ABSTRACT
OBJECTIVE: Data are lacking on the impact on pregnancy outcome of the position of the abnormal fetus in a discordant twin pregnancy undergoing selective termination (ST). Tissue maceration post ST of the presenting twin may lead to early rupture of membranes, amnionitis and preterm labor. The aim of this study was to evaluate pregnancy complications and outcome following ST of the presenting vs non-presenting twin. METHODS: This was a multicenter retrospective cohort study of dichorionic diamniotic twin pregnancies that underwent ST due to a discordant fetal anomaly (structural or genetic) between 2007 and 2021. The study population was divided into two groups according to the position of the reduced twin (presenting or non-presenting) and outcomes were studied accordingly. The primary outcome was a composite of early complications following ST, including infection, preterm prelabor rupture of membranes and pregnancy loss. RESULTS: A total of 190 dichorionic twin pregnancies were included, of which 73 underwent ST of the presenting twin and 117 of the non-presenting twin. The groups did not differ in either baseline demographic characteristics or mean gestational age at the time of the procedure. ST of the presenting twin resulted in a significantly higher rate of early complications compared with the non-presenting twin (19.2% vs 7.7%; P = 0.018). Moreover, the rates of preterm delivery (75.3% vs 37.6%; P < 0.001) and neonatal intensive care unit admission (45.3% vs 17.1%; P < 0.001) were higher, and birth weight was lower (P < 0.001), in those pregnancies in which the presenting twin was reduced. CONCLUSIONS: ST of the presenting twin resulted in a higher rate of adverse pregnancy outcome compared with that of the non-presenting twin. These findings should be acknowledged during patient counseling and, if legislation permits, taken into consideration when planning ST. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Pregnancy Complications , Premature Birth , Infant, Newborn , Female , Pregnancy , Humans , Retrospective Studies , Pregnancy Outcome/epidemiology , Twins , Pregnancy, Twin , Premature Birth/etiology , Premature Birth/epidemiology , Gestational AgeABSTRACT
Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or ß-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut. SIGNIFICANCE STATEMENT: This report introduces methodology to develop potent, gut-restricted inhibitors of divalent metal transporter 1 (DMT1) and identifies XEN602 as a suitable compound for in vivo studies. We also report novel animal models to quantify the inhibition of dietary uptake of iron in both rodents and pigs. This research shows that inhibition of DMT1 is a promising means to treat iron overload disorders.
Subject(s)
Iron Overload , Humans , Rats , Animals , Swine , Iron Overload/drug therapy , Iron/metabolism , Biological Transport , Iron-Binding Proteins/metabolism , Models, AnimalABSTRACT
PURPOSE: BRCA1/2 founder pathogenic variants (PVs) occur in various populations, but data on the mutational spectrum in Africans are limited. We examined BRCA1/2 PVs in breast cancer patients of Ethiopian Jewish (EJ) origin. METHODS: We retrospectively analyzed BRCA1/2 test results and clinical features of EJ breast cancer patients from seven medical institutions. We obtained heterozygote carrier rates in affected individuals from the laboratories of the largest Israeli HMO (Clalit). Population carrier frequency was determined in EJ controls. RESULTS: We identified three recurrent BRCA2 PVs in 11 EJ breast cancer patients (9 females, 2 males): c.7579delG, c.5159C > A, and c.9693delA. Only c.5159C > A was previously reported in Africans. In women, mean age at diagnosis was 35.7y; 8/9 were diagnosed with advanced disease. All tumors were invasive, 4/9 were triple negative. Only 3/11 carriers had relevant family history. Carrier rate in high-risk breast cancer patients was 11% (3/28; 95%CI [2.3%, 28.2%]). Combined carrier rate among controls was 1.8% (5/280; 95%CI [0.6%, 4.1%]). CONCLUSION: EJs harbor 3 recurrent BRCA2 PVs presenting with relatively severe breast cancer morbidity. Combined with the high BRCA2 carrier rate in the EJ population, these findings merit increasing awareness in this community and suggest that a culturally adapted population screening approach may be warranted.
Subject(s)
BRCA2 Protein , Breast Neoplasms, Male , Breast Neoplasms , Jews , BRCA2 Protein/genetics , Breast Neoplasms/ethnology , Breast Neoplasms/genetics , Breast Neoplasms, Male/ethnology , Breast Neoplasms, Male/genetics , Ethiopia/epidemiology , Female , Founder Effect , Genetic Predisposition to Disease , Humans , Jews/genetics , Male , Retrospective StudiesABSTRACT
Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9-10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis , Colorectal Neoplasms , Adolescent , Adult , Aged , Aged, 80 and over , Colorectal Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , DNA Mismatch Repair/genetics , Ethiopia , Germ-Line Mutation , Humans , Jews/genetics , Middle Aged , MutS Homolog 2 Protein/genetics , Young AdultABSTRACT
Lafora disease (LD) is a fatal childhood dementia with severe epilepsy and also a glycogen storage disease that is caused by recessive mutations in either the EPM2A or EPM2B genes. Aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) are both a hallmark and driver of the disease. The 6th International Lafora Epilepsy Workshop was held online due to the pandemic. Nearly 300 clinicians, academic and industry scientists, trainees, NIH representatives, and LD friends and family members participated in the event. Speakers covered aspects of LD including progress towards the clinic, the importance of establishing clinical progression, translational progress with repurposed drugs and additional pre-clinical therapies, and novel discoveries that define foundational LD mechanisms.
Subject(s)
Lafora Disease , Protein Tyrosine Phosphatases, Non-Receptor , Child , Humans , Mutation , Protein Tyrosine Phosphatases, Non-Receptor/geneticsSubject(s)
Brain Neoplasms , Colorectal Neoplasms , DNA Mismatch Repair/genetics , Neoplastic Syndromes, Hereditary , Adolescent , Brain Neoplasms/diagnosis , Brain Neoplasms/genetics , Brain Neoplasms/therapy , Child , Colonoscopy , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Colorectal Neoplasms/therapy , DNA Polymerase II/genetics , DNA Polymerase III/genetics , Diagnosis, Differential , Genetic Counseling , Germ-Line Mutation , Guidelines as Topic , Humans , Immune Checkpoint Inhibitors/therapeutic use , Li-Fraumeni Syndrome/psychology , Lupus Erythematosus, Systemic/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/therapy , Netherlands , Poly-ADP-Ribose Binding Proteins/genetics , Vaccination , Young AdultABSTRACT
The number needed to treat is often used to measure the efficacy of a binary outcome in randomized clinical trials. There are three different available measures of the number needed to treat. Two of these measures, Furukawa and Leucht's and Kraemer and Kupfer's, focus on converting Cohen's δ index into the number needed to treat, while Laupacis et al.'s measure deals primarily with the number needed to treat's estimation rather than with a reformulation. Mathematical and numerical analysis of numbers needed to treat and their estimators was conducted. Three novel number needed to treat estimators were introduced to supplement the numbers needed to treat introduced by Laupacis, Furukawa and Leucht, and Kraemer and Kupfer. The analysis showed that Laupacis et al.'s number needed to treat is intrinsically different from Kraemer and Kupfer's number needed to treat, and that Furukawa and Leucht's estimator is appropriate to use only for normally distributed outcomes with equal standard deviations. Based on the numerical analysis, the novel numbers needed to treat outperformed the existing ones under correct model specifications. Asymptotic analysis was used to test three different types of confidence intervals to supplement the numbers needed to treat. An R-package to calculate these numbers needed to treat and their confidence intervals has been developed and made available for users online.
ABSTRACT
Lafora disease (LD) is both a fatal childhood epilepsy and a glycogen storage disease caused by recessive mutations in either the Epilepsy progressive myoclonus 2A (EPM2A) or EPM2B genes. Hallmarks of LD are aberrant, cytoplasmic carbohydrate aggregates called Lafora bodies (LBs) that are a disease driver. The 5th International Lafora Epilepsy Workshop was recently held in Alcala de Henares, Spain. The workshop brought together nearly 100 clinicians, academic and industry scientists, trainees, National Institutes of Health (NIH) representation, and friends and family members of patients with LD. The workshop covered aspects of LD ranging from defining basic scientific mechanisms to elucidating a LD therapy or cure and a recently launched LD natural history study.
Subject(s)
Congresses as Topic/trends , Education/trends , Internationality , Lafora Disease/therapy , Animals , Humans , Lafora Disease/epidemiology , Lafora Disease/genetics , Mutation/genetics , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Spain/epidemiologyABSTRACT
OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public-private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration.
Subject(s)
Antidepressive Agents, Second-Generation/pharmacology , Depressive Disorder, Major/drug therapy , Outcome Assessment, Health Care/statistics & numerical data , Severity of Illness Index , Adult , Aged , Humans , Middle Aged , Young AdultABSTRACT
Regulatory B (Breg ) cells are characterized by various membrane markers and the secretion of different inhibitory cytokines. A new subset of Breg cells was identified as CD5hi Fas-ligand (FasL)hi . Their main reported role is to suppress anti-viral and anti-tumour immune responses, and, hence they have been dubbed 'killer' B cells. In this study, we aim to assess the role of these cells in chronic hepatitis C virus (HCV) infection, and determine if they contribute to the increased viral load and persistence of HCV and its related autoimmunity. (i) FasL expression on CD5hi B cells is increased significantly in HCV-infected patients compared to healthy individuals [28·06 ± 6·71 mean fluorescence intensity (MFI) ± standard error of the mean (s.e.m.), median = 27·9 versus 10·87 ± 3·97 MFI ± s.e.m., median = 10·3, respectively, P < 0·0001]. (ii) Killer B cells from HCV patients increased autologous CD4+ T cell apoptosis compared to the apoptosis in healthy individuals [39·17% ± 7·18% mean ± standard deviation (s.d.), median = 39·6 versus 25·92 ± 8·65%, mean ± s.d., median = 24·1%, P < 0·0001, respectively]. A similar increase was observed in CD8+ T cell apoptosis (54·67 ± 15·49% mean ± s.d., median = 57·3 versus 21·07% ± 7·4%, mean ± s.d., median = 20%, P = 0·0006, respectively). (iii) By neutralizing FasL with monoclonal anti-FasL antibodies, we have shown that the induction of apoptosis by killer B cells is FasL-dependent. (iv) Increased expression of FasL on CD5hi B cells is correlated positively with an increased viral load and the presence of anti-nuclear antibodies and rheumatoid factor in HCV. This is the first study in which killer B cells have been suggested to play a pathogenic role in HCV. They seem to be involved in HCV's ability to escape efficient immune responses.
Subject(s)
B-Lymphocytes, Regulatory/immunology , CD4-Positive T-Lymphocytes/immunology , Fas Ligand Protein/metabolism , Hepacivirus/physiology , Hepatitis C, Chronic/immunology , Adult , Aged , Aged, 80 and over , Antibodies, Antinuclear/blood , Antibodies, Blocking/pharmacology , Apoptosis , Autoimmunity , CD5 Antigens/metabolism , Cells, Cultured , Cytotoxicity, Immunologic , Fas Ligand Protein/immunology , Female , Humans , Male , Middle Aged , Viral LoadABSTRACT
Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1.9 mutation (L1302F) that is associated with insensitivity to pain. We investigated the effects of L1302F and a previously reported mutation (L811P) on neuronal excitability. In transfected heterologous cells, the L1302F mutation caused a large hyperpolarizing shift in the voltage-dependence of activation, leading to substantially enhanced overlap between activation and steady-state inactivation relationships. In transfected small rat dorsal root ganglion neurons, expression of L1302F and L811P evoked large depolarizations of the resting membrane potential and impaired action potential generation. Therefore, our findings implicate a cellular loss of function as the basis for impaired pain sensation. We further demonstrated that a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain.
Subject(s)
Action Potentials/genetics , Ion Channel Gating/genetics , Mutation, Missense , Neurons/metabolism , Pain Insensitivity, Congenital , Adult , Amino Acid Substitution , Female , Humans , NAV1.9 Voltage-Gated Sodium Channel/genetics , NAV1.9 Voltage-Gated Sodium Channel/metabolism , Pain Insensitivity, Congenital/genetics , Pain Insensitivity, Congenital/metabolism , Pain Insensitivity, Congenital/physiopathologyABSTRACT
BACKGROUND: Risperidone is a common psychopharmacological treatment for irritability in autism spectrum disorder (ASD). It is not well-established how effective risperidone is across the initial symptom severity range. This study aims to examine the influence of baseline severity on the efficacy of risperidone in the treatment of ASD. METHODS: Participants were from the NIMH funded RUPP multisite, randomized, double-blind trial that compared risperidone to placebo to treat autistic disorder with severe tantrums, aggression, or self-injury. Participants were aged 5 to 17, and randomly assigned to risperidone (n=49) or placebo (n=52). Baseline and change scores were computed with the Aberrant Behavior Checklist (ABC) parent assessed scales with irritability as the primary outcome, as well as the clinician assessed ABC Irritability subscale, and Clinical Global Impression Scale. RESULTS: The relationship between baseline severity and change scores for the risperdone and placebo groups was examined with eight competing three-level mixed-effects models for repeated measure models. Significant (P<0.01) interactions between treatment and baseline severity were observed for parent ABC ratings of irritability and lethargy only. Greater magnitudes of the differences between risperidone and placebo were observed from moderate to very severe baseline severity on irritability and lethargy. Initial severity values over approximately 30 had a strong effect on symptom change [irritability: effect size (ES)=1.9, number needed to treat (NNT)=2, lethargy ES=0.9, NNT=5]. CONCLUSIONS: Parents may expect benefits of risperidone on irritability and lethargy with moderate to severe symptoms of ASD. TRIAL REGISTRATION: Registry name: ClinicalTrials.gov, trial identifier: NCT00005014, URL: http://www.clinicaltrials.gov/ct2/show/NCT00005014?term=NCT00005014&rank=1, registered on March 31, 2000.
Subject(s)
Autistic Disorder/drug therapy , Risperidone , Adolescent , Aggression/drug effects , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/adverse effects , Autistic Disorder/diagnosis , Autistic Disorder/psychology , Child , Child, Preschool , Double-Blind Method , Drug Monitoring , Female , Humans , Irritable Mood/drug effects , Male , Risperidone/administration & dosage , Risperidone/adverse effects , Self-Injurious Behavior/drug therapy , Treatment OutcomeABSTRACT
BACKGROUND: No evidence exists on the association between genocide and the incidence of schizophrenia. This study aims to identify critical periods of exposure to genocide on the risk of schizophrenia. METHOD: This population-based study comprised of all subjects born in European nations where the Holocaust occurred from 1928 to 1945, who immigrated to Israel by 1965 and were indexed in the Population Register (N = 113 932). Subjects were followed for schizophrenia disorder in the National Psychiatric Case Registry from 1950 to 2014. The population was disaggregated to compare groups that immigrated before (indirect exposure: n = 8886, 7.8%) or after (direct exposure: n = 105 046, 92.2%) the Nazi or fascist era of persecutions began. The latter group was further disaggregated to examine likely initial prenatal or postnatal genocide exposures. Cox regression modelling was computed to compare the risk of schizophrenia between the groups, adjusting for confounders. RESULTS: The likely direct group was at a statistically (p < 0.05) greater risk of schizophrenia (hazard ratio = 1.27, 95% confidence interval 1.06-1.51) than the indirect group. Also, the likely combined in utero and postnatal, and late postnatal (over age 2 years) exposure subgroups were statistically at greater risk of schizophrenia than the indirect group (p < 0.05). The likely in utero only and early postnatal (up to age 2 years) exposure subgroups compared with the indirect exposure group did not significantly differ. These results were replicated across three sensitivity analyses. CONCLUSIONS: This study showed that genocide exposure elevated the risk of schizophrenia, and identified in utero and postnatal (combined) and late postnatal (age over 2 years) exposures as critical periods of risk.
Subject(s)
Adult Survivors of Child Adverse Events/statistics & numerical data , Emigration and Immigration , Exposure to Violence/statistics & numerical data , Genocide/statistics & numerical data , Holocaust/statistics & numerical data , Prenatal Exposure Delayed Effects/epidemiology , Registries , Schizophrenia/epidemiology , Adult , Adult Survivors of Child Adverse Events/psychology , Aged , Aged, 80 and over , Europe/ethnology , Exposure to Violence/psychology , Female , Genocide/psychology , Holocaust/psychology , Humans , Incidence , Israel/epidemiology , Middle Aged , Pregnancy , Prenatal Exposure Delayed Effects/psychology , Proportional Hazards Models , Risk FactorsABSTRACT
Data on the clinical presentation of constitutional mismatch repair deficiency syndrome (CMMRD) is accumulating. However, as the extraintestinal manifestations are often fatal and occur at early age, data on the systematic evaluation of the gastrointestinal tract is scarce. Here we describe 11 subjects with verified biallelic carriage and who underwent colonoscopy, upper endoscopy and small bowel evaluation. Five subjects were symptomatic and in six subjects the findings were screen detected. Two subjects had colorectal cancer and few adenomatous polyps (19, 20 years), three subjects had polyposis-like phenotype (13, 14, 16 years), four subjects had few adenomatous polyps (8, 12-14 years) and two subjects had no polyps (both at age 6). Of the three subjects in the polyposis-like group, two subjects had already developed high-grade dysplasia or cancer and one subject had atypical juvenile polyps suggesting juvenile polyposis. Three out of the five subjects that underwent repeated exams had significant findings during short interval. The gastrointestinal manifestations of CMMRD are highly dependent upon age of examination and highly variable. The polyps may also resemble juvenile polyposis. Intensive surveillance according to current guidelines is mandatory.
Subject(s)
Adenomatous Polyps/genetics , Brain Neoplasms/genetics , Colorectal Neoplasms/genetics , Mutation , Neoplastic Syndromes, Hereditary/genetics , Adenosine Triphosphatases/genetics , Adolescent , Arabs/genetics , Brain Neoplasms/diagnosis , Child , Colorectal Neoplasms/diagnosis , DNA Repair Enzymes/genetics , DNA-Binding Proteins/genetics , Endoscopy, Gastrointestinal , Female , Humans , Intestinal Polyposis/congenital , Intestinal Polyposis/diagnosis , Intestinal Polyposis/genetics , Jews/genetics , Male , Mismatch Repair Endonuclease PMS2 , MutS Homolog 2 Protein/genetics , Neoplastic Syndromes, Hereditary/diagnosis , Phenotype , Young AdultABSTRACT
Diagnosis of Lynch syndrome (LS) may be complex. Knowledge of mutation spectrum and founder mutations in specific populations facilitates the diagnostic process. Aim of the study is to describe genetic features of LS in the Israeli population and report novel and founder mutations. Patients were studied at high-risk clinics. Diagnostics followed a multi-step process, including tumor testing, gene analysis and testing for founder mutations. LS was defined by positive mutation testing. We diagnosed LS in 242 subjects from 113 families coming from different ethnicities. We identified 54 different mutations; 13 of them are novel. Sixty-seven (59%) families had mutations in MSH2, 20 (18%) in MSH6, 19 (17%) in MLH1 and 7 (6%) in PMS2; 27% of the MSH2 mutations were large deletions. Seven founder mutations were detected in 61/113 (54%) families. Constitutional mismatch repair deficiency (CMMR-D) was identified in five families. Gene distribution in the Israeli population is unique, with relatively high incidence of mutations in MSH2 and MSH6. The mutation spectrum is wide; however, 54% of cases are caused by one of seven founder mutations. CMMR-D occurs in the context of founder mutations and consanguinity. These features should guide the diagnostic process, risk estimation, and genetic counseling.
Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Adult , Age of Onset , Aged , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/epidemiology , DNA Mismatch Repair/genetics , Family , Founder Effect , Genetic Counseling , Genetic Testing , Humans , Israel/epidemiology , Middle Aged , Mutation , Surveys and QuestionnairesABSTRACT
Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.
Subject(s)
Brain Neoplasms/diagnosis , DNA Repair-Deficiency Disorders/genetics , Digestive System Neoplasms/diagnosis , Neoplasms/diagnosis , Brain Neoplasms/etiology , Colorectal Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/drug therapy , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Repair-Deficiency Disorders/complications , Humans , Leukemia/diagnosis , Mutation , Neoplasms/etiology , Population SurveillanceABSTRACT
INTRODUCTION: New mutations for Huntington disease (HD) occur due to CAG repeat instability of intermediate alleles (IA). IAs have between 27 and 35 CAG repeats, a range just below the disease threshold of 36 repeats. While they usually do not confer the HD phenotype, IAs are prone to paternal germline CAG repeat instability. Consequently, they may expand into the HD range upon transmission to the next generation, producing a new mutation. Quantified risk estimates for IA repeat instability are extremely limited but needed to inform clinical practice. METHODS: Using small-pool PCR of sperm DNA from Caucasian men, we examined the frequency and magnitude of CAG repeat instability across the entire range of intermediate CAG sizes. The CAG size-specific risk estimates generated are based on the largest sample size ever examined, including 30 IAs and 18 198 sperm. RESULTS: Our findings demonstrate a significant risk of new mutations. While all intermediate CAG sizes demonstrated repeat expansion into the HD range, alleles with 34 and 35 CAG repeats were associated with the highest risk of a new mutation (2.4% and 21.0%, respectively). IAs with ≥33 CAG repeats showed a dramatic increase in the frequency of instability and a switch towards a preponderance of repeat expansions over contractions. CONCLUSIONS: These data provide novel insights into the origins of new mutations for HD. The CAG size-specific risk estimates inform clinical practice and provide accurate risk information for persons who receive an IA predictive test result.
Subject(s)
Alleles , Genomic Instability , Huntington Disease/genetics , Trinucleotide Repeat Expansion , Gene Frequency , Genotype , Germ-Line Mutation , Humans , Male , Spermatozoa/metabolismABSTRACT
We present a case of a female neonate who had a nonimmune hydrops fetalis and severe hemolytic anemia due to a rare combination of glucose-6-phosphate dehydrogenase (G6PD) deficiency and congenital dyserythropoietic anemia. We conclude that in severe cases with persistent anemia one should search after delivery for a second reason other than G6PD deficiency alone.
Subject(s)
Anemia, Dyserythropoietic, Congenital/diagnosis , Glucosephosphate Dehydrogenase Deficiency/diagnosis , Hydrops Fetalis/diagnosis , Hydrops Fetalis/etiology , Anemia, Dyserythropoietic, Congenital/therapy , Biopsy, Needle , Bone Marrow/pathology , Cesarean Section , Diagnosis, Differential , Erythroid Precursor Cells/pathology , Exchange Transfusion, Whole Blood , Female , Glucosephosphate Dehydrogenase Deficiency/therapy , Hematocrit , Humans , Hydrops Fetalis/therapy , Infant , Infant, Newborn , Jaundice, Neonatal/diagnosis , Jaundice, Neonatal/etiology , Jaundice, Neonatal/therapy , Microscopy, Electron , Phototherapy , PregnancyABSTRACT
We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.