Journal of Huntington's disease最新文献

BackgroundHuntington's Disease (HD) is a hereditary neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) repeat expansion (CAG > 35) in the Huntingtin (HTT) gene. Intermediate alleles (IAs, CAG = 27-35) are generally not associated with HD. However, IA carriers with symptoms have been reported in literature.ObjectiveTo review the existing literature on IAs, in order to provide an overview of the clinical phenotype of IA carriers.MethodsPeer-reviewed articles published between 1993 and July 2024 from three databases (Embase, PubMed, and Web of Science) were included.ResultsIn case reports, a high percentage (90%) of IA carriers was reported to have symptoms (HD-related and -unrelated), or abnormalities in neuroimaging. Cohort studies also reported evidence of symptoms in IA carriers, although most cohorts did not obtain significant differences compared to controls.ConclusionBased on this review, we argue that there is not enough evidence to draw a clear conclusion on the clinical phenotype of individuals carrying an intermediate allele of the HTT gene. Literature reports symptomatic IA carriers, but reported symptoms are non-specific and common in the general population. Additionally, the quality of the data is suboptimal, due to lack of detailed symptom descriptions, the absence of differential diagnoses, a selection bias, and a considerable publication bias towards IA carriers with symptoms. More research is needed to provide a better insight into the clinical phenotype of IA carriers.

Background: Huntington's disease (HD) is a progressive neurodegenerative disorder primarily affecting the central nervous system (CNS). However, emerging evidence suggests that peripheral tissues, including skeletal muscle and bone, also undergo pathological changes contributing to disease burden. Objective: To characterize musculoskeletal impairments in the zQ175 knock-in (KI) mouse model of HD, through integrated behavioral, biomechanical, and imaging analyses. Methods: Motor function was assessed using grip strength, rotarod, and open field testing. Ex vivo contractility of the extensor digitorum longus (EDL) and Soleus (Sol) muscles was measured. Muscle fiber cross-sectional area (CSA) was quantified using semi-automated segmentation. Bone microarchitecture was analyzed using high-resolution micro-computed tomography (μCT). Results: Six-month-old homozygous zQ175 mice exhibited significantly reduced muscle strength and impaired contractile properties in both the EDL and Soleus muscles compared to wild-type (WT) controls. µCT analysis revealed decreased trabecular bone volume and alterations in bone structure. Conclusions: These findings provide a comprehensive musculoskeletal phenotyping of zQ175 mice, revealing early-onset muscle atrophy and skeletal fragility. Our study highlights the importance of targeting peripheral manifestations in HD and establishes zQ175 KI mice as a valuable additional model for investigating systemic disease mechanisms.

BackgroundHuntington's disease is a rare, progressive, neurodegenerative disease. Capturing symptomatic progression and treatment effects reliably in clinical therapeutic trials has shown to be a challenging task, facing the problem of small cohorts and a variable phenotype. Hence, robust and sensitive outcome measures are needed, to assess efficacy and safety of novel therapies in clinical studies with small cohorts.ObjectiveObjectives of this study were to assess feasibility, discriminative potential, and correlation to clinical and imaging endpoints of the Q-Motor isometric force matching task with visual feedback. Furthermore, a statistical comparison with the Q-Motor grasping and lifting task should be assessed.Methods220 huntingtin gene expansion carriers (HGEC) and 110 non-huntingtin gene expansion carrier (Non-HGEC) participants of the observational TRACK-HD study completed the Q-Motor force matching assessment, along with a standard battery of clinical tests (UHDRS) and MRI assessments. During the Q-Motor force matching assessments, patients were reproducing a target force in precision grip with help of visual feedback. Q-Motor utilizes a highly sensitive force transducer to record force feedback. HGEC participants were categorized into four groups by a CAG- and age-based survival score.ResultsQ-Motor force matching allowed for very good discrimination between HGEC and Non-HGEC participant groups (p < 0.001 for all but least affected HGEC group) and between different HGEC groups (all p < 0.05). Strong correlations with UHDRS scores (TMS = -0.708, TFC = -0.638), CAG-Age product scores (Survival Score = 0.626) and imaging outcomes (caudate volume = -0.609, striatum volume = -0.624) were observed. A statistical difference between correlation strength of Q-Motor force matching and Q-Motor grasping and lifting tasks could not be observed.ConclusionsCross-sectional analysis of Q-Motor force matching showed promising results, outperforming clinical rating scales in sensitivity. Further efforts are required to assess longitudinal robustness of the task, and to further explore its potential of capturing cognitive effects by increasing cognitive load during the task.

A recent retrospective analysis of Enroll HD data suggesting β-blockers slow Huntington's disease progression has triggered patient demand but requires caution. The findings rely solely on small observational subsets and are vulnerable to bias and confounding. A prior Mendelian-randomization study found no causal link between β-blockers and HD onset; instead, genetically higher blood pressure was associated with later onset, raising concern that β-blockers' BP-lowering effects could be harmful. HD patients also have lower hypertension rates, and β-blockers carry risks such as depression and bradycardia. Given their heterogeneous mechanisms, rigorous experimental and clinical trials are needed before any clinical recommendations.

In this edition of the Huntington's Disease Clinical Trials Update, we expand on the launch of the phase II/III clinical trial of SKY-0515 from Skyhawk Therapeutics and the phase I/II clinical trial of SPK-10001 from Spark Therapeutics. We also report positive topline data from uniQure's phase I/II clinical trial of AMT-130 after 36 months of follow-up. Further updates include recent developments in Roche's tominersen programme within GENERATION HD2, progress with votoplam (PTC518) in PIVOT-HD by PTC Therapeutics and developments in the collaborative PTC Therapeutics/Novartis programme. We additionally discuss regulatory developments regarding pridopidine following the negative PROOF-HD study. Finally, we provide an updated listing of all registered and ongoing clinical trials in Huntington's disease.

BackgroundThe HTT protein, mutated in Huntington's disease, is expressed throughout the body, and loss of HTT function as an autophagic scaffold may affect tissues and cellular processes. These processes include lipid metabolism potentially regulated upstream by Apolipoprotein E (APOE) and clearance of APOE itself.ObjectiveTo determine the impact of HTT reduction on autophagy and clearance of APOE in cell culture and in mouse liver in vivo.MethodsWestern blot analysis was performed on liver tissue from tamoxifen-treated mice with and without UBC-Cre expression, required for tamoxifen-induced HTT knockout (KO). siRNA was used to knockdown (KD) HTT in HepG2 immortalized liver cells.ResultsHTT KO in mouse liver reduces levels of LAMP2A, a protein essential for chaperone-mediated autophagy (CMA) which we previously found is required for optimal degradation of APOE and HTT in cultured cells. In turn, APOE levels were increased with HTT KO in mouse liver, while HTT KD in cell culture decreased levels of APOE.ConclusionsIn the context of liver tissue, reduced CMA may contribute to accumulation of APOE and autophagic cargo resulting from a loss of HTT function in autophagy. The extent to which macroautophagy is upregulated to cope with reduced CMA found with HTT KO may be tissue specific, which may relate to the selectivity of tissue pathogenesis observed in Huntington's disease where loss of normal HTT function may be involved. This study may help elucidate the consequences of systemic HTT reduction on autophagy in liver tissue.

BackgroundDeficits of emotion recognition have received increasing attention in people with Huntington's disease (HD) in the three decades since the discovery of the HD gene. However, the characterisation of such deficits across different disease stages, types of stimuli, and sensory modalities is currently unclear.ObjectiveThis study aimed to provide a comprehensive review of the evidence on emotion recognition deficits in HD gene carriers (both manifest and premanifest) over the three decades since definitive gene testing.MethodA systematic review was carried out from January 1993 to January 2025 across MEDLINE, PsycINFO, Academic Search Complete, and CINAHL (PROSPERO registration: CRD42023398649).ResultsFrom 9735 initial citations, 59 studies were eventually included. In manifest HD, facial recognition of negative emotions such as anger, fear, disgust, and sadness was consistently impaired, whereas happiness and neutral expressions were generally spared. A few auditory studies showed consistent deficits for disgust, fear, and anger, while happiness and sadness appeared less affected. Only preliminary evidence is currently available for deficits involving body language, visual and written vignettes, videos, and olfactory and gustatory tasks. Although sparser, the evidence for premanifest HD suggests that some individuals may develop significant recognition difficulties prior to motor onset, particularly due to early frontostriatal deterioration and white matter disruption.ConclusionsImpairments of facial recognition of negative emotions are reported consistently in manifest HD, while only preliminary results are available for other modalities. The evidence involving premanifest HD is much sparser. Key implications for clinical practice and future research are outlined and discussed.

BackgroundAs Huntington's disease (HD) progresses, it impairs airway protection, increasing the risk of aspiration pneumonia-the leading cause of death in HD. Although voluntary peak cough flow (vPCF) assesses cough effectiveness, its clinical use is limited by time and equipment constraints.ObjectiveThis study evaluates handgrip strength (HGS) and the Index of Pulmonary Dysfunction (IPD) as simpler screening tools and aims to define gender-specific thresholds for identifying cough dysfunction (dystussia) in HD patients.MethodsIn this prospective cross-sectional study, 71 patients with HD underwent assessments of HGS, IPD, vPCF, respiratory muscle strength, and were rated using the Unified Huntington's Disease Rating Scale. Logistic regression and ROC analyses were used to assess the predictive value of HGS and IPD for dystussia (vPCF <300 L/min).ResultsAmong 32 females and 39 males, 30 exhibited dystussia and had more advanced disease. HGS showed AUCs of 0.82 (females) and 0.89 (males), IPD 0.86 overall. Combining HGS and IPD improved accuracy.ConclusionsHGS and IPD appear to be effective tools for initial dystussia screening in HD.Trial registrationNCT06585332.

The identification of the repeat expansion which causes Huntington's disease in 1993 soon led to a clinical genetic test for the condition, enabling people at risk to have a test to determine whether they will get the disease. The primary determinant of age at onset in Huntington's disease is CAG repeat length, but in recent years there have been advances in identifying and characterising genetic modifiers which influence age at onset. This has led to the question of whether these data may be applied clinically to improve clinical practice. Here, on behalf of the European Huntington's Disease Network (EHDN) Genetic Testing and EHDN Genetic Modifiers Working Groups, we review the current state of genetic testing for Huntington's disease and consider the personal impact that pre-symptomatic genetic testing has on those that undertake it. We then discuss how genetic information could be used to improve onset prediction clinically, and whether it could be applied in clinical trials stratification. We conclude by proposing short, medium and long-term recommendations to improve the use of genetic data to in clinical practice and clinical trials.