Organic acid disorders detected by urine organic acid analysis: Twelve cases in Thailand over three-year experience
ABSTRACT 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.
During 2001-2004, we had analysed 442 urine samples in 365 patients and identified 12 cases of organic acid disorders.
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.
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.
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ABSTRACT: Diagnosis of aminoacidopathies and organic acidemias constitute a real challenge in a developing country with high consanguinity rate and no systematic newborn screening. We report a twelve-year experience with the identification of these disorders in Lebanon, based on their clinical and biochemical profiles. In this retrospective study, we reviewed clinical presentation and biochemical investigations of 294 patients. Traditional chromatographic methods were used for analyses. Findings were linked to the identified disorders. Out of 2921 patients, presenting to our metabolic program with neurological, digestive, family history and/or other symptoms suggestive of aminoacidopathy or organic acidemia, 294 patients were included with confirmed amino or organic acid disorder. The overall analytical yield was 10%. Aminoacidopathies were three-fold higher than organic acidemias. Phenylketonuria and methylmalonic acidemia were the most frequent. The majority of patients (79%) were symptomatic (median age: 14months, range: 1day-44years), mainly with neurological manifestations (87%). Intellectual disability was mostly due to phenylketonuria (73%). Chronic liver failure was frequent in maple syrup urine disease (53%). Plasma amino and urine organic acid chromatography were diagnostic in 8.8% and 3.9% of analyzed cases, respectively. Change in chromatographic technique from reversed-phase to ion-exchange enhanced the detection of many aminoacidopathies. In the absence of newborn screening, the majority of aminoacidopathy and organic acidemia cases are still diagnosed clinically. This study emphasizes the importance of clinical awareness and accurate biochemical analyses as key tools for diagnosis in countries like ours, and the necessity for a comprehensive national newborn screening program.Clinical biochemistry 08/2013; 46(18). DOI:10.1016/j.clinbiochem.2013.08.009 · 2.02 Impact Factor
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ABSTRACT: 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.World Journal of Pediatrics 02/2014; 10(1):64-8. DOI:10.1007/s12519-014-0454-4 · 1.08 Impact Factor
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ABSTRACT: A large fraction of the known human metabolome belong to organic acids. However, comprehensive profiling of the organic acid sub-metabolome is a major analytical challenge. In this work, we report an improved method for detecting organic acid metabolites. This method is based on the use of liquid-liquid extraction (LLE) to selectively extract the organic acids, followed by using differential isotope p-dimethylaminophenacyl (DmPA) labeling of the acid metabolites. The (12)C-/(13)C-labeled samples are analyzed by liquid chromatography Fourier-transform ion cyclotron resonance mass spectrometry (LC-FTICR-MS). It is shown that this LLE DmPA labeling method offers superior performance over the method of direct DmPA labeling of biofluids such as human urine. LLE of organic acids reduces the interference of amine-containing metabolites that may also react with DmPA. It can also remove water in a biofluid that can reduce the labeling efficiency. Using human urine as an example, it is demonstrated that about 2500 peak pairs or putative metabolites could be detected in a 30-min gradient LC-MS run, which is about 3 times more than that detected in a sample prepared using direct DmPA labeling. About 95% of the 1000 or so matched metabolites to the Human Metabolome Database (HMDB) are organic acids. It is further shown that this method can be used to handle as small as 10μL of urine. We believe that this method opens the possibility of generating a very comprehensive profile of the organic acid sub-metabolome that will be useful for comparative metabolomics applications for biological studies and disease biomarker discovery.Analytica chimica acta 11/2013; 803:97-105. DOI:10.1016/j.aca.2013.07.045 · 4.31 Impact Factor