Huntington Disease: Clinical, Genetic, and Social Aspects

Huntington disease (HD) is a fascinating neurodegenerative disorder whose features straddle the boundaries of psychiatry, neurology, and genetics. The clinical symptoms of HD consist of a triad of motor, cognitive, and psychiatric/behavioral disturbances. In 1993, the HD Collaborative Research Group identified the gene and the mutation responsible for HD. HD was one of the first neurodegenerative disorders discovered to be caused by a novel mutational mechanism known as trinucleotide repeat expansion. Since then, HD has been the model for autosomal dominant neurogenetic disorders. The clinical, pathological, and genetic aspects of the disease are reviewed and some of the questions that remain to be answered by researchers of the 21st century are outlined.

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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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Library preparation and MiSeq sequencing for the genotyping-by-sequencing of the Huntington disease HTT exon one trinucleotide repeat and the quantification of somatic mosaicism

10.21203/rs.2.1581/v2 ◽

2020 ◽

Author(s):

Marc Ciosi ◽

Sarah A. Cumming ◽

Asma M. Alshammari ◽

Efthymia Symeonidi ◽

Pawel Herzyk ◽

...

Keyword(s):

Huntington Disease ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Fragment Size ◽

Somatic Mosaicism ◽

Genotyping By Sequencing ◽

Amplicon Sequencing ◽

Cag Repeat ◽

Miseq Sequencing ◽

Flanking Sequence

Abstract Huntington disease \(HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the _HTT_ gene. Affected individuals inherit more than 40 repeats and the CAG repeat is genetically unstable in both the germline and soma. Molecular diagnosis and genotyping of the CAG repeat is traditionally performed by estimation of PCR fragment size. However, this approach is complicated by the presence of an adjacent polymorphic CCG repeat and provides no information on the presence of variant repeats, flanking sequence variants or on the degree of somatic mosaicism. To overcome these limitations, we have developed an amplicon-sequencing protocol that allows the sequencing of hundreds of samples in a single MiSeq run. The composition of the _HTT_ exon one trinucleotide repeat locus can be determined from the MiSeq sequencing reads generated. With sufficient sequencing depth, such MiSeq data can also be used to quantify the degree of somatic mosaicism of the _HTT_ CAG repeat in the tissue analysed.

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Single-Step Scalable-Throughput Molecular Screening for Huntington Disease

Clinical Chemistry ◽

10.1373/clinchem.2007.096503 ◽

2008 ◽

Vol 54 (6) ◽

pp. 964-972 ◽

Cited By ~ 6

Author(s):

Clara R L Teo ◽

Wen Wang ◽

Hai Yang Law ◽

Caroline G Lee ◽

Samuel S Chong

Keyword(s):

Huntington Disease ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

False Positive Rate ◽

Screening Method ◽

Melting Curve ◽

Single Step ◽

Cag Repeat ◽

Clinical Samples ◽

Melting Curve Analysis

Abstract Background: Huntington disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by an unstable expansion of the CAG trinucleotide repeat in exon 1 of the HTT (huntingtin) gene and typically has an adult onset. Molecular diagnosis and screening for HD currently involve separate amplification and detection steps. Methods: We evaluated a novel, rapid microplate-based screening method for HD that combines the amplification and detection procedures in a single-step, closed-tube format. We carried out both the PCR for the HTT CAG-repeat region and the subsequent automated melting-curve analysis of the amplicon in the same wells on the plate. To establish cutoff melting temperatures (Tms) for each allelic class, we used a panel of reference DNA samples of known CAG-repeat sizes that represent a range of HTT alleles [normal (≤26 repeats), intermediate (27–35 repeats), reduced penetrance expanded (36–39 repeats), and fully penetrant expanded (≥40 repeats)]. We also measured well-to-well variation in Tm across the thermal block and validated cutoff Tms with DNA samples from 5 different populations. We also conducted a blinded validation analysis of clinical samples from an additional 40 HD-affected and 30 unaffected individuals. Results: We observed a strong correlation between CAG-repeat size and amplicon Tm among the reference DNA samples. Use of the Tm cutoffs we established revealed that 5 samples from unaffected individuals had been misclassified as affected (1.1% false-positive rate). All samples from HD-affected and unaffected individuals were correctly identified in the blinded analysis. Conclusions: This simple and scalable homogeneous assay may serve as a convenient, rapid, and accurate screen to detect the presence of pathologic expanded HD alleles in symptomatic patients.

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Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation

Acta Endocrinologica ◽

10.1530/eje-16-0109 ◽

2016 ◽

Vol 175 (3) ◽

pp. 211-218 ◽

Cited By ~ 16

Author(s):

Sirpa Tenhola ◽

Raimo Voutilainen ◽

Monica Reyes ◽

Sanna Toiviainen-Salo ◽

Harald Jüppner ◽

...

Keyword(s):

Short Stature ◽

Autosomal Dominant ◽

Clinical Symptoms ◽

Urinary Calcium ◽

Calcium Excretion ◽

Clinical Genetic ◽

Activating Mutations ◽

Intracranial Calcifications ◽

Healthy Family ◽

Autosomal Dominant Hypocalcemia

Objective Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. Design A three-generation family with seven members (3 adults, 4 children) presenting with ADH. Methods Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. Results Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from −3.4 to −2.3 vs −0.5 in the unaffected children). Conclusions The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.

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Nonisotopic method for accurate detection of (CAG)n repeats causing Huntington disease

Clinical Chemistry ◽

10.1093/clinchem/42.10.1601 ◽

1996 ◽

Vol 42 (10) ◽

pp. 1601-1603 ◽

Cited By ~ 14

Author(s):

M Muglia ◽

O Leone ◽

G Annesi ◽

A L Gabriele ◽

E Imbrogno ◽

...

Keyword(s):

Silver Nitrate ◽

Molecular Diagnosis ◽

Huntington Disease ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

The Novel ◽

Direct Visualization ◽

Pcr Products ◽

Radioactive Background ◽

Presymptomatic Diagnosis

Abstract Huntington disease (HD) is a neurodegenerative disorder caused by an expanded trinucleotide repeat (CAG)n located at the 5' end of the novel IT15 gene. Discovery of this expansion allows the molecular diagnosis of HD by measuring repeat length. We applied a simple nonisotopic method to detect (CAG)n repeats, avoiding both radioactive and Southern transfer analysis. The assay is based on direct visualization of electrophoresed PCR products, after silver nitrate gel staining. Its accurate sizing of HD alleles allows presymptomatic diagnosis of at-risk persons. By avoiding isotopic manipulations, the method is safe and accurate, with no radioactive background bands. Furthermore, because it permits direct allele visualization after gel staining, the method is simple and rapid, allowing allele sizing within hours rather than days.

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The Influence of Huntingtin Protein Size on Nuclear Localization and Cellular Toxicity

The Journal of Cell Biology ◽

10.1083/jcb.141.5.1097 ◽

1998 ◽

Vol 141 (5) ◽

pp. 1097-1105 ◽

Cited By ~ 203

Author(s):

Abigail S. Hackam ◽

Roshni Singaraja ◽

Cheryl L. Wellington ◽

Martina Metzler ◽

Krista McCutcheon ◽

...

Keyword(s):

Nuclear Localization ◽

Huntington Disease ◽

Autosomal Dominant ◽

Neurodegenerative Disorder ◽

Mutant Huntingtin ◽

Cellular Toxicity ◽

Protein Size ◽

Protein Length ◽

Polyglutamine Tract ◽

Increased Susceptibility

Huntington disease is an autosomal dominant neurodegenerative disorder caused by the pathological expansion of a polyglutamine tract. In this study we directly assess the influence of protein size on the formation and subcellular localization of huntingtin aggregates. We have created numerous deletion constructs expressing successively smaller fragments of huntingtin and show that these smaller proteins containing 128 glutamines form both intranuclear and perinuclear aggregates. In contrast, larger NH2-terminal fragments of huntingtin proteins with 128 glutamines form exclusively perinuclear aggregates. These aggregates can form in the absence of endogenous huntingtin. Furthermore, expression of mutant huntingtin results in increased susceptibility to apoptotic stress that is greater with decreasing protein length and increasing polyglutamine size. As both intranuclear and perinuclear aggregates are clearly associated with increased cellular toxicity, this supports an important role for toxic polyglutamine-containing fragments forming aggregates and playing a key role in the pathogenesis of Huntington disease.

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A human huntingtin SNP alters post-translational modification and pathogenic proteolysis of the protein causing Huntington disease

10.1101/129536 ◽

2017 ◽

Cited By ~ 1

Author(s):

DDO Martin ◽

C Kay ◽

JA Collins ◽

YT Nguyen ◽

RA Slama ◽

...

Keyword(s):

Huntington Disease ◽

Protein Function ◽

Trinucleotide Repeat ◽

Neurodegenerative Disorder ◽

Genetic Modifier ◽

Human Cells ◽

Missense Mutations ◽

Post Translational Modification ◽

Post Translational Modifications ◽

Normal Functions

AbstractPost-translational modifications (PTMs) are key modulators of protein function. Huntington disease (HD) is a dominantly inherited neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the huntingtin (HTT) gene. A spectrum of PTMs have been shown to modify the normal functions of HTT, including proteolysis, phosphorylation and lipidation, but the full contribution of these PTMs to the molecular pathogenesis of HD remains unclear. In this study, we examine all commonly occurring missense mutations in HTT to identify potential human modifiers of HTT PTMs relevant to HD biology. We reveal a SNP that modifies post-translational myristoylation of HTT, resulting in downstream alterations to toxic HTT proteolysis in human cells. This is the first SNP shown to functionally modify a PTM in HD and the first validated genetic modifier of post-translational myristoylation. This SNP is a high-priority candidate modifier of HD phenotypes and may illuminate HD biology in human studies.

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Huntington Disease

The Oxford Handbook of Adult Cognitive Disorders ◽

10.1093/oxfordhb/9780190664121.013.30 ◽

2019 ◽

pp. 644-678

Author(s):

Jane S. Paulsen

Keyword(s):

Huntington Disease ◽

Trinucleotide Repeat ◽

Behavioral Control ◽

Time Estimation ◽

Brain Dysfunction ◽

Medium Spiny Neuron ◽

Loss Of Function ◽

Neuron Death ◽

Gene Therapies ◽

Underlying Mechanisms

Huntington disease (HD) is a autosomal dominant neurodegenerative disease caused by expansion of a trinucleotide repeat (cytosine, adenine, and guanine [CAG]) on the short arm of chromosome four. Average age of motor diagnosis is 39 years, and age at diagnosis is associated with the length of the CAG mutation. The prodrome of HD can be recognized 15 years prior to motor diagnosis and is characterized by subtle impairments in emotional recognition, smell identification, speed of processing, time estimation and production, and psychiatric abnormalities. HD shows particular vulnerability of the medium spiny neuron in the basal ganglia. Progressive brain dysfunction and neuron death lead to insidious loss of function in motor, cognitive, and behavioral control over 34 years (17 prodromal and 17 post-diagnosis). Treatment plans rely on genetic counseling, psychiatric symptom treatment as needed, physical therapy, and environmental modifications. There are two treatments for the reduction of chorea, but there are no disease-modifying therapies. Experimental therapeutics are rapidly emerging with multiple and various targets, however, and gene therapies to silence the mutant HD gene are currently ongoing. This chapter reviews clinical and neuropathological descriptions of HD and discusses potential underlying mechanisms and animal models, diagnostic and clinical assessments used to characterize and track the disease, treatment planning, and challenges for research to advance care.

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Developmental malformations in Huntington disease: neuropathologic evidence of focal neuronal migration defects in a subset of adult brains

Acta Neuropathologica ◽

10.1007/s00401-021-02269-4 ◽

2021 ◽

Vol 141 (3) ◽

pp. 399-413 ◽

Cited By ~ 1

Author(s):

R. A. Hickman ◽

P. L. Faust ◽

M. K. Rosenblum ◽

K. Marder ◽

M. F. Mehler ◽

...

Keyword(s):

New York ◽

Huntington Disease ◽

Trinucleotide Repeat ◽

Validation Cohort ◽

Hypothalamic Hamartoma ◽

Discovery Cohort ◽

Brain Bank ◽

Neuronal Precursors ◽

Neurodevelopmental Abnormalities ◽

Developmental Malformations

AbstractNeuropathologic hallmarks of Huntington Disease (HD) include the progressive neurodegeneration of the striatum and the presence of Huntingtin (HTT) aggregates that result from abnormal polyQ expansion of the HTT gene. Whether the pathogenic trinucleotide repeat expansion of the HTT gene causes neurodevelopmental abnormalities has garnered attention in both murine and human studies; however, documentation of discrete malformations in autopsy brains of HD individuals has yet to be described. We retrospectively searched the New York Brain Bank (discovery cohort) and an independent cohort (validation cohort) to determine whether developmental malformations are more frequently detected in HD versus non-HD brains and to document their neuropathologic features. One-hundred and thirty HD and 1600 non-HD whole brains were included in the discovery cohort and 720 HD and 1989 non-HD half brains were assessed in the validation cohort. Cases with developmental malformations were found at 6.4–8.2 times greater frequency in HD than in non-HD brains (discovery cohort: OR 8.68, 95% CI 3.48–21.63, P=4.8 × 10-5; validation cohort: OR 6.50, 95% CI 1.83–23.17, P=0.0050). Periventricular nodular heterotopias (PNH) were the most frequent malformations and contained HTT and p62 aggregates analogous to the cortex, whereas cortical malformations with immature neuronal populations did not harbor such inclusions. HD individuals with malformations had heterozygous HTT CAG expansions between 40 and 52 repeats, were more frequently women, and all were asymmetric and focal, aside from one midline hypothalamic hamartoma. Using two independent brain bank cohorts, this large neuropathologic series demonstrates an increased occurrence of developmental malformations in HD brains. Since pathogenic HTT gene expansion is associated with genomic instability, one possible explanation is that neuronal precursors are more susceptible to somatic mutation of genes involved in cortical migration. Our findings further support emerging evidence that pathogenic trinucleotide repeat expansions of the HTT gene may impact neurodevelopment.

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

Child Neurology Open ◽

10.1177/2329048x211036137 ◽

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.

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