Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a ...retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.
Objective
This study explored the bidirectional relationship between fibromyalgia and migraine among probands with either of the two disorders and their unaffected siblings.
Background
Evidence ...suggests a bidirectional association between fibromyalgia and migraine in individuals and in twins. However, whether a bidirectional association between fibromyalgia and migraine also occurs among siblings remains unknown.
Methods
Using the Taiwan National Health Insurance Research Database, we examined the data of 2677 probands with fibromyalgia, 2780 unaffected siblings, and 11,120 matched controls to assess the risk of migraine. In contrast, 1830 probands with migraine, 1936 unaffected siblings, and 7744 matched controls to assess the risk of fibromyalgia.
Results
Logistic regression analyses demonstrated that patients with fibromyalgia (odds ratio OR: 3.69; 95% confidence interval CI: 2.87–4.74) and unaffected siblings (OR: 1.51; 95% CI: 1.08–2.10) were more likely to develop migraine than the controls during the follow‐up period. Moreover, patients with migraine and unaffected siblings had a 4.86‐fold (95% CI: 3.86–6.09) and 1.59‐fold (95% CI: 1.18–2.12) increased risk of fibromyalgia than the controls.
Conclusion
The bidirectional association between fibromyalgia and migraine among probands and unaffected siblings suggests a familial coaggregation of these two conditions. Additional studies are required to investigate the genetic and environmental etiologies for this coaggregation.
Objective Little is known about the time from developing a first cancer to confirming the presence of a mismatch repair (MMR) gene mutation for Lynch syndrome (LS) probands. Methods This was a ...retrospective single center study. LS probands, who have an MMR gene mutation that was confirmed first in a pedigree and thereafter developed at least one cancer, were included in this study. Results There were 21 LS probands who had developed at least one cancer; 6 with MLH1 mutations, 9 with MSH2 mutations, 4 with MSH6 mutations, and 2 with EPCAM deletions. The median ages at the first cancer and the genetic diagnosis were 47 (34-71) and 62 (38-84) years old, respectively. The mean interval between the first cancer and the genetic diagnosis was 11.0 (0-25) years, and 20 years or longer interval was required for the 5 probands. Six (28.6%) probands were older than 70 years, and 3 (14.3%) were in their 80s when they were diagnosed to have LS. The genetic diagnosis was confirmed at the first, second, third, and fourth cancer or later in 5, 5, 6, and 5 probands, respectively. Of the 16 cancers examined, 2 (12.5%) were microsatellite stable (MSS), both of whom had germline MSH6 mutations. All 17 LS probands who developed colorectal cancer met the revised Bethesda guidelines at the genetic diagnosis, but only 7 of 11 (63.6%) met them at the first cancer. Twelve out of 21 (57.1%) met the revised Amsterdam criteria. Conclusion It took 11 years for the LS probands from the first cancer to the diagnostic confirmation by genetic tests. A quarter of the probands were in their 70s or 80s at genetic diagnosis.
We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva.
This microdialysis trial involved eight healthy male volunteers. Five ...participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures.
Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase.
Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.
Background: Ataxia telangiectasia (AT) is one of the most common autosomal recessive hereditary ataxia presenting in childhood. The responsible gene for AT designated ATM (AT, mutated) encodes a ...protein which is involved in cell cycle checkpoints and other responses to genotoxicity. We describe two novel disease-causing mutations in two unrelated Iranian families with Ataxiatelangiectasia.
Methods: The probands including a 6-year-old female and an 18-year-old boy were diagnosed with Ataxia-telangiectasia among two different Iranian families. In this study, Whole-Exome Sequencing (WES) was employed for the detection of genetic changes in probands. The analysis of the cosegregation of the variants with the disease in families was conducted using PCR direct sequencing.
Results: Two novel frameshift mutations, (c.4236_4236del p. Pro1412fs) and (c.8907T>G p. Tyr2969Ter) in the ataxia telangiectasia mutated ATM gene were detected using Whole-Exome Sequencing (WES) in the probands. These mutations were observed in two separate A-T families.
Conclusion: Next-generation sequencing successfully identified the causative mutation in families with ataxia-telangiectasia. These novel mutations in the ATM gene reported in the present study could assist genetic counseling, Preimplantation Genetic Diagnosis (PGD) and prenatal diagnosis (PND) of AT.
Association study of 182 candidate genes in anorexia nervosa Pinheiro, Andrea Poyastro; Bulik, Cynthia M.; Thornton, Laura M. ...
American journal of medical genetics. Part B, Neuropsychiatric genetics,
July 2010, Letnik:
153B, Številka:
5
Journal Article
Introduction: There is a dearth of data on heritability of schizophrenia in Africa. The few African studies that addressed familial psychiatric morbidity in schizophrenia involved relatively small ...sample sizes and addressed psychiatric morbidity only in first-degree relatives. The present study sought to improve upon the methodology of previous African studies, and widen the scope to second- and third-degree relatives with a view to enriching the field of genetic epidemiology in Africa.Methods: This study elicited information on the morbid risk of schizophrenia amongst 5259 relatives of schizophrenia probands (n = 138) and 6734 relatives of healthy controls (n = 138) through direct interview of patients, available relatives of patients and controls. Diagnosis of probands was confirmed using Mini International Neuropsychiatric Interview. Through a direct interview of 138 patients and their available relatives, a family history approach using the Family Interview for Genetic Studies was utilised to obtain information on the morbid risk for all relatives that could be recalled. The same approach was utilised for the interview of the controls (aged 45 years and above) and their relatives. Morbid risk estimates were calculated using the Weinberg shorter method.Results: Morbid risk for schizophrenia in the first-, second- and third-degree relatives of schizophrenia probands was 10.9% (95% confidence interval CI = 10.6–11.2), 4.2% (95% CI = 4.1–4.3) and 3.9% (95% CI = 3.6–4.2), respectively, compared with 2.6% (95% CI = 2.5–2.7), 1.6% (95% CI = 1.5–1.7) and 1.5% (95% CI = 1.4–1.6), respectively, of the healthy control group.Conclusion: The findings support the widely noted impression that schizophrenia significantly aggregates in families of schizophrenia probands more than healthy controls.
Objectives: Neurocognitive deficits have been proposed as vulnerability markers or endophenotypes for the development of bipolar I disorder (BD I). However, few research studies have examined ...whether neurocognitive deficits also exist in first‐degree relatives of individuals with BD I.
Methods: This prospective study examined neurocognitive function in individuals with BD I, their first‐degree relatives and a normal control group using a comprehensive battery of neurocognitive tests.
Results: Results indicated that individuals with bipolar disorder and their unaffected relatives demonstrated neuropsychological deficits in comparison to the normal control group in the domains of visuospatial/constructional abilities, executive function, visual learning and memory, and motor speed. In general, the unaffected relatives demonstrated an intermediate level of performance in comparison to the normal control and bipolar group. After adjustment for mood symptoms, significant differences were present for the visuospatial/constructional, executive function, and motor domains. Individuals with bipolar disorder also demonstrated a differential right versus left hemisphere deficit with respect to neurocognitive tasks.
Conclusions: Results suggest that deficits on specific neuropsychological tests, most notably Digit Symbol, Block Design and Judgment of Line Orientation, may be indicative of cognitive endophenotypes for bipolar disorder. Replication studies are needed to further identify these deficits as endophenotypes for BD I.
Objective: To investigate the presence of temperament dysregulation in healthy relatives of bipolar probands (RBP), a population at high risk for developing mood disorders, by comparing them with ...clinically recovered bipolar patients (BP) and normal controls (NC).
Method: 52 RBP and 23 BP were originally recruited for a multicenter genetic study in bipolar disorders. NC (
n=102) were also recruited by newspaper advertisement, radio and television announcements, flyers, newsletters, or word of mouth. All volunteers were asked to complete the TEMPS-A Scale, a self-report questionnaire designed to measure temperamental variations in psychiatric patients and healthy volunteers. In scoring temperaments, we relied upon the short validated version of the TEMPS-A J. Affect. Disord. (2004), from which traits with loadings <0.035 had been deleted.
Results: To examine differences in temperament dimensions among the three groups, a MANCOVA model was constructed using diagnostic group as the fixed factor (BP vs. RBP vs. NC); effects of age and gender were adjusted as covariates. MANCOVA showed overall group effect on the dependent variables (Hotelling's
F
(5,175)=6.64,
p<0.001). Four dependent variables (dysthymic, cyclothymic, irritable, and anxious temperaments) showed significant between-group differences. RBP showed lower cyclothymic temperament scores than BP, but higher scores than NC. BP and RBP showed higher anxious temperament scores than NC. Hyperthymic scores were significantly highest in the NC.
Limitation: In view of the small cell sizes, bipolar I vs. bipolar II subanalyses could not be conducted.
Conclusions: Methodologic strengths of the present analyses is that the BP group had clinically recovered, and we used the validated short version of the TEMPS-A for the present analyses. Our findings suggest that some clinically healthy relatives of bipolar probands exhibit a subclinical cyclothymic instability in mood, interest, self-confidence, sleep, and/or energy as well as anxiety proneness that is not observed among normal controls. These traits may represent vulnerability markers and could presumably be used to identify individuals at high risk for developing bipolar spectrum disorders, or specific clinical subtypes (e.g., bipolar I, bipolar II) within this spectrum. This is a conceptual perspective with many unanswered questions. Resolution of these questions will require innovative definitions of phenotypes to be included in the analyses of the temperament subscales in different populations. The temperament subscales themselves need to be calibrated properly, to find out which traits or specific combinations of trains are most promising. More extensive and complex quantitative trait analyses of these temperaments in a much expanded sample are reported elsewhere in this issue J. Affect. Disord. (2004).
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