Identification of a novel pathogenic mutation in PDHA1 gene for pyruvate dehydrogenase complex deficiency / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the molecular genetic mechanism and genetic diagnosis of pyruvate dehydrogenase complex deficiency (PHD), and to provide a basis for genetic counseling and prenatal genetic diagnosis of PHD.</p><p><b>METHODS</b>Polymerase chain reaction (PCR) was performed to amplify the 11 exons and exon junction of the PDHA1 gene from a child who was diagnosed with PHD based on clinical characteristics and laboratory examination results. The PCR products were sequenced to determine the mutation. An analysis of amino acid conservation and prediction of protein secondary and tertiary structure were performed using bioinformatic approaches to identify the pathogenicity of the novel mutation.</p><p><b>RESULTS</b>One novel duplication mutation, c.1111_1158dup48bp, was found in the exon 11 of the PDHA1 gene of the patient. No c.1111_1158dup48bp mutation was detected in the sequencing results from 50 normal controls. The results of protein secondary and tertiary structure prediction showed that the novel mutation c.1111 _1158dup48bp led to the duplication of 16 amino acids residues, serine371 to phenylalanine386, which induced a substantial change in protein secondary and tertiary structure. The conformational change was not detected in the normal controls.</p><p><b>CONCLUSIONS</b>The novel duplication mutation c.1111_1158dup48bp in the PDHA1 gene is not due to gene polymorphisms but a possible novel pathogenic mutation for PHD.</p>

Clinical features of pyruvate dehydrogenase complex deficiency and gene testing in one case / 中华儿科杂志

<p><b>OBJECTIVE</b>To analyze the clinical characteristics and genetype of one children who had been diagnosed with pyruvate dehydrogenase complex deficiency.</p><p><b>METHOD</b>Comprehensive analyses of this case were performed, including clinical symptoms, signs, biochemical examinations and therapeutic effects. The eleven exons and splicing areas of PDHA1 were amplified with genomic DNA from whole blood. And variations were investigated by sequencing the PCR product. The patient was diagnosed with pyruvate dehydrogenase complex deficiency by sequence analysis of PDHA1 gene.</p><p><b>RESULT</b>The patient was a 2 years and 4 monthes old boy. He presented with muscle hypotonia and weakness for one year, and experienced recurrent episodes of unstable head control, unable to sit by himself or stand without support, with persistently hyperlactacidemia. Metabolic testing revealed blood lactate 5.37 mmol/L, pyruvate 0.44 mmol/L, and lactate/pyruvate ratio was 12.23. MRI of the brain showed hyperintense signals on the T2 and T2 Flair weighted images in the basal ganglia bilaterally. Sequence analysis of PDHA1 gene showed a G>A point mutation at nucleotide 778, resulting in a substitution of glutarnine for arginine at position 263 (R263Q). And the diagnosis of pyruvate dehydrogenase complex deficiency was identified. By giving the therapy with ketogenic diet, vitamin B(1), coenzyme Q(10) and L-carnitine , the boy was in a stable condition.</p><p><b>CONCLUSION</b>The severity and the clinical phenotypes of pyruvate dehydrogenase complex deficiency varied. Sequence analysis of PDHA1 gene revealed a 788G>A (R263Q) mutation. Patients who presented with unexplained muscle hypotonia, weakness and hyperlactacidemia could be diveded by gene analysis. And appropriate treatment can improve the quality of life.</p>

Inherited metabolic diseases in the urine organic acid analysis of complex febrile seizure patients / 소아과

PURPOSE: Seizure associated with fever may indicate the presence of underlying inherited metabolic diseases. The present study was performed to investigate the presence of underlying metabolic diseases in patients with complex febrile seizures, using analyses of urine organic acids. METHODS: We retrospectively analyzed and compared the results of urine organic acid analysis with routine laboratory findings in 278 patients referred for complex febrile seizure. RESULTS: Of 278 patients, 132 had no abnormal laboratory findings, and 146 patients had at least one of the following abnormal laboratory findings: acidosis (n=58), hyperammonemia (n=55), hypoglycemia (n=21), ketosis (n=12). Twenty-six (19.7%) of the 132 patients with no abnormal findings and 104 (71.2%) of the 146 patients with statistically significant abnormalities showed abnormalities on the organic acid analysis (P<0.05). Mitochondrial respiratory chain disorders (n=23) were the most common diseases found in the normal routine laboratory group, followed by PDH deficiency (n=2 ) and ketolytic defect (n=1). In the abnormal routine laboratory group, mitochondrial respiratory chain disorder (n=29) was the most common disease, followed by ketolytic defects (n=27), PDH deficiency (n=9), glutaric aciduria type II (n=9), 3-methylglutaconic aciduria type III (n=6), biotinidase deficiency (n=5), propionic acidemia (n=4), methylmalonic acidemia (n=2), 3-hydroxyisobutyric aciduria (n=2), orotic aciduria (n=2), fatty acid oxidation disorders (n=2), 2-methylbranched chain acyl CoA dehydrogenase deficiency (n=2), 3-methylglutaconic aciduria type I (n=1), maple syrup urine disease (n=1), isovaleric acidemia (n=1), HMG-CoA lyase deficiency (n=1), L-2-hydroxyglutaric aciduria (n=1), and pyruvate carboxylase deficiency (n=1). CONCLUSION: These findings suggest that urine organic acid analysis should be performed in all patients with complex febrile seizure and other risk factors for early detection of inherited metabolic diseases.

Organic acidemias in Korea: Eight years experience of organic acid analysis / 소아과

PURPOSE: We have done this retrospective study to know the relative incidence and clinical manifestations of organic acidopathies in Korea during 8 years(from Jul. 1997 to May 2005). This results of organic acid analysis of 1,787 patients were compared with the results of organic acid analysis that were published three years ago. METHODS: The results of quantitative organic acid analysis of samples of 1788 patients, referred from Jul. 1997 to May 2005, were analyzed retrospectively according to four age group(-2 mon, 3 mon-2 years, 3-12 years) and major clinical manifestations. Quantification of 83 organic acids was done with gas chromatography and mass spectometry. RESULTS: We diagnosed 470 patients with 27 diseases of organic acid metabolism during this study period. Diseases found more than 10 cases are cytosolic 3-ketothiolase deficiency, mitochondrial respiratory chain disorders, PDHC deficiency, mitochondrial 3-ketothiolase deficiency, glutaric aciduria type II, biotinidase deficiency, methylmalonic aciduria and propionic aciduria. Other diseases were diagnosed in less than 10 cases. CONCLUSION: Though the incidence of individual organic acidemia is low, the overall incidence of organic acidemia as a whole seems to be relatively high in Korea. Compared with the results of organic acid analysis that were reported three years ago, we couldn't find a new disease and the difference of the relative incidences of high incident diseases. We were apprehensive of the errors that was owing to the short study period(3 years), but the relative incidences of our study(8 years) were similar to the results of organic acid analysis that were reported three years ago.

A Korean Female Patient with Thiamine-responsive Pyruvate Dehydrogenase Complex Deficiency Due to a Novel Point Mutation (Y161C)in the PDHA1 Gene

Pyruvate dehydrogenase complex (PDHC) deficiency is mostly due to mutations in the X-linked E1alpha subunit gene (PDHA1). Some of the patients with PDHC deficiency showed clinical improvements with thiamine treatment. We report the results of biochemical and molecular analysis in a female patient with lactic acidemia. The PDHC activity was assayed at different concentrations of thiamine pyrophosphate (TPP). The PDHC activity showed null activity at low TPP concentration (1 x 10(-3) mM), but significantly increased at a high TPP concentration (1 mM). Sequencing analysis of PDHA1 gene of the patient revealed a substitution of cysteine for tyrosine at position 161 (Y161C). Thiamine treatment resulted in reduction of the patient's serum lactate concentration and dramatic clinical improvement. Biochemical, molecular, and clinical data suggest that this patient has a thiamine-responsive PDHC deficiency due to a novel mutation, Y161C. Therefore, to detect the thiamine responsiveness it is necessary to measure activities of PDHC not only at high but also at low concentration of TPP.

Organic Acidemias in Korea: Three Years Experience of Organic Acid Analysis

PURPOSE: We have done this retrospective study to know the relative incidences and clinical manifestations of organic acidopathies in Korea. METHODS: The results of quantitative organic acid analysis of 1,125 samples of 712 patients, referred from Jul. 1997 to Jun. 2000, were analyzed retrospectively according to four age groups (-2 mon, 3 mon-2 year, 3 years-12 years, over 12 years) and major clinical manifestations. Quantification of 83 organic acids was done with gas chromatography and mass spectrometry(GC/MS). RESULTS: We diagnosed 214 patients with 27 diseases of organic acid metabolism during this study period. Diseases found more than 10 cases are cytosolic 3-ketothiolase deficiency, mitochondrial repsiratory chain disorders, PDHC deficiency, glutaric aciduria type II and propionic aciduria. Other diseases were diagnosed in less than 10 cases, mostly one or two cases during this study period. Most of the patients had some symptoms of neurological dysfunction such as seizure activity(195 patients), developmental delay(122), mental retardation(99), hypotonia(84), movement disorders(81) and vomiting(68). CONCLUSION: Though the incidence of individual organic acidemia is low, the overall incidence of organic acidemia as a whole seems to be relatively high in Korea. Most of the patients showed some signs of neurological dysfunction.