Genotype-specific spinal cord damage in spinocerebellar ataxias: an ENIGMA-Ataxia study.

BACKGROUND: Spinal cord damage is a feature of many spinocerebellar ataxias (SCAs), but well-powered in vivo studies are lacking and links with disease severity and progression remain unclear. Here we characterise cervical spinal cord morphometric abnormalities in SCA1, SCA2, SCA3 and SCA6 using a large multisite MRI dataset. METHODS: Upper spinal cord (vertebrae C1-C4) cross-sectional area (CSA) and eccentricity (flattening) were assessed using MRI data from nine sites within the ENIGMA-Ataxia consortium, including 364 people with ataxic SCA, 56 individuals with preataxic SCA and 394 nonataxic controls. Correlations and subgroup analyses within the SCA cohorts were undertaken based on disease duration and ataxia severity. RESULTS: Individuals in the ataxic stage of SCA1, SCA2 and SCA3, relative to non-ataxic controls, had significantly reduced CSA and increased eccentricity at all examined levels. CSA showed large effect sizes (d>2.0) and correlated with ataxia severity (r<-0.43) and disease duration (r<-0.21). Eccentricity correlated only with ataxia severity in SCA2 (r=0.28). No significant spinal cord differences were evident in SCA6. In preataxic individuals, CSA was significantly reduced in SCA2 (d=1.6) and SCA3 (d=1.7), and the SCA2 group also showed increased eccentricity (d=1.1) relative to nonataxic controls. Subgroup analyses confirmed that CSA and eccentricity are abnormal in early disease stages in SCA1, SCA2 and SCA3. CSA declined with disease progression in all, whereas eccentricity progressed only in SCA2. CONCLUSIONS: Spinal cord abnormalities are an early and progressive feature of SCA1, SCA2 and SCA3, but not SCA6, which can be captured using quantitative MRI.

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.

Spatiotemporal Gait Analysis of Patients with Spinocerebellar Ataxia Types 3 and 10 Using Inertial Measurement Units: A Comparative Study.

Given the high morbidity related to the progression of gait deficits in spinocerebellar ataxias (SCA), there is a growing interest in identifying biomarkers that can guide early diagnosis and rehabilitation. Spatiotemporal parameter (STP) gait analysis using inertial measurement units (IMUs) has been increasingly studied in this context. This study evaluated STP profiles in SCA types 3 and 10, compared them to controls, and correlated them with clinical scales. IMU portable sensors were used to measure STPs under four gait conditions: self-selected pace (SSP), fast pace (FP), fast pace checking-boxes (FPCB), and fast pace with serial seven subtractions (FPS7). Compared to healthy subjects, both SCA groups had higher values for step time, variability, and swing time, with lower values for gait speed, cadence, and step length. We also found a reduction in speed gain capacity in both SCA groups compared to controls and an increase in speed dual-task cost in the SCA10 group. However, there were no significant differences between the SCA groups. Swing time, mean speed, and step length were correlated with disease severity, risk of falling and functionality in both clinical groups. In the SCA3 group, fear of falling was correlated with cadence. In the SCA10 group, results of the Montreal cognitive assessment test were correlated with step time, mean speed, and step length. These results show that individuals with SCA3 and SCA10 present a highly variable, short-stepped, slow gait pattern compared to healthy subjects, and their gait quality worsened with a fast pace and dual-task involvement.

Imbalance and gait impairment in Parkinson's disease: discussing postural instability and ataxia.

Gait and balance difficulties pose significant clinical challenges in Parkinson's disease (PD). The impairment of physiological mechanisms responsible for maintaining natural orthostatism plays a central role in the pathophysiology of postural instability observed in PD. In addition to the well-known rigidity and abnormalities in muscles and joints, various brain regions involved in the regulation of posture, balance, and gait, such as the basal ganglia, cerebellum, and brainstem regions like the pontine peduncle nucleus, are affected in individuals with PD. The recognition of the cerebellum's role in PD has been increasingly acknowledged. Cortical areas and their connections are associated with freezing of gait, a type of frontal lobe ataxia commonly observed in PD. Furthermore, impairments in the peripheral nervous system, including those caused by levodopatherapy, can contribute to gait impairment and imbalance in PD patients. Consequently, individuals with PD may exhibit frontal ataxia, sensory ataxia, and even cerebellar ataxia as underlying causes of gait disturbances and imbalance, starting from the early stages of the disease. The complex interplay between dysfunctional brain regions, impaired cortical connections, and peripheral nervous system abnormalities contributes to the multifaceted nature of gait and balance difficulties in PD. Understanding the intricate mechanisms is crucial for the development of effective therapeutic approaches targeting these specific deficits in PD.

Diagnostic Yield of NGS Tests for Hereditary Ataxia: a Systematic Review.

Next-generation sequencing (NGS), comprising targeted panels (TP), exome sequencing (ES), and genome sequencing (GS) became robust clinical tools for diagnosing hereditary ataxia (HA). Determining their diagnostic yield (DY) is crucial for optimal clinical decision-making. We conducted a comprehensive systematic literature review on the DY of NGS tests for HA. We searched PubMed and Embase databases for relevant studies between 2016 and 2022 and manually examined reference lists of relevant reviews. Eligible studies described the DY of NGS tests in patients with ataxia as a significant feature. Data from 33 eligible studies showed a median DY of 43% (IQR = 9.5-100%). The median DY for TP and ES was 46% and 41.9%, respectively. Higher DY was associated with specific phenotype selection, such as episodic ataxia at 68.35% and early and late onset of ataxia at 46.4% and 54.4%. Parental consanguinity had a DY of 52.4% (p = 0.009), and the presumed autosomal recessive (AR) inheritance pattern showed 62.5%. There was a difference between the median DY of studies that performed targeted sequencing (tandem repeat expansion, TRE) screening and those that did not (p = 0.047). A weak inverse correlation was found between DY and the extent of previous genetic investigation (rho = - 0.323; p = 0.065). The most common genes were CACNA1A and SACS. DY was higher for presumed AR inheritance pattern, positive family history, and parental consanguinity. ES appears more advantageous due to the inclusion of rare genes that might be excluded in TP.

An Exploratory Survey on the Care for Ataxic Patients in the American Continents and the Caribbean.

Little is known about access of rare disease carriers to health care. To increase this knowledge, the Pan American Hereditary Ataxia Network (PAHAN) conducted an exploratory survey about care for hereditary ataxias in American continents and the Caribbean. A questionnaire was sent to health professionals about the hereditary ataxias identified; access to care; and local teaching and research. The number of ataxics under current care per 100,000 inhabitants was subtracted from the expected overall prevalence of 6/100,000, to estimate the prevalence of uncovered ataxic patients. Local Human Development Indexes (HDI) were used to measure socio-economic factors. Twenty-six sites participated. Twelve sites had very high, 13 had high, and one site had medium HDI. Participants reported on 2239 and 602 patients with spinocerebellar ataxias and recessive forms under current care. The number of patients under current care per inhabitants varied between 0.14 and 12/100,000. The estimated prevalence of uncovered ataxic patients was inversely proportional to HDIs (rho = 0.665, p = 0.003). Access to diagnosis, pre-symptomatic tests, and rehabilitation were associated with HDIs. More and better molecular diagnostic tools, protocols and guidelines, and professional training for ataxia care were the top priorities common to all respondents. Evidence of inequalities was confirmed. Lower HDIs were associated with high potential numbers of uncovered ataxic subjects, and with lack of molecular diagnosis, pre-symptomatic testing, and rehabilitation. More and better diagnostic tools, guidelines, and professional training were priorities to all sites. PAHAN consortium might help with the last two tasks.

Epidemiological and clinical characteristics predictive of ICU mortality of patients with traumatic brain injury treated at a trauma referral hospital - a cohort study.

BACKGROUND: Traumatic brain injury (TBI) has substantial physical, psychological, social and economic impacts, with high rates of morbidity and mortality. Considering its high incidence, the aim of this study was to identify epidemiological and clinical characteristics that predict mortality in patients hospitalized for TBI in intensive care units (ICUs). METHODS: A retrospective cohort study was carried out with patients over 18 years old with TBI admitted to an ICU of a Brazilian trauma referral hospital between January 2012 and August 2019. TBI was compared with other traumas in terms of clinical characteristics of ICU admission and outcome. Univariate and multivariate analyses were used to estimate the odds ratio for mortality. RESULTS: Of the 4816 patients included, 1114 had TBI, with a predominance of males (85.1%). Compared with patients with other traumas, patients with TBI had a lower mean age (45.3 ± 19.1 versus 57.1 ± 24.1 years, p < 0.001), higher median APACHE II (19 versus 15, p < 0.001) and SOFA (6 versus 3, p < 0.001) scores, lower median Glasgow Coma Scale (GCS) score (10 versus 15, p < 0.001), higher median length of stay (7 days versus 4 days, p < 0.001) and higher mortality (27.6% versus 13.3%, p < 0.001). In the multivariate analysis, the predictors of mortality were older age (OR: 1.008 [1.002-1.015], p = 0.016), higher APACHE II score (OR: 1.180 [1.155-1.204], p < 0.001), lower GCS score for the first 24 h (OR: 0.730 [0.700-0.760], p < 0.001), greater number of brain injuries and presence of associated chest trauma (OR: 1.727 [1.192-2.501], p < 0.001). CONCLUSION: Patients admitted to the ICU for TBI were younger and had worse prognostic scores, longer hospital stays and higher mortality than those admitted to the ICU for other traumas. The independent predictors of mortality were older age, high APACHE II score, low GCS score, number of brain injuries and association with chest trauma.

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.

The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

"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.

A Diagnostic Approach to Spastic ataxia Syndromes.

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.

BRPF1-associated syndrome: A patient with congenital ptosis, neurological findings, and normal intellectual development.

In 2017, Mattiolli et al. and Yan et al. described a series of patients with clinical findings essentially characterized by intellectual disabilities, ptosis, hypotonia, epilepsy, and weakness. They also found in these patients distinct heterozygous mutations in the BRPF1 gene, which plays a role in epigenetic regulation by promoting histone acetylation. The disease is known as Intellectual Developmental Disorder with Dysmorphic Facies and Ptosis (IDDDFP, OMIM #617333). Later, another 20 patients were also described by distinct reports, suggesting IDDDFP could be a more frequent cause of intellectual disability as it was thought before. Here, we describe a patient with normal intellectual development who had congenital ptosis, hypotonia, muscular weakness, atlanto-axial malformation, and pyramidal at the neurological examination. The patient has a rare nonsense variant on exon 3 of BRPF1 gene. We also describe a phenotypic amplification for conditions related to deficiency in histone modifications.

Treatment of occipital neuralgia using onabotulinum toxin A.

OBJECTIVES: To determine the effectiveness of botulinum toxin in a sample of patients diagnosed with greater occipital nerve neuralgia. MATERIAL AND METHODS: Twenty-nine patients (28 females, 1 male) were treated for greater occipital nerve neuralgia with onabotulinum toxin type A; the Visual Analog Pain Scale was used to determine pain severity at treatment and again 12 weeks after application. RESULTS: Average doses of onabotulinum toxin type A of 18.66±6.44 U per nerve and 35.96±12.89 U per patient were utilized. Average pain severity among the sample was 9.81±0.89 prior to botulinum toxin application and 3.68±2.31 points (p<0.0001) twelve weeks after application. Pain frequency decreased from 29.93±0.37 to 12.17±11.05 days with pain per month (p<0.0001). Six patients reported absence of pain after application (p=0.023). Dose did not correlate with the degree of clinical response observed, and no side effects were reported. CONCLUSION: Our findings suggest onabotulinum toxin type A is a safe and effective treatment alternative for patients suffering from refractory greater occipital nerve neuralgia.

Aphasia localization: was Pierre Marie right?

Language and its associated disorders have puzzled humanity since the dawn of civilization. The first descriptions of aphasia go back to classical antiquity. The Egyptians and Babylonians believed speech was a divine gift to mortals, and their descriptions of aphasia attributed these events to their Gods' anger and disfavour. The Edwin Smith Surgical Papyrus and the Hippocratic Corpus report several aphasia cases, relating this phenomenology to apoplexy, epilepsy, and other illnesses.

Désiré Bourneville: A Socialist in Charcot's Inner Circle.

Désiré Bourneville was one of Jean-Martin Charcot's most important disciples. His previous works as an alienist allowed him to influence his master's interest in hysteria, which led to the creation of a service regarded as a neurological mecca. During his time under Charcot, Bourneville, a passionate left-wing radical, had to coexist with characters representative of the conservative, bourgeois Parisian society. The aim of this study is to describe Bourneville's life and work, as well as the ambiguity of a progressive man such as him, immersed within the economic and cultural elites.

Charcot's Anglophilia.

Jean-Martin Charcot was one of the most influential physicians of the nineteenth century and is now rightly considered the father of Neurology. The aim of this paper was to review and describe Charcot's close relationships to Britain and the influence of this particular affinity on his career.

Autosomal Recessive Cerebellar Ataxia 1: First Case Report Depicting a Variant in SYNE1 Gene in a Chilean Patient.

Autosomal recessive cerebellar ataxia type 1 (ARCA-1) or spinocerebellar ataxia autosomal recessive type 8 (SCAR8) is a slowly progressive neurodegenerative disorder that occurs due to mutations in the spectrin repeat containing nuclear envelope protein 1 (SYNE1) gene. Previously considered a rare cause of ARCA, related to French-Canadian patients from Beauce, Quebec, Canada, SYNE1 ataxia is now known to be of worldwide distribution. We present the case report of a 54-year-old male patient with the genetic diagnosis of SYNE1 ataxia, presenting with a SYNE1 gene mutation never described in Chilean population before.

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.

Balance and physical functioning in Spinocerebellar ataxias 3 and 10.

OBJECTIVES: Limitations of functional capacity and balance are common features of the natural history of spinocerebellar ataxias (SCA). However, their onset and progression patterns differ according to subtype. The aim of our study was to compare physical functionality and balance parameters in SCA10 and SCA3 patients, correlating with clinical variables. MATERIALS & METHODS: Cross-sectional study evaluating ninety-five SCA patients (60 with SCA3 and 35 with SCA10) with validated scales for functional independence, balance and the severity of signs and symptoms. RESULTS: The groups were similar in terms of age and gender, and results were adjusted for age at symptom onset. The SCA10 patients had better results for balance and functional independence (p < 0.007). They also had lower scores for disease severity (p < 0.0002) and the subitems gait (p < 0.0005), posture (p < 0.0021) and sitting balance (p < 0.0008). Symptom progression in both groups was similar for patients with a disease duration of up to ten years, but there was a more marked decline in SCA3 patients after this period. CONCLUSIONS: We have shown that disease progression as assessed by balance and physical functioning is slower in SCA10 patients than SCA3 patients, particularly after 10 years of disease. These findings are important as they can help to characterize the disease, assisting in the development of new therapies and rehabilitation programs.

Freezing of gait (FOG) in Parkinson's disease patients-the contribution of Garcin and Melaragno.

Raymond Garcin, professor of neurology in Paris, France, and his Brazilian assistant, Professor Roberto Melaragno described in 1948 the phenomenon defined as "bégaiement de la mise en route du mouvement" in patients with Parkinson's disease. This was one of the first descriptions of freezing of gait (FOG) in the world.

Charcot: Buddhist Leanings?

Jean-Martin Charcot, considered the father of modern neurology, had a complex personality featuring well-defined characteristics of introversion, competitiveness, irony, and skepticism. While biographers have described him as Republican, anticlerical, and agnostic, the literature also presents evidence that he came to admire Buddhism toward the end of his life; Charcot's involvement with numerous patients suffering from incurable and insidious neurological diseases may have contributed to this change in attitude.