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.

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.

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.

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.

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.

Classical hemocystinuria in two Filipino patients

Classical hemocystinuria is an inborn error of metabolism caused by a deficiency of cystathionine beta-synthase that converts hemocysteine to cystathionine. This then leads to elevation of hemocysteine which results in abnormalities of the eyes, skeleton, central nervous system and vascular hemocystinuria. Patient 1 presented with lens dislocation and mental retardation while Patient 2 presented with thromboembolism, mental retardation and lens dislocation. The elevated plasma hemocysteine and methionine levels lead to the diagnosis of hemocystinuria.

Early diagnosis and specialist care in the management of congenital hypothyroidism

Background. Newborn screening for congenital hypothyroidism (CH) in the Philippines was introduced in 1996. It is universally accepted that early detection through newborn screening and timely treatment can improve the physical and neuro-cognitive development of patients. As of December 2010, the prevalence of CH is 1 in 3,324 among 2,389,959 newborns screened. Objective. We sought to evaluate the role of timing of diagnosis, compliance with treatment, and specialist care on growth and development (mental and physical) of patients with congenital hypothyroidism detected through newborn screening. Methods. Of the 326 patients identified through newborn screening between July 1996-December 2008 at the Newborn Screening Center-National Institutes of Health, 86 patients participated in the study. With the parents' or guardians' consent, general physical examination and neuro-cognitive evaluation were done; FT4 and TSH were determined. Prevalence of poor control of disease (high TSH with normal or low FT4 or normal TSH with low FT4), stunting, and cognitive delay were each estimated at 95% confidence level and the associations of early diagnosis, initial and continuing specialist care with these conditions were determined by multiple logistic regression analyses. Results. The prevalences (95% confidence interval) were: poor control of disease 63% (52-73%), stunting 24% (15-34%) and neuro-developmental delay 17% (8-25%). Delay in one aspect of neuro-development was seen in 54% (43-66%). Early diagnosis was protective against poor control of disease (adjusted Odds Ratio, ORa=0.24 [CI: 0.08-0.77]). Trends towards protection were seen for initial and continuing specialist care. For delay in at least one cognetive aspect, early diagnosis was found to be protective (ORa=0.19 [CI 0.05-0.76]); results for specialist care were inconclusive. For stunting, low parent education was found to be a risk factor. (ORa of 5.45 [CI: 1.3-22.7]). Conclusion. Fifty-four percent of the study patients had delay in one aspect of neuro-development. While other factors play a role in the outcome of CH, early diagnosis and treatment were shown to be protective of patients from poor control of disease and cognitive delays. Observed trends of positive benefits of specialist care at onset and continuing medical management, and the association of low parent education with poor growth should be considered in drafting specific guidelines for the long term follow-up care and monitoring of CH patients detected through newborn screening. The low percentage of participation and incomplete retrieval of information are major limitations of this retrospective study. This stresses the need for better monitoring tools that will ensure proper tracking, medical care and evaluation of CH patients.

Cost-benefit analysis of the newborn screening program of the Philippines

BACKGROUND: Newborn Screening (NBS) is a public health activity aimed at the early identification of infants who are affected by certain genetic/metabolic/infectious conditions. A cost analysis is critical for national implementation for integration as a public health program. OBJECTIVES: 1) To determine the incidence rates of congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH), galactosemia (GAL), phenylketonuria (PKU) and glucose-6-phosphate dehydrogenase (G6PD) deficiency; and 2) To determine whether NBS is cost-beneficial for each disorder individually or in combination, from a societal perspective. STUDY DESIGN: Cross sectional survey and cost-benefit analysis. SUBJECTS AND METHODS: The study was conducted through a screening survey of the original 24 Metro Manila hospitals. Newborns were screened for CH, CAH, GAL, PKU and G6PD deficiency after the 24th hour of life. Those who screened positive underwent serum confirmatory testing. Using incidence rates from the screening survey, a population of 1.5 million, and different screening combinations, the costs for the detection and treatment of the five disorders were compared to the benefits projected from preventing the corresponding complications and consequent productivity losses. For economic evaluation, we compared sequential analysis of doing tandem/multiple testing for the different disorders vs a "do-nothing" alternative. Sensitivity analyses for different incidence and discount rates were conducted to test the strength of the conclusions. RESULTS: The incidences of the disorders with 95% confidence intervals are: CH is 1:3 235 (1:2 219 - 1:5 946); CAH is 1:7 455 (1:4 046 - 1: 14245); GAL is 1: 106 006 (1: 44 218-1:266 796); and G6PD deficiency is 1:167 (1:151 - 1: 186). Screened individually, CH and G6PD deficiency had net benefits of US$ 5.29 M and US$ 15.44 M, respectively. The other conditions yielded net costs when screened individually - CAH (US$ 2.61 M), GAL (US$ 0.90 M) and PKU (US$ 6.74 M). Pairing the disorders with CH showed the following benefit:cost ratios - CH + CAH, 1.3; CH + GAL, 2.0; CH + G6PD deficiency, 3.4; and CH + PKU, 0.9. Combining disorders resulted in the following benefit:cost ratios - CH + CAH + GAL, 1.2; CH + CAH + GAL + PKU, 0.8; and CH + CAH + GAL + G6PD deficiency, 2.1. Screening for the 5 disorders in tandem resulted in a benefit:cost ratio of 1.4 and a net benefit of US$ 11.42 M.

Mutations of the phenylalanine hydroxylase (PAH) gene in Filipino patients with phenylketonuria

INTRODUCTION: Phenylketonuria (PKU), an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency, leads to hyperphenylalaninemia and neurological damage if untreated. This is the first study in the Philippines to identify the disease-causing mutations in the PAH gene of clinically diagnosed Filipino PKU patients. METHODS: The study included four unrelated PKU patients detected by the Philippine Newborn Screening Program from 1996 to 2008. Plasma amino acid analyses for all patients showed increased phenylalanine and low to normal tyrosine levels consistent with the diagnosis of PKU. Mutations in the PAH gene were identified by genomic DNA extraction from dried blood spots of the patients, PAH exon amplification by polymerase chain reaction and subsequent bi-directional DNA sequence analysis. RESULTS: All patients presented with significantly elevated phenylalanine levels on bacterial inhibition assay and thin layer chromatography. Urinary pterins confirmed the diagnosis of Tetrahydrobiopterin deficiency in two patients while the other 2 patients had the Classical PKU phenotype. Four previously identified mutations in the PAH gene (p.I65T, p.R413P, p.EX6-96A>G, p.R243Q) were identified in those with Classical PKU. CONCLUSION: The present results confirm the heterogeneity of mutations at the PAH locus in Filipinos. Neonatal screening and the use of molecular diagnosis significantly aid in the medical management and genetic counseling of patients and their families.

Mutations of the steroid 21-hydroxylase gene among Filipino patients with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH), an autosomal recessive disorder, is due to deficiency of the enzymes involved in adrenal steroidogenesis. Phenotypic manifestations vary as a result of the degree of glucocorticoid or mineralocorticoid deficiency and androgen excess present. Among Filipinos, the estimated crude incidence of CAH is approximately 1 in 7,000, which is higher than what is reported in most populations. More than 90% of all cases result from a 21-hydroxylase (21-OH) (cytochrome P450c21) enzyme deficiency involving two 21-OH genes, the active gene (CYP21) and a pseudogene (CYP21P). Studies have shown that mutations result from unequal crossover during meiosis which leads to complete deletion of the gene, gene conversion events or to point mutations. To date, there are no published data on the types of mutations present among Filipinos diagnosed with congenital adrenal hyperplasia. The objective of this study is to describe the profile of Filipino patients diagnosed with CAH and to determine the disease-causing alleles in the 21-OH gene of these patients. Using a method of combined differential polymerase chain reaction and amplification created restriction site approach, direct probing for the presence of known mutations in exons 1,3,4,6,7,8 and intron 2 of the CYP21 and CYP21P genes among Filipino patients with CAH was performed. A total of 12 unrelated CAH patients were examined. A majority of these cases had a premature splicing error mutation at nucleotide 656 of intron 2. The determination of the most frequent alleles in our population can facilitate rapid screening for mutations in the 21-OH gene and lead to a definitive diagnosis of CAH.

Improved screening efficiency for phenylketonuria using a modified bacterial inhibition assay protocol- Autoclaving the bloodspot

The Guthrie bacterial inhibition assay (BIA) tests for elevated phenylalanine (PHE) by measuring B. subtilis growth zone density in an agar medium. Dried blood spots with elevated PHE on initial BIA screening undergo repeat BIA testing and thin-layer chromatography (TLC). Specimens with elevated PHE by TLC or BIA on second-tier testing require recall. To streamline PKU screening and reduce the recall rate, we tested a modified BIA protocol incorporating autoclaving of dried blood spots. Autoclaving improves growth zone appearance and has been previously reported to reduce the number of specimen requiring repeat testing. From June to October 2006, dried blood spot samples with initially elevated PHE were autoclaved at 110°C for 5 min, then retested by BIA. Samples with still-elevated PHE were analyzed by TLC. 1078 of 37,268 samples (2.89%) had initially elevated PHE. After autoclaving, 1036 no longer exhibited elevated PHE decreasing to 42 (0.11%) the number requiring TLC. By comparison, the unmodified algorithm resulted in 3.14% of samples received from July - December 2006 requiring both repeat BIA and TLC testing. We have since modified our PKU screening algorithm to require repeat BIA testing from autoclaved samples prior to TLC analysis. This translates to a significant reduction in time and resources for second-tier testing and follow-up, and prevents stress for the parents of a newborn who would have been recalled unnecessarily.

Detection of maple syrup urine disease on newborn screening second tier testing for phenylketonuria

Newborn screening for phenylketonuria (PKU) in the Philippines uses a bacterial inhibition assay to detect elevations in phenylalanine (PHE). The BIA sensitivity is affected by substances such as antimicrobials. Semiquantitative second-tier screening with thin layer chromatography (TLC) verifies inconclusive PKU screens. Maple syrup urine disease (MSUD) is a prevalent inborn error of metabolism in the Philippines that is currently not part of the Philippine newborn screening program. We report on the incidental detection of MSUD by second-tier TLC PKU screening in order to begin to establish the evidence necessary for its inclusion in the Philippine Newborn Screening Program. We reviewed the PKU newborn screening database from September 1, 1996 to June 12, 2008 to document the number of cases of elevated LEU detected incidental to confirming PHE elevations by second-tier TLC. Elevated LEU findings were studied further to document the number of MSUD cases. From September 1, 1996 to June 12, 2008, 966,096 babies were screened for PKU and 28,248 (2.9%) required second-tier testing. Of these, 403 had elevated PHE and 9 were confirmed to have either classic PKU or hyperphenylalaninemia. Fifty-three of 28,248 babies had normal PHE concentrations but elevated LEU concentrations. These babies were recalled and a second dried blood spot was requested. Of these, 15 had elevated LEU and were subsequently confirmed to have MSUD. Two babies had concurrent elevations of PHE and LEU, but both were deceased at the time of recall. Confirmation of 15 MSUD cases was almost twice as high as the number of PKU/HPA confirmed cases. Since MSUD patients were detected incidental to PKU screening and there was no initial MSUD screening, the incidence of MSUD is almost certainly much greater. The number of MSUD cases incidentally detected confirms that MSUD exists at a significantly higher prevalence in the Philippine newborn population than PKU, and its inclusion in the newborn screening panel should be considered as soon as feasible.

Galactosemia in three Filipino patients - The importance of newborn screening

Disorders of galactose metabolism can be fatal if not treated early. Newborn screening has made it possible to detect and treat this disease. Three cases of galactosemia, one with galactokinase deficiency and two with galactose-1-phosphate uridyltransferase deficiency detected by newborn screening, are presented. Because of early detection and management, the first patient was spared the early complications of galactosemia and continues to grow and develop normally. The two other patients were diagnosed at 1 month, initial presentation included hepatomegaly and failure to thrive. Institution of treatment was able to reverse the acute complications and both are currently doing well. The importance of galactosemia newborn screening in preventing complications resulting from the disease is emphasized.

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.