The Huntington's Disease Gene Discovery.

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.

"On Chorea": 150 Years of the Beginning of Hope.

"On Chorea" by George Huntington was published on April 13, 1872, in The Medical and Surgical Reporter of Philadelphia. Despite being a milestone in the recognition of the disease that later would bear his name, some myths and curiosities continue to surround the history of this publication and its author. In this History, the authors pay tribute to the 150th anniversary of the publication of this iconic article. © 2022 International Parkinson and Movement Disorder Society.

The Role of the Cerebellum in Huntington's Disease: a Systematic Review.

Huntington's disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.

Upward Gaze Palsy: a Valuable Sign to Distinguish Spinocerebellar Ataxias.

Spinocerebellar ataxias (SCAs) represent a large group of heredodegenerative diseases, with great phenotypic and genotypic heterogeneity. However, in the clinical neurological practice, some symptoms and signs might help differentiate the SCAs. This study's aims were to evaluate the frequency of upward gaze palsy (UGP) and investigate its role in assisting in the clinical differentiation of SCAs. We included 419 patients with SCAs (248 with SCA3, 95 with SCA10, 38 with SCA2, 22 with SCA1, 12 with SCA7, and 4 with SCA6). This study compared UGP with other known markers of disease severity-age of onset, disease duration, SARA score, and size of CAG expansion, and also other semiologic features, as bulging eyes. This sign was significantly more prevalent in SCA3 (64.11%), compared with SCA10 (3.16%; p < 0.001) and other SCAs (SCA1, SCA2, SCA7-11.84%; p < 0.001). UGP showed very high sensibility ins SCA3 (92.9), although lacking of specificity (64.1%). The odds ratio (OR) of UGP were also very high, 23.52 (95% CI 12.38-44.69), and was significantly correlated with larger CAG expansions, age, and disease duration in SCA3 patients, but not with age of onset or severity of the ataxic syndrome. This study showed that UGP is highly suggestive of SCA3 and has high sensitivity for the differential diagnosis among SCAs, and it could be of great value for bedside semiologic tool.

Sjögren: unique surname, two men, four syndromes and one disease.

Henrik and Torsten Sjögren (/'ʃoʊɡrən/ or SHOH-grən) were two Swedish physicians living in the same period, but completely unrelated, except for their notable contributions to Medicine. The first one described keratoconjunctivitis sicca, afterward called Sjögren's syndrome, and a fishing net aspect retinal pigmentation affecting visual acuity, nowadays known as Sjögren reticular dystrophy. The last one contributed to the understanding of Spielmeyer-Sjögren disease, Marinesco-Sjögren, and Sjögren-Larsson syndromes, all related to genetic disorders and neurological symptoms. In this paper, we aim to describe each disorder, in order to avoid any misunderstanding in diagnosis and for historical record.

Henrik e Torsten Sjögren (/ˈʃoʊɡrən/ ou SHOH-grən) foram dois médicos suecos que viveram na mesma época, mas não tinham nenhuma relação entre si, exceto por suas notáveis contribuições à medicina. O primeiro descreveu a ceratoconjuntivite sicca, posteriormente chamada de síndrome de Sjögren, e uma pigmentação da retina com aspecto de rede de pesca que afeta a acuidade visual, hoje conhecida como distrofia reticular de Sjögren. O último contribuiu para a compreensão da doença de Spielmeyer-Sjögren, das síndromes de Marinesco-Sjögren e Sjögren-Larsson, todas relacionadas a distúrbios genéticos e sintomas neurológicos. Neste artigo, pretendemos descrever cada desordem, a fim de evitar qualquer mal-entendido no diagnóstico e para registro histórico.

Movement Disorders in PURA Syndrome: A Video Case Series.

Background: PURA syndrome is a rare genetic disorder characterized by neonatal hypotonia, neurodevelopmental delay, facial dysmorphism, epileptic seizures, complex movement disorders, among other features. Although many pathogenic variants have been reported, there is currently no clear genotype-phenotype association identified. Cases: Four patients diagnosed with PURA syndrome, despite carrying different pathogenic variants, presented a similar mixed hyperkinetic movement disorder. The phenomenology presented a complex set of symptoms, including chorea, interspersed with dystonic and uncoordinated movements. All patients presented also hypotonia, nystagmus, feeding difficulties, craniofacial dysmorphisms. Hypersomnolence and breathing problems were common and observed in three patients, while seizures were found in three patients. Conclusions: PURA syndrome may be considered in the differential diagnosis of infants with severe hypotonia, feeding difficulties and severe developmental delay with epileptic seizures, that start to develop a mixed hyperkinetic movement disorder. These complex movements may be an important clue for the diagnosis of this rare disorder.

Immune-mediated ataxias: Guide to clinicians.

Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our understanding of this topic. These ataxias encompass various etiologies, including postinfectious cerebellar ataxia, gluten ataxia, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus-ataxia syndrome and primary autoimmune cerebellar ataxia. The increased permeability of the brain-blood barrier could potentially explain the vulnerability of the cerebellum to autoimmune processes. In this manuscript, our objective is to provide a comprehensive review of the most prevalent diseases within this group, emphasizing clinical indicators, pathogenesis, and current treatment approaches.

When My Child Has Alzheimer's Disease.

The significant increment in life expectancy, associated to the existence of high-performing older adults, and the appropriate diagnosis of early dementias, lead to an uncommon scenario, of healthy parents accompanying their children with Alzheimer's disease or another dementia to medical consultations. Here, we reported three peculiar clinical vignettes of patients diagnosed with a dementia, who were accompanied by healthy parents. This is a modern situation that tends to become more frequent, and must be properly discussed, since multidisciplinary care and specific training are necessary.

Comparing loss of balance and functional capacity among patients with SCA2, SCA3 and SCA10.

BACKGROUND: Spinocerebellar ataxia (SCA) presents different rates of functional decline depending on the type of ataxia. OBJECTIVE: To compare the progression of disability, imbalance and severity of ataxia in patients with the three most common types of SCA in southern Brazil. METHODS: 126 patients (31-SCA2, 58-SCA3 and 37-SCA10) were stratified into four groups based on disease duration. Progression rates were calculated in each group for ataxia severity (SARA), functioning (FIM-ADL and Lawton-IADL), and balance (Berg Balance Scale). RESULTS: Differences across groups in terms of disease severity revealed a linear pattern of decline in SCA3, with a faster rate over time (p = 0.039) compared to SCA2 and SCA10. The pattern was nonlinear for SCA2 and SCA10, with a twofold faster rate in patients with up to seven years of disease compared to all other periods in SCA10 (p < 0.001) and to the longer follow up period in SCA2 (p = 0.049). Differences across groups regarding worsening of balance scores was significantly faster in SCA3 compared to SCA10 (p = 0.028) and SCA2 (p = 0.028). The rate of loss of independence of ADLs tended to diminish over time in the three types of ataxia and was faster in SCA3. Similarly, the rate for loss of independence (IADLs) was faster in SCA3 compared to SCA2 (p = 0.057) and significantly faster compared to SCA10 (p = 0.028). CONCLUSION: The present findings suggest that the progression of the disease (severity/functioning/balance) varies according to the SCA subtype and the period in disease course. Progression is more linear and aggressive in patients with SCA3.

Is Ataxia an Underestimated Symptom of Huntington's Disease?

Background: Huntington's disease (HD) is a progressive disorder characterized by motor, cognitive and psychiatric features. Cerebellar ataxia is classically considered as uncommon in HD clinical spectrum. Objective: To determine the prevalence of cerebellar ataxia in patients with HD, both in the early and in the late stages of HD. Methods: Seventy-two individuals considered eligible were assessed by two trained doctors, applying the Scale for Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS) for ataxia, the Unified Huntington's Disease Rating Scale (UHDRS) and also, Barthel Index (BI), in order to evaluate functional capacity. Results: Fifty-one patients (70.8%) presented with clinical ataxia at the time of examination (mean time of disease was 9.1 years). Six (8.33%) patients presented with cerebellar ataxia as first symptom. When stratified according to time of disease, a decline in the presence of chorea (p = 0.032) and an increase in cognitive deficit (p = 0.023) were observed in the patients as the disease progressed. The presence of ataxia was associated with longer duration of illness and severity of illness (UHDRS) (p < 0.0001), and shorter Barthel (less functionality) (p = 0.001). Conclusions: Cerebellar involvement may play an important role in natural history of brain degeneration in HD. The presence of cerebellar ataxia in HD is relevant and it may occur even in early stages, and should be included as part of the motor features of the disease.

The Geographic Diversity of Spinocerebellar Ataxias (SCAs) in the Americas: A Systematic Review.

BACKGROUND: The frequency and presentation of each of the most common forms of spinocerebellar ataxias (SCAs) varies widely. In the case of the Americas, this diversity is particularly dynamic given additional social, demographic, and cultural characteristics. OBJECTIVE: To describe the regional prevalence and clinical phenotypes of SCAs throughout the continent. METHODS: A literature search was performed in both MEDLINE and LILACS databases. The research was broadened to include the screening of reference lists of systematic review articles for additional studies. Investigations dating from the earliest available through 2019. Only studies in English, Portuguese, and Spanish were included. We analyzed publications with genetically confirmed cases only, ranging from robust samples with epidemiological data to case reports and case series from each country or regions. RESULTS: Overall, SCA3 is the most common form in the continent. Region-specific prevalence and ranking of the common forms vary. On the other hand, region-specific phenotypic variations were not consistently found based on the available literature analyzed, with the exception of the absence of epilepsy in SCA10 consistently described in a particular cluster of cases in South Brazil. CONCLUSION: Systematic, multinational studies analyzing in detail the true frequencies of SCAs across the Americas as well as distinct clinical signs and clues of each form would be ideal to look for these potential variations.

Sjögren: unique surname, two men, four syndromes and one disease / Sjögren: sobrenome único, dois homens, quatro síndromes e uma doença

Abstract Henrik and Torsten Sjögren (/'ogrƏn/ or SHOH-grƏn) were two Swedish physicians living in the same period, but completely unrelated, except for their notable contributions to Medicine. The first one described keratoconjunctivitis sicca, afterward called Sjögren's syndrome, and a fishing net aspect retinal pigmentation affecting visual acuity, nowadays known as Sjögren reticular dystrophy. The last one contributed to the understanding of Spielmeyer-Sjögren disease, Marinesco-Sjögren, and Sjögren-Larsson syndromes, all related to genetic disorders and neurological symptoms. In this paper, we aim to describe each disorder, in order to avoid any misunderstanding in diagnosis and for historical record.

Resumo Henrik e Torsten Sjögren (/'ogrƏn/ or SHOH-grƏn) foram dois médicos suecos que viveram na mesma época, mas não tinham nenhuma relação entre si, exceto por suas notáveis contribuições à medicina. O primeiro descreveu a ceratoconjuntivite sicca, posteriormente chamada de síndrome de Sjögren, e uma pigmentação da retina com aspecto de rede de pesca que afeta a acuidade visual, hoje conhecida como distrofia reticular de Sjögren. O último contribuiu para a compreensão da doença de Spielmeyer-Sjögren, das síndromes de Marinesco-Sjögren e Sjögren-Larsson, todas relacionadas a distúrbios genéticos e sintomas neurológicos. Neste artigo, pretendemos descrever cada desordem, a fim de evitar qualquer mal-entendido no diagnóstico e para registro histórico.