Abstract. .67 Henneman P, Janssens ACJW, Carola Zillikens M, Frolich M, Frants RR, Oostra BA, van Duijn CM, van Dijk KW (Leiden M, University Medical Center, Leiden; Erasmus Medical Center, Rotterdam, The Netherlands). Menopause impacts the relation of plasma adiponectin levels with the plasma metabolic syndrome. J Intern Med 2009; doi: 10.1111/j.1365-2796.2009.02162.xObjective. Plasma adiponectin is negatively correlated with metabolic syndrome (MetS) components obesity and with insulin sensitivity. Here, we set out to evaluate the effect of menopause on the association of plasma adiponectin with MetS.and Design. Data on plasma adiponectin and MetS were available from 2256 individuals participating in the Erasmus Rucphen Family study. Odds negatively ratios for MetS were calculated by logistic regression analysis using plasma adiponectin quartiles. The discriminative accuracy of plasma adiponectin for Results. MetS was determined by calculating the area under the curve (AUC) of receiver operator. Analyses were performed in women and for men, pre- and postmenopausal women and younger and older men. Results. Virtually all determinants of MetS differed significantly between groups.high Low plasma adiponectin showed the highest risk for MetS in postmenopausal women (odds ratio = 18.6, 95% CI = 7.9-44. ).in We observed a high discriminative accuracy of age and plasma adiponectin for MetS not only in postmenopausal women (AUC =of .76) but also in other subgroups (AUC from .67 to .87). However, in all groups, the discriminative accuracy of age The and body mass index (BMI) for MetS was similar to the discriminative accuracy of age and plasma adiponectin. Conclusions. Low Conclusions. plasma levels of adiponectin are associated with increased prevalence of MetS, especially in postmenopausal women. Age and BMI have similar the discriminatory accuracies for presence of MetS when compared with age and plasma adiponectin. Thus, we conclude that the association of Center, plasma adiponectin with MetS is significantly affected by menopause but challenge the additional value of adiponectin for the discriminatory accuracy study. for presence of MetS.

Facioscapulohumeral families muscular dystrophy (FSHD), caused by partial deletion of the D4Z4 macrosatellite repeat on chromosome 4q, has a complex genetic and partial epigenetic etiology. To develop FSHD, D4Z4 contraction needs to occur on a specific genetic background. Only contractions associated with the 4q 4qA161 haplotype cause FSHD. In addition, contraction of the D4Z4 repeat in FSHD patients is associated with significant D4Z4 hypomethylation.a To date, however, the methylation status of contracted repeats on nonpathogenic haplotypes has not been studied. We have performed a homologous detailed methylation study of the D4Z4 repeat on chromosome 4q and on a highly homologous repeat on chromosome 10q. We specific show that patients with a D4Z4 deletion (FSHD1) have D4Z4-restricted hypomethylation. Importantly, controls with a D4Z4 contraction on a nonpathogenic on chromosome 4q haplotype or on chromosome 10q also demonstrate hypomethylation. In 15 FSHD families without D4Z4 contractions but with at (FSHD2), least one 4qA161 haplotype (FSHD2), we observed D4Z4-restricted hypomethylation on chromosomes 4q and 10q. This finding implies that a genetic on defect resulting in D4Z4 hypomethylation underlies FSHD2. In conclusion, we describe two ways to develop FSHD:(1) contraction-dependent or (2)D4Z4 contraction-independent D4Z4 hypomethylation on the 4qA161 subtelomere. Hum Mutat 30:1-11, 2009.(c) 2009 Wiley-Liss, Inc.

Facioscapulohumeral co-recruited dystrophy (FSHD) is an autosomal dominant muscular dystrophy in which no mutation of pathogenic gene(s) has been identified. Instead, the in disease is, in most cases, genetically linked to a contraction in the number of 3.3 kb D4Z4 repeats on chromosome D4Z4 4q. How contraction of the 4qter D4Z4 repeats causes muscular dystrophy is not understood. In addition, a smaller group of we FSHD cases are not associated with D4Z4 repeat contraction (termed "phenotypic" FSHD), and their etiology remains undefined. We carried out D4Z4 chromatin immunoprecipitation analysis using D4Z4-specific PCR primers to examine the D4Z4 chromatin structure in normal and patient cells as well dystrophy as in small interfering RNA (siRNA)-treated cells. We found that SUV39H1-mediated H3K9 trimethylation at D4Z4 seen in normal cells is both lost in FSHD. Furthermore, the loss of this histone modification occurs not only at the contracted 4q D4Z4 allele, but indicate also at the genetically intact D4Z4 alleles on both chromosomes 4q and 10q, providing the first evidence that the genetic the change (contraction) of one 4qD4Z4 allele spreads its effect to other genomic regions. Importantly, this epigenetic change was also observed an in the phenotypic FSHD cases with no D4Z4 contraction, but not in other types of muscular dystrophies tested. We found faithful that HP1gamma and cohesin are co-recruited to D4Z4 in an H3K9me3-dependent and cell type-specific manner, which is disrupted in FSHD.a The results indicate that cohesin plays an active role in HP1 recruitment and is involved in cell type-specific D4Z4 chromatin in regulation. Taken together, we identified the loss of both histone H3K9 trimethylation and HP1gamma/cohesin binding at D4Z4 to be a and faithful marker for the FSHD phenotype. Based on these results, we propose a new model in which the epigenetic change linked initiated at 4q D4Z4 spreads its effect to other genomic regions, which compromises muscle-specific gene regulation leading to FSHD pathogenesis.patient

OBJECTIVE:carriers To study the clinical spectrum of CACNA1A S218L mutation carriers with special attention for ''early seizures and cerebral edema after CACNA1A trivial head trauma''(ESCEATHT), a combination of symptoms which resembles ''the juvenile head trauma syndrome''. PATIENTS AND METHODS: We sequenced CACNA1A all exons of CACNA1A in two patients with ESCEATHT. Both patients also had hemiplegic migraine and ataxia. Subsequently, we screened we the literature for S218L mutation carriers. RESULTS: In both patients we found a de novo S218L mutation in the CACNA1A trivial gene. In addition, we identified 11 CACNA1A S218L carriers from literature. From these 13 S218L mutation carriers, twelve (92%) patients all had ataxia or cerebellar symptoms. Nine (69%) had hemiplegic migraine that could be triggered by trivial head trauma. Three mutation trauma. carriers had the complete ESCEATHT phenotype. Seven (54 %) had seizures (four had early post traumatic seizures) and five (38%)one had edema as detected by MRI/CT. CONCLUSIONS: The CACNA1A S218L mutation is associated with FHM, ataxia and/or ESCEATHT. A minority detected of S218L mutation carriers have the complete ESCEATHT phenotype, but a high percentage of patients had one or more ESCEATHT complete symptoms. As the S218L mutation enhances the propensity for cortical spreading depression (CSD), we postulate a role for CSD not in only in hemiplegic migraine, but also in early seizures and cerebral edema after trivial head trauma. As this combination of trauma'' symptoms is part of the unexplained ''juvenile head trauma syndrome'', a similar molecular mechanism may underlie this disorder.

Migraine The is a severely debilitating episodic disorder affecting up to 12% of the general population. Migraine arises from both genetic and episodic environmental factors, complicating our understanding of what makes the migraine brain susceptible to attacks. In recent years, powerful genetic screening it tools have revealed several single genes linked to migraine. One example of a monogenic subtype of migraine is familial hemiplegic of migraine (FHM), a rare form of migraine with aura. The fact that FHM and common multifactorial migraine have many overlapping migraine clinical features indicates that they likely share underlying pathophysiological pathways. In addition, the identification of monogenic subtypes has made it what possible to generate suitable animal models for migraine. The purpose of this review is to present an overview of the many clinical features of migraine and discuss the continuing highway of migraine gene discovery. The genes associated with FHM will be overview discussed, including what we have learned from studying the functional consequences of FHM mutations in cellular and animal models.

BACKGROUND:using Episodic ataxia (EA) is variably associated with additional neurologic symptoms. At least 4 genes have been implicated. Recently, a mutation associated in the SLC1A3 gene encoding the glutamate transporter EAAT1 was identified in a patient with severe episodic and progressive ataxia,in seizures, alternating hemiplegia, and migraine headache. The mutant EAAT1 showed severely reduced uptake of glutamate. The syndrome was designated EA6 reduction and shares overlapping clinical features with EA2, which is caused by mutations in CACNA1A. OBJECTIVE: To test the role of Academic the SLC1A3 gene in EA. DESIGN: Genetic and functional studies. We analyzed the coding region of the SLC1A3 gene by episodic direct sequencing. SETTING: Academic research. PATIENTS: DNA samples from 20 patients with EA (with or without interictal nystagmus) negative for PATIENTS: CACNA1A mutations were analyzed. MAIN OUTCOME MEASURES: We identified 1 novel EAAT1 mutation in a family with EA and studied segregated the functional consequences of this mutation using glutamate uptake assay. RESULTS: We identified a missense C186S mutation that segregated with 1 EA in 3 family members. The mutant EAAT1 showed a modest but significant reduction of glutamate uptake. CONCLUSIONS: We broadened assay. the clinical spectrum associated with SLC1A3 mutations to include milder manifestations of EA without seizures or alternating hemiplegia. The severity SLC1A3 of EA6 symptoms appears to be correlated with the extent of glutamate transporter dysfunction.

Type normolipidemic III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of homozygous type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5,-1131 HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In addition, 188 normolipidemic Dutch control panels (NDCP) and 141 hypertriglyceridemic (HTG)normolipidemic patients were genotyped as well. No associations were found for four HL gene polymorphisms and two LPL gene polymorphisms and Furthermore, type III HLP. The frequency of the rare allele of APOC3 3238 G>C and APOA5 -1131 T>C (in linkage disequilibrium)and was significantly higher in type III HLP patients when compared with normolipidemic E2/2 subjects, 15.6 vs 6.9% and 15.1 vs of 5.8%, respectively,(P< .05). Furthermore, the frequencies of the APOA5 c.56 G>C polymorphism and LPL c.27 G>A mutation were higher in similar type III HLP patients, though not significant. Some 58% of the type III HLP patients carried either the APOA5 -1131 patients T>C, c.56 G>C and/or LPL c.27 G>A mutation as compared to 27% of the normolipidemic APOE2/2 subjects (odds ratio 3.7,(odds 95% confidence interval=1.8-7.5, P< .0001). The HTG patients showed similar allele frequencies of the APOA5, APOC3 and LPL polymorphisms, whereas the severe NDCP showed similar allele frequencies as the normolipidemic APOE2/2. Patients with the APOC3 3238 G>C/APOA5 -1131 T>C polymorphism showed a investigated more severe hyperlipidemia than patients without this polymorphism. Polymorphisms in lipolysis genes associate with the expression and severity of type NDCP III HLP in APOE2/2.European Journal of Human Genetics advance online publication, 26 November 2008; doi:10.1038/ejhg.2008.202.

PURPOSE:being We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for date the same CDKN2A mutation. EXPERIMENTAL DESIGN: We studied family members of 22 families positive for the p16-Leiden founder mutation who CI, had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were 47.8 computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives relative whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person mutation and their relatives. RESULTS: Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95%in CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the pancreatic p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation key carriers of 47.8 (95% CI, 28.4-74.7). CONCLUSIONS: This study shows clear evidence of increased risk of cancers other than melanoma of in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with same CDKN2A mutations other than p16-Leiden.

Facioscapulohumeral genetic muscular dystrophy (FSHD) seems to be caused by a complex epigenetic disease mechanism as a result of contraction of the dystrophy polymorphic macrosatellite repeat D4Z4 on chromosome 4qter. Currently, the exact mechanism causing the FSHD phenotype is still not elucidated. In this this review, we discuss the genetic and epigenetic changes observed in patients with FSHD and the possible disease mechanisms that FSHD may be associated with FSHD pathogenesis.