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1.
Mov Disord ; 38(1): 113-122, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36318082

RESUMO

BACKGROUND: Juvenile-onset Huntington's disease (JOHD) is a rare form of Huntington's disease (HD) characterized by symptom onset before the age of 21 years. Observational data in this cohort is lacking. OBJECTIVES: Quantify measures of disease progression for use in clinical trials of patients with JOHD. METHODS: Participants who received a motor diagnosis of HD before the age of 21 were included in the Kids-JOHD study. The comparator group consisted of children and young adults who were at-risk for inheriting the genetic mutation that causes HD, but who were found to have a CAG repeat in the non-expanded range (gene non-expanded [GNE]). RESULTS: Data were obtained between March 17, 2006, and February 13, 2020. There were 26 JOHD participants and 78 GNE participants who were comparable on age (16.03 vs. 14.43, respectively) and sex (53.8% female vs. 57.7% female, respectively). The mean annualized decrease in striatal volume in the JOHD group was -3.99% compared to -0.06% in the GNE (mean difference [MD], -3.93%; 95% confidence intervals [CI], [-4.98 to -2.80], FDR < 0.0001). The mean increase in the Unified Huntington's Disease Rating Scale Total Motor Score per year in the JOHD group was 7.29 points compared to a mean decrease of -0.21 point in the GNE (MD, 7.5; 95% CI, [5.71-9.28], FDR < 0·0001). CONCLUSIONS: These findings demonstrate that structural brain imaging and clinical measures in JOHD may be potential biomarkers of disease progression for use in clinical trials. Collaborative efforts are required to validate these results in a larger cohort of patients with JOHD. © 2022 International Parkinson and Movement Disorder Society.


Assuntos
Doença de Huntington , Transtornos dos Movimentos , Criança , Adulto Jovem , Humanos , Feminino , Adulto , Masculino , Doença de Huntington/genética , Doença de Huntington/diagnóstico , Encéfalo , Progressão da Doença , Biomarcadores , Estudos Longitudinais
3.
Brain Behav ; 12(7): e2630, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35604958

RESUMO

INTRODUCTION: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development. METHODS: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms. RESULTS: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety. CONCLUSIONS: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.


Assuntos
Doença de Huntington , Adolescente , Ansiedade/genética , Criança , Corpo Estriado/diagnóstico por imagem , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Mutação , Neostriado
4.
J Huntingtons Dis ; 11(2): 173-178, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35275555

RESUMO

BACKGROUND: Molecular studies provide evidence that mutant huntingtin (mHTT) affects early cortical development; however, cortical development has not been evaluated in child and adolescent carriers of mHTT. OBJECTIVE: To evaluate the impact of mHTT on the developmental trajectories of cortical thickness and surface area. METHODS: Children and adolescents (6-18 years) participated in the KidsHD study. mHTT carrier status was determined for research purposes only to classify participants as gene expanded (GE) and gene non-expanded (GNE). Cortical features were extracted from 3T neuroimaging using FreeSurfer. Nonlinear mixed effects models were conducted to determine if age, group, and CAG repeat were associated with cortical morphometry. RESULTS: Age-related changes in cortical morphometry were similar across groups. Expanded CAG repeat was not significantly associated with cortical features. CONCLUSION: While striatal development is markedly different in GE and GNE, developmental change of the cortex appears grossly normal among child and adolescent carrier of mHTT.


Assuntos
Doença de Huntington , Adolescente , Criança , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética
5.
J Huntingtons Dis ; 9(3): 245-251, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32894247

RESUMO

BACKGROUND: The gene (Huntingtin or HTT) causing Huntington's disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT) may influence growth and development. OBJECTIVE: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. METHODS: Children ages 6-18 years of age (n = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. RESULTS: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. CONCLUSION: Measures of growth are abnormal in child and adolescent carriers of mHTT, decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology.


Assuntos
Desenvolvimento do Adolescente/fisiologia , Estatura/fisiologia , Índice de Massa Corporal , Peso Corporal/fisiologia , Desenvolvimento Infantil/fisiologia , Proteína Huntingtina/fisiologia , Adolescente , Estatura/genética , Peso Corporal/genética , Criança , Feminino , Humanos , Masculino , Risco , Fatores Sexuais
6.
Brain Sci ; 10(8)2020 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784364

RESUMO

Huntington's disease (HD) is a fatal neurodegenerative disease caused by the expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin gene. An increased CAG repeat length is associated with an earlier disease onset. About 5% of HD cases occur under the age of 21 years, which are classified as juvenile-onset Huntington's disease (JOHD). Our study aims to measure subcortical metabolic abnormalities in JOHD participants. T1-Rho (T1ρ) MRI was used to compare brain regions of 13 JOHD participants and 39 controls. Region-of-interest analyses were used to assess differences in quantitative T1ρ relaxation times. We found that the mean relaxation times in the caudate (p < 0.001), putamen (p < 0.001), globus pallidus (p < 0.001), and thalamus (p < 0.001) were increased in JOHD participants compared to controls. Furthermore, increased T1ρ relaxation times in these areas were significantly associated with lower volumes amongst participants in the JOHD group. These findings suggest metabolic abnormalities in brain regions previously shown to degenerate in JOHD. We also analyzed the relationships between mean regional T1ρ relaxation times and Universal Huntington's Disease Rating Scale (UHDRS) scores. UHDRS was used to evaluate participants' motor function, cognitive function, behavior, and functional capacity. Mean T1ρ relaxation times in the caudate (p = 0.003), putamen (p = 0.005), globus pallidus (p = 0.009), and thalamus (p = 0.015) were directly proportional to the UHDRS score. This suggests that the T1ρ relaxation time may also predict HD-related motor deficits. Our findings suggest that subcortical metabolic abnormalities drive the unique hypokinetic symptoms in JOHD.

7.
Brain Sci ; 10(8)2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796698

RESUMO

Reports of behavioral disturbance in Juvenile-Onset Huntington's Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington's Disease, but who did not inherit the disease themselves (Gene-Non-Expanded; GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p < 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p < 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD.

8.
Neurology ; 94(18): e1908-e1915, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32265233

RESUMO

OBJECTIVE: To test the hypothesis that the trajectory of functional connections over time of the striatum and the cerebellum differs between presymptomatic patients with the Huntington disease (HD) gene expansion (GE) and patients with a family history of HD but without the GE (GNE), we evaluated functional MRI data from the Kids-HD study. METHODS: We utilized resting-state, functional MRI data from participants in the Kids-HD study between 6 and 18 years old. Participants were divided into GE (CAG 36-59) and GNE (CAG <36) groups. Seed-to-seed correlations were calculated among 4 regions that provide input signals to the anterior cerebellum: (1) dorsocaudal putamen, (2) globus pallidus externa, (3) subthalamic nucleus, and (4) pontine nuclei; and 2 regions that represented output from the cerebellum: the dentate nucleus to the (1) ventrolateral thalamus and (2) dorsocaudal putamen. Linear mixed effects regression models evaluated differences in developmental trajectories of these connections over time between groups. RESULTS: Four of the six striatal-cerebellum correlations showed significantly different trajectories between groups. All showed a pattern where in the early age ranges (6-12 years) there was hyperconnectivity in the GE compared to the GNE, with those trajectories showing linear decline in the latter half of the age range. CONCLUSION: These results parallel previous findings showing striatal hypertrophy in children with GE as early as age 6. These findings support the notion of developmentally higher connectivity between the striatum and cerebellum early in the life of the child with HD GE, possibly setting the stage for cerebellar compensatory mechanisms.


Assuntos
Cerebelo/patologia , Corpo Estriado/patologia , Doença de Huntington/patologia , Vias Neurais/patologia , Adolescente , Cerebelo/crescimento & desenvolvimento , Criança , Corpo Estriado/crescimento & desenvolvimento , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/crescimento & desenvolvimento
9.
Neurology ; 93(10): e1021-e1030, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31371571

RESUMO

OBJECTIVE: The huntingtin gene is critical for the formation and differentiation of the CNS, which raises questions about the neurodevelopmental effect of CAG expansion mutations within this gene (mHTT) that cause Huntington disease (HD). We sought to test the hypothesis that child and adolescent carriers of mHTT exhibit different brain growth compared to peers without the mutation by conducting structural MRI in youth who are at risk for HD. We also explored whether the length of CAG expansion affects brain development. METHODS: Children and adolescents (age 6-18) with a parent or grandparent diagnosed with HD underwent MRI and blinded genetic testing to confirm the presence or absence of mHTT. Seventy-five individuals were gene-expanded (GE) and 97 individuals were gene-nonexpanded (GNE). The GE group was estimated to be on average 35 years from clinical onset. Following an accelerated longitudinal design, age-related changes in brain regions were estimated. RESULTS: Age-related striatal volume changes differed significantly between the GE and GNE groups, with initial hypertrophy and more rapid volume decline in GE. This pattern was exaggerated with CAG expansion length for CAG > 50. A similar age-dependent group difference was observed for the globus pallidus, but not in other major regions. CONCLUSION: Our results suggest that pathogenesis of HD begins with abnormal brain development. An understanding of potential neurodevelopmental features associated with mHTT may be needed for optimized implementation of preventative gene silencing therapies, such that normal aspects of neurodevelopment are preserved as neurodegeneration is forestalled.


Assuntos
Doença de Huntington/genética , Adolescente , Encéfalo , Criança , Corpo Estriado , Testes Genéticos , Humanos , Proteína Huntingtina/genética , Mutação
10.
Neurology ; 92(17): e1939-e1947, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30971481

RESUMO

OBJECTIVE: To assess brain morphometry in a sample of patients with juvenile-onset Huntington disease (JOHD) and several mouse models of Huntington disease (HD) that likely represent the human JOHD phenotype. METHODS: Despite sharing the mutation in the Huntingtin gene, adult-onset HD characteristically presents as a hyperkinetic motor disorder, while JOHD typically presents as a hypokinetic motor disease. The University of Iowa Kids-JHD program enrolls individuals 5 to 25 years of age who have already received the clinical diagnosis. A total of 19 children with juvenile HD (JHD) (mean CAG = 72) were studied. Patients with JHD were compared to healthy controls (n = 234) using a cross-sectional study design. Volumetric data from structural MRI was compared between groups. In addition, we used the same procedure to evaluate brain morphology of R6/2, zQ175, HdhQ250 HD mice models. RESULTS: Participants with JHD had substantially reduced intracranial volumes. After controlling for the small intracranial volume size, the volumes of subcortical regions (caudate, putamen, globus pallidus, and thalamus) and of cortical white matter were significantly decreased in patients with JHD. However, the cerebellum was proportionately enlarged in the JHD sample. The cerebral cortex was largely unaffected. Likewise, HD mice had a lower volume of striatum and a higher volume of cerebellum, mirroring the human MRI results. CONCLUSIONS: The primary pathology of JOHD extends beyond changes in the striatal volume. Brain morphology in both mice and human patients with JHD shows proportional cerebellar enlargement. This pattern of brain changes may explain the unique picture of hypokinetic motor symptoms in JHD, which is not seen in the hyperkinetic chorea-like phenotype of adult-onset HD.


Assuntos
Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Doença de Huntington/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Animais , Encéfalo/patologia , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Substância Cinzenta/patologia , Humanos , Doença de Huntington/patologia , Imageamento por Ressonância Magnética , Masculino , Camundongos , Tamanho do Órgão/fisiologia , Substância Branca/patologia , Adulto Jovem
11.
EBioMedicine ; 31: 47-53, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29685790

RESUMO

BACKGROUND: Huntington's Disease (HD) is caused by an abnormality in the HTT gene. This gene includes trinucleotide repeats ranging from 10 to 35, and when expanded beyond 39, causes HD. We previously reported that CAG repeats in the normal range had a direct and beneficial effect on brain development with higher repeats being associated with higher cognitive function. The current study now expands this line of inquiry to evaluate the effects of CAG repeat throughout the entire spectrum of repeats from 15 to 58. METHODS: We evaluated brain function in children ages 6-18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. Linear regression was used to determine if number of CAG repeats predicted measures of brain function. FINDINGS: The number of repeats in HTT, had a non-linear effect on a measure of general intelligence with an inverted U shape pattern. Increasing repeat length was associated with higher GAI scores up until roughly 40-41 repeats. After this peak, increasing repeat length was associated with declining GAI scores. INTERPRETATION: HTT may confer an advantage or a disadvantage depending upon the repeat length, playing a key role in the determination of intelligence, or causing a uniquely human brain disease.


Assuntos
Proteína Huntingtina/genética , Doença de Huntington , Inteligência , Expansão das Repetições de Trinucleotídeos , Repetições de Trinucleotídeos , Adolescente , Criança , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Masculino
12.
Neurodegener Dis Manag ; 7(5): 307-315, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29043929

RESUMO

AIM: The symptoms of Huntington's disease are well known, yet the symptoms of juvenile Huntington's disease (JHD) are less established due to its rarity. The study examined a cluster of symptoms considered to be common, but under-recognized in JHD: pain, itching, sleeping difficulties, psychosis and tics. MATERIALS & METHODS: A symptom survey was constructed using the online tool Qualtrics and dispersed to JHD caregivers through websites. RESULTS: A total of 33 surveys were completed. Disrupted sleep was the most prevalent symptom (87%), followed by tics (78%), pain (69%), itching (60%) and psychosis (39%). CONCLUSION: Despite limitations, the study supports that there are symptoms in the JHD population that are not considered classic, however, are common and significant for patients and caregivers.


Assuntos
Doença de Huntington/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Proteína Huntingtina/genética , Doença de Huntington/epidemiologia , Doença de Huntington/genética , Masculino , Fenótipo , Inquéritos e Questionários , Expansão das Repetições de Trinucleotídeos , Adulto Jovem
13.
J Neurosci Res ; 95(1-2): 398-408, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27870408

RESUMO

Huntington disease is a neurodegenerative disorder caused by a gene (HTT) with a unique feature of trinucleotide repeats ranging from 10 to 35 in healthy people; when expanded beyond 39 repeats, Huntington disease develops. Animal models demonstrate that HTT is vital to brain development; however, this has not been studied in humans. Moreover, evidence suggests that triplet repeat genes may have been vital in evolution of the human brain. Here we evaluate brain structure using magnetic resonance imaging and brain function using cognitive tests in a sample of school-aged children ages 6 to 18 years old. DNA samples were processed to quantify the number of CAG repeats within HTT. We find that the number of repeats in HTT, below disease threshold, confers advantageous changes in brain structure and general intelligence (IQ): the higher the number of repeats, the greater the change in brain structure, and the higher the IQ. The pattern of structural brain changes associated with HTT is strikingly different between males and females. HTT may confer an advantage or a disadvantage depending on the repeat length, playing a key role in either the evolution of a superior human brain or development of a uniquely human brain disease. © 2016 Wiley Periodicals, Inc.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteína Huntingtina/genética , Inteligência/genética , Caracteres Sexuais , Repetições de Trinucleotídeos/genética , Adolescente , Encéfalo/diagnóstico por imagem , Criança , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Doença de Huntington/genética , Doença de Huntington/patologia , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Adulto Jovem
14.
Am J Psychiatry ; 173(2): 184-92, 2016 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-26472629

RESUMO

OBJECTIVE: Psychiatric symptoms are a significant aspect of Huntington's disease, an inherited neurodegenerative illness. The presentation of these symptoms is highly variable, and their course does not fully correlate with motor or cognitive disease progression. The authors sought to better understand the development and longitudinal course of psychiatric manifestations in individuals who carry the Huntington's disease mutation, starting from the prodromal period prior to motor diagnosis. METHOD: Longitudinal measures for up to 10 years of psychiatric symptoms from the Symptom Checklist-90-Revised were obtained from 1,305 participants (1,007 carrying the Huntington's disease mutation and 298 without [classified as controls]) and 1,235 companions enrolled in the Neurobiological Predictors of Huntington's Disease (PREDICT-HD) study. Participants with the mutation were stratified into three groups according to probability of motor diagnosis within 5 years. Using linear mixed-effects regression models, differences in psychiatric symptoms at baseline and over time between the mutation-positive groups and the controls were compared, as well as between ratings by mutation-positive participants and their companions. RESULTS: Nineteen of 24 psychiatric measures (12 participant ratings and 12 companion ratings) were significantly higher at baseline and showed significant increases longitudinally in the individuals with the Huntington's disease mutation compared with controls. The differences were greatest in comparisons of symptom reports from companions compared with self-reports, especially in participants who were closest to motor diagnosis. CONCLUSIONS: The results indicate that psychiatric manifestations develop more often than previously thought in the Huntington's disease prodrome. Symptoms also increase with progression of disease severity. Greater symptom ratings by companions than by mutation-positive participants suggest decreasing awareness in those affected.


Assuntos
Ansiedade/psicologia , Comportamento Compulsivo/psicologia , Depressão/psicologia , Doença de Huntington/psicologia , Relações Interpessoais , Comportamento Obsessivo/psicologia , Sintomas Prodrômicos , Adulto , Estudos de Casos e Controles , Progressão da Doença , Feminino , Hostilidade , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtornos Fóbicos/psicologia , Estudos Prospectivos , Procurador , Transtornos Psicóticos/psicologia , Autorrelato , Transtornos Somatoformes/psicologia
15.
Front Hum Neurosci ; 9: 408, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26236221

RESUMO

We sought to characterize the relationship between integrity of the white matter underlying the ventral anterior cingulate (vAC) and depressive symptoms in older adults with atherosclerotic vascular disease (AVD), a condition associated with preferential degeneration of the white matter. The vAC was defined as including white matter underlying ventral Brodmann Area 24 and Brodmann Area 25, corresponding with the "subcallosal" and "subgenual" cingulate respectively. This region of interest was chosen based on the preponderance of evidence that the white matter in the region plays a critical role in the manifestation of depressive symptoms. Participants had current unequivocal diagnoses of AVD and were between 55 and 90 years-old. Fractional anisotropy (FA) was used as an index of white matter integrity and organization. Whole-brain mean diffusivity (MD) was used as an index of global white matter lesion burden. Depressive symptoms were measured using the Symptom Checklist-90-Revised (SCL-90-R) Depression Scale. Depressive symptoms were significantly related to low FA in the right vAC (r = -0.356, df = 30, p = 0.045) but not the left vAC (r = 0.024, df = 30, p = 0.896) after controlling for total brain MD (a statistical control for global white matter lesion burden). Further, depressive symptoms were significantly related to low FA in the right vAC (r = -0.361, df = 31, p = 0.039), but not the left vAC (r = 0.259, df = 31, p = 0.145) when controlled for the contralateral vAC FA. The correlation coefficients for this follow-up analysis were found to be significantly different between left and right vAC (Z = 2.310, p = 0.021). Poor white matter health in the vAC may be a biological mechanism for depressive symptoms in older adults with vascular disease. Further studies may corroborate that the right vAC plays a unique role in depressive symptom manifestation in cases where the white matter is preferentially affected, as is the case in AVD. This could lead to future targeting of the region for somatic antidepressant treatment, as well as the development of a precise approach for patients with white matter damage, which could produce significant improvement in quality of life, medical morbidity, and mortality.

16.
Clin Case Rep ; 3(4): 201-7, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25914809

RESUMO

Childhood-onset schizophrenia is rare, comprising 1% of known schizophrenia cases. Here, we report a patient with childhood-onset schizophrenia who has three large chromosomal abnormalities: an inherited 2.2 Mb deletion of chromosome 3p12.2-p12.1, a de novo 16.7 Mb duplication of 16q22.3-24.3, and a de novo 43 Mb deletion of Xq23-q28.

17.
Am J Med Genet B Neuropsychiatr Genet ; 165B(8): 619-26, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25228354

RESUMO

Schizophrenia is a chronic and severe psychiatric disorder that is highly heritable. While both common and rare genetic variants contribute to disease risk, many questions still remain about disease etiology. We performed a genome-wide analysis of copy number variants (CNVs) in 166 schizophrenia subjects and 52 psychiatrically healthy controls. First, overall CNV characteristics were compared between cases and controls. The only statistically significant finding was that deletions comprised a greater proportion of CNVs in cases. High interest CNVs were then identified as conservative using the following filtering criteria: (i) known deleterious CNVs; (ii) CNVs > 1 Mb that were novel (not found in a database of control individuals); and (iii) CNVs < 1 Mb that were novel and that overlapped the coding region of a gene of interest. Cases did not harbor a higher proportion of conservative CNVs in comparison to controls. However, similar to previous reports, cases had a slightly higher proportion of individuals with clinically significant CNVs (known deleterious or conservative CNVs > 1 Mb) or with multiple conservative CNVs. Two case individuals with the highest burden of conservative CNVs also share a recurrent 15q11.2 BP1-2 deletion, indicating a role for a potential multiple-hit CNV model for schizophrenia. In total, we report three 15q11.2 BP1-2 deletion individuals with schizophrenia, adding to a growing body of evidence that this CNV is involved in disease etiology.


Assuntos
Variações do Número de Cópias de DNA/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Adolescente , Adulto , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Deleção de Sequência/genética , Adulto Jovem
18.
Neurology ; 81(13): 1141-7, 2013 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-23966256

RESUMO

OBJECTIVE: To determine whether Huntington disease (HD) mutation carriers have motor symptoms (complaints) when definite motor onset (motor phenoconversion) is diagnosed and document differences between the groups with and without unawareness of motor signs. METHODS: We analyzed data from 550 HD mutation carriers participating in the multicenter PREDICT-HD Study followed through the HD prodrome. Data analysis included demographics, the Unified Huntington's Disease Rating Scale (UHDRS) and the Participant HD History of symptoms, self-report of progression, and cognitive, behavioral, and imaging measures. Unawareness was identified when no motor symptoms were self-reported but when definite motor HD was diagnosed. RESULTS: Of 38 (6.91%) with onset of motor HD, almost half (18/38 = 47.36%) had no motor symptoms despite signs of disease on the UHDRS motor rating and consistent with unawareness. A group with motor symptoms and signs was similar on a range of measures to the unaware group. Those with unawareness of HD signs reported less depression. Patients with symptoms had more striatal atrophy on imaging measures. CONCLUSIONS: Only half of the patients with newly diagnosed motor HD had motor symptoms. Unaware patients were less likely to be depressed. Self-report of symptoms may be inaccurate in HD at the earliest stage.


Assuntos
Conscientização , Transtornos Cognitivos/etiologia , Doença de Huntington/complicações , Doença de Huntington/psicologia , Adulto , Análise de Variância , Distribuição de Qui-Quadrado , Transtornos Cognitivos/diagnóstico , Progressão da Doença , Feminino , Humanos , Doença de Huntington/genética , Doença de Huntington/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenótipo , Desempenho Psicomotor , Autorrelato , Índice de Gravidade de Doença , Estatística como Assunto
19.
J Psychiatr Res ; 47(10): 1423-31, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23790259

RESUMO

Depression causes significant morbidity and mortality, and this also occurs in Huntington Disease (HD), an inherited neurodegenerative illness with motor, cognitive, and psychiatric symptoms. The presentation of depression in this population remains poorly understood, particularly in the prodromal period before development of significant motor symptoms. In this study, we assessed depressive symptoms in a sample of 803 individuals with the HD mutation in the prodromal stage and 223 mutation-negative participants at the time of entry in the Neurobiological Predictors of HD (PREDICT-HD) study. Clinical and biological HD variables potentially related to severity of depression were analyzed. A factor analysis was conducted to characterize the symptom domains of depression in a subset (n=168) with clinically significant depressive symptoms. Depressive symptoms were found to be more prevalent in HD mutation carriers but did not increase with proximity to HD diagnosis and were not associated with length of the HD mutation. Increased depressive symptoms were significantly associated with female gender, self-report of past history of depression, and a slight decrease in functioning, but not with time since genetic testing. The factor analysis identified symptom domains similar to prior studies in other populations. These results show that individuals with the HD mutation are at increased risk to develop depressive symptoms at any time during the HD prodrome. The clinical presentation appears to be similar to other populations. Severity and progression are not related to the HD mutation.


Assuntos
Depressão/diagnóstico , Depressão/etiologia , Doença de Huntington/complicações , Doença de Huntington/psicologia , Sintomas Prodrômicos , Adulto , Análise de Variância , Feminino , Testes Genéticos , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Escalas de Graduação Psiquiátrica , Suicídio/psicologia , Expansão das Repetições de Trinucleotídeos/genética
20.
Arch Gen Psychiatry ; 69(9): 885-92, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22945618

RESUMO

CONTEXT The single-nucleotide polymorphism rs1344706 in the gene ZNF804a has been associated with schizophrenia and with quantitative phenotypic features, including brain structure volume and the core symptoms of schizophrenia. OBJECTIVE To evaluate associations of rs1344706 with brain structure and the core symptoms of schizophrenia. DESIGN Case-control analysis of covariance. SETTING University-based research hospital. PARTICIPANTS Volunteer sample of 335 individuals with schizophrenia spectrum disorders (306 with core schizophrenia) and 198 healthy volunteers. MAIN OUTCOME MEASURES Cerebral cortical gray matter and white matter (WM) volumes (total and frontal, parietal, temporal, and occipital lobes), lateral ventricular cerebrospinal fluid volume, and symptom severity from the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms divided into 3 domains: psychotic, negative, and disorganized. RESULTS The rs1344706 genotype produced significant main effects on total, frontal, and parietal lobe WM volumes (F = 3.98, P = .02; F = 4.95, P = .007; and F = 3.08, P = .05, respectively). In the schizophrenia group, rs1344706 produced significant simple effects on total (F = 3.93, P = .02) and frontal WM volumes (F = 7.16, P < .001) and on psychotic symptom severity (F = 6.07, P = .003); the pattern of effects was concordant with risk allele carriers having larger volumes and more severe symptoms of disease than nonrisk homozygotes. In the healthy volunteer group, risk allele homozygotes had increased total WM volume compared with nonrisk allele carriers (F = 4.61, P = .03), replicating a previously reported association. CONCLUSIONS A growing body of evidence suggests that the risk allele of rs1347706 is associated with a distinctive set of phenotypic features in healthy volunteers and individuals with schizophrenia. Our study supports this assertion by finding that specific genotypes of the polymorphism are associated with brain structure volumes in individuals with schizophrenia and healthy volunteers and with symptom severity in schizophrenia.


Assuntos
Alelos , Fatores de Transcrição Kruppel-Like/genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/genética , Psicologia do Esquizofrênico , Adulto , Estudos de Casos e Controles , Córtex Cerebral/patologia , Feminino , Frequência do Gene/genética , Triagem de Portadores Genéticos , Predisposição Genética para Doença/genética , Genótipo , Homozigoto , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão/fisiologia , Fenótipo , Escalas de Graduação Psiquiátrica , Valores de Referência , Esquizofrenia/diagnóstico , Adulto Jovem
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