A novel presenilin 1 mutation (V261L) associated with presenile Alzheimer's disease and spastic paraparesis

Background and purpose:  We report a novel mutation in exon 8 of the presenilin 1 (PSEN1) gene (V261L) associated with early-onset autosomal dominant Alzheimer's disease and spastic paraparesis.
Methods and results:  The proband was a woman who developed insidious cognitive decline with predominant memory loss and gait disorder secondary to spasticity at the age of 40. Her brother and her mother had a similar disease in the fifth decade of life. The feature of amnestic presentation with spastic paraparesis is consistent with the majority of mutations in the exon 8 of the PSEN1 1 gene.
Conclusions:  Screening for PSEN1 mutations is especially likely to be productive when directed toward persons with positive family history and with age at onset of under 60.     

常染色体隐性遗传早发性帕金森病1个家系临床特征及parkin基因突变分析

目的探讨1个常染色体隐性遗传早发性帕金森病（autosomal recessive early-onset parkinson-ism，AREP）家系的临床特征及parkin基因突变情况。方法对1个AREP家系2例患者的临床资料进行回顾性分析，同时应用DNA直接测序、限制性内切酶酶切、荧光半定量PCR等技术方法进行parkin基因的突变分析。结果该家系共2例患者，发病年龄轻，分别为22岁和23岁；病情进展相对缓慢，症状有波动，呈晨轻暮重，腱反射活跃；对小剂量多巴制剂反应良好。基因突变发现该家系存在parkin基因的复合杂合突变（第7号外显子杂合的G859T和第4外显子杂合缺失突变），其中G859T为新报道的点突变。结论我国的AREP家系有帕金森病的一般临床表现，又有其独特的临床特征，存在parkin基因的突变。     

Crevicular fluid level of β-glucuronidase in relation to clinical periodontal parameters and putative periodontal pathogens in early-onset periodontitis

Abstract. Analysis of β-glucuronidase (βG) in the gingival crevicular fluid (GCF) provides an indication of neutrophil influx into the crevicular environment. The aim of this study was to test the hypotheses that: (1) βG is significantly elevated in individuals with early-onset periodontitis (EOP) and that βG activity correlates with disease severity: and (2) βG level may reflect the local bacterial challenge in the gingival crevice. The study subjects consisted of a sub-sample of individuals examined in the National Survey of Oral Health of United States Children, which was undertaken during the 1986/87 school year. A total of 249 individuals were selected based on presence or absence of clinical attachment loss at baseline. The individuals were examined a second time 6 years later and the clinical attachment loss was assessed, and subgingival plaque and GCF were collected. The subjects were classified into 3 types of EOP and a control group, βG activity in the GCF and the levels of 7 putative micro-organisms in the pocket were assessed. The generalized EOP group had the highest βG activity, followed by the localized and incidental EOP groups, and the controls, respectively. There was a significant increase in βG activity with the increase in probing depth. Also, sites with bleeding on probing had a significantly higher βG activity than sites without bleeding. However, the effect of gingival inflammation on βG activity was more evident in the generalized and localized EOP groups. Sites harboring high levels of one or more of the micro-organisms tended to have high βG activity. There were moderate differences between the organisms with respect to their effect on βG activity, but sites with high numbers of Porphyromonas gingivalis, Prevotella intermedia, or Treponema dentieola also had the highest βG activity. The present findings suggest that βG activity in GCF from patients with EOP can be of value in the early identification of individuals at higher risk of developing EOP, The findings also suggest that host mechanisms leading to higher βG activity in EOP represent systemic responses and are only partly related to the presence of local factors at the site-level.     

早发型重度子痫前期期待治疗的综合权衡

目的对不同孕周入院的早发型重度子痫前期患者行期待治疗的母儿双方作用进行综合权衡,探讨不同孕周患者行期待治疗时的把握倾向。方法回顾分析我院2008年7月～2011年6月收治的128例早发型重度子痫前期患者临床治疗的情况。按照入院孕周分为三组,A组:<29周27例,B组:29～31+6周49例,C组:32～33+6周52例。比较不同孕周入院患者接受期待治疗至终止妊娠的时长、期间孕产妇并发症的发生情况、围产儿不良结局情况,分析不同孕周患者行期待治疗对母儿状况的正面和负面作用,综合权衡两方。结果三组孕产妇期待治疗至终止妊娠的时长以B组为最长,A组次之,C组最短;A、B组孕妇并发症发生率差异无统计学意义,P>0.05,C组与A、B组差异有统计学意义,P<0.05;三组围产儿结局以C组为最佳,B组次之,A组最差,围产儿不良结局率差异有统计学意义P<0.05。结论经比较权衡不同孕周早发型重度子痫前期患者期待治疗对孕妇造成的负面作用和给围产儿带来的正面效果,不同孕周患者在采取期待治疗时在把握倾向上应有所侧重:对于<29周的患者,负面作用严重时宜倾向于放弃期待治疗;对于>29周的患者,期待治疗的正面效果使得尽可能延长孕周的治疗方案成为相对可取;对于32～34周的患者,主动选择提前终止妊娠的做法使改善围产儿结局的潜力没有得到充分挖掘,在条件允许的情况下,宜于坚持期待治疗直至终止妊娠的客观指征出现。     

Genotype-independent in vivo oxidative stress following a methionine loading test: maximal platelet activation in subjects with early-onset thrombosis

Background

methionine ingestion (100 mg/kg) identifies subjects in whom fasting total homocysteine (tHcy) may be normal but the post-methionine load (PML) tHcy is abnormally high.

Methods

In 96 subjects [54 M/42 F, 40.4 ± 12.3 yrs old; 28 with the 68 bp844 ins of the Cystathionine-β-synthase gene (CBSins+); 20 homozygotes for the C677T mutation of the methylene-tetrahydrofolate reductase gene (MTHFR++); 13 with the combination of the two, and 35 without any of them], we have evaluated in vivo oxidative stress and platelet activation, as reflected by urinary excretions of 8-iso-PGF_2α and of 11-dehydro-TXB₂ respectively, before and after a methionine load test (PML). A history of early-onset thrombosis (18 arterial, 32 venous, 2 both) was present in 52/96 of them.

Results

Baseline; tHcy was highest in MTHFR++ carriers (p < 0,05); 8-iso-PGF_2α and 11-dehydro-TXB₂ levels were independent of sex, MTHFR++ and/or CBSins + (p > 0.05). PML; The ~ 3-fold increase (p < 0.01 vs baseline) in tHcy reached a plateau within 6–8 hrs. Mean PML tHcy was maximal in MTHFR++ carriers (p = 0.000). 8-iso-PGF_2α and 11-dehydro-TXB₂ increase reached a maximum within 4 hrs. 11-dehydro-TXB₂ increase was highest (p = 0.023 vs baseline) in subjects with a history of thrombosis. Baseline 11-dehydro-TXB₂ and a history of thrombosis independently predicted PML 11-dehydro-TXB₂ (β = 0.287, p = 0.000 and β = 0.308, p = 0.026, respectively).The PML increase in 8-iso-PGF_2α or in 11-dehydro-TXB₂ were comparable in the different genotypes (p > 0.05).

Conclusion

regardless genotypes associated with moderate hyperhomocysteinemia, following a methionine loading test, in vivo oxidative stress and platelet activation occur, being the latter maximal in subjects with a history of early-onset thrombosis.     

ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations

Heterozygous carriers of ATM (ataxia telangiectasia mutated gene) mutations have increased risk of breast cancer (BC). We have estimated the prevalence of mutations in the ATM gene among Spanish patients with early-onset BC. Forty-three patients diagnosed with BC before the age of 46 years, and negative for BRCA1 and BRCA2 mutations, were analysed for the presence of ATM mutations. A total of 34 ATM sequence variants were detected: 1 deleterious mutation, 10 unclassified variants and 23 polymorphisms. One patient (2.3%) carried the ATM deleterious mutation (3802delG that causes ataxia telangiectasia in the homozygous state) and 13 patients carried the 10 ATM unclassified variants. The truncating mutation 3802delG and eight of the rare variants were not detected in a control group of 150 individuals. Different bioinformatic sequence analysis tools were used to evaluate the effects of the unclassified ATM changes on RNA splicing and function protein. This in silico analysis predicted that the missense variants 7653 T>C and 8156 G>A could alter the splicing by disrupting an exonic splicing enhancer motif and the 3763 T>G, 6314 G>C, and 8156 G>A variants would affect the ATM protein function. These are the initial results concerning the prevalence of germline mutations in the ATM gene among BC cases in a Spanish population, and they suggest that ATM mutations can confer increased susceptibility to early-onset BC.     

The neurobiology of depression in later-life: clinical, neuropsychological, neuroimaging and pathophysiological features

As the population ages, the economic and societal impacts of neurodegenerative and neuropsychiatric disorders are expected to rise sharply. Like dementia, late-life depressive disorders are common and are linked to increased disability, high healthcare utilisation, cognitive decline and premature mortality. Considerable heterogeneity in the clinical presentation of major depression across the life cycle may reflect unique pathophysiological pathways to illness; differentiating those with earlier onset who have grown older (early-onset depression), from those with illness onset after the age of 50 or 60 years (late-onset depression). The last two decades have witnessed significant advances in our understanding of the neurobiology of early- and late-onset depression, and has shown that disturbances of fronto-subcortical functioning are implicated. New biomedical models extend well beyond perturbations of traditional monoamine systems to include altered neurotrophins, endocrinologic and immunologic system dysfunction, inflammatory processes and gene expression alterations. This more recent research has highlighted that a range of illness-specific, neurodegenerative and vascular factors appear to contribute to the various phenotypic presentations. This review highlights the major features of late-life depression, with specific reference to its associated aetiological, clinical, cognitive, neuroimaging, neuropathological, inflammatory and genetic correlates. Data examining the efficacy of pharmacological, non-pharmacological and novel treatments for depression are discussed. Ultimately, future research must aim to evaluate whether basic biomedical knowledge can be successfully translated into enhanced health outcomes via the implementation of early intervention paradigms.     

Epidemiology of overall and early-onset serrated polyps versus conventional adenomas in a colonoscopy screening cohort

Serrated polyps (SPs) are precursors to one-third of colorectal cancers (CRCs), with histological subtypes: hyperplastic polyps (HPs), sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs). The incidence of early-onset CRC before the age of 50 is increasing, with limited understanding of SPs in younger cohorts. Using a large colonoscopy-based cohort, we characterized epidemiologic profiles of SP subtypes, compared to conventional adenomas, with secondary analysis on early-onset polyps. Ninety-four thousand four hundred and twenty-seven patients underwent screening colonoscopies between 2010 and 2018. Demographic, endoscopic and histopathologic characteristics of each polyp subtype were described. High-risk polyps included SSLs ≥10 mm/with dysplasia and conventional adenomas ≥10 mm/with tubulovillous/villous histology/high-grade dysplasia. We examined polyp prevalence with age and compared early- (age < 50) and late-onset polyps (age ≥ 50). Eighteen thousand one hundred and twenty-five patients had SPs (4357 SSLs, 15 415 HPs, 120 TSAs) and 26 699 had conventional adenomas. High-risk SSLs were enriched in the ascending colon (44.1% vs 2.6-35.8% for other locations; P < .003). Early- and late-onset SPs had similar subsite distribution. Early-onset conventional adenomas were more enriched in the distal colon/rectum (51.8% vs 43.4%, P < .001). Multiple conventional adenomas were more represented in late-onset groups (40.8% vs 33.8%, P < .001), with no difference in SSLs. The prevalence of conventional adenomas/high-risk conventional adenomas increased continuously with age, whereas the prevalence of SSLs/high-risk SSLs was stable from age 40 years onwards. A higher proportion of women were diagnosed with early-onset than late-onset SSLs (62.9% vs 57.6%, P = .03). Conventional adenomas, SSLs, early- and late-onset polyps have distinct epidemiology. The findings have implications for improved colonoscopy screening and surveillance and understanding the etiologic heterogeneity of CRC.     

New advances in Amyotrophic Lateral Sclerosis genetics: Towards gene therapy opportunities for familial and young cases

Due to novel gene therapy opportunities, genetic screening is no longer restricted to familial cases of ALS (FALS) cases but also aplies to the sporadic populations (SALS). Screening of four main genes (C9orf72, SOD1, TARDBP and FUS) identified the causes in 15% of Amyotrophic Lateral Sclerosis (ALS) patients (two third of the familial cases and 8% of the sporadic ones) but their respective contribution to ALS phenotype varies according the age of disease onset. The genetic overlap between ALS and other diseases is expanding and includes frontotemporal dementia, Paget's Disease of Bone, myopathy for adult cases, HSP and CMT for young cases highlighing the importance of retrieving the exhaustive familial history for each indivdual with ALS. Incomplete disease penetrance, diversity of the possible phenotypes, as well as the lack of confidence concerning the pathogenicity of most identified variants and/or possible oligogenic inheritance are burdens of ALS genetic counseling to be delivered to patients and at risk individuals. The multitude of rare ALS genetic causes identifed seems to converge to similar cellular pathways leading to inapropriate response to stress emphacising new potential therapeutic options for the disease.