Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Alterações neonatais de sífilis congênita em um hospital universitário do município de Niterói, RJ

INTRODUÇÃO: A prevalência da infecção pelo Treponema pallidum diminuiu sensivelmente com a penicilina, porém se observa tendência mundial no recrudescimento da sífilis, em particular dos casos de sífilis congênita (SC). OBJETIVO: Descrever as repercussões neonatais da SC nos recém-nascidos (RN) notificados como caso de SC em um hospital público de Niterói – RJ, no período de janeiro de 2005 a junho de 2006. Observar o peso ao nascer e a sorologia dos RN com notificação de SC. Descrever o tratamento dos casos de SC. METODOLOGIA: Amostra constituída de 35 fichas de notificação de SC do Centro de Vigilância Hospitalar do Hospital Universitário Antônio Pedro (HUAP) – Niterói-RJ, no período de janeiro de 2005 a junho de 2006. Utilizaram-se dados da notificação e realizou-se visita domiciliar para coleta de sangue. RESULTADOS: A população foi constituída 29 pacientes nascidos vivos, quatro nascidos mortos e dois abortamentos. Apenas dois casos (6,9%) evidenciavam alterações ósseas de SC. O VDRL realizado no líquido cefalorraquidiano (LCR) dos casos demonstrou-se não reator para todos os pacientes avaliados. O VDRL do soro dos RN no nascimento foi positivo para 23 (79,31%) pacientes. A penicilina G cristalina (PGC) foi administrada em 26 (89,65%) casos, a penicilina G procaína (PCP) em dois (6,9%) e um individuo utilizou PGC e PGP. CONCLUSÃO: O óbito fetal e aborto foram o desfecho mais ominoso como repercussão da SC. A alteração dos ossos longos foi pouco encontrada na amostra. O baixo peso ao nascer foi observado em poucos casos. O VDRL do LCR foi não reator em todos os casos. A utilização de diversos esquemas de antibiótico estava em desacordo com o protocolo proposto pelo Ministério da SaúdeINTRDUCTION: The prevalence of Treponema pallidum’s infection has been significantly decreasing with the penicillin, however observed trend in global resurgence of syphilis, particularly, cases of congenital syphilis (CS). OBJECTIVE: To describe the precocious neonatal repercussions of CS in newborns (NB) notified as a case of CS in a public hospital of Niterói – RJ, between January of 2005 and July of 2006. To observe the weight and the serology of the NB that has CS. To describe the cases of CS’s treatment. METODOLOGY: The sample constituted of 35 CS’s reported from the Hospital Surveillance Centre of the Hospital Universitário Antônio Pedro (HUAP) – Niterói-RJ, from January 2005 to June 2006. Data notifications were utilized and home visits were made for blood collecting. RESULTS: The population was constituted of 29 births, four stillbirths and two abortions. Only two cases (6.9%) shown bone alterations by CS. The VDRL test made on the cerebrospinal fluid (CSF) revealed to be non-reactive for all the analyzed patients. The VDRL test made on the NB’s serum at their birth was positive for 23 (79.31%) patients. The G crystallin penicillin (GCP) was administered in 26 (89.65%) of the cases, the G procaine penicillin (GPP) in two (6.9%) of the cases and one case utilized GCP and GPP. CONCLUSION: The fetus death and the abortion were the most ominous denouement as CS’s repercussion. The alteration of the long bones was lees found in the sample. The birth’s low weight was observed in only a few cases. The VDRL test made on the CSF was not reactive in all cases. The utilization of diverse antibiotic schemes were disaccording to the protocol proposed by the Brazilian Health Ministry43 f

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

Background: People with Huntington's disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis