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

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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Late-onset Huntington’s disease with 40–42 CAG expansion

Neurological Sciences ◽

10.1007/s10072-019-04177-8 ◽

2019 ◽

Vol 41 (4) ◽

pp. 869-876 ◽

Cited By ~ 1

Author(s):

Elisa Capiluppi ◽

Luca Romano ◽

Paola Rebora ◽

Lorenzo Nanetti ◽

Anna Castaldo ◽

...

Keyword(s):

Huntington's Disease ◽

Huntington’S Disease ◽

Rating Scale ◽

Neurodegenerative Disorder ◽

Age Of Onset ◽

Late Onset ◽

Age At Onset ◽

Clinical Manifestations ◽

Cag Repeats ◽

Cag Expansion

Abstract Introduction Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by a CAG expansion greater than 35 in the IT-15 gene. There is an inverse correlation between the number of pathological CAG and the age of onset. However, CAG repeats between 40 and 42 showed a wider onset variation. We aimed to investigate potential clinical differences between patients with age at onset ≥ 60 years (late onset-HD) and patients with age at onset between 30 and 59 years (common-onset HD) in a cohort of patients with the same CAG expansions (40–42). Methods A retrospective analysis of 66 HD patients with 40–41–42 CAG expansion was performed. Patients were investigated with the Unified Huntington’s Disease Rating Scale (subitems I–II–III and Total Functional Capacity, Functional Assessment and Stage of Disease). Data were analysed using χ2, Fisher’s test, t test and Pearson’s correlation coefficient. GENMOD analysis and Kaplan-Meier analysis were used to study the disease progression. Results The age of onset ranged from 39 to 59 years in the CO subgroup, whereas the LO subgroup showed an age of onset from 60 to 73 years. No family history was reported in 31% of the late-onset in comparison with 20% in common-onset HD (p = 0.04). No difference emerged in symptoms of onset, in clinical manifestations and in progression of disease between the two groups. Conclusion There were no clinical differences between CO and LO subgroups with 40–42 CAG expansion. There is a need of further studies on environmental as well genetic variables modifying the age at onset.

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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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Molecular diagnosis of Huntington disease in Brazilian patients

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2000000100002 ◽

2000 ◽

Vol 58 (1) ◽

pp. 11-17 ◽

Cited By ~ 12

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.

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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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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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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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CCG•CGG interruptions in high penetrance SCA8 families increase RAN translation and protein toxicity

10.1101/2021.02.08.430311 ◽

2021 ◽

Author(s):

Barbara A. Perez ◽

Hannah K. Shorrock ◽

Monica Banez-Coronel ◽

Lauren A. Laboissonniere ◽

Tammy Reid ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Age At Onset ◽

Spinocerebellar Ataxia Type ◽

Protein Levels ◽

Cag Expansion ◽

Disease Penetrance ◽

Sporadic Cases ◽

Steady State Levels ◽

Rna Hairpin ◽

Protein Toxicity

AbstractSpinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8 we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (N=77). We show that repeat expansion mutations from individuals with two or more affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability and steady state levels of SCA8 RAN polyAla and polySer proteins. Additionally, the CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame increase the toxicity of the resulting proteins. In summary, CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.

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Genetic Anticipation in Portuguese Families With Bipolar Mood Disorder

CNS Spectrums ◽

10.1017/s109285290001169x ◽

1999 ◽

Vol 4 (5) ◽

pp. 25-31 ◽

Cited By ~ 3

Author(s):

Antonio Macedo ◽

M. Helena Azevedo ◽

Isabel Coelho ◽

Ana Dourado ◽

Jose Valente ◽

...

Keyword(s):

Mood Disorder ◽

Disease Severity ◽

Second Generation ◽

Age Of Onset ◽

Age At Onset ◽

Specific Effect ◽

Data Sampling ◽

Genetic Anticipation ◽

Sampling Schemes ◽

Bipolar Mood Disorder

AbstractGenetic anticipation refers to an inheritance pattern within a pedigree showing a decrease in age of onset or an increase in disease severity or both in successive generations. This phenomenon has become the focus of important research in schizophrenia and bipolar mood disorder. The results to date have been controversial and far from conclusive. To attempt to resolve some of the earlier findings, we compared age at onset and disease severity between two generations in 24 Portuguese families ascertained for genetic linkage studies of bipolar mood disorder. There was a significant decrease in age of onset (P<. 00001) and increase in frequency of episodes (P<.0001)from the first to the second generation. This difference was significant under each of the four data-sampling schemes, one of which excluded probands. The second generation experienced onset 12.4 to 15.9 years earlier and illness 2.3 to 2.6 times more severe than did the first generation. We found no evidence for a specific effect in anticipation related to the transmitting parent's sex. Results of the present study, analyzed carefully for a variety of possible biases, suggest evidence for genetic anticipation in these Portuguese bipolar families.

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Huntington Disease and Other Genetic Causes of Choreas

10.2310/psych.6357 ◽

2016 ◽

Author(s):

Ainhi Ha ◽

Débora Maia ◽

Victor S C Fung ◽

Francisco Cardoso

Keyword(s):

Movement Disorders ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Age At Onset ◽

Body Distribution ◽

Behavioral Abnormalities ◽

Expected Outcome ◽

Common Etiology ◽

Hereditary Chorea ◽

Benign Hereditary Chorea

The aim of this review is to provide an overview of Huntington disease (HD) and other genetic choreas with an emphasis on clinical presentation, diagnosis, treatment, and expected outcome. Chorea is a syndrome characterized by brief, abrupt, involuntary movements resulting from a continuous flow of random muscle contractions. The first step in approaching a subject with chorea is to define the underlying etiology because the natural history and management vary accordingly. Age at onset, body distribution, other neurologic features, and family history are important in establishing the cause of chorea. HD is the most common etiology of genetic choreas worldwide. It is a progressive neurodegenerative disorder transmitted as an autosomal dominant trait characterized by a combination of movement disorders, cognitive decline, and behavioral abnormalities that causes progressive disability and death. When an HD phenotype test is negative for this condition, other causes, such as neuroacanthocytosis; spinocerebellar ataxia 17; Huntington disease–like syndrome 2, 3, or 4; benign hereditary chorea; and dentatorubral-pallidoluysian atrophy, as well as others, should be investigated. Key words: Huntington, movement disorders, genetic choreas, neurodegenerative disorder

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NATURAL SELECTION AT THE MJD LOCUS: PHENOTYPIC DIVERSITY, SURVIVAL AND FERTILITY AMONG MACHADO-JOSEPH DISEASE PATIENTS FROM THE AZORES

Journal of Biosocial Science ◽

10.1017/s0021932001003613 ◽

2001 ◽

Vol 33 (3) ◽

pp. 361-373 ◽

Cited By ~ 4

Author(s):

M. LIMA ◽

M. SMITH ◽

C. SILVA ◽

A. ABADE ◽

F. MAYER ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Phenotypic Diversity ◽

Age At Onset ◽

Cag Repeats ◽

Early Age ◽

Coding Region ◽

Differential Survival ◽

Clinical Type ◽

Machado Joseph Disease

Machado-Joseph Disease (MJD) is an autosomal dominant neurodegenerative disorder of adult onset, associated with the expansion of a (CAG)n tract in the coding region of the causative gene, localized on 14q32.1. Machado-Joseph Disease shows non-Mendelian features typical of other triplet repeat disorders, including clinical heterogeneity, variable age at onset and anticipation. Three phenotypes have been proposed (clinical types 1, 2 and 3). Type 1 is associated with early age at onset and a high repeat number of the CAG sequence, and Types 2 and 3 have later onset and lower numbers of CAG repeats. This paper investigates whether there is selection against the MJD gene, acting through differential survival, nuptiality and fertility associated with clinical type and age at onset. The study sample comprised 40 MJD patients from the Azores (Portugal) having fully documented reproductive histories and known dates of death. The proportion of married patients of each clinical type increased from 0·22 among Type 1 patients, to 0·40 in Type 2 and 0·95 in Type 3. Age at onset and length of survival were also associated with marital status, with the married cases having later mean age at onset and longer mean survival time. In the whole sample, clinical type was associated with fertility, with significantly fewer children born to Type 1 patients. Among married patients clinical type was not associated with age at marriage, reproductive span or number of children. No reduction of fertility was detected among married patients in whom the onset of MJD was below the age of 50. The authors’ interpretation of these results is that the high-repeat CAG haplotypes associated with early age at onset and clinical Type 1 are selected against through reduced survival and fertility. The fertility component of selection is mediated by nuptiality rather than marital fertility.

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