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1.  DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss 
Neurology  2013;80(9):824-828.
Background:
Mutations in DNA methyltransferase 1 (DNMT1) have been identified in 2 autosomal dominant syndromes: 1) hereditary sensory autonomic neuropathy with dementia and hearing loss (HSAN1E); and 2) cerebellar ataxia, deafness, and narcolepsy. Both syndromes have mutations in targeting sequence (TS) domain (exons 20–21), which is important in mediating DNA substrate binding to the DNMT1 catalytic domain. Frontal lobe hypometabolism has been documented in an HSAN1E family, but memory loss has been the primary cognitive complaint. The chromosomal location of the DNMT1 gene at 19p13.2 has been linked to familial late-onset Alzheimer disease.
Methods:
We sequenced 41 exons of DNMT1 and their flanking regions in 1) 2 kindreds with HSAN1E; 2) 48 patients with HSAN1 alone without dementia and hearing loss; and 3) 5 probands of familial frontotemporal dementia (FTD) kindreds. We also sequenced exon 20 and 21 in 364 autopsy-confirmed late-onset Alzheimer disease cases.
Results:
Mutations in DNMT1 were specific to 2 HSAN1E kindreds with dementia and hearing loss (no narcolepsy). One family carried previously identified mutation Tyr495Cys; the other carried a novel Tyr495His, both in the TS domain. The symptoms of these patients include prominent personality, psychiatric manifestations, and seizures in one and the onset time is later than the previously reported cases.
Conclusion:
Clinicians should consider DNMT1 mutations in patients presenting with FTD or primary memory decline who also have sensory neuropathy and hearing loss. Amino acid Tyr495 is a hot spot for HSAN1E, distinct from exon 21 mutations associated with narcolepsy.
doi:10.1212/WNL.0b013e318284076d
PMCID: PMC3598458  PMID: 23365052
2.  C9ORF72 hexanucleotide repeat expansions in clinical Alzheimer’s disease 
JAMA neurology  2013;70(6):736-741.
Objective
Hexanucleotide repeat expansions in C9ORF72 underlie a significant fraction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study investigates the frequency of C9ORF72 repeat expansions in clinically diagnosed late-onset Alzheimer’s disease (AD).
Design, setting and patients
This case-control study genotyped the C9ORF72 repeat expansion in 872 unrelated familial AD cases and 888 controls recruited as part of the NIA-LOAD cohort, a multi-site collaboration studying 1000 families with two or more individuals clinically diagnosed with late-onset-AD.
Main Outcome Measure
We determined the presence or absence of the C9ORF72 repeat expansion by repeat-primed PCR, the length of the longest non-expanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.
Results
Three families showed large C9ORF72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the NIA-LOAD series, the C9ORF72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.
Interpretation
C9ORF72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and highlight the necessity of screening “FTD genes” in clinical AD cases with strong family history.
doi:10.1001/2013.jamaneurol.537
PMCID: PMC3681841  PMID: 23588422
3.  Macrophage derived Wnt signalling opposes Notch signalling in a Numb mediated manner to specify HPC fate in chronic liver disease in human and mouse 
Nature medicine  2012;18(4):572-579.
During chronic injury, regeneration of the adult liver becomes impaired. In this context bipotent Hepatic Progenitor Cells (HPCs) become activated and can regenerate both cholangiocytes and hepatocytes. Notch and Wnt signalling during hepatic ontogeny are described, but their roles in HPC mediated liver regeneration are unclear. Here we show in human diseased liver and murine models of the ductular reaction with biliary and hepatocyte regeneration that Notch and Wnt signalling direct HPC specification within the activated myofibroblasts and macrophages HPC niche. During biliary regeneration, Numb is downregulated in HPCs, Jagged1 promotes biliary specification within HPCs. During hepatocyte regeneration, macrophage derived canonical Wnt signalling maintains Numb within HPCs, and Notch signalling is reduced promoting hepatocyte specification. This dominant Wnt state is stimulated through engulfment of hepatocyte debris by niche macrophages and can directly influence the HPCs. Macrophage Wnt3a expression in turn facilitates hepatocyte regeneration – thus exemplifying a novel positive feedback mechanism in adult parenchymal regeneration.
doi:10.1038/nm.2667
PMCID: PMC3364717  PMID: 22388089
5.  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families 
PLoS ONE  2012;7(2):e31039.
Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
doi:10.1371/journal.pone.0031039
PMCID: PMC3270040  PMID: 22312439
6.  Deaths in early childhood in west Cumbria 
Investigation of deaths in early childhood is one method of assessing the quality of child care in a district. This paper describes a study carried out in one health district, on children in the age group one week to five years: 28 deaths occurred over a two-year period, 25 of these in the first year of life. The deaths are classified according to potential preventable factors. The study gave a more detailed picture of mortality patterns in the district than was previously available. Parents found the home interview in the study helpful in allowing them to explore their worries about the child's death.
PMCID: PMC1959720  PMID: 6737358

Results 1-6 (6)