scholarly journals Huntington disease update: new insights into the role of repeat instability in disease pathogenesis

2021 ◽  
Vol 33 (4) ◽  
pp. 293-300
Author(s):  
Larissa Arning ◽  
Huu Phuc Nguyen
Keyword(s):  
Disease Progression ◽  
Dna Sequences ◽  
Huntington Disease ◽  
Trinucleotide Repeat ◽  
Age At Onset ◽  
Repeat Sequence ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cognitive Disability

Abstract The causative mutation for Huntington disease (HD), an expanded trinucleotide repeat sequence in the first exon of the huntingtin gene (HTT) is naturally polymorphic and inevitably associated with disease symptoms above 39 CAG repeats. Although symptomatic medical therapies for HD can improve the motor and non-motor symptoms for affected patients, these drugs do not stop the ongoing neurodegeneration and progression of the disease, which results in severe motor and cognitive disability and death. To date, there is still an urgent need for the development of effective disease‐modifying therapies to slow or even stop the progression of HD. The increasing ability to intervene directly at the roots of the disease, namely HTT transcription and translation of its mRNA, makes it necessary to understand the pathogenesis of HD as precisely as possible. In addition to the long-postulated toxicity of the polyglutamine-expanded mutant HTT protein, there is increasing evidence that the CAG repeat-containing RNA might also be directly involved in toxicity. Recent studies have identified cis- (DNA repair genes) and trans- (loss/duplication of CAA interruption) acting variants as major modifiers of age at onset (AO) and disease progression. More and more extensive data indicate that somatic instability functions as a driver for AO as well as disease progression and severity, not only in HD but also in other polyglutamine diseases. Thus, somatic expansions of repetitive DNA sequences may be essential to promote respective repeat lengths to reach a threshold leading to the overt neurodegenerative symptoms of trinucleotide diseases. These findings support somatic expansion as a potential therapeutic target in HD and related repeat expansion disorders.

scholarly journals Huntington disease: DNA analysis in brazilian population

2000 ◽  
Vol 58 (4) ◽  
pp. 977-985 ◽  
Author(s):  
SALMO RASKIN ◽  
NASSER ALLAN ◽  
HÉLIO A.G. TEIVE ◽  
FRANCISCO CARDOSO ◽  
MÔNICA SANTORO HADDAD ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Dna Analysis ◽  
Trinucleotide Repeat ◽  
Age At Onset ◽  
Normal Subjects ◽  
Clinical Findings ◽  
Repeat Sequence ◽  
Cag Repeat ◽  
Major Increase ◽  
Hd Gene

Huntington disease (HD) is associated with expansions of a CAG trinucleotide repeat in the HD gene. Accurate measurement of a specific CAG repeat sequence in the HD gene in 92 Brazilian controls without HD, 44 Brazilian subjects with clinical findings suggestive of HD and 40 individuals from 6 putative HD families, showed a range from 7 to 33 repeats in normal subjects and 39 to 88 repeats in affected subjects. A trend between early age at onset of first symptoms and increasing number of repeats was seen. Major increase of repeat size through paternal inheritance than through maternal inheritance was observed. Data generated from this study may have significant implications for the etiology, knowledge of the incidence, diagnosis, prognosis, genetic counseling and treatment of HD Brazilian patients.

scholarly journals Modulation at Age of Onset in Tunisian Huntington Disease Patients: Implication of New Modifier Genes

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Dorra Hmida-Ben Brahim ◽  
Marwa Chourabi ◽  
Sana Ben Amor ◽  
Imed Harrabi ◽  
Saoussen Trabelsi ◽  
...  
Keyword(s):  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Age Of Onset ◽  
Age At Onset ◽  
Specific Effect ◽  
Modifier Genes ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Cag Expansion ◽  
Tunisian Patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder. The causative mutation is an expansion of more than 36 CAG repeats in the first exon of IT15 gene. Many studies have shown that the IT15 interacts with several modifier genes to regulate the age at onset (AO) of HD. Our study aims to investigate the implication of CAG expansion and 9 modifiers in the age at onset variance of 15 HD Tunisian patients and to establish the correlation between these modifiers genes and the AO of this disease. Despite the small number of studied patients, this report consists of the first North African study in Huntington disease patients. Our results approve a specific effect of modifiers genes in each population.

scholarly journals Overlap between age-at-onset and disease-progression determinants in Huntington disease

Neurology ◽  
2018 ◽  
Vol 90 (24) ◽  
pp. e2099-e2106 ◽  
Author(s):  
N. Ahmad Aziz ◽  
Jorien M.M. van der Burg ◽  
Sarah J. Tabrizi ◽  
G. Bernhard Landwehrmeyer
Keyword(s):  
Weight Loss ◽  
Disease Progression ◽  
Huntington Disease ◽  
Age At Onset ◽  
Cag Repeat ◽  
Optimal Timing ◽  
Mixed Effect ◽  
Mixed Effect Models ◽  
Intuitive Method ◽  
Average Body

ObjectiveA fundamental but still unresolved issue regarding Huntington disease (HD) pathogenesis is whether the factors that determine age at onset are the same as those that govern disease progression. Because elucidation of this issue is crucial for the development as well as optimal timing of administration of novel disease-modifying therapies, we aimed to assess the extent of overlap between age-at-onset and disease-progression determinants in HD.MethodsUsing observational data from Enroll-HD, the largest cohort of patients with HD worldwide, in this study we present, validate, and apply an intuitive method based on linear mixed-effect models to quantify the variability in the rate of disease progression in HD.ResultsA total of 3,411 patients with HD met inclusion criteria. We found that (1) about two-thirds of the rate of functional, motor, and cognitive progression in HD is determined by the same factors that also determine age at onset, with CAG repeat–dependent mechanisms having by far the largest effect; (2) although expanded HTT CAG repeat size had a large influence on average body weight, the rate of weight loss was largely independent of factors that determine age at onset in HD; and (3) about one-third of the factors that determine the rate of functional, motor, and cognitive progression are different from those that govern age at onset and need further elucidation.ConclusionOur findings imply that targeting of CAG repeat–dependent mechanisms, for example through gene-silencing approaches, is likely to affect the rate of functional, motor, and cognitive impairment, but not weight loss, in manifest HD mutation carriers.

scholarly journals Molecular diagnosis of Huntington disease in Brazilian patients

2000 ◽  
Vol 58 (1) ◽  
pp. 11-17 ◽  
Author(s):  
TEREZA C. LIMA E SILVA ◽  
HELIANE GUERRA SERRA ◽  
CARMEN S. BERTUZZO ◽  
ISCIA LOPES-CENDES
Keyword(s):  
Molecular Diagnosis ◽  
Huntington Disease ◽  
Neurodegenerative Disorder ◽  
Age At Onset ◽  
Disease Onset ◽  
Significant Negative Correlation ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Unrelated Control ◽  
Intermediate Size

Huntington disease (HD) is a progressive neurodegenerative disorder with autosomal dominant inheritance, characterized by choreiform movements and cognitive impairment. Onset of symptoms is around 40 years of age and progression to death occurs in approximately 10 to 15 years from the time of disease onset. HD is associated with an unstable CAG repeat expansion at the 5' and of the IT15 gene. We have genotyped the CAG repeat in the IT15 gene in 44 Brazilian individuals (42 patients and 2 unaffected family members) belonging to 34 unrelated families thought to segregate HD. We found one expanded CAG allele in 32 individuals (76%) belonging to 25 unrelated families. In these HD patients, expanded alleles varied from 43 to 73 CAG units and normal alleles varied from 18 to 26 CAGs. A significant negative correlation between age at onset of symptoms and size of the expanded CAG allele was found (r=0.6; p=0.0001); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2=0.4). In addition, we genotyped 25 unrelated control individuals (total of 50 alleles) and found normal CAG repeats varying from 16 to 33 units. The percentage of heterozigocity of the normal allele in the control population was 88%. In conclusion, our results showed that not all patients with the "HD" phenotype carried the expansion at the IT15 gene. Furthermore, molecular diagnosis was possible in all individuals, since no alleles of intermediate size were found. Therefore, molecular confirmation of the clinical diagnosis in HD should be sought in all suspected patients, making it possible for adequate genetic counseling.

scholarly journals Molecular characteristics of Machado-Joseph disease mutation in 25 newly described Brazilian families

1997 ◽  
Vol 20 (4) ◽  
pp. 717-724 ◽  
Author(s):  
Iscia Lopes-Cendes ◽  
Hélio G.A. Teive ◽  
Francisco Cardoso ◽  
Erika M. Viana ◽  
Maria E. Calcagnotto ◽  
...  
Keyword(s):  
Late Onset ◽  
Age At Onset ◽  
Collaborative Study ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Causative Mutation ◽  
Molecular Characteristics ◽  
Spinocerebellar Ataxias ◽  
Extrapyramidal Signs ◽  
Machado Joseph Disease

Machado-Joseph disease (MJD) is a form of autosomal dominant spinocerebellar ataxia first described in North-American patients originating from the Portuguese islands of the Azores. Clinically this disorder is characterized by late onset progressive ataxia with associated features, such as: ophthalmoplegia, pyramidal and extrapyramidal signs and distal muscular atrophies. The causative mutation is an expansion of a CAG repeat in the coding region of the MJD1 gene. We have identified 25 unrelated families segregating the MJD mutation during a large collaborative study of spinocerebellar ataxias in Brazil. In the present study a total of 62 family members were genotyped for the CAG repeat in the MJD1 gene, as well as 63 non-MJD individuals (126 normal chromosomes), used as normal controls. We observed a wide gap between the size range of the normal and expanded CAG repeats: the normal allele had from 12 to 33 CAGs (mean = 23 CAGs), whereas the expanded alleles ranged from 66 to 78 CAGs (mean = 71.5 CAGs). There were no differences in CAG tract length according to gender of affected individuals or transmitting parent. We observed a significant negative correlation between age at onset of the disease and length of the CAG tract in the expended allele (r = -0.6, P = 0.00006); however, the size of the expanded CAG repeat could explain only about 40% of the variability in age at onset (r2 = 0.4). There was instability of the expanded CAG tract during transmission from parent to offspring, both expansions and contractions were observed; however, there was an overall tendency for expansion, with a mean increase of +2.4 CAGs. The tendency for expansion appeared to the greater in paternal (mean increase of +3.5 CAGs) than in maternal transmissions (mean increase of +1.3 CAGs). Anticipation was observed in all transmissions in which ages at onset for parent and offspring were known; however, anticipation was not always associated with an increase in the expanded CAG repeat length. Our results indicate that the molecular diagnosis of MJD can be confirmed or excluded in all suspected individuals, since alleles of intermediary size were not observed.

scholarly journals Patients With Extreme Early Onset Juvenile Huntington Disease Can Have Delays in Diagnosis: A Case Report and Literature Review

2021 ◽  
Vol 8 ◽  
pp. 2329048X2110361
Author(s):  
Ashley A. Moeller ◽  
Marcia V. Felker ◽  
Jennifer A. Brault ◽  
Laura C. Duncan ◽  
Rizwan Hamid ◽  
...  
Keyword(s):  
Symptom Onset ◽  
Huntington Disease ◽  
Early Onset ◽  
Trinucleotide Repeat ◽  
Cerebellar Atrophy ◽  
Cag Repeats ◽  
Ataxic Gait ◽  
Repeat Expansions ◽  
Delays In Diagnosis ◽  
Juvenile Huntington Disease

Huntington disease (HD) is caused by a pathologic cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the HTT gene. Typical adult-onset disease occurs with a minimum of 40 repeats. With more than 60 CAG repeats, patients can have juvenile-onset disease (jHD), with symptom onset by the age of 20 years. We report a case of a boy with extreme early onset, paternally inherited jHD, with symptom onset between 18 and 24 months. He was found to have 250 to 350 CAG repeats, one of the largest repeat expansions published to date. At initial presentation, he had an ataxic gait, truncal titubation, and speech delay. Magnetic resonance imaging showed cerebellar atrophy. Over time, he continued to regress and became nonverbal, wheelchair-bound, gastrostomy-tube dependent, and increasingly rigid. His young age at presentation and the ethical concerns regarding HD testing in minors delayed his diagnosis.

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

scholarly journals Incidence of Huntington disease in a northeastern Spanish region: a 13-year retrospective study at tertiary care centre

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Paula Sienes Bailo ◽  
Raquel Lahoz ◽  
Juan Pelegrín Sánchez Marín ◽  
Silvia Izquierdo Álvarez
Keyword(s):  
Retrospective Study ◽  
Huntington Disease ◽  
Tertiary Care ◽  
Genetic Diagnosis ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Incomplete Penetrance ◽  
Predictive Test ◽  
Incident Cases

Abstract Background Despite the progress in the knowledge of Huntington disease (HD) in recent years, the epidemiology continues uncertain, so the study of incidence becomes relevant. This is important since various factors (type of population, diagnostic criteria, disease-modifying factors, etc.) make these data highly variable. Therefore, the genetic diagnosis of these patients is important, since it unequivocally allows the detection of new cases. Methods Descriptive retrospective study with 179 individuals. Incidence of HD was calculated from the ratio of number of symptomatic cases newly diagnosed per 100,000 inhabitants per year during the period 2007–2019 in Aragon (Spain). Results 50 (27.9%) incident cases of HD (CAG repeat length ≥ 36) were identified from a total of 179 persons studied. The remaining 129/179 (72.1%) were HD negative (CAG repeat length < 36). 29 (58.0%) females and 21 (42.0%) males were confirmed as HD cases. The overall incidence was 0.648 per 100,000 patient-years. 11/50 positive HD cases (22.0%) were identified by performing a predictive test, without clinical symptoms. The minimum number of CAG repeats found was 9 and the most common CAG length among HD negative individuals was 16. Conclusions Our incidence lied within the range reported for other Caucasian populations. Implementation of new techniques has allowed to determine the exact number of CAG repeats, which is especially important in patients with triplet expansions in an HD intermediate and/or incomplete penetrance allele, both in diagnostic, predictive and prenatal tests.

scholarly journals A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

2017 ◽  
Vol 7 (1) ◽  
pp. 136-144
Author(s):  
Catherine R. Miller ◽  
Nobby C. Mambo ◽  
Jianli Dong ◽  
Gerald A. Campbell
Keyword(s):  
Genetic Testing ◽  
Huntington Disease ◽  
Clinical Symptoms ◽  
Neurodegenerative Disorder ◽  
Case Reports ◽  
Neuronal Loss ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Psychiatric Disturbances ◽  
Personality Changes

Huntington disease (HD) is a neurodegenerative disorder with a worldwide prevalence of four to ten per 100 000. It is characterized by choreiform movements, behavioral/psychiatric disturbances, and eventual cognitive decline. Symptoms usually present between 30 and 50 years of age and the diagnosis is based on the combination of clinical symptoms, family history, and genetic testing. A variation of HD, juvenile Huntington disease (JHD), presents earlier, with more severe symptoms and with a worse prognosis. Symptoms are different in JHD, with personality changes and learning difficulties being the predominant presenting features. Seizures are common in JHD, and chorea is uncommon; movement disorders at presentation of JHD are predominantly nonchoreiform. The inheritance pattern for both HD and JHD is autosomal dominant and the disease is caused by an elongation of the CAG repeat in the huntingtin gene. There are many published case reports of Huntington disease that were confirmed at autopsy, but to our knowledge, there are no reports in the literature where the diagnosis of Huntington disease was first made at autopsy. We present a case of a 28-year-old African-American male who was in a state of neglect due to a lifetime of abuse, cognitive difficulties, and seizures, whose cause of death was pneumonia. The gross autopsy findings included bilateral caudate nucleus atrophy and lateral ventricular dilation. Microscopically, severe bilateral neuronal loss and gliosis of the caudate and putamen nuclei were seen. Genetic testing for the number of CAG repeats confirmed the diagnosis and was consistent with JHD.

204. Isolation of CAG repeat containing genes from human placenta and decidua

2005 ◽  
Vol 17 (9) ◽  
pp. 77
Author(s):  
K. A. Freed ◽  
S. P. Brennecke ◽  
E. K. Moses
Keyword(s):  
Mutation Rate ◽  
Dna Sequences ◽  
Human Placenta ◽  
Trinucleotide Repeat ◽  
Normal Population ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
High Mutation Rate ◽  
Strong Negative Selection ◽  
Expansion Mutation

Pre-eclampsia is a serious disorder of pregnancy that manifests clinically in the mother as new-onset hypertension and proteinuria. Although the precise cause remains unknown, the placenta and the decidua play a fundamental role. The worldwide incidence of pre-eclampsia is 2–5% and such a high incidence, in the face of strong negative selection, suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. In these diseases repeated trinucleotide DNA sequences within specific genes multiply or expand up to 1000-fold. The result of this gene expansion/mutation is altered gene function that confers genetic susceptibility. Thus, the overall objective of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-eclampsia. The specific aim of this study was to isolate CAG repeat containing genes from human placenta and decidua. An adaptation of the mRNA differential display technique and traditional cDNA library screening was used. In total, 72 placental and 51 decidual sequences were analyzed using the BLAST nucleotide comparison program. Five cDNAs were analyzed further. The unique sequences surrounding the CAG repeat regions of these five genes will be used to generate primers to ascertain if any of these repeat DNA sequences vary in number in the normal population. If polymorphic genes are identified, the primers will be used on pre-eclamptic pedigrees to determine if pre-eclampsia is associated with a repeat expansion mutation.

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