Carrier Mothers Research Articles

NOVEL DAX-1 (NR0B1) MUTATION IN A THAI BOY WITH X-LINKED ADRENAL HYPOPLASIA CONGENITA (AHC): A FIRST REPORT

Background:Adrenal hypoplasia congenita (AHC) is a rare inherited disorder of adrenal development resulting in hypoplasia of adrenal gland and inability to produce glucocorticoids, mineralocorticoids and sex steroids. X-linked AHC is the most common form and is caused by mutation of the DAX1 gene. Here we report a case of 4-year-old Thai boy with X-linked AHC, the first case of genetically confirmed novel DAX1 mutation in Thailand. Patient and Method:A 4-year-old Thai boy presented with fever and vomiting for 3 days. He was the fifth child of unrelated parents. The past medical history was unremarkable except his skin had been progressively more pigmented since early infancy. Physical examination revealed normal genital development and addisonian hyperpigmentation which prominent at skin crease, gum and knuckles. Laboratory investigations showed hyponatremia, hyperkalemia, and hypochloremia. Hormonal evaluation revealed low baseline cortisol level which is not rising after 250 mg ACTH stimulation test. ACTH level and plasma renin activity were elevated. A diagnosis of X-linked AHC was established. Glucocorticoid and mineralocorticoid replacement therapy were initiated. Molecular analysis by direct DNA sequencing of the DAX1 gene was performed in the patient and family members. Result:Mutation analysis revealed a novel hemizygous GG deletion (c.1148_1149delGG) resulting in a premature termination codon at the position 387 (p.Gly383Aspfs*5). This frameshift mutation was predicted to encode a truncated DAX1 protein missing a portion of ligand binding domain. The mutation identified in our proband was inherited from his carrier mother. Conclusion:We report a case of classical X-linked AHC with established a novel frameshift mutation in the DAX1 gene. Genetic analysisis important not only for diagnostic confirmation in the index case but also for carrier detection in his mother which provided a proper management and appropriate genetic counseling for this famity.

Next-generation mapping: a novel approach for detection of pathogenic structural variants with a potential utility in clinical diagnosis

BackgroundMassively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient’s phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100–300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations.MethodsTo overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene.ResultsWe identified deletion, duplication, and inversion breakpoints within DMD. The sizes of deletions were in the range of 45–250 Kbp, whereas the one identified insertion was approximately 13 Kbp in size. This method refined the location of the break points within introns for cases with deletions compared to current polymerase chain reaction (PCR)-based clinical techniques. Heterozygous SV were detected in the known carrier mothers of the DMD patients, demonstrating the ability of the method to ascertain carrier status for large SV. The method was also able to identify a 5.1-Mbp inversion involving the DMD gene, previously identified by RNA sequencing.ConclusionsWe showed the ability of NGM technology to detect pathogenic structural variants otherwise missed by PCR-based techniques or chromosomal microarrays. NGM is poised to become a new tool in the clinical genetic diagnostic strategy and research due to its ability to sensitively identify large genomic variations.

Effects of Intrapartum Antibiotic Prophylaxis on Neonatal Acquisition of Group B Streptococci

To assess the incidence of colonization with group B streptococci (GBS) among neonates as influenced by maternal GBS carriage and intrapartum antibiotic prophylaxis (IAP). Between October 2014 and May 2015, nasopharyngeal and rectal swab samples were collected from 730 neonates at 1 week and 1 month after birth. GBS and capsular serotype were identified by real-time polymerase chain reaction and by culture. IAP at delivery was determined retrospectively from hospital records. Sixty-four neonates (8.8%) were GBS-positive by real-time polymerase chain reaction and culture. Among neonates born to mothers who were GBS carriers (n = 107), 94.4% (101/107) had maternal IAP; 19.6% nonetheless were GBS-positive, compared with 6.5% of neonates born to noncarrier mothers (P <.01). Among neonates born to mothers receiving IAP, more were positive only at 1 month of age than at both 1 week and 1 month. The frequency of GBS in neonates born to mothers receiving IAP was significantly lower than that in neonates born to mothers not receiving IAP (P <.05). Capsular serotypes V (25%) and III (23.4%) were common, followed by Ib (15.6%), Ia (14.1%), II (7.8%), IV (6.3%), nontypeable (4.7%), and VI and VIII (each 1.6%). Delayed colonization with GBS occurs in infants born to GBS carrier mothers receiving IAP. GBS should be considered in all infants at 1 month after birth with signs of infection.

Comparative Effectiveness of Prophylactic Strategies for Perinatal Transmission of Hepatitis B Virus: A Network Meta-analysis of Randomized Controlled Trials.

BackgroundPerinatal transmission is the main route of hepatitis B virus (HBV) transmission. While several measures have been attempted as means of preventing perinatal HBV transmission, the optimal strategy remains inconclusive.MethodsWe conducted a comprehensive search, through December 2016, for randomized controlled trials (RCTs) that compared the following measures among pregnant women with HBV infection: placebo/none, active immunoprophylaxis (hepatitis B vaccine series starting at birth [HBVac]), passive-active immunoprophylaxis (hepatitis B immunoglobulin and vaccine [HBIG+HBVac]), prenatal HBIG administration (HBIG/HBIG+HBVac), and prenatal antiviral therapy (AVT/HBIG+HBVac). Direct, indirect, and network meta-analyses were performed for all treatment comparisons.ResultsFifteen RCTs involving 2706 infants of HBV carrier mothers were eligible for analysis. Network meta-analysis demonstrated similar results as direct and indirect comparisons. HBVac alone significantly reduced the risk of hepatitis B infection in infants of HBV carrier mothers (relative risk [RR], 0.32; 95% confidence interval [CI], 0.21–0.50). The combination of immunoglobulin with vaccine is superior to vaccine alone (RR, 0.37; 95% CI, 0.20–0.67). Prenatal HBIG administration and antiviral therapy offer further advantages over current passive-active immunoprophylaxis for infants of highly viremic (HBV DNA level higher than 2 × 105 IU/mL) mothers (RR, 0.47; 95% CI, 0.29–0.75; and RR, 0.31; 95% CI, 0.10–0.99, respectively). There was no significant publication bias.ConclusionsBased on the universal infantile vaccination program, HBIG for infants born to HBV carrier mothers further reduces transmission. For highly viremic mothers whose children are still at risk for transmission under current immunoprophylaxis, prenatal HBIG administration or antiviral therapy in late pregnancy may be considered if more long-term evidence supports its efficacy and safety.

Reduced prevalence of hepatitis B surface antigen positivity among pregnant women born after the national implementation of immunoprophylaxis for babies born to hepatitis B virus-carrier mothers in Japan.

We aimed to estimate hepatitis B surface antigen (HBsAg) positivity among birth year-stratified pregnant women in Hiroshima, Japan, and compare prevalence rates between women born before and after implementation of a national immunoprophylactic vaccination program for babies born to hepatitis B virus (HBV) carrier mothers in Japan. Pregnant women who gave birth at all delivery hospitals/clinics in Hiroshima prefecture between 1 April 2010 and 31 March 2011 were eligible. Lists collected from each institution included survey items such as age (pregnant woman's birth year) and HBsAg and hepatitis C virus (HCV) antibody (anti-HCV) test results, which were posted anonymously and non-consolidated from medical records. We calculated the HBsAg and anti-HCV prevalence in our cohort according to the mothers' birth year. In 41 of 58 hospitals/clinics, 15 233 and 15 035 pregnant women underwent HBsAg and anti-HCV testing, corresponding to 59.6% and 58.9% of 25 546 births in the 2010 fiscal year, respectively. The overall HBsAg positive rate was 0.51% (95% confidence interval [CI], 0.40-0.63%), and an extremely low prevalence (0.10%; 95% CI, 0.00-0.25%) was observed among pregnant women born after 1986. However, the prevalence in this study was slightly higher than the nationwide value (0.31%) and the Chugoku region-specific value (0.46%) among first-time blood donors at Japanese Red Cross blood centers between 2001 and 2006. No significant difference in anti-HCV positivity was observed. Only two pregnant women born after the preventive program implementation were HBsAg-positive. Perinatal HBV transmission is estimated to be almost completely inhibited in the next generation.

Efficacy of Antiviral Therapy in HBsAg-Positive Pregnant Women to Reduce Mother-to-Infant Transmission of Hepatitis B Virus.

Hepatitis B is a major health concern in Asia. Chronic hepatitis B virus (HBV) infection may cause hepatic cirrhosis and liver cancer. HBV is transmitted horizontally through blood and blood products and vertically from mother to infant. Perinatal infection is the main route of transmission in regions with high prevalence of hepatitis B surface antigen (HbsAg) carriage, and perinatal transmission leads to high rates of chronic infection. Therefore, it is important to prevent mother-to-child transmission (MTCT) of HBV1. The present study aims at comparing the use of antivirals (lamivudine vs tenofovir) in reducing MTCT. A total of 60 HbsAg-positive pregnant women were enrolled in the prospective study to test the efficacy of antiviral (lamivudine vs tenofovir-category B drug) to reduce mother-to-child transmission and monitor hepatitis B viral status in infant. HbsAg-positive pregnant women aged 18-43years at gestational age between 28 and 32weeks were followed up. They were tested for HBsAg, liver function test and HBeAg. In whom HbeAg was positive, HBV viral load was tested. Sixty patients with high viral load (>6log copies/ml) were recruited in the study. Alternate patients were randomized into two groups. Group A comprised 31 subjects treated with lamivudine 100mg daily starting from 28 to 32weeks of gestation (third trimester) and continued to 1month after delivery. Group B comprised 29 pregnant women who were treated with tenofovir 300mg daily from 28 to 32weeks of gestation and continued to 1month post-partum. The newborn babies were given HBIG within 24h after delivery and HBV vaccines at 0, 1 and 6months. HBsAg infectivity was tested in the infant at 1year after birth. Antivirals, lamivudine/tenofovir treatment in HBV carrier mothers from 28weeks of gestation along with active and passive immunization of new born may interrupt MTCT of HBV efficiently. Tenofovir, category B drug, is more effective in preventing transmission of HBV infection to infants (p=0.004).

Clinical evaluation of early acquisition of Staphylococcus aureus carriage by newborns

BackgroundLittle is known about neonatal Staphylococcus aureus carriage. Sites and clinical outcomes of S. aureus colonization during the first month of life were evaluated in this study. MethodsA cohort of 279 infants born at term to 277 mothers was included. Maternal S. aureus colonization status was examined before labor. Newborns were screened for nasal, auricular, umbilical, and rectal colonization, one to three times within 100h after birth, and infants of carrier mothers were re-screened at 1 month. Medical data were recorded from the medical charts at discharge and at the 1-month follow-up interview. ResultsOverall 43 out of 279 (15.4%) infants acquired S. aureus within the first days of life. The only two predictors of S. aureus carriage in the postnatal period were maternal S. aureus carriage (odds ratio 7.905, 95% confidence interval 3.182–19.638) and maternal antibiotic treatment during labor (odds ratio 0.121, 95% confidence interval 0.016–0.949). Among colonized children, the nose (56%) and rectum (40%) were more frequently colonized, while ear (26%) and umbilicus (16%) colonization were less common. Co-colonization at two sites was rare (4%), but always predicted carriage at 1 month of age. Maternal and neonatal characteristics, including neonatal outcomes, were similar between S. aureus carrier and non-carrier infants during the first month of life. ConclusionsMaternal carriage is the major predictor of neonatal S. aureus carriage. The nose and rectum are the main sites of neonatal carriage. S. aureus carriage was not associated with neonatal complications throughout the first month of life. The long-term significance of early S. aureus carriage is yet to be determined.

A 15-year-long Southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan.

Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15-year period. In total, 725 high-risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low-risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low-risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156-1/539). A total of 100 carriers were found to be in the high-risk group, thus revealing a significantly higher frequency than the low-risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre-mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low-risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high-risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing.

Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?

Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.

Executive Functioning Mediates the Effect of Behavioral Problems on Depression in Mothers of Children With Developmental Disabilities.

The present investigation explored long-term relationships of behavioral symptoms of adolescents and adults with developmental disabilities with the mental health of their mothers. Fragile X premutation carrier mothers of an adolescent or adult child with fragile X syndrome (n = 95), and mothers of a grown child with autism (n = 213) were included. Behavioral symptoms at Time 1 were hypothesized to predict maternal depressive symptoms at Time 3 via maternal executive dysfunction at Time 2. Results provided support for the mediating pathway of executive dysfunction. Additionally, the association of behavioral symptoms with executive dysfunction differed across the two groups, suggesting that premutation carriers may be more susceptible to caregiving stress due to their genotype.

An Accurate, Simple, and Inexpensive Assay to Diagnose F8 Gene Inversion Mutations in Hemophilia a Patients and Carriers

The most frequent mutations resulting in hemophilia A are an intron 22 or intron 1 F8 gene inversion, which together result in ~50% of severe hemophilia A cases. We report simple and accurate RNA- and DNA-based assays to detect these mutations in patients and carrier mothers. They do not require specialized equipment or expensive reagents, and therefore they may provide useful and economic protocols that could be standardized for central laboratory testing.RNA is purified from a whole-blood RNA-stabilized sample or from peripheral blood mononuclear cells, and a two-step nested PCR (RT-PCR followed by PCR) reaction is carried out to amplify complementary DNA (cDNA) fragments with F8 sequences spanning the exon 22-23 splice site (intron-22 inversion test) or the exon 1-2 splice site (intron-1 inversion test). These sequences will be amplified from F8 mRNA without an intron-22 or intron-1 inversion mutation, respectively. Additional RT-PCR reactions are carried out to amplify a unique intron 22 inverted-gene mRNA sequence extending from F8 exon 19 to the first in-frame stop codon within intron 22, or a chimeric intron 1 inverted-gene transcript containing sequences from F8 exon 1 and the adjacent VBP1 gene. These latter two DNA products will be amplified only from F8 mRNA isolated from patients with an intron-22 or an intron-1 inversion mutation, respectively. Amplification of a FVIII C2 domain sequence serves as an internal control for the RT-PCR reactions, as this product will be generated from samples with and without an inversion mutation. Primers were designed to amplify PCR products having different lengths (between 200 and 600 bp) that could be clearly distinguished following electrophoresis on agarose gels. Samples from carrier mothers amplified the normal control as well as the inversion-mutation-specific bands, as expected.A nested PCR protocol reliably produced interpretable results from low template mRNA concentrations, while a one-step multiplexed RT-PCR version of the assay produced the expected bands, with fewer experimental steps, from higher template mRNA concentrations.The standard DNA-based inverse-shifting PCR (IS-PCR) reaction may be used for primary diagnosis and/or to classify intron 22 inversions as type 1 or type 2 (reflecting the specific homologous recombination site). We utilized a commercially available Bcl I enzyme that efficiently cleaves DNA in 5 minutes, a substantial improvement over previous IS-PCR protocols that required overnight DNA digests.These rapid, accurate protocols can economically detect or rule F8 inversion mutations via same-day testing of patient samples, providing timely information that is useful to families and in clinical evaluations. DisclosuresDutta:Grifols, Inc: Research Funding. Ragni:OPKO: Research Funding; Vascular Medicine Institute: Research Funding; Tacere Benitec: Consultancy; SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding.

Evaluation of the G145R Mutant of the Hepatitis B Virus as a Minor Strain in Mother-to-Child Transmission.

The role of the hepatitis B virus (HBV) mutant G145R, with a single change in amino acid 145 of the surface protein, as a minor population remains unknown in mother-to-child transmission. The minor strain as well as the major strain of the G145R mutant were evaluated in three cohorts using a locked nucleic acid probe-based real-time PCR. The breakthrough cohort consisted of children who were born to HBV carrier mothers and became HBV carriers despite immnoprophylaxis (n = 25). The control cohort consisted of HBV carriers who had no history of receiving the hepatitis B vaccine, hepatitis B immunoglobulin or antiviral treatment (n = 126). The pregnant cohort comprised pregnant women with chronic HBV infection (n = 31). In the breakthrough cohort, 6 showed positive PCR results (major, 2; minor, 4). In the control cohort, 13 showed positive PCR results (major, 0; minor, 13). HBeAg-positive patients were prone to have the G145R mutant as a minor population. Deep sequencing was performed in a total of 32 children (PCR positive, n = 13; negative, n = 19). In the breakthrough cohort, the frequency of the G145R mutant ranged from 0.54% to 6.58%. In the control cohort, the frequency of the G145R mutant ranged from 0.42% to 4.1%. Of the 31 pregnant women, 4 showed positive PCR results (major, n = 0; minor, n = 4). All of the pregnant women were positive for HBeAg and showed a high viral load. Three babies born to 3 pregnant women with the G145R mutant were evaluated. After the completion of immunoprophylaxis, 2 infants became negative for HBsAg. The remaining infant became negative for HBsAg after the first dose of HB vaccine. G145R was detected in one-fourth of the children with immunoprophylaxis failure. However, the pre-existence of the G145R mutant as a minor population in pregnant women does not always cause breakthrough infection in infants.

Genetic variants in oxytocin receptor and arginine-vasopressin receptor 1A are associated with the neural correlates of maternal and paternal affection towards their child

There is extensive evidence in animal studies, particularly in vole species (Microtus), that oxytocin (OT) receptor and arginine-vasopressin (AVP) receptor 1a is critical for the regulation of maternal and paternal behavior, respectively. Human studies have gained insight into the relationship between both hormone receptor gene variants and behavior, but not between the variants and the underlying brain activity. To study this, we investigated the association between neural activation of the anterior prefrontal cortex (APFC) in mothers and fathers in response to their child smiling video stimuli to induce the positive affect related to attachment with their child, and genetic variants of OT receptor (OXTR) and AVP receptor 1A (AVPR1A). Overall, 43 mothers and 41 fathers participated, and each parent's child smiling was video recorded. Participants were then genotyped and underwent near-infrared spectroscopy to measure neural activation of the APFC while observing their own child smiling compared with an unfamiliar child. We found that the right inferior APFC was activated in response to child video stimuli in mothers and differential hemispheric activation of the inferior APFC in OXTR rs2254298-G/G mothers compared with -A carrier mothers, but not in fathers. Furthermore, we found a difference in the left inferior APFC activation between AVPR1A RS3-non-334 and -334 carrier fathers, but not mothers. Our results indicate a sex-dependent association between the genetic variants and the inferior APFC activations of maternal and paternal positive affect, analogous to the results reported in voles.

De novo loss of function mutations in KIAA2022 are associated with epilepsy and neurodevelopmental delay in females.

Intellectual disability (ID) affects about 3% of the population and has a male gender bias. Of at least 700 genes currently linked to ID, more than 100 have been identified on the X chromosome, including KIAA2022. KIAA2022 is located on Xq13.3 and is expressed in the developing brain. The protein product of KIAA2022, X‐linked Intellectual Disability Protein Related to Neurite Extension (XPN), is developmentally regulated and is involved in neuronal migration and cell adhesion. The clinical manifestations of loss‐of‐function KIAA2022 mutations have been described previously in 15 males, born from unaffected carrier mothers, but few females. Using whole‐exome sequencing, we identified a cohort of five unrelated female patients with de novo probably gene damaging variants in KIAA2022 and core phenotypic features of ID, developmental delay, epilepsy refractory to treatment, and impaired language, of similar severity as reported for male counterparts. This study supports KIAA2022 as a novel cause of X‐linked dominant ID, and broadens the phenotype for KIAA2022 mutations.

Duchenne/Becker Muscular Dystrophy: advances in reproductive testing options

Duchenne/Becker Muscular Dystrophy (DMD/BMD) is an X-linked recessive disorder associated with progressive limb muscle weakness, atrophy, and cardiac disease in affected males. Approximately two-thirds of diagnosed cases have a carrier mother. Due to the size of the DMD gene, population-based genetic carrier screening for DMD/BMD was previously cost-prohibitive. However, recent advances in genetic testing now make carrier screening for DMD/BMD feasible.

Earlier Age of Breast Cancer Onset in Israeli BRCA Carriers-Is it a Real Phenomenon?

Data on genetic anticipation in breast cancer are sparse. We sought to evaluate age at diagnosis of breast cancer in daughters with a BRCA mutation and their mothers. A review of all carriers of the BRCA mutation diagnosed with breast cancer at the Genetics Institute of a tertiary medical center in 2000-2013 yielded 80 women who could be paired with a mother with breast cancer who was either a carrier of the BRCA mutation or an obligate carrier according to pedigree analysis. Age at diagnosis, type of mutation (BRCA1, BRCA2), year of birth, and ethnicity were recorded. Paired t-test was used to analyze differences in age at cancer diagnosis between groups and subgroups. Mean age at diagnosis of breast cancer was 50.74 years (range 22-88) in the mothers and 43.85 years (range 24-75) in the daughters. The difference was statistically significant (p < 0.001). These findings were consistent regardless of type of BRCA mutation, ethnicity, or mother's year of birth. However, on separate analysis of pairs in which the mother was diagnosed before the age of 50 years, there was no significant difference in mean age at diagnosis between mothers and daughters (~42 years for both). Daughters who carry a BRCA mutation are diagnosed with breast cancer at an earlier age than their carrier mothers, with the exception of pairs in which the mother was diagnosed before the age of 50 years. Future breast-screening guidelines may need to target specific subpopulations of BRCA mutation carriers.

Treatment of hemophilia: A qualitative study of mothers' perspectives.

In Norway, boys with hemophilia usually begin treatment after their first bleeding episode. Boys with severe hemophilia usually start prophylactic treatment around 18-24 months. Health professionals administer factor concentrate initially, but when boys are around 4 years old most parents start treating their children at home. There is a lack of research on how parents, and especially how carrier mothers, experience the medical treatment for their sons' hemophilia. Our aim was to investigate how carrier mothers experience this treatment in the hospital setting and at home. In this qualitative study, we interviewed 16 mothers of boys or men with hemophilia A or B. Data were collected via semistructured interviews and analyzed using an inductive thematic analytical approach. Mothers experienced both practical and emotional challenges in relation to their sons' treatment, and repeated venipuncture was especially difficult emotionally. Parents preferred home treatment to hospital treatment because it was less time-consuming, less disruptive to family life, and provided a greater sense of control. Encountering healthcare professionals who were unfamiliar with hemophilia was a second major stress factor, especially when parents felt that health professionals lacked competence and were unwilling to seek advice. While home treatment for hemophilia enables freedom, flexibility, and autonomy for the boys as well as for the family, mothers may experience treatment of hemophilia as a burden. Health professionals should provide tailored practical and emotional support to parents by probing into their experiences with treating their sons' hemophilia.

Psychopathology Increases With Age in Fragile X Carrier Mothers

Psychopathology Increases With Age in Fragile X Carrier Mothers

Haemophilia: A disease of women as well

Background. While haemophilia is a disease phenotype in males only, it has an effect on females too. In South Africa, there is no documentation on the views and experiences of haemophilia carrier mothers regarding the disease, or about their response to carrier testing for daughters or other female members of their families. The burden of child care may fall entirely on the mother in some cultures, and having a son with haemophilia may make coping difficult. Knowing their carrier status would allow daughters of carrier mothers to be aware of the chances of themselves having a son with haemophilia. Knowing their own factor levels may also be useful in understanding possible excessive bleeding in themselves. Objectives. To record the experiences of haemophilia carrier mothers in KwaZulu-Natal and their attitudes and opinions on carrier testing for female members of their families. Methods. Forty mothers of haemophiliac sons were interviewed using a structured questionnaire specifically designed and tested for this study. Results. From this cohort, there were 21 potential carrier daughters and 25 potential carrier sisters who would be eligible for further testing and counselling. All the study participants expressed their desire to have carrier testing available for female family members. They also expressed their concerns regarding raising a son with haemophilia, including some culture-specific issues. Conclusion. A diagnosis of haemophilia carriership is seen by mothers of haemophiliac sons as important for female members of their families. A protocol for the care of haemophilia carrier women is therefore necessary.

Wide allelic heterogeneity with predominance of large IDS gene complex rearrangements in a sample of Mexican patients with Hunter syndrome

Hunter syndrome or mucopolysaccharidosis type II (MPSII) is caused by pathogenic variants in the IDS gene. This is the first study that examines the mutational spectrum in 25 unrelated Mexican MPSII families. The responsible genotype was identified in 96% of the families (24/25) with 10 novel pathogenic variants: c.133G>C, c.1003C>T, c.1025A>C, c.463_464delinsCCGTATAGCTGG, c.754_767del, c.1132_1133del, c.1463del, c.508-1G>C, c.1006+1G>T and c.(-217_103del). Extensive IDS gene deletions were identified in four patients; using DNA microarray analysis two patients showed the loss of the entire AFF2 gene, and epilepsy developed in only one of them. Wide allelic heterogeneity was noted, with large gene alterations (e.g. IDS/IDSP1 gene inversions, partial to extensive IDS deletions, and one chimeric IDS-IDSP1 allele) that occurred at higher frequencies than previously reported (36% vs 18.9-29%). The frequency of carrier mothers (80%) is consistent with previous descriptions (>70%). Carrier assignment allowed molecular prenatal diagnoses. Notably, somatic and germline mosaicism was identified in one family, and two patients presented thrombocytopenic purpura and pancytopenia after idursulfase enzyme replacement treatment. Our findings suggest a wide allelic heterogeneity in Mexican MPSII patients; DNA microarray analysis contributes to further delineation of the resulting phenotype for IDS and neighboring loci deletions.