A Case of Previously Unsuspected Huntington Disease Diagnosed at Autopsy

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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Deep Brain Stimulation in Adult Huntington Disease for Treatment of Axial Dystonia

Deep Brain Stimulation ◽

10.1093/med/9780190647209.003.0040 ◽

2020 ◽

pp. 211-216

Author(s):

Jessica A. Karl ◽

Kathleen Shannon ◽

Konstantin Slavin ◽

Leo Verhagen Metman

Keyword(s):

Deep Brain Stimulation ◽

Brain Stimulation ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Case Reports ◽

Common Symptom ◽

Psychiatric Disturbances ◽

Optimal Medical Management ◽

Recent Case Study ◽

Deep Brain

Huntington disease (HD) is a progressive neurodegenerative disorder characterized by chorea and cognitive and psychiatric disturbances. Dystonia is also a common symptom, and a recent case study points toward 50% of HD patients having truncal dystonia. Although tetrabenazine is approved for treatment of Huntington chorea, no medications have proved efficacious for the dystonia and bradykinesia that become more prominent as the disease progresses. Although several reports have outlined the effect of globus pallidus interna (GPi) deep brain stimulation (DBS) in HD patients with a choreic phenotype, less is known about the effect of DBS in HD patients with a predominately dystonic phenotype. When specific symptoms known to respond well to DBS, such as dystonia, interfere significantly with a patient’s quality of life, and optimal medical management has failed, DBS could be considered a viable option. This case reports demonstrates the utility of bilateral GPi DBS for dystonia in a patient with HD, so long as there is no neuropsychiatric impairment that would interfere with the patient’s comprehension of the potential risks of surgery. The patient and caregivers should have realistic expectations of outcomes and be willing to follow through with regular programming.

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Robust Preimplantation Genetic Testing of Huntington Disease by Combined Triplet-Primed PCR Analysis of the HTT CAG Repeat and Multi-Microsatellite Haplotyping

Scientific Reports ◽

10.1038/s41598-019-52769-3 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Mingjue Zhao ◽

Felicia Siew Hong Cheah ◽

Arnold Sia Chye Tan ◽

Mulias Lian ◽

Gui Ping Phang ◽

...

Keyword(s):

Genetic Testing ◽

Huntington Disease ◽

Neurodegenerative Disorder ◽

Cag Repeat ◽

Pcr Analysis ◽

Monogenic Disorder ◽

Preimplantation Genetic Testing ◽

Haplotype Phasing ◽

Repeat Locus ◽

Disease Haplotype

Abstract Huntington disease (HD) is a lethal neurodegenerative disorder caused by expansion of a CAG repeat within the huntingtin (HTT) gene. Disease prevention can be facilitated by preimplantation genetic testing for this monogenic disorder (PGT-M). We developed a strategy for HD PGT-M, involving whole genome amplification (WGA) followed by combined triplet-primed PCR (TP-PCR) for HTT CAG repeat expansion detection and multi-microsatellite marker genotyping for disease haplotype phasing. The strategy was validated and tested pre-clinically in a simulated PGT-M case before clinical application in five cycles of a PGT-M case. The assay reliably and correctly diagnosed all embryos, even where allele dropout (ADO) occurred at the HTT CAG repeat locus or at one or more linked markers. Ten of the 27 embryos analyzed were diagnosed as unaffected. Four embryo transfers were performed, two of which involved fresh cycle double embryo transfers and two were frozen-thawed single embryo transfers. Pregnancies were achieved from each of the frozen-thawed single embryo transfers and confirmed to be unaffected by amniocentesis, culminating in live births at term. This strategy enhances diagnostic confidence for PGT-M of HD and can also be employed in situations where disease haplotype phase cannot be established prior to the start of PGT-M.

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

10.21203/rs.3.rs-31294/v3 ◽

2020 ◽

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 (73.4%) 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 64.8 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 10 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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