Glutaric acidemia type 2 (GA2) is an autosomal recessive disorder resulting from a deficiency of electron transfer flavoprotein (ETF) or ETF dehydrogenase (ETFDH) that manifests from most severe neonatal to late-onset forms. However, the genetic defect responsible for the disease and clinical severity is not well-characterized. In order to understand the relationship between the phenotype and genetic defect, we investigated the clinical and molecular features of 15 Japanese patients, including 4 previously reported cases. Three patients had the neonatal form and 8 patients had the late-onset form, 1 of whom presented an extremely mild phenotype. Immunoblot analysis showed that either ETFalpha, ETFbeta, or ETFDH was significantly reduced or absent in all patients. However, no specific enzyme deficiency predominated, and there were no associations with the clinical severity. Genetic analyses identified 15 mutations including non-sense, missense, splice site mutations, and small deletions, in ETFA, ETFB and ETFDH genes. Although almost all mutations were unique to Japanese patients and no common mutations were found, some of them appeared to be associated with a specific phenotype. Our results suggest that clinical and mutational spectrums of Japanese GA2 patients are heterogeneous and that genetic diagnoses may help to predict a prognosis and provide more accurate diagnostic information for patients and families with GA2.
To assess the usefulness of newborn mass screening by ESI-MS/MS in Japan, an acylcarnitine analysis of blood spots on filter paper from collected from newborn infants at the age of 5 days was retrospectively conducted on 18 cases of inherited metabolic diseases that had already been diagnosed. The patients had organic acid disorders in 8 cases, fatty acid oxidation disorders in 7 cases, and amino acid disorders in 3 cases. The time of onset was from 0 days to 1 year 8 months of age. In 16 out of the 18 cases studied, it was confirmed that the analysis of the blood spots on filter paper collected during the newborn period could detect disorders. One case each of CPT-2 deficiency and citrin deficiency could not be detected in the newborn period. Regarding CPT-2 deficiency, the establishment of sufficient nutrition might have interfered with the detection of the disorder because the blood was collected at 5 days of age. The disorders occurred within 1 week after birth in 4 out of 18 cases, 2 of which died at an early stage. Among 13 cases in which the disorders occurred after 1 month, 10 cases were caused by defective metabolism due to infections. The prognoses of inherited metabolic diseases that occur in the early newborn period are limited. However, this study suggests that prognoses of metabolic disorders that occur after the newborn period can expect to be improved by early detection.
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