Enfermedad de Huntington de inicio en la infancia. Una presentación poco frecuente / Childhood-onset Huntignton´s disease. A rare presentation

Introducción La enfermedad de Huntington (EH) es una enfermedad de herencia autosómica dominante caracterizada por la expansión de tripletes de citosina-adenina-guanina (CAG) en el gen que codifica la huntingtina. Los síntomas en la descendencia suelen ser más tempranos por el fenómeno de anticipación. La clínica de inicio en la infancia, antes de los 10 años, difiere de la observada en la adultez. Se manifiesta por afectación motora, dificultades conductuales y retraso o regresión del desarrollo. La corea es infrecuente. El objetivo del caso es describir aspectos clínicos de una paciente con EH de inicio infantil. Caso clínico Niña de 5 años con antecedentes familiares de EH y desarrollo típico hasta los 3 años. Presentó progresivamente afectación del lenguaje con habilidades descendidas para su edad en aspectos expresivos y comprensivos, sin afectación en las habilidades pragmáticas y sociales. En cuanto a la motricidad, la marcha y la bipedestación eran inestables, y mostraba rigidez, distonía y movimientos coreicos. Presentó atrofia de los núcleos lenticulares y caudados en la resonancia magnética, y posteriormente se realizó el diagnóstico molecular con la expansión de tripletes CAG (51 copias). Conclusión La EH de inicio en la infancia presenta manifestaciones clínicas distintas a la forma del adulto. Debe considerarse en pacientes con afectación motora y cognitiva progresiva. Por la herencia familiar, es importante interrogar cuidadosamente sobre los antecedentes familiares y tenerla en cuenta aun sin familiares afectados por el fenómeno de anticipación. (AU)

INTRODUCTIO NHuntington’s disease (HD) is a rare autosomal dominant disease caused by the expansion of CAG triplets in the gene that encodes huntingtin. There are earlier symptoms’ onset in offspring due to the phenomenon of anticipation. The clinical features of childhood-onset HD, before age 10 years, differs from adult-onset form. It is characterized by motor impairment, behavioral difficulties and delay or regression in areas of development; while chorea is rarely seen. In this case we describe clinical aspects of a patient with childhood-onset Huntington’s disease. CASE REPORT A 5-year-old girl with a family history of HD and typical development up to 3 years of age. She progressively acquired language impairment with skills that were below her age in expressive and receptive areas, without deficits in pragmatic and social skills. Regarding motor skills, she manifested instability at walking and standing, with rigidity, dystonia and choreic movements. Atrophy of the basal ganglia was evident on MRI, EEG was normal, and molecular confirmation of CAG triplet revealed repeat length of 51 copies. CONCLUSION. Childhood-onset HD differs from adult-form´s clinical manifestations. It should be considered in patients with progressive motor and cognitive impairment. Due to family inheritance, it is important to carefully examine family history and take it into account even without relatives affected, considering the anticipation phenomenon. (AU)

Associations of inflammatory cytokines and cortisol with nonmotor features of Huntington's disease.

OBJECTIVE: Huntington's disease (HD) is an inherited neurodegenerative disease involving progressive motor abnormalities, cognitive decline, and psychiatric disturbances. Depression and cognitive difficulties are among the most impactful symptoms of HD, yet the pathogenesis of these symptoms is not fully understood. HD involves low-level chronic inflammation and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, which are linked to depression and cognitive impairment in non-HD populations. However, previous research on the relationships of these pathologies with depression and cognition in HD is limited and inconsistent. METHODS: Fifty-three adults with the HD gene expansion (30 premanifest and 23 manifest) completed measures of depression and cognitive functioning. Forty-eight out of 53 participants provided hair samples for quantification of cortisol, and 34 participants provided blood samples for quantification of peripheral inflammatory cytokines. We examined the associations of four cytokines (interleukin [IL]-6, IL-10, IL-1ß, and tumor necrosis factor [TNF]-α) and cortisol levels with depression and cognitive scores. RESULTS: In unadjusted models, higher levels of plasma IL-6, IL-10, and TNF-α correlated with higher depression scores, and higher levels of IL-10 and TNF-α correlated with poorer cognitive performance. After controlling for age, sex, and body mass index, only the correlations of IL-10 with depression and cognitive performance remained significant. No correlations were evident with hair cortisol. INTERPRETATIONS: Peripheral inflammation is associated with depression symptoms and cognitive impairment in HD. Our findings suggest that interactions between the immune and nervous systems are important in HD, and highlight the potential of chronic inflammation as a therapeutic target in early stages of HD.

The potential roles of salivary biomarkers in neurodegenerative diseases.

Current research efforts on neurodegenerative diseases are focused on identifying novel and reliable biomarkers for early diagnosis and insight into disease progression. Salivary analysis is gaining increasing interest as a promising source of biomarkers and matrices for measuring neurodegenerative diseases. Saliva collection offers multiple advantages over the currently detected biofluids as it is easily accessible, non-invasive, and repeatable, allowing early diagnosis and timely treatment of the diseases. Here, we review the existing findings on salivary biomarkers and address the potential value in diagnosing neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and Amyotrophic lateral sclerosis. Based on the available research, ß-amyloid, tau protein, α-synuclein, DJ-1, Huntington protein in saliva profiles display reliability and validity as the biomarkers of neurodegenerative diseases.

[The value of re-evaluation and thorough family history taking for the diagnostic work-up of chorea]. / Het diagnostisch proces bij chorea: het belang van heroverwegen en de familieanamnese.

The differential diagnosis of chorea encompasses a broad range of disorders. In psychiatry, tardive dyskinesia may be difficult to discern from other causes, particularly when the family history is negative. A 59-year-old man with an unclear medical history had been using risperidone for over a decade when we first saw him. He presented with severe dyskinesia in all extremities. The family history for neuropsychiatric disorders was negative. We interpreted the movement disorder as tardive dyskinesia, but later he turned out to suffer from Huntington’s disease. To improve diagnostic accuracy, we should have more frequently re-evaluated the differential diagnosis and our family history should have been more thorough. We outline the diagnostic considerations in patients presenting with chorea. Finally, we highlight the value of diagnostic re-evaluation and thorough family history taking to optimize diagnostic accuracy in neuropsychiatry.

Prodromal Cognitive Changes as a Prognostic Indicator of Forthcoming Huntington's Disease Severity: A Retrospective Longitudinal Study.

BACKGROUND: Cognitive changes in Huntington's disease (HD) precede motor manifestations. ENROLL-HD platform includes four cognitive measures of information processing speed (IPS). Our group is eager to seek clinical markers in the life stage that is as close as possible to the age of onset (ie, the so called prodromal HD phase) because this is the best time for therapeutic interventions. OBJECTIVES: Our study aimed to test whether cognitive scores in prodromal ENROLL-HD mutation carriers show the potential to predict the severity of motor and behavioral changes once HD became fully manifested. METHODS: From the global ENROLL-HD cohort of 21,343 participants, we first selected a premanifest Cohort#1 (ie, subjects with Total Motor Score (TMS) <10 and Diagnostic Confidence Level (DCL) <4, N = 1.222). From this cohort, we then focused on a prodromal Cohort#2 of subjects who were ascertained to phenoconvert into manifest HD at follow-up visits (ie, subjects from 6 ≤ TMS≤9 and DCL <4 to TMS≥10 and DCL = 4, n = 206). RESULTS: The main results of our study showed that low IPS before phenoconversion in Cohort#2 predicted the severity of motor and behavioral manifestations. By combining the four IPS cognitive measures (eg, the Categorical Verbal Fluency Test; Stroop Color Naming Test; Stroop Word Reading; Symbol Digit Modalities Test), we generated a Composite Cognition Score (CCS). The lower the CCS score the higher the TMS and the apathy scores in the same longitudinally followed-up patients after phenoconversion. CONCLUSIONS: CCS might represent a clinical instrument to predict the prognosis of mutation carriers who are close to manifesting HD.

A rare case report of Huntington's disease with severe psychiatric symptoms as initial manifestations.

INTRODUCTION: Huntington's disease (HD) stands as an inherited and progressive neurodegenerative ailment distinguished by chorea-esque movement patterns, which manifest as archetypal symptoms. The presence of pronounced psychiatric onset symptoms in patients can considerably amplify the intricacies of accurate diagnosis. CASE PRESENTATION: A 43-year-old gentleman was admitted with a five-year chronicle of delusions, hallucinations, and irritability. He had previously received a diagnosis of schizophrenia and had been subjected to a regimen of antipsychotic medications for a span exceeding four years. However, subsequent to the application of cerebral MRI and genetic testing, his condition was conclusively redetermined as HD. CONCLUSION: The salient attribute of this case resides in the deferred diagnosis of HD attributable to the presence of acute psychiatric initial symptoms, a scenario bearing noteworthy ramifications for disease oversight and prognostication. This instance warrants attentive scrutiny and discourse within the professional community.

Validity, diagnostics and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in Huntington's disease.

BACKGROUND: This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). METHODS: N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. RESULTS: The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC = .92), yielding optimal diagnostics at the cut-off of < 19.945 (J = .78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p = .037), as well as to differentiate HD patients from both HCs (p < .001) and PD patients (p < .001). CONCLUSIONS: The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research.

Underestimated olfactory domains in Huntington's disease: odour discrimination and threshold.

BACKGROUND: Olfaction has recently found clinical value in prediction, discrimination and prognosis of some neurodegenerative disorders. However, data originating from standard tests on olfactory dysfunction in Huntington's disease are limited to odour identification, which is only one domain of olfactory perceptual space. METHOD: Twenty-five patients and 25 age- and gender-matched controls were evaluated by the Sniffin' Sticks test in three domains of odour threshold, odour discrimination, odour identification and the sum score of them. Patients' motor function was assessed based on the Unified Huntington's Disease Rating Scale. RESULTS: Compared with controls, patients' scores of all olfactory domains and their sum were significantly lower. Besides, our patients' odour threshold and odour discrimination impairments were more frequently impaired than odour identification impairment (86 per cent and 81 per cent vs 34 per cent, respectively). CONCLUSION: Olfactory impairment is a common finding in patients with Huntington's disease; it is not limited to odour identification but is more pronounced in odour discrimination and odour threshold.

Evaluating motor progression of juvenile-onset Huntington's Disease: An Enroll-HD analysis.

INTRODUCTION: Juvenile-onset Huntington's disease (JOHD) is characterized by a unique motor phenotype relative to patients with adult-onset Huntington's Disease (AOHD). This study characterized motor progression of JOHD to propose improved outcome measures for this group. METHODS: We used linear mixed effect regression models to compare progression of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score (TMS) and the chorea score between patients with JOHD and AOHD. We then evaluated all 31 subscales that make up the UHDRS over time within patients with JOHD to identify measures that may be used to track motor progression most reliably. RESULTS: The JOHD cohort had faster TMS progression compared to AOHD (p = 0.006) but no group difference in the rate of change of chorea. Patients with JOHD did not show significant change in any of the chorea subscales. The subscales that changed most reliably over time amongst patients with JOHD were dysarthria, upper extremity dystonia, tandem walking, gait, bilateral pronate/supinate, bilateral finger-tapping, and tongue protrusion. When these subscales were summed, they progressed at a faster rate (7.07%, 95% CI [5.96-8.18]) than the TMS (4.92%, 95% CI [3.95-5.89]). CONCLUSION: While the TMS changes at a significant rate in JOHD subjects, not all subscales that make up the TMS accurately represent the unique motor features of JOHD. A JOHD-specific scale performed better at tracking motor progression relative to the TMS. This scale may improve clinical care for patients with JOHD and allow for the development of more efficient clinical trials.

How to estimate body composition in Huntington's disease. A cross-sectional, observational study using multiple frequencies bioimpedance. / Cómo estimar la composición corporal en la enfermedad de Huntington. Estudio transversal y observacional con bioimpedancia de múltiples frecuencias.

INTRODUCTION: Huntington´s disease (HD) is a rare neurodegenerative disorder. Reliable information about nutritional status, especially body composition from individuals with HD is critical for clinical care and research. The ease of application and portability of multiple frequencies bioelectrical impedance analysis (mfBIA) make it an attractive tool for measuring body composition, but its accuracy in HD is unknown. AIM: To evaluate the accuracy of mfBIA vs. Dual X-ray absorptiometry (DEXA) in HD. PATIENTS AND METHODS: Cross-sectional, observational, and single-center study. HD severity was measured using motor subscale of the unified Huntington´s disease rating scale (m-UHDRS) and the total functional capacity (TFC). Body composition was measured in terms of fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI). Using Bland-Altman plots, we analyzed reliability between DEXA and mfBIA using the Intraclass Correlation Coefficient with 95% confidence intervals (CI) and bias estimates for all. RESULTS: We included 16 patients with HD, 7 men, and 9 women, median age of 58.5 (32;68) years, TFC: 10 (3;13), and m-UHDRS: 31 (7;85). The reliability between mfBIA and DEXA were high for FFMI in men: 0.88 (95% CI 0.17-0.98), and women: 0.90 (95% CI 0.61- 0.98); for FMI, men: 0.97 (95% CI 0.83-0.99), and women: 0.91 (95% CI 0.68-0.98). Compared to DEXA, mfBIA slightly overestimated FFM, FM, FMI and FFMI in men and underestimated FFMI in women. CONCLUSIONS: mfBIA is an easy-to-use, safe, non-invasive, accurate method for measuring body composition and nutritional status in patients with mild-moderate HD.

TITLE: Cómo estimar la composición corporal en la enfermedad de Huntington. Estudio transversal y observacional con bioimpedancia de múltiples frecuencias.Introducción. La enfermedad de Huntington (EH) es un trastorno raro neurodegenerativo. La información fiable del estado nutricional, especialmente de la composición corporal, es crítica en clínica y en investigación. La facilidad de aplicación y portabilidad del análisis de la bioimpedancia de múltiples frecuencias (mfBIA) la convierten en una herramienta atractiva para medirla, pero se desconoce su precisión en la EH. Objetivo. Evaluar la precisión del mfBIA frente a la absorciometría dual de rayos X (DEXA) en la EH. Pacientes y métodos. Estudio transversal, observacional y unicéntrico. La EH se midió con la subescala motora de la escala unificada de valoración de la EH y con la capacidad funcional total. La composición corporal se valoró según la masa libre de grasa (MLG), la masa grasa (MG), el índice de masa libre de grasa (IMLG) y el índice de masa grasa (IMG). Se utilizó el coeficiente de correlación intraclase con intervalos de confianza al 95% y estimaciones de sesgo mediante gráficos de Bland-Altman. Resultados. Se incluyó a 16 pacientes, siete hombres y nueve mujeres, con edad media de 58,5 (32-68) años, capacidad funcional total de 10 (3-13) y escala unificada de valoración de la EH de 31 (7-85). La fiabilidad era alta entre el mfBIA y la DEXA para el IMLG en hombres, 0,88 (intervalo de confianza al 95%: 0,17-0,98), y mujeres, 0,9 (intervalo de confianza al 95%: 0,61-0,98); y para el IMG en hombres, 0,97 (intervalo de confianza al 95%: 0,83-0,99), y mujeres, 0,91 (intervalo de confianza al 95%: 0,68-0,98). El mfBIA sobreestimó ligeramente la MLG, la MG, el IMG y el IMLG en los hombres, pero subestimó el IMLG en las mujeres. Conclusiones. El mfBIA es un método fácil de usar, seguro, no invasivo y preciso para medir la composición corporal y el estado nutricional en pacientes con EH leve-moderada.

Raman spectroscopy of brain and skin tissue in a minipig model of Huntington's disease.

We applied Raman spectroscopy to brain and skin tissues from a minipig model of Huntington's disease. Differences were observed between measured spectra of tissues with and without Huntington's disease, for both brain tissue and skin tissue. There are linked to changes in the chemical composition between tissue types. Using machine learning we correctly classified 96% of test spectra as diseased or wild type, indicating that the test would have a similar accuracy when used as a diagnostic tool for the disease. This suggests the technique has great potential in the rapid and accurate diagnosis of Huntington's and other neurodegenerative diseases in a clinical setting.

Chorea in the Elderly: A Differential Diagnosis and Case Report of Late-Onset Huntington's Disease in an Octogenarian.

The term "senile chorea" was previously used to describe cases of insidious onset chorea in elderly patients who lacked family history of chorea. However, many of these patients have an identifiable etiology for their chorea. In this article, we discuss a case of generalized, insidious onset chorea in an 89-year-old man and apply a systematic diagnostic approach to chorea in the elderly to arrive at a diagnosis of late-onset Huntington's disease. He is to our knowledge the second oldest case of late-onset Huntington's disease reported in the literature and his case lends support to the expanding phenotype of Huntington's disease.

Uncovering the Genetic and Molecular Features of Huntington's Disease in Northern Colombia.

Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.

Memantine administration prevented chorea movement in Huntington's disease: a case report.

BACKGROUND: Huntington's disease is an autosomal dominant inherited disorder characterized by personality changes (such as irritability and restlessness) and psychotic symptoms (such as hallucinations and delusions). When the personality changes become noticeable, involuntary movements (chorea) also develop. The disease is caused by the CAG repeat expansion in the coding region of the HTT gene, and the diagnosis is based on the presence of this expansion. However, there is currently no effective treatment for the progression of Huntington's disease and its involuntary motor symptoms. Herein, we present a case in which memantine was effective in treating the chorea movements of Huntington's disease. CASE PRESENTATION: A 75-year-old Japanese woman presented to the hospital with involuntary movements of Huntington's disease that began when she was 73 years old. In a cerebral blood flow test (N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography), decreased blood flow was observed in the precuneus (anterior wedge) and posterior cingulate gyrus. Usually, such areas of decreased blood flow are observed in patients with Alzheimer's-type dementia. So, we administered memantine for Alzheimer's-type dementia, and this treatment suppressed the involuntary movements of Huntington's disease, and the symptoms progressed slowly for 7 years after the onset of senility. In contrast, her brother died of complications of pneumonia during the course of Huntington's disease. CONCLUSIONS: We recorded changes in parameters such as the results of the N-isopropyl-p-iodoamphetamine-single-photon emission computed tomography and gait videos over 7 years. Treatment with memantine prevented the chorea movement and the progression of Huntington's disease. We believe this record will provide clinicians with valuable information in diagnosing and treating Huntington's disease.

Tau: a biomarker of Huntington's disease.

Developing effective treatments for patients with Huntington's disease (HD)-a neurodegenerative disorder characterized by severe cognitive, motor and psychiatric impairments-is proving extremely challenging. While the monogenic nature of this condition enables to identify individuals at risk, robust biomarkers would still be extremely valuable to help diagnose disease onset and progression, and especially to confirm treatment efficacy. If measurements of cerebrospinal fluid neurofilament levels, for example, have demonstrated use in recent clinical trials, other proteins may prove equal, if not greater, relevance as biomarkers. In fact, proteins such as tau could specifically be used to detect/predict cognitive affectations. We have herein reviewed the literature pertaining to the association between tau levels and cognitive states, zooming in on Alzheimer's disease, Parkinson's disease and traumatic brain injury in which imaging, cerebrospinal fluid, and blood samples have been interrogated or used to unveil a strong association between tau and cognition. Collectively, these areas of research have accrued compelling evidence to suggest tau-related measurements as both diagnostic and prognostic tools for clinical practice. The abundance of information retrieved in this niche of study has laid the groundwork for further understanding whether tau-related biomarkers may be applied to HD and guide future investigations to better understand and treat this disease.

Microprobes for Label-Free Detection of Short Tandem Repeats: An Insight into Alleviating Secondary Structure Effects.

Overgrowth of short tandem repeat sequences in our genes can cause various neurodegenerative disorders. Such repeat sequences are ideal targets for the label-free electrochemical detection of such potential expansions. However, their length- and sequence-dependent secondary structures may interfere with the interfacial charge transfer of a detection platform, making them complex targets. In addition, the gene contains sporadic repeats that may result in false-positive signals. Therefore, it is necessary to design a platform capable of mitigating these effects and ultimately enhancing the specificity of tandem repeats. Here, we analyzed three different backbones of nucleic acid microprobes [DNA, peptide nucleic acid, and lock-nucleic acid (LNA)] to detect in vitro transcribed RNA carrying CAG repeats, which are associated with Huntington's disease, based on the charge-transfer resistance of the interface. We found that the LNA microprobe can distinguish lengths down to the attomolar concentration level and alleviate the effect of secondary structures and sporadic repeats in the sequence, thus distinguishing the "tandem repeats" specifically. Additionally, the control experiments conducted with and without Mg2+ demonstrated the LNA microprobe to perform better in the presence of the divalent cation. The results suggest that the LNA-based platform may eventually lead to the development of a reliable and straightforward biosensor for genetic neurodegenerative disorders.

Pearls & Oy-sters: Epilepsy Is a Key Feature of Pediatric-Onset Huntington Disease.

Pediatric-onset Huntington disease (PoHD) presents differently from adult-onset disease. Children typically exhibit regression in school performance, psychiatric features such as inattention, and oral motor dysfunction. Unlike adult-onset HD, in which seizures occur at approximately the rate of the general public, at least half of children with HD develop epilepsy, and seizures can be a presenting feature of PoHD. Here we present the case of a 10-year-old boy with a history of language delay, motor regression, oral motor dysfunction, and tremor who presented with a first lifetime seizure. Given a family history of Huntington disease in his father, PoHD was considered, and a pathogenic allele with 88 repeats was confirmed in the child. As symptoms progressed, history alone could not differentiate abnormal movements from seizures. Continuous video electroencephalography helped to demonstrate epileptic myoclonic jerks and guide treatment.