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The authors present a historical review of the seminal clinical contribution of Professor Américo Negrette, a Venezuelan neurologist, to the evolution of scientific knowledge about Huntington's disease.
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Progressive neurological diseases, such as multiple sclerosis, Parkinson's disease, Huntington's disease, significantly interfere with patients' lives, and those of their families. The aim of the research was to establish whether the extent of the information on patients' health conditions, and the way patients learn this information f...
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... Almost 75 years after Huntington's report, a Venezuelan physician, Americo Negrette, observed similar "dancing propensities," along with dementia and death in subjects near Lake Maracaibo, Venezuela. After a detailed study of their family history, he proposed that they all descended from a single woman Maria Concepcion Soto, whose father was probably a European sailor [5,6]. Similarly, most of Huntington's studies were based on families which had immigrated to the USA from England [1,2], thus pointing at the autosomal dominant inheritance of HD and its Caucasian origin. ...
Huntington’s disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.
... In Latin America, the groundbreaking work of Dr. Americo Negrette a Venezuelan Neurologist, alongside Dr. Milton Wexler and the Hereditary Disease Foundation, led to a better understanding of Huntington's disease including the thorough clinical descriptions of patients in Maracaibo, and the description of the huntingtin gene (16). ...
St. Vitus of Lucania was a third century roman saint, who became posthumously associated with abnormal movements and chorea. He was put to death by command of Emperor Diocletian (Ruled from 284 A.D. – 305 A.D.) and was thrown into a cauldron of boiling oil. People who witnessed this monstrous execution saw Vitus dancing enthusiastically whilst he was being burned alive, and regarded it as a miracle. We explore in the present paper the historical context and the medical implications of what became known henceforth as St. Vitus dance, a term still used today to describe chorea, mainly minor chorea or Sydenham’s chorea, in patients with rheumatic fever. Very few people today, including physicians, are aware of the origin of many commonplace words used in medical jargon. Key Words: Chorea, St. Vitus Dance, Rheumatic Fever, History, Neurology. San Vito de Lucania fue un santo romano del siglo III, que fue asociado después de su muerte con la presencia con movimientos anormales y corea. Fue ejecutado por orden del emperador Diocleciano y arrojado a un caldero de aceite hirviendo. Las personas que presenciaron esta monstruosa ejecución vieron a Vito bailando con entusiasmo mientras lo quemaban vivo, y lo consideraron un milagro. En este artículo exploramos el contexto histórico y las implicaciones médicas de lo que se conocería en adelante como la danza de San Vito o el mal de San Vito, un término que aún se usa hoy para describir la corea, principalmente la corea menor o corea de Sydenham, en pacientes con fiebre reumática. Muy pocas personas en la actualidad, incluidos los médicos, conocen el origen de muchas palabras comunes usadas en el argot médico.
Palabras Clave: Corea, Mal de San Vito, Fiebre Reumática, Historia, Neurología
... In the United States alone about 30,000 people are believed to have HD; in addition, 35,000 people will exhibit some symptoms and 75,000 people are gene carriers in whom the disease will appear during a normal life span (National Human Genome Research Institute, 2011). In isolated regions, such as Lake Maracaibo in Venezuelan, prevalence is higher [91]; in fact, the Venezuelan Kindred's comprise the world's largest genetically related community of HD [72]. ...
Extracellular signals regulate various intracellular functions like neuron excitability, neurotransmitter biosynthesis and release, neuronal growth, differentiation, neurite growth, synaptic plasticity and cognition through secondary messengers (cAMP and cGMP). Secondary messengers subsequently activate target enzymes Protein kinase A (PKA) and Protein kinase G (PKG) that activate cyclic AMP responsive element binding protein (CREB) which plays an important role in learning and memory function especially long term memory following new protein synthesis. The second messenger concept of signalling was born with the discovery of cyclic AMP (cAMP) and its ability to influence metabolism, cell shape and gene transcription (via reversible protein phosphorylations). cAMP plays an important role as second messenger molecule controlling multiple cellular processes in the brain. cAMP is produced from ATP by the action of adenyl cyclase (AC) in response to a variety of extracellular signals such as hormones, growth factors and neurotransmitters. Elevated levels of cAMP in the cell lead to activation of different cAMP targets. cAMP function as an intracellular mediator for neurotransmitters and hormones regulate BDNF expression that regulate neuronal survival. cAMP also regulate syn-aptic plasticity, learning and memory, restore energy levels, reduce excitotoxicity damage, prevent Aβ toxicity, inhibit apoptotic and necrotic cell death and also increase synaptic strength. On the basis of these evidences it is clearly demonstrate that via activating of cAMP levels in brains with the help of synthetic and natural precursors should be a proper treatment criteria for neurodegenerative disorders like Alzheimer's and Huntington's diseases.
... He further observed, following the detailed family history, that the transmission of the disease could be traced back to the preceding generations and thus, it conformed to an autosomal dominant pattern and concluded with his extraordinary vision that he was in reality, dealing with cases of HD. [1] Okun and Thommi, his collaborators, wrote that when he presented his observations at the Venezuelan Sixth Congress of Medical Science in 1955, he was met with reluctance in the local scientific community and a passive ear from government authorities, and Moscovich et al., further wrote accounts of his life and works. [6,7] He left for posterity his remarkable treatise, "Chorea de Huntington. Maracaibo, Venezuela: University of Zulia 1958," that has firmly found its pride of place in the history of medicine and his autobiography, "Ciudad de Fuego" contains a detailed account of how he identified the illness. ...
George Huntington described some families with choreiform movements in 1872 in the United States of America and since then many such families have been described in other parts of the world and works on the genetics of the disease have brought new vistas in the understanding of the disease. In 1958, Americo Negrette, a young Venezuelan physician observed similar subjects in the vicinity of Lake Maracaibo which was presented by his co-worker, Ramon Avilla Giron at New York in 1972 when United States of America had been commemorating the centenary year of Huntington's disease. Nancy Wexler, a psychoanalyst, whose mother had been suffering from the disease attended the meeting and organized a research team to Venezuela and they systematically studied more than 18,000 individuals in order to work out a common pedigree. They identified the genetic locus of the disease in the short arm of chromosome 4 and observed that it was a trinucleotide repeat disorder. © 2006 - 2016 Annals of Indian Academy of Neurology | Published by Wolters Kluwer - Medknow.
... In the United States alone about 30,000 people are believed to have HD; in addition, 35,000 people will exhibit some symptoms and 75,000 people are gene carriers in whom the disease will appear during a normal life span (National Human Genome Research Institute, 2011). In isolated regions, such as Lake Maracaibo in Venezuelan, prevalence is higher [91]; in fact, the Venezuelan Kindred's comprise the world's largest genetically related community of HD [72]. ...
Extracellular signals regulate various intracellular functions like neuron excitability, neurotransmitter biosynthesis and release, neuronal growth, differentiation, neurite growth, synaptic plasticity and cognition through secondary messengers (cAMP and cGMP). Secondary messengers subsequently activate target enzymes Protein kinase A (PKA) and Protein kinase G (PKG) that activate cyclic AMP responsive element binding protein (CREB) which plays an important role in learning and memory function especially long term memory following new protein synthesis. The second messenger concept of signalling was born with the discovery of cyclic AMP (cAMP) and its ability to influence metabolism, cell shape and gene transcription (via reversible protein phosphorylations). cAMP plays an important role as second messenger molecule controlling multiple cellular processes in the brain. cAMP is produced from ATP by the action of adenyl cyclase (AC) in response to a variety of extracellular signals such as hormones, growth factors and neurotransmitters. Elevated levels of cAMP in the cell lead to activation of different cAMP targets. cAMP function as an intracellular mediator for neurotransmitters and hormones regulate BDNF expression that regulate neuronal survival. cAMP also regulate synaptic plasticity, learning and memory, restore energy levels, reduce excitotoxicity damage, prevent Aβ toxicity, inhibit apoptotic and necrotic cell death and also increase synaptic strength. On the basis of these evidences it is clearly demonstrate that via activating of cAMP levels in brains with the help of synthetic and natural precursors should be a proper treatment criteria for neurodegenerative disorders like Alzheimer’s and Huntington’s diseases.
The gene for Huntington's disease (HD) was discovered in 1993, after an international collaborative initiative that led researchers to remote regions of South America. It was the most remarkable milestone, since George Huntington's initial description. Through the phenomenological discussions led by Jean‐Martin Charcot and Willian Osler, and finally Americo Negrette's reports, which served as the inspiration for the Venezuela Project led by Nancy Wexler, the journey toward discovering the Huntington's disease (HD) gene was marked by substantial efforts. This monumental achievement involved the analysis of more than 18,000 blood samples and gathered dozens of researchers in an integrated effort, enabling the mapping of the gene on chromosome 4 in 1983 and leading, a decade later, to the precise localization and identification of the HTT gene. The discovery of the HD mutation represented a pivotal moment in the field of genetics and neurology, significantly enhancing our understanding of the disease and creating opportunities for future treatments. The progress made and the knowledge gained during this journey catalyzed the development of many innovative molecular techniques that have advanced research in other medical conditions. In this article, the authors celebrate three decades of this memorable event, revisiting the historical aspects, providing insights into the techniques developed, and delving into the paths that ultimately led to the discovery of the HD gene. © 2024 International Parkinson and Movement Disorder Society.
Described first by George Huntington in 1872, Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder characterized by cognitive, motor and neuropsychiatric features. Neuropsychological assessment plays a crucial role in identifying cognitive changes in the early stages of the disease that can be used as biomarkers. In accordance with the Movement Society’s HD task force’s recommendations, this thesis reviews the characteristic features of HD, including a review of history, pathogenesis, and neural substrate (Chapter 1) before exploring the motor and nonmotor features (Chapter 2) and clinical tests commonly used for screening and longitudinal monitoring of those features (Chapter 3). The clinical characterization, the new diagnosis criteria established by the Movement Society, and treatments are also reviewed (Chapter 4). Finally the prevalence and clinical characterization in a cohort of HD population assessed in the Neurology Clinic at Padova University Hospital is explored and results discussed (Chapter 5).
The original descriptions of chorea date from the Middle Ages, when an epidemic of ‘‘dancing mania’’ swept throughout Europe. The condition was initially considered a curse sent by a saint, but was named ‘‘Saint Vitus’s dance’’ because afflicted individuals were cured if they touched churches storing Saint Vitus’s relics.Paracelsus coined the term chorea Sancti Viti and recognized different forms of chorea (imaginativa, lasciva, and naturalis). In the 17th century, Thomas Sydenham provided an accurate description of what he termed chorea minor. He also described rheumatic fever but did not associate it with chorea. It was only in 1850 that See established a relationship between chorea and rheumatic disease. A connection with cardiac involvement was soon recognized and in 1866 Roger postulated that chorea, arthritis, and heart disease had a common cause. The last quarter of the 19th century is marked by the works of Jean-Martin Charcot, Silas Weir Mitchell, William Osler, and William Richard Gowers, all of paramount importance in the refinement of the definition of chorea, its causes, and differential diagnosis. In 1841, Charles Oscar Waters gave a concise account of a syndrome, likely to be Huntington’s disease (HD), later described further by George Huntington and named after him. In 1955, the Venezuelan physician Americo Negrette published a book describing communities in the State of Zulia in
Venezuela, with unusual numbers of individuals with chorea. Negrette’s works culminated in the creation of the Venezuela project and the subsequent discovery of seminal findings in HD. We review the historical facts and outstanding physicians that mark both HD and Sydenham’s chorea’s history in various sections.
