RESUMO
PURPOSE: To determine the frequency and clinical impact of loss-of-interruption (LOI) and duplication-of-interruption (DOI) modifier variants of the HTT CAG and CCG repeat in a cohort of individuals with Huntington disease (HD). METHODS: We screened symptomatic HD participants from the UBC HD Biobank and five research sites for sequence variants. Following variant identification, we examined the clinical impact and frequency in the reduced penetrance range. RESULTS: Participants with CAG-CCG LOI and CCG LOI variants have a similar magnitude of earlier onset of HD, by 12.5 years. The sequence variants exhibit ancestry-specific differences. Participants with the CAG-CCG LOI variant also have a faster progression of TMS by 1.9 units per year. Symptomatic participants with the CAG-CCG LOI variant show enrichment in the reduced penetrance range. The CAG-CCG LOI variant explains the onset of two symptomatic HD participants with diagnostic repeats below the pathogenetic range. CONCLUSION: Our findings have significant clinical implications for participants with the CAG-CCG LOI variant who receive inaccurate diagnoses near diagnostic cut-off ranges. Improved diagnostic testing approaches and clinical management are needed for these individuals. We present the largest and most diverse HTT CAG and CCG sequence variant cohort and emphasize their importance in clinical presentation in HD.
RESUMO
Neurodegenerative diseases are characterized by the accumulation of misfolded proteins in the brain. Insights into protein quality control mechanisms to prevent neuronal dysfunction and cell death are crucial in developing causal therapies. Here, we report that various disease-associated protein aggregates are modified by the linear ubiquitin chain assembly complex (LUBAC). HOIP, the catalytic component of LUBAC, is recruited to misfolded Huntingtin in a p97/VCP-dependent manner, resulting in the assembly of linear polyubiquitin. As a consequence, the interactive surface of misfolded Huntingtin species is shielded from unwanted interactions, for example with the low complexity sequence domain-containing transcription factor Sp1, and proteasomal degradation of misfolded Huntingtin is facilitated. Notably, all three core LUBAC components are transcriptionally regulated by Sp1, linking defective LUBAC expression to Huntington's disease. In support of a protective activity of linear ubiquitination, silencing of OTULIN, a deubiquitinase with unique specificity for linear polyubiquitin, decreases proteotoxicity, whereas silencing of HOIP has the opposite effect. These findings identify linear ubiquitination as a protein quality control mechanism and hence a novel target for disease-modifying strategies in proteinopathies.
Assuntos
Proteína Huntingtina/metabolismo , Doença de Huntington/metabolismo , Poliubiquitina/metabolismo , Processamento de Proteína Pós-Traducional , Fator de Transcrição Sp1/metabolismo , Proteína com Valosina/metabolismo , Adulto , Idoso , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Estudos de Casos e Controles , Células Cultivadas , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Feminino , Fibroblastos/citologia , Fibroblastos/metabolismo , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Fator de Transcrição Sp1/genética , Ubiquitinação , Proteína com Valosina/genéticaRESUMO
The expanded HTT CAG repeat causing Huntington's disease (HD) exhibits somatic expansion proposed to drive the rate of disease onset by eliciting a pathological process that ultimately claims vulnerable cells. To gain insight into somatic expansion in humans, we performed comprehensive quantitative analyses of CAG expansion in ~50 central nervous system (CNS) and peripheral postmortem tissues from seven adult-onset and one juvenile-onset HD individual. We also assessed ATXN1 CAG repeat expansion in brain regions of an individual with a neurologically and pathologically distinct repeat expansion disorder, spinocerebellar ataxia type 1 (SCA1). Our findings reveal similar profiles of tissue instability in all HD individuals, which, notably, were also apparent in the SCA1 individual. CAG expansion was observed in all tissues, but to different degrees, with multiple cortical regions and neostriatum tending to have the greatest instability in the CNS, and liver in the periphery. These patterns indicate different propensities for CAG expansion contributed by disease locus-independent trans-factors and demonstrate that expansion per se is not sufficient to cause cell type or disease-specific pathology. Rather, pathology may reflect distinct toxic processes triggered by different repeat lengths across cell types and diseases. We also find that the HTT CAG length-dependent expansion propensity of an individual is reflected in all tissues and in cerebrospinal fluid. Our data indicate that peripheral cells may be a useful source to measure CAG expansion in biomarker assays for therapeutic efforts, prompting efforts to dissect underlying mechanisms of expansion that may differ between the brain and periphery.
Assuntos
Doença de Huntington/genética , Ataxias Espinocerebelares/genética , Expansão das Repetições de Trinucleotídeos/genética , Repetições de Trinucleotídeos/genética , Adulto , Idoso , Autopsia , Sistema Nervoso Central/patologia , Criança , Feminino , Humanos , Proteína Huntingtina/genética , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/patologia , Masculino , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Neostriado/patologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/patologiaRESUMO
BACKGROUND: Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. METHODS: We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF. RESULTS: Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). CONCLUSIONS: Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT02519036.).
Assuntos
Proteína Huntingtina/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Nucleotídeos/farmacologia , Oligonucleotídeos/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Feminino , Humanos , Proteína Huntingtina/líquido cefalorraquidiano , Proteína Huntingtina/genética , Injeções Espinhais , Masculino , Pessoa de Meia-Idade , Mutação , Nucleotídeos/síntese química , Oligonucleotídeos/líquido cefalorraquidianoRESUMO
OBJECTIVE: We aimed to investigate costly punishment in patients with Huntington's disease (HD). BACKGROUND: HD is an autosomal dominant neurodegenerative disease with motor, cognitive, and psychiatric symptoms. As neuropsychiatric abnormalities often precede motor symptoms, we wanted to assess whether costly punishment is part of the neuropsychological profile of patients with HD. METHODS: A total of 40 non-demented subjects were prospectively enrolled in this study with a between-subject design comparing manifest HD patients (n = 18) to healthy controls (HC; n = 22). All participants performed 8 rounds of a costly punishment task, in which money was shared unevenly in 5 rounds or in a fair manner in the remaining 3 rounds. Participants then had to decide whether they wanted to punish the trustee. Furthermore, all participants underwent neuropsychological background tasks. RESULTS: HD patients performed worse in the neuropsychological background tests compared to HC (all p values <0.05). Moreover, HD patients punished more often in fair (Wald χ2 = 5.03, p = 0.025) but not in unfair rounds (Wald χ2 = 1.63, p = 0.202). CONCLUSIONS: Our results demonstrate increased costly punishment during fair conditions in HD patients. Whether this behaviour is due to a lack of recognition of social norms, an impairment in top-down inhibition, or an effect of antidopaminergic medication remains unclear.
Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Humanos , Testes Neuropsicológicos , PuniçãoRESUMO
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a gene mutation in chromosome 4 that leads to an expansion of CAG - triplet repeats. It occurs mainly between the age of 30 and 50. Only less than 10 % of HD patients are younger than 20 years. In contrast to adult patients young HD patients show more often psychiatric and cognitive symptoms at disease onset than chorea. One third of the children with HD develops an epilepsy.We present 6 children diagnosed with HD in different stages of childhood. We describe first symptoms as well as genetic characteristics and other distinctive features.Both, the clinical presentation and the course of HD in childhood differ from HD in adults. In adolescents the clinical symptoms at onset are often psychiatric (like depression or attention deficit disorder). Choreatic movements typical for adult HD patients are missing.Due to the low prevalence of HD in childhood and the variability of clinical symptoms the process of diagnosing HD in children is difficult. Very often the diagnosis is made years after the first symptoms. Early diagnosis, however, is often important for managing social problems and problems in school.
Assuntos
Coreia , Doença de Huntington , Adolescente , Idade de Início , Criança , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Mutação , Repetições de TrinucleotídeosRESUMO
We present a prospective study of counselees seeking predictive testing for Huntington's disease at the Huntington Center North Rhine-Westphalia (Bochum, Germany) between 2010 and 2012. The aim was to observe the decision-making process of at-risk individuals and explore their experiences following the decision as well as the impacts of positive and negative mutation results. Data were collected using two standardized questionnaires as well as via a semi-standardized telephone interview one year after the initial counseling session. Seventy-two individuals participated in at least one of the three phases of the survey, including 31 individuals in the telephone interview. Sociodemographic data were in accordance with previous reports. The process of predictive testing was generally perceived in a positive manner, with almost all interviewees reporting a balanced emotional state one year after initial counseling, regardless of the decision for or against the test. The most important reasons named in favor of or against testing were assembled as well as different aspects regarding the satisfaction with the reached decision. In line with and expanding previous observations on gender-related differences in decision-making, our results suggest that gender-related aspects should be more strongly taken into account in genetic counseling during the predictive testing and counseling processes.
Assuntos
Análise Mutacional de DNA , Aconselhamento Genético/organização & administração , Testes Genéticos/métodos , Doença de Huntington/genética , Adulto , Tomada de Decisões , Feminino , Humanos , Masculino , Estudos Prospectivos , Inquéritos e QuestionáriosRESUMO
BACKGROUND: This study investigated the hypothesis that AFQ056 (mavoglurant), a selective metabotropic glutamate receptor 5 antagonist, reduces chorea in Huntington's disease (HD). METHODS: This 32-day randomized, double-blind, parallel-group, proof-of-concept study investigated AFQ056 (25-150 mg [incremental doses], twice-daily) versus placebo in patients with HD. Primary efficacy assessments were the chorea-sum score and orientation index (nondominant hand) from the quantitative motor (Q-Motor) grasping task at day 28. Key secondary efficacy assessments included finger-tapping in the Unified Huntington's Disease Rating Scale-Total Motor Score and Q-Motor measures. Safety and tolerability were assessed. RESULTS: Overall, 42 patients were randomized. At day 28, no improvement was observed on the primary efficacy assessments (P > 0.10) with AFQ056 versus placebo. The Q-Motor speeded-tapping interonset interval variability was reduced with AFQ056 versus placebo for the nondominant hand (P = 0.01). The incidence of adverse events was 66.7% with AFQ056 and 57.1% with placebo. CONCLUSIONS: AFQ056 did not reduce choreatic movements in HD, but was well tolerated. The clinical relevance of the Q-Motor findings (speeded-tapping) are unknown and may warrant further investigation.
Assuntos
Coreia/tratamento farmacológico , Coreia/etiologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Doença de Huntington/complicações , Indóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Avaliação da Deficiência , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do TratamentoRESUMO
In Huntington's disease (HD), a neurodegenerative-inherited disease, chorea as the typical kind of movement disorder is described. Beside chorea, however, all other kinds of movement disturbances, such as bradykinesia, dystonia, tremor or myoclonus can occur. Aim of the current study was to investigate alterations in the echogenicity of basal ganglia structures in different Huntington's disease phenotypes. 47 patients with manifest and genetically confirmed HD were recruited. All participants underwent a thorough neurological examination. According to a previously described method, classification into predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes was performed depending on subscores of the Unified Huntington's Disease Rating Scale. In addition, findings in juvenile HD were compared to adult HD. Transcranial sonography was performed by investigators blinded to clinical classification. There were no significant differences in basal ganglia echogenicities between the three phenotypes. Size of echogenic area of substantia nigra (SN) correlated positively with CAG repeat and bradykinesia subscore, and negatively with age of onset and chorea subscore. Comparing juvenile and adult HD subtypes, SN hyperechogenicity was significantly more often detectable in the juvenile form (100 vs. 29.3 %, p = 0.002). Regarding echogenicity of caudate or lentiform nuclei, no significant differences were detected. HD patients with the juvenile variant exhibit marked hyperechogenicity of substantia nigra. No significant differences in basal ganglia echogenicities between predominantly choreatic, mixed or bradykinetic-rigid motor phenotypes were detected.
Assuntos
Gânglios da Base/diagnóstico por imagem , Doença de Huntington/classificação , Doença de Huntington/diagnóstico por imagem , Adolescente , Adulto , Idade de Início , Idoso , Coreia/classificação , Coreia/diagnóstico por imagem , Coreia/genética , Coreia/fisiopatologia , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Hipocinesia/classificação , Hipocinesia/diagnóstico por imagem , Hipocinesia/genética , Hipocinesia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia , Adulto JovemRESUMO
AIMS: Selisistat, a selective SirT1 inhibitor is being developed as a potentially disease-modifying therapeutic for Huntington's disease (HD). This was the first study of selisistat in HD patients and was primarily aimed at development of pharmacodynamic biomarkers. METHODS: This was a randomized, double-blind, placebo-controlled, multicentre exploratory study. Fifty-five male and female patients in early stage HD were randomized to receive 10 mg or 100 mg of selisistat or placebo once daily for 14 days. Blood sampling, clinical and safety assessments were conducted throughout the study. Candidate pharmacodynamic markers included circulating soluble huntingtin and innate immune markers. RESULTS: Selisistat was found to be safe and well tolerated, and systemic exposure parameters showed that the average steady-state plasma concentration achieved at the 10 mg dose level (125 nm) was comparable with the IC50 for SirT1 inhibition. No adverse effects on motor, cognitive or functional readouts were recorded. While circulating levels of soluble huntingtin were not affected by selisistat in this study, the biological samples collected have allowed development of assay technology for use in future studies. No effects on innate immune markers were seen. CONCLUSIONS: Selisistat was found to be safe and well tolerated in early stage HD patients at plasma concentrations within the anticipated therapeutic concentration range.
Assuntos
Carbazóis/uso terapêutico , Doença de Huntington/tratamento farmacológico , Sirtuína 1/antagonistas & inibidores , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Carbazóis/administração & dosagem , Carbazóis/efeitos adversos , Carbazóis/sangue , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Doença de Huntington/sangue , Doença de Huntington/psicologia , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de Doença , Distribuição Tecidual , Resultado do Tratamento , Adulto JovemAssuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Ataxia de Friedreich/diagnóstico por imagem , Ataxia de Friedreich/patologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
PURPOSE: To study cerebral adenosine receptors (AR) in premanifest and manifest stages of Huntington's disease (HD). METHODS: We quantified the cerebral binding potential (BP ND) of the A1AR in carriers of the HD CAG trinucleotide repeat expansion using the radioligand [(18) F]CPFPX and PET. Four groups were investigated: (i) premanifest individuals far (preHD-A; n = 7) or (ii) near (preHD-B; n = 6) to the predicted symptom onset, (iii) manifest HD patients (n = 8), and (iv) controls (n = 36). RESULTS: Cerebral A1AR values of preHD-A subjects were generally higher than those of controls (by up to 31%, p < .01, in the thalamus on average). Across stages a successive reduction of A1AR BPND was observed to the levels of controls in preHD-B and undercutting controls in manifest HD by down to 25%, p < .01, in the caudatus and amygdala. There was a strong correlation between A1AR BP ND and years to onset. Before onset of HD, the assumed annual rates of change of A1AR density were -1.2% in the caudatus, -1.7% in the thalamus and -3.4% in the amygdala, while the corresponding volume losses amounted to 0.6%, 0.1% and 0.2%, respectively. CONCLUSIONS: Adenosine receptors switch from supra to subnormal levels during phenoconversion of HD. This differential regulation may play a role in the pathophysiology of altered energy metabolism.
Assuntos
Doença de Huntington/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Receptor A1 de Adenosina/metabolismo , Xantinas/farmacocinética , Adulto , Idade de Início , Idoso , Encéfalo/metabolismo , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Doença de Huntington/diagnóstico , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Ligação Proteica , Distribuição TecidualRESUMO
BACKGROUND: A subclinical, hepatic involvement in manifest and premanifest Huntington's disease (HD) was recently demonstrated by using the (1) (3) C-methionine breath test (MeBT). In this longitudinal pilot study, we investigated whether there is evidence for progressive hepatic mitochondrial dysfunction in premanifest HD. METHODS: The MeBT was performed within a group of 25 well-characterized premanifest HD mutation carriers at baseline and in a 14.5-month follow-up. RESULTS: The total group of mutation carriers (P = 0.033; Cohen's d = 0.6) and the subgroup of mutation carriers from our PreHD-B subgroup (nearer to disease onset; P = 0.030; Cohen's d = 1.12) revealed a lower amount of exhaled (13) CO2 in the follow-up. CONCLUSIONS: This study demonstrates in vivo progressive, subclinical, hepatic involvement in premanifest HD. Limitations of the study, such as high variance in breath test results, are discussed.
Assuntos
Doença de Huntington/complicações , Hepatopatias/etiologia , Doenças Mitocondriais/etiologia , Adulto , Progressão da Doença , Feminino , Seguimentos , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Hepatopatias/diagnóstico , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Proteínas do Tecido Nervoso/genética , Estatística como Assunto , Repetições de Trinucleotídeos/genética , Adulto JovemRESUMO
Dysarthria is a common symptom of Huntington's disease and has been reported, besides other features, to be characterized by alterations of speech rate and regularity. However, data on the specific pattern of motor speech impairment and their relationship to other motor and neuropsychological symptoms are sparse. Therefore, the aim of the present study was to describe and objectively analyse different speech parameters with special emphasis on the aspect of speech timing of connected speech and non-speech verbal utterances. 21 patients with manifest Huntington's disease and 21 age- and gender-matched healthy controls had to perform a reading task and several syllable repetition tasks. Computerized acoustic analysis of different variables for the measurement of speech rate and regularity generated a typical pattern of impaired motor speech performance with a reduction of speech rate, an increase of pauses and a marked disability to steadily repeat single syllables. Abnormalities of speech parameters were more pronounced in the subgroup of patients with Huntington's disease receiving antidopaminergic medication, but were also present in the drug-naïve patients. Speech rate related to connected speech and parameters of syllable repetition showed correlations to overall motor impairment, capacity of tapping in a quantitative motor assessment and some score of cognitive function. After these preliminary data, further investigations on patients in different stages of disease are warranted to survey if the analysis of speech and non-speech verbal utterances might be a helpful additional tool for the monitoring of functional disability in Huntington's disease.
Assuntos
Disartria/etiologia , Doença de Huntington/complicações , Adulto , Idoso , Disartria/diagnóstico , Feminino , Humanos , Hipocinesia/etiologia , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Fenótipo , Medida da Produção da Fala , Estatística como Assunto , Estatísticas não ParamétricasRESUMO
Speech alterations have been reported in manifest Huntington's disease (HD) and premanifest mutation carriers (preHD). The aim of our study was to explore these alterations in preHD and whether they can be used as biomarkers. 13 preHD mutation carriers performed reading task, sustained phonation task and syllable repetition tasks at baseline and after 21 months, as well as clinical examination and MRI. Syllable repetition capacity and self-chosen velocity of single syllable repetition differed significantly between time points. There were no changes in clinical ratings or MRI volumetry. Measurements of speech might be sensitive tools for monitoring subclinical changes in preHD.
RESUMO
Juvenile Huntington's disease (JHD) is rare. In the first decade of life speech difficulties, rigidity, and dystonia are common clinical motor symptoms, whereas onset in the second decade motor symptoms may sometimes resemble adult-onset Huntington's disease (AOHD). Cognitive decline is mostly detected by declining school performances. Behavioral symptoms in general do not differ from AOHD but may be confused with autism spectrum disorder or attention deficit hyperactivity disorder and lead to misdiagnosis and/or diagnostic delay. JHD specific features are epilepsy, ataxia, spasticity, pain, itching, and possibly liver steatosis. Disease progression of JHD is faster compared to AOHD and the disease duration is shorter, particularly in case of higher CAG repeat lengths. The diagnosis is based on clinical judgement in combination with a positive family history and/or DNA analysis after careful consideration. Repeat length in JHD is usuallyâ>â55 and caused by anticipation, usually via paternal transmission. There are no pharmacological and multidisciplinary guidelines for JHD treatment. Future perspectives for earlier diagnosis are better diagnostic markers such as qualitative MRI and neurofilament light in serum.
Assuntos
Doença de Huntington , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Adolescente , Criança , Progressão da Doença , Idade de InícioRESUMO
BACKGROUND: Understanding the relation between predominantly choreatic and hypokinetic-rigid motor subtypes and cognitive and general functioning may contribute to knowledge about different motor phenotypes in Huntington's disease. METHODS: In the European Huntington's Disease Network Registry study, 1882 subjects were classified as being predominantly choreatic (n=528) or hypokinetic-rigid (n=432), according to their scores on items of the total motor score a priori labeled as choreatic or hypokinetic-rigid; the other 922 patients were of a mixed type. The relationship between motor type and cognitive (verbal fluency, symbol digit modalities, Stroop color, word and interference tests) and functional (total functional capacity) capacity was investigated using multiple linear regression. RESULTS: Motor subtype contributed significantly to the total functional capacity score (partial r(2) : 7.8%; P<.001) and to the 5 cognitive scores (partial r(2) ranged from 2.0% to 8.4%; all P<.001). CONCLUSIONS: Patients with a predominantly choreatic motor phenotype performing better in all areas than patients with a hypokinetic-rigid motor phenotype.
Assuntos
Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/etiologia , Doença de Huntington/complicações , Hipocinesia/complicações , Rigidez Muscular/complicações , Adulto , Avaliação da Deficiência , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Índice de Gravidade de DoençaRESUMO
Chorea-acanthocytosis is an inevitably lethal genetic disease characterized by a progressive hyperkinetic movement disorder and cognitive and behavioral abnormalities as well as acanthocytosis. The disease is caused by loss-of-function mutations of the gene encoding vacuolar protein sorting-associated protein 13A (VPS13A) or chorein, a protein with unknown function expressed in various cell types. How chorein deficiency leads to the pathophysiology of chorea-acanthocytosis remains enigmatic. Here we show decreased phosphoinositide-3-kinase (PI3K)-p85-subunit phosphorylation, ras-related C3 botulinum toxin substrate 1 (Rac1) activity, and p21 protein-activated kinase 1 (PAK1) phosphorylation as well as depolymerized cortical actin in erythrocytes from patients with chorea-acanthocytosis and in K562-erythrocytic cells following chorein silencing. Pharmacological inhibition of PI3K, Rac1, or PAK1 similarly triggered actin depolymerization. Moreover, in K562 cells, both chorein silencing and PAK1 inhibition with IPA-3 decreased phosphorylation of Bad, a Bcl2-associated protein, promoting apoptosis by forming mitochondrial pores, followed by mitochondrial depolarization, DNA fragmentation, and phosphatidylserine exposure at the cell surface, all hallmarks of apoptosis. Our observations reveal chorein as a novel powerful regulator of cytoskeletal architecture and cell survival, thus explaining erythrocyte misshape and possibly neurodegeneration in chorea-acanthocytosis.