Huntington’s Disease Pathogenesis: Two Sequential Components

Trends in Neurosciences, 1995

American journal of human genetics, 1996

To those of us who began life when humans had 48 chromosomes and who began working in genetics when the (by then 46) chromosomes had no bands and chromosome 4 could not reliably be distinguished from chromosome 5, the mere ability to diagnose and correlate the clinical phenotypes of genetic disorders with their molecular genotypes is a source of continuing astonishment and pleasure. Indeed, molecular genetic analysis of neurogenetic disorders such as Huntington disease (HD) has provided a steady stream of challenges and surprises to all who believe the genetic principles that they were taught about these disorders. The paper by Rubinsztein et al. in this issue of the journal highlights yet another surprise, which was adumbrated even in the initial paper announcing the discovery of the HD gene: incomplete penetrance of HD gene mutations.

F1000Research, 2018

Background: Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase. Methods: Using peripheral blood samples from HD patients and healthy controls we used EpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of the HTT gene. We evaluated chromatin conformations at 20 sites across 225 kb of the HTT locus in healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms o...

JAMA neurology, 2016

Huntington disease (HD), a prototypic monogenic disease, is caused by an expanded CAG repeat in the HTT gene exceeding 35 units. However, not all patients with an HD phenotype carry the pathological expansion in HTT, and the positive diagnosis rate is poor. To examine patients with HD phenotypes to determine the frequency of HD phenocopies with typical features of HD but without pathological CAG repeat expansions in HTT in an attempt to improve the positive diagnosis rate. Between January 1, 2004, and April 18, 2011, a total of 226 consecutive index patients with an HD phenotype were referred to specialized clinics of the French National Huntington Disease Reference Centre for Rare Diseases. They underwent detailed clinical examination and follow-up, as well as neuropsychological, biological, imaging, and genetic examinations. Nucleotide expansions in JPH3, ATN1, TBP, and C9ORF72 and mutations in PRNP, as well as acquired conditions commonly causing HD phenocopies, were first screen...

American Journal of Neuroradiology, 2013

Huntington's disease (HD) is a hereditary autosomal dominant disorder of central nervous system . The underlying genetic defect involves abnormal expansion of the CAG triple repeats (>40) in exon 1 of huntingtin gene (htt) . The htt gene located near the telomere of the short arm of chromosome 4 (locus 4p16.3) encodes for huntingtin (Htt) protein . Although, mutation in htt gene was discovered more than 17 years ago, the role of Htt in pathophysiology of HD is still under investigation . The most striking neuropathological hallmark of this disorder is the atrophy of the striatal region, that control movement, memory and emotions suggesting that striatal degeneration is an important aspect of HD pathophysiology . In patients with HD, selective loss of medium spiny neurons has not only been observed in the caudate and putamen of the striatum of basal ganglia, but also in pyramidal neurons of the cerebral cortex and to lesser extent in hippocampal and subthalamus neurons . In patients with severe HD, neuronal loss to an extent of 80% has been observed . HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment and emotional disturbances . HD usually occurs in mid 40s with some exceptional cases of early onset (2 years of age) and of late onset (in the mid 80s) is reported .

Genetics in Medicine, 2014

Disease-specific statements are intended to augment the general American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for Clinical Genetics Laboratories. Individual laboratories are responsible for meeting the Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP) quality assurance standards with respect to appropriate sample documentation, assay validation, general proficiency, and quality control measures. This 2014 edition of the guideline updates and supersedes the original laboratory guideline on this topic, which was published in 2004 1 and reaffirmed once during the ensuing decade. Gene symbol/protein name HTT (historically known as IT15)/Huntingtin. The GenBank accession number for the reference sequence is NM_002111. The OMIM gene/locus code is 613004. OMIM phenotype number 143100. Huntington disease (HD) is a neurodegenerative disease of mid-life onset that produces choreic movements and cognitive decline, often accompanied by psychiatric changes. It affects ~3-5 out of 100,000 individuals. However, the prevalence of HD exceeds 15 per 100,000 in some populations, mostly of western European origin. 2 Juvenile-onset HD occurs in approximately 5% of affected patients, is a rapidly progressive variant, and presents with rigidity, spasticity, and intellectual decline before the age of 20 years. The symptoms result from the selective loss of neurons, most notably in the caudate nucleus and putamen, and there is currently no effective treatment. For more information, see the online Gene Reviews profile at .

Archivos de Neurociencias

Introduction: Huntington's Disease (HD) is a hereditary, neurodegenerative disorder due to abnormal repeats of the CAG triplet in the IT-15 gene. It is characterized by a triad of progressive motor, psychiatric and cognitive symptoms, resulting from striatal neuronal loss. The impact of HD in Latin America is evidenced by the prevalence rates in Maracaibo (Venezuela) and Juan de Acosta (Colombia), which are the highest recorded in the world. This contrasts with the social abandonment and the scarce intervention of local governments. Aim: Provide an approach to the most relevant aspects of HD from its pathogenesis and associated genetic polymorphisms, to the current treatment options. Methodology: A literature review was performed of the state of the art of prognosis and treatment strategies in HD, including the identification of different polymorphic markers in the genes coding for UCHL1, HIP1, PGC1α, GRIK2, TBP, BDNF, among others, and its associations in the evolution of the d...

The American Journal of Human Genetics, 2000

A consanguineous family affected by an autosomal recessive, progressive neurodegenerative Huntington-like disorder, was tested to rule out juvenile-onset Huntington disease (JHD). The disease manifests at ∼3-4 years and is characterized by both pyramidal and extrapyramidal abnormalities, including chorea, dystonia, ataxia, gait instability, spasticity, seizures, mutism, and intellectual impairment. Brain magnetic resonance imaging (MRI) findings include progressive frontal cortical atrophy and bilateral caudate atrophy. Huntington CAG trinucleotide-repeat analyses ruled out JHD, since all affected individuals had repeat numbers within the normal range. The presence of only four recombinant events () between the disease and the Huntington locus v = .2 in 20 informative meioses suggested that the disease localized to chromosome 4. Linkage was initially achieved with marker D4S2366 at 4p15.3 (LOD 3.03). Highdensity mapping at the linked locus resulted in homozygosity for markers D4S431 and D4S394, which span a 3-cM region. A maximum LOD score of 4.71 in the homozygous interval was obtained. Heterozygosity at the distal D4S2366 and proximal D4S2983 markers defines the maximum localization interval (7 cM). Multiple brain-related expressed sequence tags (ESTs) with no known disease association exist in the linkage interval. Among the three known genes residing in the linked interval (ACOX3, DRD5, QDPR), the most likely candidate, DRD5, encoding the dopamine receptor D5, was excluded, since all five affected family members were heterozygous for an intragenic dinucleotide repeat. The inheritance pattern and unique localization to 4p15.3 are consistent with the identification of a novel, autosomal recessive, neurodegenerative Huntington-like disorder.

Proceedings of the …, 1988