG-CCG loss-of-interruption (CAG-CCG LOI) modifier, the proportion of MSNs with large and very large expansions is increased ∼5-fold despite reduced small somatic expansions in blood, and caudate MSN counts are reduced. Our findings suggest that increased somatic CAG expansion contributes to accelerated striatal MSN pathology and onset of HD but that MSNs with very large genomic CAG expansions can persist among surviving neurons of the HD brain.

Huntington’s disease↗
PubMed1996

Clinical implications of unstable DNA repeat sequences.

In this article we review the clinical and genetic features characteristic of a number of diseases recently explained by a novel genetic mechanism: unstable segments of the genome containing trinucleotide repeat sequences. Disorders identified to date are mostly progressive, and display unusual inheritance patterns such as anticipation. Anticipation is manifested as an earlier age at onset or a more severe phenotype in later generations of a family, and can be correlated to an increased repeat expansion size. Thus in later generations the disease onset can take place in childhood whereas affected individuals in earlier generations had only adult symptoms. Paediatric cases of typically adult disorders have been shown to be caused by exceptionally long repeat sequences. Anticipation has been observed in a number of disorders not yet identified at the molecular level. Such disorders could be caused by repeat expansions, and are presently subject to intense research efforts. If repeat sequence expansions are related to these disorders, the longest expansions should be seen in the childhood cases, making these the optimal cases to study. Various DNA-based methods have been developed for the detection of these mutations, making possible preclinical and prenatal diagnostics as well as detection of novel expansions.

Adult↗
PubMed2004

Rate and correlates of weight change in Huntington's disease.

OBJECTIVE: To determine the rate and correlates of weight change in a large, well characterised sample of patients with Huntington's disease followed at 44 sites by the Huntington Study Group. PARTICIPANTS AND METHODS: Weight change was assessed in 927 adults with a definite diagnosis of Huntington's disease who were followed prospectively for (mean (SD)) 3.4 (1.4) years. The unified Huntington's disease rating scale was used to assess weight, motor dysfunction (including chorea and dystonia), depressive symptoms, and functional decline. RESULTS: Random effects modelling determined that patients gained an average of 0.11 (1.7) kg/year and their chorea scores increased by 0.36 (0.78) points/year. There were significant but weak relations between weight loss and increasingly severe chorea (r = -0.13), worse baseline motor performance (r = -0.12), less severe baseline depressed mood (r = 0.14), and poorer baseline independence ratings (r = 0.07). Patients who were within 0 to 2 years of symptom onset at the time of the baseline visit gained more weight than those with longer disease duration. CONCLUSIONS: Weight loss following symptom onset is not a consistent feature of Huntington's disease. The mechanisms contributing to weight change in this condition are unclear and probably multifactorial. Future studies examining asymptomatic carriers of the mutation could be helpful in identifying incipience of low body weight and may be better suited for identifying clinical correlates of weight loss than studies in symptomatic patients.

Chorea↗
PubMed1997

[Genetic studies in neurology].

The use of either direct or indirect genetic analyses in neurology is becoming ever greater as more genes are identified thanks to the human genome project. Often the methodologies are complex and difficult to understand. The aim of this review is to present various approaches to molecular diagnosis using several different inherited neurological diseases as examples. These include inherited mitochondriopathies, monogenetic disorders like trinucleotid repeat instability syndromes, duplication anomalies and specific point mutations as well as heterogenetic diseases such as limb girdle dystrophy and familial amyotrophic lateral sclerosis. Possible pathogenetic implications can now be proposed as the basis of new therapeutic modalities.

Genetic Markers↗
PubMed2002

Reelin gene alleles and susceptibility to autism spectrum disorders.

A polymorphic trinucleotide repeat (CGG/GCC) within the human Reelin gene (RELN) was examined as a candidate gene for autism spectrum disorders (ASDs). This gene encodes a large extracellular matrix protein that orchestrates neuronal positioning during corticogenesis. The CGG-repeat within the 5' untranslated region of RELN exon 1 was examined in 126 multiple-incidence families. The number of CGG repeats varied from three to 16 in affected individuals and controls, with no expansion or contraction observed during maternal (n = 291) or paternal (n = 287) transmissions in families with autistic probands. Although the frequencies of the RELN alleles and genotypes in affected children were not different from those in the comparison group, a family-based association test (FBAT) showed that the larger RELN alleles (> or = 11 repeats) were transmitted more often than expected to affected children (S = 43, E(S) = 34.5, P = 0.035); this was particularly the case for the 13-repeat RELN allele (S = 22, E(S) = 16, P = 0.034). Affected sib-pair (ASP) analysis found no evidence of excess sharing of RELN alleles in affected siblings. The impact of genotypes with large alleles (> or = 11 repeats) on the phenotypes in individuals with ASD was analyzed by ANOVA in a subset of the families for which results of the Autism Diagnostic Interview-Revised were available. Children with large RELN alleles did not show any difference in scores for questions related to the core symptoms of autistic disorder, but there was a tendency for children with at least one large RELN allele to have an earlier age at first phrase (chi(2) = 3.538, P = 0.06). Thus, although the case-control and affected sib-pair findings did not support a role for RELN in susceptibility to ASD, the more powerful family-based association study demonstrated that RELN alleles with larger numbers of CGG repeats may play a role in the etiology of some cases of ASD, especially in children without delayed phrase speech.

Autistic Disorder↗
PubMed2001

[Myotonic dystrophy (DM/Curschmann-Steinert disease) and proximal myotonic myopathy (PROMM/Ricker syndrome). Myotonic muscle diseases with multisystemic manifestations].

Myotonic disorders are characterised by slowed muscle relaxation and myotonic discharges in the electromyogram. "Pure" myotonic disorders affect only muscle and can be separated into ion channel disorders affecting either the chloride channel (myotonia congenita Thomsen or myotonia congenita Becker) or those affecting the sodium channel (paramyotonia, hyperkalemic periodic paralysis, and myotonia fluctuans). The genetic defects in these disorders are point mutations or deletions within the respective channel genes. A second group of myotonias consists of multisystem disorders with muscle weakness and atrophy plus extramuscular symptoms and signs including cardiac arrhythmias, cataracts, hypogonadism, and pain. Classic myotonic dystrophy (Steinert's disease or DM 1), and proximal myotonic myopathy (PROMM or Ricker's syndrome) are the major syndromes. PROMM is characterised by predominantly proximal muscle weakness and myalgias. Similarly to DM 1, anticipation also occurs in PROMM, but the disease course is usually milder. Steinert's disease belongs to the group of trinucleotide repeat-associated disorders. The DM 1 mutation is an unstable CTG trinucleotide repeat expansion on chromosome 19q13.3 which is diagnostic for the disease. A number of families with PROMM have been linked to a gene locus on chromosome 3q, but the mutation is still unknown. Therefore, direct molecular genetic testing for PROMM is not yet possible.

Biopsy↗
PubMed2007

Autopsy-proven Huntington's disease with 29 trinucleotide repeats.

Huntington's disease (HD) is a neurodegenerative disorder associated with expansion of CAG trinucleotide repeats in the huntingtin gene. A minimum of 36 CAG repeats is usually reported in patients with clinical features of HD; 30 to 35 repeats represent an intermediate range. Here we report a 65-year-old male with autopsy-proven HD and 29 CAG repeats.

Autopsy↗
PubMed2003

Anticipation and repeat expansion in bipolar disorder.

Anticipation is the phenomenon whereby a disease becomes more severe and/or presents with earlier onset as it is transmitted down through generations of a family. The only known mechanism for true anticipation is a class of mutations containing repetitive sequences exemplified by the pathogenic trinucleotide repeat. Studies of bipolar disorder (BPD) are consistent with the presence of anticipation and, by inference, the possibility that trinucleotide repeats contribute to this disorder, although it is possible that these data are the result of methodological problems. On the assumption that anticipation in BPD may be real, several surveys of the genome of BPD probands for large trinucleotide repeats have been conducted, as have studies of many repeat-containing candidate genes. No pathogenic triplet repeat has yet been unambiguously implicated.

Age of Onset↗
PubMed1996

Trinucleotide instability: a repeating theme in human inherited disorders.

In recent years, a completely new mechanism of mutation has emerged in a number of disorders that display perplexing and paradoxical features of genetic inheritance. This mechanism involves the expansion and intergenerational instability of stretches of consecutive identical nucleotide triplets that also exist as shorter stable segments on normal chromosomes. The unstable nature of the trinucleotide segments has solved many of the genealogic puzzles in these disorders and has provided a new tool for predictive testing. Treatments for the disorders await a better understanding of the different pathogenic processes that are triggered by various expanded repeats. The existence of numerous other disorders with peculiarities of genetic inheritance suggests that this mutational mechanism may be a major cause of human inherited disease.

Chromosome Aberrations↗
PubMed1998

Detection of polymorphic triplet repeats in the genomes of patients suffering from bipolar affective disorder.

Evidence for the operation of expanded trinucleotide repeats in the pathogenesis of bipolar affected disorder has recently been found at the molecular genetic level. For the screening of these repeat motifs in genomes of patients with bipolar affective disorder, we established a modified PCR-based fingerprinting technique, called triplet repeat enhanced arbitrarily primed PCR (TREAP-PCR). Using this approach, 40 patients suffering from bipolar affective disorder (ICD10: F31) and 15 healthy controls were investigated. Interindividual polymorphisms generated by TREAP-PCR seemed to depend on the type of triplet. Using CCG triplet primers, polymorphisms could be observed more often in the genomes of patients compared with controls, whereas no significant differences could be found using primers of the CAG or AAT type. These data might indicate the existence of subgroups of manic-depressive patients based on molecular genetic differences.

Adult↗