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Phenylketonuria (PKU) is an autosomal recessive amino acid metabolism disorder caused by variants in the gene encoding phenylalanine hydroxylase (PAH; EC1.14.16.1). This study aimed to assess the specific heterogeneity of PAH variants found in Thai population as well as evaluate enzyme activity and expression of novel variants. PAH gene from 13 patients was analyzed by PCR amplification and direct Sanger-sequencing of 13 exons of the coding region. The novel variants were transiently transfected in COS-7 cells for functional verification. Eleven different PAH variants were identified: all pathogenic variants were missense variants, of which the most frequent variant was p.R169L, accounting for 24% (6/25) of all identified alleles. Two novel variants p.R169L and p.Y317N and previously reported variants with mutated residues at the same positions (p.R169H and p.Y317H) were expressed in COS-7 cells. These showed mildly impaired residual activity levels (42.3-63.1% of wild type), while the protein levels were well expressed (82.8-110%), except for p.R169L, which showed decreased protein expression of 55.7% compared to the wild type enzyme. All subjects with p.R169L identified in at least one of pathogenic alleles (one case is homozygous) had a metabolic phenotype of mild hyperphenylalaninemia (HPA). Our data has expanded the information on the genetic heterogeneity of Thai patients with PAH deficiency. This finding emphasizes the importance of genotyping in patients with HPA, and in vitro studies can provide additional information for prediction of phenotype.

© 2015 Thiboonboon et al. Background: Inborn errors of metabolism (IEM) are a rare group of genetic diseases which can lead to several serious long-term complications in newborns. In order to address these issues as early as possible, a process called tandem mass spectrometry (MS/MS) can be used as it allows for rapid and simultaneous detection of the diseases. This analysis was performed to determine whether newborn screening by MS/MS is cost-effective in Thailand. Method: A cost-utility analysis comprising a decision-tree and Markov model was used to estimate the cost in Thai baht (THB) and health outcomes in life-years (LYs) and quality-adjusted life year (QALYs) presented as an incremental cost-effectiveness ratio (ICER). The results were also adjusted to international dollars (I$) using purchasing power parities (PPP) (1 I$ = 17.79 THB for the year 2013). The comparisons were between 1) an expanded neonatal screening programme using MS/MS screening for six prioritised diseases: phenylketonuria (PKU); isovaleric acidemia (IVA); methylmalonic acidemia (MMA); propionic acidemia (PA); maple syrup urine disease (MSUD); and multiple carboxylase deficiency (MCD); and 2) the current practice that is existing PKU screening. A comparison of the outcome and cost of treatment before and after clinical presentations were also analysed to illustrate the potential benefit of early treatment for affected children. A budget impact analysis was conducted to illustrate the cost of implementing the programme for 10 years. Results: The ICER of neonatal screening using MS/MS amounted to 1,043,331 THB per QALY gained (58,647 I$ per QALY gained). The potential benefits of early detection compared with late detection yielded significant results for PKU, IVA, MSUD, and MCD patients. The budget impact analysis indicated that the implementation cost of the programme was expected at approximately 2,700 million THB (152 million I$) over 10 years. Conclusion: At the current ceiling threshold, neonatal screening using MS/MS in the Thai context is not cost-effective. However, the treatment of patients who were detected early for PKU, IVA, MSUD, and MCD, are considered favourable. The budget impact analysis suggests that the implementation of the programme will incur considerable expenses under limited resources. A long-term epidemiological study on the incidence of IEM in Thailand is strongly recommended to ascertain the magnitude of problem. Copyright

Propionic acidemia (PA) is caused by a deficiency of propionyl CoA carboxylase. A characteristic urine organic acid profile includes 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine. The diagnosis of PA is confirmed by detection of mutations in the PCCA or PCCB genes. We herein report the clinical and molecular findings of four Thai patients with PA. Clinical findings of four Thai patients with PA were retrospectively reviewed. Urine organic acids were analyzed by gas chromatography-mass spectrometry. PCR-sequencing analyses of encoding exons and intron/exon boundaries of the PCCA and PCCB genes were performed. All patients had neonatal onset of PA. One patient died of cardiomyopathy, and another one of pneumonia and metabolic decompensation. The remainder experienced significant neurocognitive impairment. Mutation analysis of the PCCA gene identified homozygous c.1284+1G>A in patient 1, c.230G>A (p.R77Q) and c.1855C>T (p.R619X) in patient 2, homozygous c.2125T>C (p.S709P) in patient 3, and only one mutant allele, c.231+1G>T in patient 4. No PCCB mutation was identified. Four mutations including c.230G>A, c.231+1G>T, c.1855C>T, and c.2125T>C have not been reported previously. The clinical and molecular study of these Thai patients provided additional knowledge of the genotype and phenotype characteristics of PA. The results of the study suggested that PCCA mutations in Asian populations were distinct from those of other populations.

Isovaleric acidemia (IVA) is an autosomal recessive disorder caused by deficiency of isovaleryl-CoA dehydrogenase (IVD). Clinical features include vomiting, lethargy, metabolic acidosis, and "sweaty feet" odor. The pathognomonic metabolite, isovalerylglycine, is detected on urine organic acid analysis. Clinical diagnosis of IVA can be confirmed on mutation analysis of the IVD gene.The cases of five unrelated Thai patients with IVA, identified on urine organic acid analysis, are described. Mutation analysis of the IVD gene was performed using polymerase chain reaction sequencing of the entire coding regions.Four out of the five IVA patients had an acute neonatal form. The hematologic abnormalities were common and thus could be presenting symptoms in the absence of metabolic acidosis. As for the neurological outcome, only one patient had normal intelligence. Mutation analysis of the IVD gene identified the mutations c.457-3_2CAGG, c.1199AG (p.Y371C), c.281CG (p.A65G), c.358GA (p.G91R), and c.827TC (p.L247P). The poor outcome in most patients might be explained by the delayed diagnosis and initial unavailability of the metabolic formulas and medications in Thailand. The c.457-3_2CAGG mutation was identified in all of the present patients. This suggests that it is the most common mutation in the Thai population. Therefore, it could be a founder mutation in Thai subjects. One of the present Thai IVA patients also had the p.Y371C mutation, which is common in Han Chinese subjects. In addition, two novel mutations, p.A65G and p.L247P, were identified.The present study provides additional knowledge on the genotype-phenotype of IVA, suggesting that IVD mutations in Asian populations are distinct from these in Western populations.

Background Amino acid disorders are a major group of inborn errors of metabolism (IEM) with variable clinical presentations. This study was aimed to provide the data of amino acid disorders detected in high-risk Thai patients referred to our metabolic lab from all over the country. Methods From 2001 to 2009, we analyzed amino acids by HPLC in 1214 plasma and cerebrospinal fluid specimens. These specimens were obtained from patients with clinical suspicion of IEM or with positive newborn screening. The clinical data of the patients with confirmed diagnoses of amino acid disorders were also analyzed. Results Fifty-eight patients were diagnosed with amino acid disorders, including 20 cases (34.5%) with maple syrup urine disease, 13 (22.4%) with phenylketonuria and hyperphenylalaninemia, 13 (22.4%) with nonketotic hyperglycinemia, 9 (15.5%) with urea cycle defects, 2 (3.4%) with classical homocystinuria, and 1 (1.7%) with ornithine aminotransferase deficiency. There was considerable delay in diagnoses which led to poor outcomes in most patients. Conclusion The prevalence of amino acid disorders in Thailand is distinct from other countries. This will guide the selection of the prevalent IEM for the future expansion of newborn screening program in this country.

The study of inherited metabolic disorders (IMD) in Thailand is in its infancy when compare with developed countries. Prior to 1987, majority of these disorders were clinically diagnosed since there were only a handful of clinicians and scientists with expertise in inborn errors of metabolism, lack of well-equipped laboratory facilities and government support. In developing countries, inherited metabolic disorders are not considered a priority due to the prevalence of infectious diseases such as HIV infection and congenital infections. A multicentre survey conducted in 1994 and 2001 revealed the existence of numerous cases of IMD from all over the country. Case reports and publications on IMD in Thai (and international) medical journals in past 20 years had undoubtedly raised its awareness among Thai paediatricians and scientists. In 2001, the Genetic Metabolic Centre was first established in Siriraj Hospital Faculty of Medicine, Thailand. Numerous new cases of IMD had been identified since then.

Down Syndrome Parents' Support Group Siriraj Hospital was established on February 14, 1993. It consists of a group of pediatricians, nurses, parents of children with Down Syndrome (DS) who received care at the Genetics Clinic, Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital. The objective is to educate parents with DS children whose diagnosis of DS given at birth causing grief and disappointment which led to abandonment of these children at Siriraj Hospital almost every other month (fifteen years ago) due to lack of education on the part of the medical professionals. Down Syndrome Parents' Support Group Siriraj Hospital received financial support from Terres des hommes of the Netherlands in the first 6 years. Later it received partial financial support from a government agency; however, the majority of the funding came from private donations. Throughout the years, the group had several successful activities: Siriraj Down Syndrome Annual Meeting since 1991 (total of 17 years) and Down Syndrome Provincial Lecture tour, so called "Down Sunjorn" since 1997. The latest in 2008 (the tenth) which was organized with major provincial hospitals of the Ministry of Public Health (MOPH). Moreover the group took part in (1) working with the Ministry of Education for Thailand Educational Act B.E. 1999 which promotes integration of DS children into normal schools all over the country, (2) working with the Department of MaternalChild Health, MOPH started the Child Development Center in the provincial community hospitals where the service was lacking; (3) working with Ministry of Social Development' and Human Security to initiate an educational program for the DS families in the rural areas (from 2001 - 2006) to help educate families with DS children and raise awareness for their educationallegal rights. In the past 15 years, there was no more abandonment of DS children at Siriraj Hospital and others; these children received better care and improved quality of life.

To analyze factors influencing development of Down syndrome children in the first three years of life.A cross-sectional study was conducted in 100 Down syndrome (DS) children attending at the Genetics clinic, Department of Pediatrics, Siriraj Hospital between January 2002 and December 2005. All individuals were three to six years of age. The data was collected from January to December 2006, including general information and factors on the child and their families. The child developmental quotient (DQ) was evaluated by Capute Scales Cognitive Adaptive Test/Clinical LinguisticAuditory Milestones Scale (CAT/CLAMS) at three years of age. Data were analyzed by descriptive statistic and multiple linear regression with the significant level at p-value0. 05.The mean development quotient (DQ) was 63.78 +/- 11.25 (range 32-91) with the majority being mild developmental delay. The child and family factors contributing to developmental quotient (DQ) outcome were birthplace, congenital heart disease, age at the first genetic counseling, regular follow-up in the Genetics clinic, age at the first early stimulation program/speech training program, parental education/occupation, and family income. Only family income and age at the first speech-training program were found to be independently associated with developmental quotient (DQ) at the age of three years (p-value0.05).Down syndrome is the most common genetic cause of mental retardation. Various factors contribute to developmental quotient (DQ) outcome but the most important factors are family income and age at the first speech-training program. Therefore, Down syndrome children with the above factors should be followed-up and monitored closely for the optimal long-term outcome.

Tetrahydrobiopterin (BH(4)) deficiency comprises heterogeneous disorders resulting in hyperphenylalaninaemia (HPA) and lack of monoamine neurotransmitters. Among these, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency is the most common disorder. We report a female Thai patient with PTPS deficiency who was initially detected by newborn screening for HPA, and later treated by supplements of BH(4), L-dopa/carbidopa, and 5-hydroxytryptophan. Monitoring of serum prolactin representing dopamine sufficiency is used for optimizing the dosage of L-dopa. She showed a remarkable progress of development despite delayed treatment at 5 months of age. Mutation analysis revealed two heterozygous missense mutations of the PTS gene: c.259C>T (p.P87S) inherited from the father; and c.147T>G (p.H49Q) inherited from the mother. The latter is a novel mutation that affects the pterin-binding site of the PTPS enzyme. This novel mutation expands the mutation spectrum of PTPS deficiency. Notably, some PTS mutations have been reported in both Thai and Chinese patients. Whether these common mutations are the result of a founder effect with common ancestors of Thai and Chinese people or intermarriage between Thai and Chinese descents in Thailand remain unclear. In conclusion, severe neurological impairment from BH(4) deficiency could be prevented by newborn screening for HPA and proper metabolic management. However, pterin analysis for early diagnosis of BH(4) deficiency is still not available in most developing countries.

Molecular defects in the gene encoding the enzyme iduronate-2-sulfatase (IDS) result in Hunter disease (mucopolysaccharidosis type II, MPS II). To determine the molecular basis of MPS II in Thailand, the IDS gene was analysed in 20 Thai patients with Hunter syndrome from 18 unrelated families. A total of 19 different mutations, including 9 missense mutations, 3 nonsense mutations, 3 splice site alterations, 1 deletion, 2 indels, and 1 rearrangement were identified, 8 of which were novel (p.R101C, p.D148V, p.G224A, p.K227E, p.E254X, p.W337X, c.440_442delinsTT and c.720_731delinsTTTCAGATGTTCTCCCCAG). Evaluation of the IDS activity of two hemizygous variants identified in the same patient, p.R101C and p.R468Q, by expression of IDS with the individual mutations in COS 7 cells indicated that only the p.R468Q mutation affected IDS protein activity. Two exonic mutations, c.257C>T (p.P86L) and c.418G>A, were found to activate multiple cryptic splice sites, resulting in aberrantly spliced transcripts. Thus, MPS II in Thailand is caused by a diverse set of defects affecting both IDS protein production and activity.

Background Prader-Willi Syndrome (PWS) is a complex human genetic disease arising from a loss of paternal allele expression of imprinting genes on chromosome 15q11-q13. Normally the CpG islands at this site are heavily methylated in the maternal allele, but unmethylated in the paternal allele and therefore activated in gene expression. only the methylated allele should present in pws patients when methylation-specific pcr (msp) is analyzed. Methods This paper reports an analysis of PWS in Thai patients using consensus diagnostic criteria based on a combination of clinical data, basic G-banding and fluorescence in situ hybridization (FISH) cytogenetics, PCR-based methylation assay, and bisulfite sequencing of the CpG islands of SNRPN to confirm 15q deletion or the methylation pattern of the SNRPN promoter and exon 1. Lack of complete clinical reports or inadequacy of the minimum laboratory support required had made it difficult to diagnose PWS, Angelman syndrome and other microdeletion disorders. Results Accuracy of 100% was obtained for diagnosis of the PWS study patients using the minimum requirements necessary. A total of 20 patients were diagnosed as PWS based on clinical criteria and the scoring tool for PWS, and the same approach was applied to four separate patients with some unmatched criteria but phenotypic similarity to PWS. Findings showed that 70% of those clinically diagnosed as PWS patients (14/20) had a deletion at 15q11-q13 according to FISH, while all 20 patients showed MSP positive of SNRPN gene. Six cases (30%) without a paternal deletion were confirmed to have maternal uniparental disomy (mUPD) of PWS by MSP and methylation sequencing approaches. Noteworthy, two of the six cases with mUPD were 3.5 year-old twins. None of the five cases with scores lower than the reported consensus criteria showed positive G-band, FISH or MSP results. Conclusions We demonstrate here the high power of combining clinical findings, FISH and MSP in definitive diagnosis of PWS and in distinguishing between the two major different types of molecular mechanisms. No false positives or false negatives were observed in our analysis.

Background Disorders of organic acid (OA) metabolism are generally detected by qualitative analysis of urine organic acids by gas chromatography/mass spectrometry (GC/MS) which was well established in developed countries since 1980s. Confirmation of the diagnosis of organic acid disorders by OA analysis, enzyme analysis and molecular study is a difficult task in developing countries. Methods During 2001–2004, we had analysed 442 urine samples in 365 patients and identified 12 cases of organic acid disorders. Results We identified the following disorders: alkaptonuria (ALK) = 1, isovaleric acidemia (IVA) = 3, propionic acidemia (PA) = 2, methylmalonic acidemia (MMA) = 3, glutaric aciduria, type I (GA-I) = 1, multiple carboxylase deficiency (MCD) = 1, and glutaric acidemia, type II (GA-II) = 1. Conclusions OA disorders had never been diagnosed in Thailand before, until GC/MS technology was introduced to Thailand in 2001. Urine OA analysis also provided a diagnostic clue to other inborn errors of metabolism including amino acid disorders, urea cycle disorders, disorders of carbohydrate metabolism, and mitochondrial fatty acid oxidation disorders. Since then, we were able to diagnose numerous disorders, which led to prompt treatment and better outcome in our patients.

Molecular genetic analysis of three patients diagnosed with isolated methylmalonic acidemia (MMA) revealed that one was mut 0 MMA, with a mutation in the MUT gene encoding the l-methylmalonyl-CoA mutase (MCM), and two were cblB MMA, with mutations in the MMAB gene required for synthesizing the deoxyadenosylcobalamin cofactor of MCM. The mut 0 patient was homozygous for a novel nonsense mutation in MUT, p.R31X (c.167C → T), and heterozygous for three previously described polymorphisms, p.K212K (c.712A → G), p.H532R (c.1671A → G), and p.V671I (c.2087G → A). The new MMAB mutation, p.E152X (c.454G → T), was found to be homozygous in one cblB patient and heterozygous in the other patient, who also had four intron polymorphisms in this gene.

Neural tube defects (NTDs), (including anencephaly, meningomyelocele and encephalocele), are among the most common birth defects, with high associated mortality and morbidity. NTDs occur in 1-5 per 1,000 births, with marked geographic and ethnic variations. However, there are few data concerning the incidence, associated anomalies, treatment and outcome of NTDs in Thailand. The objective of this study is to analyze data on NTD cases from 1990-1999 at Siriraj Hospital, a hospital with 18,000-20,000 deliveries annually.A retrospective chart review of patients with NTDs who were born at or referred to Siriraj Hospital 1990-1999 was performed.During the 10 year period we examined, there were 115 patients with NTDs treated in the Department of Pediatrics as well as in other Departments at Siriraj Hospital. The incidence of NTD is 0.67 per 1,000 births. The sex distribution was equal among NTD cases, 55 (48%) females, 59 (51%) males and one (1%) unidentified sex. Isolated NTDs accounted for 105 (91%) cases, and 10 (8.7%) had at least 1 other structural anomaly such as cleft lip/palate, imperforate anus, amniotic band sequence, or ambiguous genitalia. Among all NTD cases, there were 55 (48%) with myelomeningocele, 45 (39%) with anencephaly, and 14 (12%) with encephalocele. Seventeen (15%) cases died; among these, 7 (41% of deaths) died in utero, 8 (47% of deaths) died in the early neonatal period, and 2 (12%) died after 1 year of age. Regarding treatment, 95 surgical corrections, 47 excisions and repairs, 45 excisions and VP shunts, 1 laminectomy and 2 club feet corrections were performed.In this hospital-based study of 115 patients with NTD, we found an incidence of 0.67/1000 births; however, as this was a hospital-based study, the community incidence is likely higher. Most cases were isolated NTDs, and almost half of NTDs were meningomyelocele. There was a high rate of mortality. Further studies are warranted to better elucidate the health burden from NTDs in Thailand. Public health interventions aimed at increasing the periconceptional consumption of folic acid should be implemented or enhanced to reduce the incidence of NTDs in Thailand.

Two Thai patients diagnosed with Hurler syndrome (mucopolysaccharidosis type 1, MPS I) were found to have no detectable alpha-iduronidase (E.C. 3.2.1.76) activity in leukocytes, while normal Thai children all had significant activity, with a mean of 135 +/- 30 nmol/mg/18h. One patient was heterozygous for A75T (311GA) and S633L (1986CT) mutation, previously reported to cause MPS I, together with 9 other heterozygous polymorphisms also found in normal controls. The other patient had the previously described frameshift mutation 252insert C and a new nonsense mutation E299X (983GT).

This retrospective clinical study was carried out on patients with suspected inborn errors of metabolism (IEM) at Siriraj Hospital during 1997-2001. The authors investigated 114 patients by quantitative plasma amino acid analysis.The objective of this study was to collect and analyze epidemiologic and specific clinical data of IEM, especially in small-molecule diseases.All patients were categorized into 2 major groups. 1) positive diagnoses for IEM 2) negative diagnoses for IEM. The two groups were investigated, studied including statistical analysis.The authors found that most IEM ascertained through plasma amino acid analysis were small-molecule diseases (74.3%) and amino acid disorders consisted of the most frequent disorders. The presented data demonstrated that the ratio of positive diagnoses to all patients studied was 1:8. Epidemiological data showed there were more male than female patients. Onset of diseases occurred predominantly during the first month of age, and was rarely found after 3 years of age. There were histories of consanguinity in half of the IEM patients. The most common presenting symptom was acute metabolic encephalopathy and specific signs for small-molecule disorders included hepatomegaly, unusual urine odor, acidosis, hyperammonemia, alteration of consciousness, and ketosis/ketonuria. These signs or symptoms indicated further metabolic investigations.Comparison of the data from Thailand with other countries showed both similarities and differences to the Caucasian population. Thus, further studies in IEM are much needed for the Thai population.

Maternal serum screening has gained widespread acceptance as a major prenatal screening tool for chromosomal abnormalities in the US and Europe since Merkatz et al described an association between low maternal serum alpha fetoprotein (AFP) levels and increased risk for trisomy 21 in 1984. In 1988, Wald et al proposed a screening program based on maternal age in combination with three biochemical markers--AFP, hCG and unconjugated estriol. This study from January 1996--September 2002 included 1,793 pregnant women (between 14-22 weeks gestation) which were divided into 2 groups--1,083 women35 years (60.40%) and 710 women35 years (39.60%). A second trimester risk for trisomy 211 : 270 was considered a positive screen and genetic counseling to discuss risks and benefits of amniocentesis was offered. This study had 1,376 cases (76.7%) with negative screening (not increased risk for DS and NTD), 21 (1.2%) with negative screening (not increased risk for DS only) ; 292 (16.3%) with increased risk for DS; 5 cases (0.3%) with increased risk for DS and elevated AFP; 19 cases (1.1%) with elevated AFP; 33 cases (1.8%) with previous DS only; and 9 cases (0.5%) with previous NTD only. Two percent (2.1%) of the results could not be interpreted either because the test was done too early, too late or were grand multiple pregnancies. This study demonstrated that multiple marker screening offers another option for older women who traditionally have all been considered candidates for amniocentesis.

Paternal microdeletion of chromosome 15 at q11-q13 has been reported in 75% of Prader-Willi syndrome (PWS) patients in western countries. Diagnosis of PWS in Thailand is mainly based on clinical observation and, in some cases, confirmed by conventional cytogenetic analysis. Loss of a tiny segment in this region (microdeletion) has made it difficult to discriminate from the normal karyotype. An attempt to solve this problem has been made by using a high resolution chromosome culture. However, this method is a tedious and time-consuming technique which is suitable for only experienced cytogeneticists. We report molecular cytogenetic analysis for PWS in Thai patients using FISH in addition to standard GTG- banding chromosome analysis. Nine Thai patients clinically diagnosed or with a suspicion of PWS were investigated. The FISH probes consist of the region-specific probes (SNRPN or D15S10 probe) and two chromosome 15-specific control probes (D15Z1 centromeric and PML chromosome 15 long arm probe). Bright field and FISH programs of an automatic karyotyper were applied to facilitate the efficiency of the chromosome analysis. We found that 2 out of 9 patients showed a deletion at 15q11-q13 region by standard GTG chromosome analysis while 4 out of 9 patients showed a delation in this region by FISH. Consistent losing of SNRPN and D15S10 signals in FISH was observed in these patients. This forty-four per cent deletion is considerably lower than those reported from western countries. We propose that DNA methylation at SNRPN promoter as well as structural abnormalities in other chromosome regions might also play a role in the etiology of this disorder in Thais, which should be investigated further.

The study of inborn errors of metabolism (IEM) in Thailand is in its infancy. The majority are clinically diagnosed since there are only a handful of clinicians and scientists with expertise in inherited metabolic disorders, shortage of well-equipped laboratory facilities and lack of governmental financial support. Genetic metabolic disorders are usually not considered a priority due to prevalence of infectious diseases and congenital infections. From a retrospective study at the Medical Genetics Unit, Department of Pediatrics, Siriraj Hospital; estimated pediatrics patients with suspected IEM were approximately 2-3 per cent of the total pediatric admissions of over 5,000 annually. After more than 10 years of research and accumulated clinical experiences, a genetic metabolic center is being established in collaboration with expert laboratories both in Bangkok (Chulabhorn Research Institute) and abroad (Japan and the United States). Numerous inherited metabolic disorders were identified--carbohydrate, amino acids, organic acids, mitochondrial fatty acid oxidation, peroxisomal, mucopolysaccharidoses etc. This report includes the establishment of genetic metabolic center in Thailand, research and pilot studies in newborn screening in Thailand and a multicenter study from 5 institutions (Children's National Center, King Chulalongkorn Memorial Hospital, Pramongkutklao Hospital, Ramathibodi and Siriraj Hospitals). Inherited metabolic disorders reported are fructose-1,6-bisphosphatase deficiency, phenylketonuria, homocystinuria, nonketotic hyperglycinemia, urea cycle defect (arginino succinate lyase deficiency, argininosuccinate synthetase deficiency), Menkes disease, propionic acidemia and mucopolysaccharidoses (Hurler, Hurler-Scheie).

Urea Cycle Disorders (UCD) is an inborn error of urea synthesis in which ammonium and other nitrogenous precursors of urea accumulate leading to episodic coma and a high mortality rate. Therapy with peritoneal dialysis, essential amino acids or their nitrogen-free analogues has increased survival. The authors report 5 cases of urea cycle disorders, all of whom developed and were rescued from hyperammonemic coma. However, the eventual outcome was quite variable. Argininosuccinate lyase deficiency (ALD) Case 1. A 2 month old male infant, a product of a consanguineous marriage (Suphanburi province); developed poor feeding on day 7, lethargy, convulsion, hepatomegaly and respiratory alkalosis leading to respiratory failure and coma. Hyperammonemia, elevation of glutamic acid and argininosuccinic acid and its anhydrides confirmed the diagnosis of ALD. He is now 9 years old and severely retarded. Case 2. A male infant with history of lethargy, poor feeding on day 3, treated as sepsis and required respiratory support for 6 days; subsequently readmitted at age 2 weeks with vomitting, lethargy, seizure activity and hyperammonemia, and was treated by a local pediatrician in Songkhla province. There was a history of parental consanguinity and he was referred to Siriraj Hospital on day 64 with severe essential amino acid deficiency and acrodermatitis enteropathica with markedly elevated plasma citrulline level. In spite of aggressive treatment; the patient developed sepsis and he expired on day 78. Ornithine transcarbamylase deficiency (OTC) Case 3. An eleven-month-old male infant, the product of a non-consanguineous marriage, developed neonatal onset of hyperammonemia on day 5 after poor feeding, lethargy, hypothermia, seizure, apnea and coma. He was rescued from neonatal hyperammonemic coma on day 9 after aggressive treatment, but expired at eleven months of age after overwhelming sepsis. Case 4. A male infant, sibling of case 3 was referred to Siriraj Hospital on day 8 with hyperammonemia and coma. In spite of intensive genetic counseling given after the birth of their first child with OTC, the couple chose to have another baby without informing any physician. The baby developed vomiting and lethargy on day 2; subsequently hyperammonemia was noted. In spite of aggressive treatment given; hepatic dysfunction, renal failure and disseminated intravascular coagulation defects occurred on day 15. He expired on day 18 after parental permission for discontinuation of all treatment. Argininosuccinate synthetase deficiency (ASS) or Citrullinemia. Case 5. A seven week old female infant, the product of a consanguineous marriage and of Pakistani ethnic origin; developed intermittent vomiting from day 6. Initial diagnoses included ruminations, sepsis and pyloric stenosis for which she was operated on (day 30); however, vomiting continued; subsequently seizures, hyperammonemic coma developed and she was rescued from hyperammonemic coma within 30 hours. Significant elevations of citrulline and L-glutamine were demonstrated. She was discharged in excellent condition to her home in Dubai, the United Arab Emirates.

Three infants with documented mitochondrial fatty acid oxidation disorders are described in this report. Case 1. Carnitine/acylcarnitine translocase deficiency. (CACT) (OMIM 212138) A two-day-old male developed sudden cardiac arrest 48 hours postpartum, with a previous history of early death (day 2) in siblings with a history of parental consanguinity; somnolence, inactivity, refusal to suck within 24 h, hepatomegaly, persistent hypoglycemia, hypocalcemia, hyperkalemia and severe metabolic acidosis prior to cardiac arrest. Dried blood spots by tandem mass spectrometry demonstrated 10 x elevation of palmitoylcarnitine, moderate elevation of oleylcarnitine, steroylcarnitine and myristoylcarnitine. Case 2. Medium chain acyl CoA dehydrogenase (MCAD) deficiency. (OMIM 212139) A six-week-old male infant, developed sudden cardiac arrest after contacting a viral illness, resuscitated successfully in the first episode, only to succumb during the second episode, 2 weeks apart. Plasma acylcarnitine via tandem mass spectrometry was reported normal; however, urine organic acids via gas liquid chromatography and mass spectrometry demonstrated characteristic metabolites consistent with MCADD. Case 3. Carnitine deficiency, systemic primary. (CDSP) (OMIM 212140) A one-year-old girl with progressive dyspnea since birth and a history of parental consanguinity. Severe dilated cardiomyopathy with episodes of cardiac decompensations, hepatomegaly, anemia, generalized hypotonia, but no hypoglycemia were demonstrated prior to cardiac arrest. Extremely low carnitine level noted in dried blood spots via tandem mass spectrometry.