11/50. Aromatic L-amino acid decarboxylase deficiency: clinical features, treatment, and prognosis.BACKGROUND: Deficiency of aromatic L-amino acid decarboxylase (AADC) is associated with severe developmental delay, oculogyric crises (OGC), and autonomic dysfunction. Treatment with dopamine agonists and MAO inhibitors is beneficial, yet long-term prognosis is unclear. OBJECTIVE: To delineate the clinical and molecular spectrum of AADC deficiency, its management, and long-term follow-up. RESULTS: The authors present six patients with AADC deficiency and review seven cases from the literature. All patients showed reduced catecholamine metabolites and elevation of 3-O-methyldopa in CSF. Residual plasma AADC activity ranged from undetectable to 8% of normal. Mutational spectrum was heterogeneous. All patients presented with hypotonia, hypokinesia, OGC, and signs of autonomic dysfunction since early life. Diurnal fluctuation or improvement of symptoms after sleep were noted in half of the patients. Treatment response was variable. Two groups of patients were detected: Group I (five males) responded to treatment and made developmental progress. Group II (one male, five females) responded poorly to treatment, and often developed drug-induced dyskinesias. CONCLUSIONS: The molecular and clinical spectrum of AADC deficiency is heterogeneous. Two groups, one with predominant male sex and favorable response to treatment, and the other with predominant female sex and poor response to treatment, can be discerned.- - - - - - - - - - ranking = 1keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
12/50. propionic acidemia: unusual course with late onset and fatal outcome.A 4 1/2-year-old girl with a so far unremarkable medical history became comatose during a simple infection. She showed severe metabolic acidosis without elevation of lactate. In blood the branched-chain amino acids were increased. In urine ketone-bodies, increased 3-OH-isovaleric and 3-OH propionic acid excretion were detected, while methylmalonate was not found. The profile of acylcarnitines revealed increased propionylcarnitine. Despite restriction of protein supply, high-caloric nutrition, correction of acidosis, and supplementation of biotin and carnitine, the girl died 2 days after admission due to arrhythmia of the heart. In skin fibroblasts the activity of propionyl-coenzyme a carboxylase (PCC) was markedly decreased. mutation analysis confirmed the diagnosis of propionic acidemia (PA) with compound heterozygosity for 2 new missense mutations L417W/Q293E in the PCCA gene, with the mother carrying the Q293E and the father the L417W mutation. Late-onset PA should be included in the differential diagnosis of unclear coma. Determination of the acylcarnitines using tandem mass spectrometry as well as organic acids in urine is recommended.- - - - - - - - - - ranking = 0.054390479043816keywords = carboxylase (Clic here for more details about this article) |
13/50. NMR spectroscopic studies on the late onset form of 3-methylglutaconic aciduria type I and other defects in leucine metabolism.A diagnosis of 3-methylglutaconic aciduria type I (OMIM: 250950) based on elevated urinary excretion of 3-methylglutaconic acid (3MGA), 3-methylglutaric acid (3MG) and 3-hydroxyisovaleric acid (3HIVA) was made in a 61-year-old female patient presenting with leukoencephalopathy slowly progressing over more than 30 years. The diagnosis was confirmed at the enzymatic and molecular level. In vivo brain MR spectroscopic imaging (MRSI) was performed at 3.0 T, and one-dimensional and two-dimensional in vitro NMR spectroscopy of body fluids of the patient was performed at 11.7 T. Additionally, we measured 1D (1)H-NMR spectra of urine of seven patients with a total of four different inborn errors of leucine metabolism. Increased concentrations of 3HIVA, 3MGA (cis and trans) and 3MG were observed in the NMR spectra of the patient's urine. In the cerebrospinal fluid, the 3HIVA concentration was 10 times higher than in the plasma of the patient and only the cis isomer of 3MGA was observed. In vivo brain MRSI showed an abnormal resonance at 1.28 ppm that may be caused by 3HIVA. Comparison of (1)H-NMR spectra of urine samples from all eight patients studied, representing five different inborn errors of leucine metabolism, showed that each disease has typical NMR characteristics. Our leukoencephalopathy patient suffers from a late-onset form of 3-methylglutaconic aciduria type I. In the literature, only very few adult patients with this conditions have been described, and 3HIVA accumulation in white matter in the brain has not been presented before in these patients. Our data demonstrate that (1)H-NMR spectroscopy of urine can easily discriminate between the known inborn errors of leucine metabolism and provide the correct diagnosis.- - - - - - - - - - ranking = 0.00018846939040612keywords = late-onset (Clic here for more details about this article) |
14/50. Isolated 3-methylcrotonyl-coenzyme a carboxylase deficiency in a child with metabolic stroke.We report a 3-year-old boy with isolated 3-methylcrotonyl-coenzyme a deficiency with unexpectedly severe presentation, seizures and history of cerebral ischae-mic episode.- - - - - - - - - - ranking = 0.94560952095618keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
15/50. 3-Methylcrotonyl-CoA carboxylase deficiency: metabolic decompensation in a noncompliant child detected through newborn screening.We report a 19-month-old girl with a 3-methylcrotonyl-coenzyme a carboxylase deficiency that was detected through newborn screening. She was treated for the first 12 months but was lost to follow-up after the initial year. Her parents did not comply with the recommendations for management during periods of illness or for regular medical evaluations. During an acute illness, she presented with severe acidosis, hypoglycemia, and a low plasma carnitine level at 19 months of age. This report highlights the importance of more extensive follow-up plans to improve parental compliance.- - - - - - - - - - ranking = 1.1820119011952keywords = carboxylase deficiency, carboxylase (Clic here for more details about this article) |
16/50. Mass spectrometric analysis of metabolite excretion in five Japanese patients with the late-onset form of glutaric aciduria type II.The variability of clinical and biochemical features in five Japanese patients with the late-onset form of glutaric aciduria type II (GAII) was studied using mass spectrometric procedures. The age at onset ranged from 5 months to five years, presenting acute episodes such as lethargy, hypotonia, hyperammonaemia, hypoglycaemia or Reye's syndrome-like illness, while one of the five cases was asymptomatic at 1 year of age. Organic acid analysis as oxime-trimethylsilyl derivatives by gas chromatography/mass spectrometry revealed the presence of several abnormalities characteristic of GAII in clinically asymptomatic conditions of three patients but not of the two others. Quantitative acylglycine analysis using a stable isotope dilution method and qualitative acylcarnitine analysis by fast atom bombardment mass spectrometry provided diagnostic information in all five patients, regardless of their clinical conditions. However, significant differences in the respective metabolite profiles as well as in their clinical pictures were noted. Although an increased excretion of both isovalerylglycine and isovalerylcarnitine was found in four patients, the fifth showed normal isovalerylglycine excretion during both the acute stage and in remission, despite the increased amount of isovalerylcarnitine in urine. From these results, it was suggested that the variations in clinical severity and metabolite excretion among GAII patients may be attributed not only to the residual enzyme activity at the defective site but also to differences in the capability to conjugate accumulated acyl-coenzyme a.- - - - - - - - - - ranking = 0.0009423469520306keywords = late-onset (Clic here for more details about this article) |
17/50. Structural and expression analyses of normal and mutant mRNA encoding glycine decarboxylase: three-base deletion in mRNA causes nonketotic hyperglycinemia.Full-length cDNA clone encoding human glycine decarboxylase (P-protein) was isolated from the human placental lambda gt11 expression library using specific antibodies. This clone was 3,705 bp in length and encoded 1,020 amino acids. We studied the structure of the mutant P-protein mRNA expressed in the liver of a patient with nonketotic hyperglycinemia (NKH) deficient of P-protein. A three-base deletion, which resulted in deletion of Phe756, was found. Cos7 cells in which normal P-protein cDNA was expressed presented an activity of 6.9 /- 0.41 nmole/milligram of protein/hour, which was almost equivalent to that of human liver. In contrast, Cos7 cells in which the mutant cDNA was expressed showed no activity, indicating that the three-base deletion could cause NKH.- - - - - - - - - - ranking = 0.27195239521908keywords = carboxylase (Clic here for more details about this article) |
18/50. Late-onset form of partial N-acetylglutamate synthetase deficiency.A 13-month-old female presented with neurological deterioration of 1 month duration and hyperammonaemia. N-acetylglutamate synthetase activity in the liver was reduced to 33% of the control. A male cousin and a female sister had died following a similar clinical course. This is the first report of late-onset N-acetylglutamate synthetase deficiency. An autosomal-recessive mode of inheritance is suggested.- - - - - - - - - - ranking = 0.00018846939040612keywords = late-onset (Clic here for more details about this article) |
19/50. Acute neonatal nonketotic hyperglycinemia: normal propionate and methylmalonate metabolism.Propionyl-CoA carboxylase and combined methylmalonyl-CoA (MMA-CoA) racemase and -mutase activities were studied in liver and fibroblasts of two patients with the acute neonatal form of nonketotic hyperglycemia. In all experiments, these enzyme activities studied in tissues of the patients were within the range of healthy control subjects, whereas no propionyl-CoA carboxylase activity was measurable in the fibroblasts of a patient with propionic acidemia. Subcellular fractionation of liver and fibroblasts indicated that the normal amounts of MMA-CoA found after incubation of whole tissue homogenate were formed by propionyl-CoA carboxylase, a mitochondrial enzyme, and not be acetyl-coa carboxylase, which theoretically could also be involved in the carboxylation of propionyl-CoA. From the above data as well as from clinical and biochemical observations in three patients, it was concluded that there exists a true nonketotic hyperglycinemia which is not related etiologically to the different disorders of the ketotic hyperglycinemia syndrome. True nonketotic hyperglycinemia is not associated with ketoacidosis even after loading with propionate- and MMA precursors. It must be distinguished by exclusion from mild forms of the ketotic hyperglycinemia syndrome which may present clinically as hyperglycinemia without ketosis.- - - - - - - - - - ranking = 0.21756191617526keywords = carboxylase (Clic here for more details about this article) |
20/50. Mitochondrial encephalomyopathy with associated aminoacidopathy in a male sibship.We report two brothers with a previously undescribed type of mitochondrial encephalomyopathy and associated aminoacidopathy. Both have growth failure, progressive intellectual decline, deafness, neurologic dysfunction, exercise intolerance, lactic acidosis, and abnormal plasma and cerebrospinal fluid amino acid levels (elevated levels of alanine and low levels of threonine, methionine, citrulline, tryptophan, ornithine, arginine, and lysine). A muscle biopsy specimen taken from the younger, more severely affected brother showed abnormal mitochondrial morphology. Activities of the following enzymes in cultured fibroblasts from both boys were normal: pyruvate dehydrogenase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, cytochrome oxidase, reduced nicotinamide-adenine dinucleotide-cytochrome c reductase, and succinate cytochrome c reductase. Fibroblast mitochondria from the younger boy showed undetectable (less than 1% of control values) adenosine triphosphate synthesis with pyruvate and malate, whereas adenosine triphosphate synthesis with succinate was 70% of control values. These data indicate probably deficient activity of complex I of the electron transport chain. The boys' mother has progressive neurosensory hearing loss; their sister is clinically normal. Both mother and sister have many of the biochemical abnormalities found in the boys. It is possible, but not proved, that this disorder is inherited through maternal mitochondria.- - - - - - - - - - ranking = 0.054390479043816keywords = carboxylase (Clic here for more details about this article) |
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