Molecular diagnosis of Huntington disease in Brazilian patients

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.

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

Genetics Research International ◽

10.1155/2014/210418 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 2

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.

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A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

Academic Forensic Pathology ◽

10.23907/2017.016 ◽

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.

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

Medizinische Genetik ◽

10.1515/medgen-2021-2101 ◽

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.

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

BMC Medical Genetics ◽

10.1186/s12881-020-01174-z ◽

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.

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FACS-array–based cell purification yields a specific transcriptome of striatal medium spiny neurons in a murine Huntington disease model

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.012983 ◽

2020 ◽

Vol 295 (29) ◽

pp. 9768-9785 ◽

Cited By ~ 1

Author(s):

Haruko Miyazaki ◽

Tomoyuki Yamanaka ◽

Fumitaka Oyama ◽

Yoshihiro Kino ◽

Masaru Kurosawa ◽

...

Keyword(s):

Gene Expression ◽

Huntington Disease ◽

Fluorescent Protein ◽

Neurodegenerative Disorder ◽

Disease Model ◽

Medium Spiny Neuron ◽

Cag Repeats ◽

Specific Gene ◽

Protein Marker ◽

Gene Sets

Huntington disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene. Results from previous studies have suggested that transcriptional dysregulation is one of the key mechanisms underlying striatal medium spiny neuron (MSN) degeneration in HD. However, some of the critical genes involved in HD etiology or pathology could be masked in a common expression profiling assay because of contamination with non-MSN cells. To gain insight into the MSN-specific gene expression changes in presymptomatic R6/2 mice, a common HD mouse model, here we used a transgenic fluorescent protein marker of MSNs for purification via FACS before profiling gene expression with gene microarrays and compared the results of this “FACS-array” with those obtained with homogenized striatal samples (STR-array). We identified hundreds of differentially expressed genes (DEGs) and enhanced detection of MSN-specific DEGs by comparing the results of the FACS-array with those of the STR-array. The gene sets obtained included genes ubiquitously expressed in both MSNs and non-MSN cells of the brain and associated with transcriptional regulation and DNA damage responses. We proposed that the comparative gene expression approach using the FACS-array may be useful for uncovering the gene cascades affected in MSNs during HD pathogenesis.

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Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease

Neurology Genetics ◽

10.1212/nxg.0000000000000430 ◽

2020 ◽

Vol 6 (3) ◽

pp. e430 ◽

Cited By ~ 1

Author(s):

Daniel O. Claassen ◽

Jody Corey-Bloom ◽

E. Ray Dorsey ◽

Mary Edmondson ◽

Sandra K. Kostyk ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Huntington Disease ◽

Prospective Observational Study ◽

Cag Repeat ◽

Cag Repeats ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Cag Repeat Expansion ◽

Long Read ◽

Selective Therapy

BackgroundThe huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments.ObjectiveThis prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG expansions.MethodsAcross 7 US sites, 202 individuals with HD provided blood samples that were processed centrally to determine the number and size of CAG repeats, presence and heterozygosity of SNPs, and whether SNPs were present on the mutant HTT allele using long-read sequencing and phasing.ResultsHeterozygosity of SNP1 and/or SNP2 was identified in 146 (72%) individuals. The 2 polymorphisms were associated only with the mHTT allele in 61% (95% high density interval: 55%, 67%) of individuals.ConclusionsThese results are consistent with previous reports and demonstrate the feasibility of genotyping, phasing, and targeting of HTT SNPs for personalized treatment of HD.

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Predicting Disease Onset from Mutation Status Using Proband and Relative Data with Applications to Huntington's Disease

Journal of Probability and Statistics ◽

10.1155/2012/375935 ◽

2012 ◽

Vol 2012 ◽

pp. 1-19 ◽

Cited By ~ 3

Author(s):

Tianle Chen ◽

Yuanjia Wang ◽

Yanyuan Ma ◽

Karen Marder ◽

Douglas R. Langbehn

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Family Member ◽

Disease Onset ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Observational Research ◽

Accurate Estimation ◽

Combined Data

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expansion of CAG repeats in the IT15 gene. The age-at-onset (AAO) of HD is inversely related to the CAG repeat length and the minimum length thought to cause HD is 36. Accurate estimation of the AAO distribution based on CAG repeat length is important for genetic counseling and the design of clinical trials. In the Cooperative Huntington's Observational Research Trial (COHORT) study, the CAG repeat length is known for the proband participants. However, whether a family member shares the huntingtin gene status (CAG expanded or not) with the proband is unknown. In this work, we use the expectation-maximization (EM) algorithm to handle the missing huntingtin gene information in first-degree family members in COHORT, assuming that a family member has the same CAG length as the proband if the family member carries a huntingtin gene mutation. We perform simulation studies to examine performance of the proposed method and apply the methods to analyze COHORT proband and family combined data. Our analyses reveal that the estimated cumulative risk of HD symptom onset obtained from the combined data is slightly lower than the risk estimated from the proband data alone.

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Spinocerebellar ataxia type 6

Neurology ◽

10.1212/wnl.49.5.1238 ◽

1997 ◽

Vol 49 (5) ◽

pp. 1238-1243 ◽

Cited By ~ 101

Author(s):

R. Matsumura ◽

N. Futamura ◽

Y. Fujimoto ◽

S. Yanagimoto ◽

H. Horikawa ◽

...

Keyword(s):

Family History ◽

Cerebellar Ataxia ◽

Age At Onset ◽

Repeat Expansion ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Spinocerebellar Ataxia Type ◽

Cag Repeat Expansion ◽

Spinocerebellar Ataxia Type 6

Spinocerebellar ataxia type 6 (SCA6) is a newly classified autosomal-dominant cerebellar ataxia (ADCA) associated with CAG repeat expansion. We screened 111 patients with cerebellar ataxia for the SCA6 mutation. Of these, 35 patients were found to have expanded CAG repeats in the SCA6 gene, indicating that second to SCA3, SCA6 is the most common ADCA in Japan. Expanded alleles ranged from 21 to 29 repeats, whereas normal alleles had seven to 17 repeats. There was no change in the CAG repeat length during meiosis. The age at onset was inversely correlated with the repeat length. The main clinical feature of the 35 patients with SCA6 was slowly progressive cerebellar ataxia; multisystem involvement was not common. The 35 patients included nine cases without apparent family history of cerebellar ataxia. The sporadic cases had smaller CAG repeats (21 or 22 repeats) and a later age at onset (64.9 ± 4.9 years) than the other cases with established family history. We also identified one patient who was homozygous for the SCA6 repeat expansion. The homozygote showed an earlier age of onset and more severe clinical manifestations than her sister, a heterozygote carrying an expanded allele with the same repeat length as the homozygote. This finding suggests that the dosage of the CAG repeat expansion plays an important role in phenotypic expression in SCA6.

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Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

10.1101/699033 ◽

2019 ◽

Author(s):

Galen E.B. Wright ◽

Nicholas S. Caron ◽

Bernard Ng ◽

Lorenzo Casal ◽

Xiaohong Xu ◽

...

Keyword(s):

Gene Expression ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Age Of Onset ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Cag Repeat ◽

Biologically Relevant ◽

Clinical Onset ◽

Genome Wide Data

ABSTRACTHuntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in the HTT gene. In an attempt to identify genomic modifiers that contribute towards the age of onset of HD, we performed a transcriptome wide association study assessing heritable differences in genetically determined expression in diverse tissues, employing genome wide data from over 4,000 patients. This identified genes that showed evidence for colocalization and replication, with downstream functional validation being performed in isogenic HD stem cells and patient brains. Enrichment analyses detected associations with various biologically-relevant gene sets and striatal coexpression modules that are mediated by CAG length. Further, cortical coexpression modules that are relevant for HD onset were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder.

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Expanded huntingtin CAG repeats disrupt the balance between neural progenitor expansion and differentiation in human cerebral organoids

10.1101/850586 ◽

2019 ◽

Cited By ~ 3

Author(s):

Jinqiu Zhang ◽

Jolene Ooi ◽

Kagistia Hana Utami ◽

Sarah R. Langley ◽

Obed Akwasi Aning ◽

...

Keyword(s):

Cell Cycle ◽

Neurodegenerative Disorder ◽

Ventricular Zone ◽

Neural Progenitor ◽

Repeat Length ◽

Cag Repeat ◽

Cag Repeats ◽

Normal Brain ◽

Dependent Manner ◽

The Impact

AbstractHuntington disease (HD) manifests in both adult and juvenile forms. Mutant HTT gene carriers are thought to undergo normal brain development followed by a degenerative phase, resulting in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD have raised the possibility of abnormal neurodevelopment. Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Using a panel of isogenic HD human embryonic pluripotent stem cells and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in an HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids, driven by cell intrinsic processes. Transcriptional profiling and imaging analysis revealed impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors, collectively contributing to premature neuronal differentiation. We demonstrate increased activity of the ATM-p53 pathway, an up-stream regulator of cell cycle processes, and show that treatment with ATM antagonists partially rescues the blunted neuroepithelial progenitor expansion in HD organoids. Our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our results further support the view that HD, at least in its early-onset forms, may not be a purely neurodegenerative disorder, and that abnormal neurodevelopment may be a component of HD pathophysiology.

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