Novel cystathionine ß-synthase gene mutations in a Filipino patient with classic homocystinuria.

BACKGROUND: Classic homocystinuria due to cystathionine ß-synthase (CBS) deficiency is an autosomal recessive disorder of sulfur metabolism. Clinical manifestations include mental retardation, dislocation of the optic lens (ectopia lentis), skeletal abnormalities and a tendency to thromboembolic episodes. We present the first mutational analysis of CBS in a Filipino patient with classic homocystinuria. METHODS: Genomic DNA was extracted from peripheral blood collected from a diagnosed Filipino patient with classic homocystinuria. The entire coding region of CBS (17 exons) was amplified using polymerase chain reaction and bidirectionally sequenced using standard protocols. RESULTS: The patient was found to be compound heterozygous for two novel mutations, g.13995G>A [c.982G>A; p.D328K] and g.15860-15868dupGCAGGAGCT [c.1083-1091dupGCAGGAGCT; p. Q362-L364dupQEL]. Four known single-nucleotide polymorphisms (rs234706, rs1801181, rs706208 and rs706209) were also detected in the present patient's CBS. The patient was heterozygous for all the identified alleles. CONCLUSIONS: This is the first mutational analysis of CBS done in a Filipino patient with classic homocystinuria who presented with a novel duplication mutation and a novel missense mutation. Homocystinuria due to CBS deficiency is a heterogeneous disorder at the molecular level.

Current diagnosis and management of mucopolysaccharidosis VI in the Asia-Pacific region.

INTRODUCTION: Mucopolysaccharidosis (MPS) type VI (Maroteaux-Lamy syndrome) is a clinically heterogeneous lysosomal storage disorder. It presents significant diagnostic and treatment challenges due to the rarity of the disease and complexity of the phenotype. As information about MPS VI in Asia-Pacific countries is limited, a survey was conducted to assess current practices for diagnosis and management of MPS VI in this region. The participants were selected based on their experience in diagnosing and managing MPS patients. METHODS: The survey comprised 29 structured quantitative or qualitative questions. Follow-up consultations were undertaken to discuss the data further. RESULTS: Thirteen physicians from eight countries or regions (Australia, China, Hong Kong, Japan, Malaysia, Philippines, Taiwan and Thailand) were surveyed. At the time of the survey twenty-two patients with MPS VI were directly treated by the respondents and most (~80%) had rapidly progressing disease. A wide range of medical specialists are involved in managing patients with MPS VI, the most common being orthopedic surgeons, pediatricians and geneticists. The availability/accessibility of diagnostic tools, therapies and national insurance coverage vary greatly across the countries/regions and, in some cases, between different regions within the same country. Currently, there are national MPS management groups in Australia and Japan. Australia, Taiwan and Hong Kong have local guidelines for managing MPS and local MPS registries are available in Australia, Taiwan, and Japan. CONCLUSIONS: This survey highlights differences in the diagnosis and management of MPS VI between Asia-Pacific countries/regions. Important barriers to advancing the identification, understanding and treatment of MPS VI include the paucity of epidemiological information, limited access to laboratory diagnostics and therapies, low disease awareness, and a lack of monitoring and treatment guidelines. There is a clear need to facilitate communications between physicians and establish regional or national disease registries, a multidisciplinary referral network, and a centralized diagnostic and management framework.

Diversity of approaches to classic galactosemia around the world: a comparison of diagnosis, intervention, and outcomes.

Without intervention, classic galactosemia is a potentially fatal disorder in infancy. With the benefit of early diagnosis and dietary restriction of galactose, the acute sequelae of classic galactosemia can be prevented or reversed. However, despite early and lifelong dietary treatment, many galactosemic patients go on to experience serious long-term complications including cognitive disability, speech problems, neurological and/or movement disorders and, in girls and women, ovarian dysfunction. Further, there remains uncertainty surrounding what constitutes a 'best practice' for treating this disorder. To explore the extent and implications of this uncertainty, we conducted a small but global survey of healthcare providers who follow patients with classic galactosemia, seeking to compare established protocols for diagnosis, intervention, and follow-up, as well as the outcomes and outcome frequencies seen in the patient populations cared for by these providers. We received 13 survey responses representing five continents and 11 countries. Respondents underscored disparities in approaches to diagnosis, management and follow-up care. Notably, we saw no clear relationship between differing approaches to care and long-term outcomes in the populations studied. Negative outcomes occurred in the majority of cases regardless of when treatment was initiated, how tightly galactose intake was restricted, or how closely patients were monitored. We document here what is, to our knowledge, the first global comparison of healthcare approaches to classic galactosemia. These data reinforce the idea that there is currently no one best practice for treating patients with classic galactosemia, and underscore the need for more extensive and statistically powerful comparative studies to reveal potential positive or negative impacts of differing approaches.

Maple syrup urine disease associated with nephrotic syndrome in a Filipino child.

A 22-month-old female child with maple syrup urine disease (MSUD) presented with generalised oedema. Diagnostic evaluation revealed nephrotic range proteinuria, hypoalbuminaemia and dyslipidaemia supporting the diagnosis of nephrotic syndrome (NS). Diet, being at the core of the management plan for both MSUD and NS, necessitated regular monitoring and evaluation via dried blood spot collection of leucine. The opposing requirement for total protein for both disorders (that is protein restriction in MSUD and protein supplementation in NS) prompted a careful balancing act of the dietary management. The monitoring, which revealed normal leucine levels on multiple determinations, allowed an eventual increase in dietary protein and daily administration of albumin to address the NS. Dietary protein increase, both in total protein (3.5 g/kg/day) and natural protein (1 g/kg/day) levels, was instituted. It was observed that NS does not trigger leucinosis and allowed easing of protein restriction in MSUD.

Menopausal Status and Outcomes of BRCA Mutation Carriers with Breast Cancer.

Outcomes based on menopausal status of breast cancer (BC) patients who are BRCA mutations carriers (BRCAm) are not well known. A prospective database identified 88 BRCAm with BC from 2005 to 2015. Of the 88 patients, 68 (77.3%) women were premenopausal (Pre-M) and 20 (22.7%) were postmenopausal (Post-M). In the Pre-M group, 52.9 per cent of patients had triple-negative (TN) BC, whereas in the Post-M group, there were more estrogen receptor +(65%; P = 0.129) and less TN (25%; P = 0.041) tumors. Median tumor size was significantly larger in the Pre-M group compared with the Post-M group (P <0.001). Pre-M women were more likely to present with stage III cancers (14.7% vs 0%, respectively, P = 0.082). Ten-year overall survival was 87.9 per cent in the Pre-M group and 93.8 per cent in the Post-M group (P = 0.44), and 25.3 per cent of Pre-M women had recurrences compared with 11.5 per cent of Post-M women (P = 0.24). Premenopausal BRCAm with BC are more likely to have TN, higher stage disease, and twice the number of recurrences at 10 years than Post-M BRCAm. Our study is the first to show worse BC outcomes for Pre-M BRCAm compared with Post-M BRCAm women.

Challenges in the management of patients with maple syrup urine disease diagnosed by newborn screening in a developing country.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism resulting from a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. MSUD has been reported to be the most common inborn error of metabolism in the Philippines. We described all patients with maple syrup urine disease patients diagnosed through newborn screening during its first 2 years of implementation and the challenges encountered during their medical management. There were 24 patients diagnosed with maple syrup urine disease for the 2-year period. All patients needed hospital admission. The most common complication during hospital admission was infection, needing intravenous antibiotics which were given to 21 of the patients. Out of the 24 diagnosed, 16 patients are alive, while eight have died. Several neurologic and non-neurologic complications have been observed during the follow-up of the patients. The common challenges of MSUD management in a low-resource setting identified in this study were late diagnosis, lack of access to metabolic specialists and medical supplies, nosocomial septicemia, and protein deficiency. Aside from early properly timed collection, improvement in other logistical concerns will also help in earlier diagnosis. Mechanisms of transfer of critically ill patients must be improved. Hospitals in difficult-to-reach areas must be equipped to handle critical metabolic cases when transfers are not possible. Newborn screening has been proven to improve outcome in patients with MSUD but the success of the program in preventing disability is also dependent on improvements in other aspects of healthcare.

Next-Generation Gene Sequencing: Looking Beyond Hereditary Breast and Ovarian Cancer.

Oncology nurses have long been aware of the significance of recognizing patients' hereditary risk of cancer. Obtaining an accurate family history is an integral part of patient assessment and has helped to guide referrals for genetic counseling and testing for hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome.

Hyperphenylalaninemia in the Philippines.

To present patients with hyperphenylalaninemia (HPA) diagnosed by routine newborn screening and to discuss the principles in managing hyperphenylalaninemia, retrospective clinical chart review was conducted. Newborn screening for phenylketonuria (PKU) was performed using the Guthrie Test or Bacterial Inhibition Assay, utilizing dried blood spots on special filter cards. Positive screens were confirmed through plasma amino acid determination, urinary pterins for tetrahydrobiopterin deficiency, enzyme analysis. Once confirmed, the patients were kept on low-phenylalanine diet and regularly monitored for blood phenylalanine levels and developmental profile. A total of 189,720 newborns were screened from 1996--2001. Seventy five screened positive for PKU; 41 returned for retest; 3 were confirmed positive for HPA. This paper presents the first two cases of HPA detected by the Philippine Newborn Screening Program. The management of each case upon diagnosis is discussed. The significance of early detection and treatment of HPA is emphasized.

6-pyruvoyl tetrahydropterin synthase deficiency: a case report.

A 5 day old girl screened positive for hyperphenylalaninemia on routine newborn screening. Initial diagnostic work-up showed elevated blood phenylalanine of 1100 mmol/L and low tyrosine. Limited protein diet and phenylalanine-free formula were prescribed. Further investigation revealed a defect in biopterin metabolism. Urine had no detectable biopterin (BH4) and an elevated level of neopterin at 24.31 mmol/mole Cr. Enzymatic assay showed zero level of 6-pyruvoyl tetrahydropterin synthase. The activity in the mother was 3.5 or 19.9% of controls consistent with heterozygosity. The concentrations of 5-hydroxyindoleacetic acid and homovanillic acid in the cerebrospinal fluid were below the reference ranges. A treatment regimen of BH4 tablets, 5 hydroxytryptophan and DOPA was initiated. The diagnostic evaluation, management and follow-up of patients with this disorder will be outlined. This is the first reported case of a Filipino with a defect in biopterin metabolism.

Initial versus confirmatory thyroid stimulating hormone (TSH) levels: is there a correlation?

Newborn screening for congenital hypothyroidism (CH) in the Philippines began in 1996. The screening method used is the fluoroimmunometric assay of thyroid stimulating hormone (TSH) from dried blood spot. In the past five years (June 1996--Sept 2001), 176,548 newborns have been screened. Of these, 237 had elevated TSH levels and 51 (22%) were confirmed to have CH. One hundred forty-six (61%) had normal TSH levels on confirmatory testing; five (2%) expired; 25 (11%) were lost to follow-up, while 10 (4%) were being recalled at the time of this study. Thirty-three out of 51(65%) CH patients are female. Only 38 of 51 patient charts were available for data analysis. Thirteen of 51 CH patients were lost to follow-up after confirmation of the disorder. The mean age at which levo-thyroxine was initiated is 1 1/2 months at a modal dosage of 25 microg OD. The initial TSH levels as determined by the Philippine Newborn Screening Laboratory directly correlates with the confirmatory TSH levels done in other endocrine laboratories (Spearman's rho=0.57, p value=0.0002, at a=0.05). However, the time of heel prick on the newborn was independent of the TSH levels, (Spearman's rho=-0.16, p value=0.377 at a=0.05) hence there was no significant difference with respect to the initial TSH level of blood samples taken at 48 hours, less than one week, one to two weeks; or even more than two weeks after birth (Kruskall Wallis test, p value=0.064 at a=0.05). Using Fisher's exact test, there is no sufficient evidence to say that there is an association between gender and the incidence of CH among screened newborns whose TSH levels were initially elevated (p 2-tailed=0.183, p 1-tailed=0.113 at a=0.05).

Cost-benefit analysis of newborn screening for galactosemia in the Philippines.

To determine the incidence of galactosemia (GAL) in the Philippines and to determine whether newborn screening for GAL is cost-beneficial from a societal perspective, cost-benefit analysis was performed. Newborn screening for GAL was done after the 24th hour of life using the Beutler test. Patients screened positive were recalled for confirmatory testing. Using incidence rates obtained from the different participating hospitals of the Philippine Newborn Screening Program (PNSP), the costs for the detection and treatment of GAL were compared to the expected benefits by preventing mental retardation, cataracts and other physical disabilities caused by the disorder that would lead to a loss of productivity for the individual. Sensitivity analyses for incidence and discount rates were also included. Of the 157,186 newborns screened by the PNSP since its inception in 1996, 8 screened positive results. Confirmatory testing of these patients showed that 2 had galactosemia. The incidence of galactosemia in this population therefore, is 1 in 106,006 (95% CI= 1:44,218 - 1:266,796). Projecting the figures to the actual birth rate (1.5M newborns/year), the total costs of the screening program amounted to $1.1M, while the total benefits amounted only to $0.2M, yielding net cost of $0.9M. A cost-benefit analysis of the screening program for galactosemia using the incidence 1 in 106,006 demonstrated that the costs of the program outweigh the benefits. The true incidence of galactosemia in the Philippine population may yield an incidence rate that will result in greater net benefits for the program.

Mutational analysis of the GALT gene in Filipino patients.

Classic galactosemia is an inherited metabolic disorder due to mutations in the galactose-1-phosphate uridyltransferase (GALT) gene. This study describes the results of the GALT gene analysis of four unrelated Filipino patients with Classic Galactosemia. DNA extracted from dried blood spots and peripheral blood of the patients, age one month to two and a half years, underwent PCR-amplification with subsequent bidirectional sequencing of all eleven exons with their flanking intronic regions following standard protocols. Clinical data of these patients were reviewed. The patients presented with jaundice, hepatomegaly, diarrhea, vomiting, poor feeding and seizures during their neonatal period. They were diagnosed with elevated blood galactose and galactose-1-phosphate and absent GALT activity. Four missense mutations were found wherein two were previously reported (p.V168L and p.A345D) and two were novel (p.L116P and p.M178R). The most frequent mutation in our cohort is p.V168L. This study suggests that GALT mutations are ethnic-specific and that galactosemia is a heterogeneous disorder at the molecular level. The importance of early detection, immediate and proper medical management and genetic counseling of the patients and their families cannot be overemphasized.

Exploring potential use of internet, E-mail, and instant text messaging to promote breast health and mammogram use among immigrant Hispanic women in Los Angeles County.

Breast cancer is now the leading cause of death in Hispanic women (HW). Internet, e-mail, and instant text messaging may be cost-effective in educating HW about breast health and in reducing breast cancer mortality. We surveyed 905 HW women attending a free health fair about their technology use, acculturation, insurance status, mammography use, and breast cancer knowledge. Data were analyzed by t test or χ(2) tests. Mean age was 51.9 ± 14.2 years (range, 18 to 88 years). Ninety-two per cent were foreign-born. Most had completed some high school (39%) or elementary (38%) education. Most (62%) were uninsured. The majority spoke (67%) and read (66%) only Spanish. Only 60 per cent of HW older than 40 years had a recent mammogram. HW older than 40 years who had not had a recent mammogram were younger (mean 54.9 ± 10.8 vs 58 ± 10.4 years) and less likely to have health insurance (25 vs 44%; P < 0.001). Most HW never use the Internet (58%) or e-mail (64%). However, 70 per cent have mobile phones (66% older than 40 years), and 65 per cent use text messaging daily (58% older than 40 years, P = 0.001). In fact, 45 per cent wish to receive a mammogram reminder by text. Text messaging may be an inexpensive way to promote breast health and screening mammography use among uninsured HW.

What motivates women to take part in clinical and basic science endometriosis research?

BACKGROUND: The objective of this study was to identify factors motivating women to take part in endometriosis research and to determine if these factors differ for women participating in clinical versus basic science studies. METHODS: A consecutive series of 24 women volunteering for participation in endometriosis-related research were asked to indicate, in their own words, why they chose to volunteer. In addition, the women were asked to rate, on a scale of 0 to 10, sixteen potentially motivating factors. The information was gathered in the form of an anonymous self-administered questionnaire. RESULTS: Strong motivating factors (mean score > 8) included potential benefit to other women's health, improvement to one's own condition, and participation in scientific advancement. Weak motivating factors (mean score < 3) included financial compensation, making one's doctor happy, and use of 'natural' products. No difference was detected between clinical and basic science study participants. CONCLUSION: This study is the first study to specifically investigate the factors that motivate women to take part in endometriosis research. Understanding why women choose to take part in such research is important to the integrity of the informed consent process. The factors most strongly motivating women to participate in endometriosis research related to improving personal or public health; the weakest, to financial compensation and pleasing the doctor.