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A 50-day-old boy with severe lactose intolerance is described. In addition to vomiting, failure to thrive, dehydration, metabolic acidosis and amino aciduria, bilateral cataracts were also found. At three months of age, a computerized axial tomography scan and an electroencephalogram were abnormal, and myoclonic spasms began at the age of seven months.
A low activity galactose-1-phosphate uridyl transferase (transferase) variant in a newborn infant has been demonstrated by biochemical studies in erythrocytes and cultured skin fibroblasts. The newborn infant was a galactosaemic suspect identified in a neonatal metabolic screening programme. On breast feeding, he did well without clinical symptoms of galactosaemia during the first 15 days of life. However, substantial amounts of erythrocyte galactose-1-phosphate and urinary galactitol corresponding to the levels in untreated galactosaemic patients, along with mild amino aciduria, were found. The transferase activity, as measured by a sensitive micro kinetic radioisotopic method, was about 7--10% of the normal. On starch gel electrophoresis, the enzyme from the haemolysate had similar mobility as the normal in Tris--glycine buffer, pH 8.8 and phosphate buffer, pH 7.0, but had a slower mobility than that of the normal in the histidine buffer, pH 7.8. The mobility difference was much clearer in a semipurified enzyme preparation. The transferase enzyme in the haemolysate appeared to be more heat labile.
Progressive hepatocellular dysfunction in a neonate, resulting in elevated serum alpha-fetoprotein together with raised blood levels of tyrosine and methionine, a generalized amino aciduria and the absence of urinary delta-aminolevulinic acid and succinylacetone, suggests a diagnosis of tyrosinemia type Ib. Classical tyrosinemia type I arises from a deficiency of fumarylacetoacetate hydrolase while the variant tyrosinemia type Ib results from a deficiency of maleylacetoacetate isomerase.
The renal tubular toxicity of various halogenated xenobiotics has been attributed to their enzymatic bioactivation to reactive intermediates by S-conjugation. A combination of high resolution proton nuclear magnetic resonance (1H NMR) spectroscopy of urine, renal histopathology and more routinely used clinical chemistry methods has been used to explore the acute toxic and biochemical effects of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP) up to 48 h following their administration to male Fischer 344 (F344) rats. In the absence of gross renal pathology, 1H NMR urinalysis revealed increased excretion of the tricarboxylic acid cycle intermediates citrate and succinate following DCVC administration. In contrast, both DCVHC and TCTFP produced functional defects in the S2 and S3 segments of the proximal tubule that were confirmed histologically. In these cases, 1H NMR urinalysis revealed increased excretion of glucose, L-lactate, acetate and 3-D-hydroxybutyrate (HB) as well as selective amino aciduria (alanine, valine, glutamate and glutamine). The significance of the proximal nephropathies induced by DCVHC and TCTFP is discussed in relation to biochemical observations on other xenobiotics that are toxic by similar mechanisms.
Amino acid analysis of plasma and urine obtained from 12 patients with epilepsy indicated that the plasma concentrations of taurine and glutamic acid were much higher than might have been expected. Glutamic acid in urine was also increased in these patients. Oral administration of taurine did not appreciably affect the levels of amino acids in plasma or urine with the exception of that of glutamic acid. In patients with an abnormal plasma concentration of glutamic acid, the administration of taurine caused glutamic acid levels to change in the direction of normal values along with a decrease in the urinary excretion of this amino acid. This action of taurine was independent of either its initial or final plasma concentration. Amino acid concentrations in the CSF were within normal range and were not influenced by taurine administration. The selective elevation of both taurine and glutamic acid in the plasma, combined with previous findings of a deficiency of these same amino acids in human and experimental epileptogenic brain, implies that some patients with epilepsy may suffer from an aberration in taurine and glutamic acid metabolism. Taurine administration appears to partially correct these biochemical abnormalities. Theoretically, such normalization of the amino acid profile in epileptogenic brain may be beneficial, but clinical signs of improvement may only become apparent after a long delay. The present study was designed to determine only the biochemical parameters implicated in taurine administration and no definite conclusions can be drawn as to the clinical efficacy of the amino acid in epilepsy. However, this study suggests that in future clinical trials investigating the potential use of taurine as an antiepileptic agent, the oral dose of taurine should not exceed 1.0 g/day and optimal doses may be as low as 0.1-0.5 g/day. In one patient who received 2.0-2.5 g of taurine/day for 2 weeks, a generalized amino aciduria occurred.
Three children displaying hypotonia, cardiac involvement and defects of the mitochondrial respiratory chain complexes are reported. The first case showed severe neonatal hypotonia, failure to thrive, hepatomegaly, dilation of the right cardiac cavities, profound lactic acidosis and amino aciduria. The boy died at the age of 7 weeks. In the second case hypotonia, severe cardiomyopathy, cyclic neutropenia, lactic acidosis and 3-methylglutaconic aciduria occurred. The boy died at the age of 27 months. The third case presented at the age of 16 months as an acute hypokinetic hypertrophic cardiomyopathy with transient hypotonia and mild lactic acidosis. Spontaneous clinical remission occurred. In all cases muscle biopsy was performed. Morphological studies failed to show ragged-red fibers but there was lipid storage myopathy and decreased cytochrome c oxidase activity. Biochemical studies confirmed the cytochrome c oxidase deficiency in muscle in all cases. It was associated with complex I III deficiency in case 1 and with severe deficits of all respiratory chain complexes in case 2. Post-mortem studies in case 1 indicated that complex IV was reduced in the liver but not in the heart and quantitative analysis of mtDNA revealed a depletion in muscle. Cases 1 and 2 shared some clinical features with fatal infantile myopathy associated with cytochrome c oxidase deficiency, while case 3 displayed a very unusual clinical presentation. The histochemical enzyme reaction of cytochrome c oxidase is useful for the diagnosis of mitochondrial myopathy because ragged-red fibers may be lacking. Finally, biochemical measurement of the different mitochondrial respiratory chain complexes is required because multiple defects are frequent and occasionally related to mtDNA depletion.
The pyrimidine bases uracil and thymine are degraded via the consecutive action of three enzymes to beta-alanine and beta-aminoisobutyric acid, respectively. To date, a number of patients have been described with a deficiency of dihydropyrimidine dehydrogenase and dihydropyrimidinase, the first two enzymes of the pyrimidine degradation pathway. In this study, we demonstrate that the first patient presenting with N-carbamyl-beta-amino aciduria, due to a deficiency of beta-ureidopropionase, was easily diagnosed at the metabolite level using HPLC-tandem mass spectrometry. Urinary analysis showed strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid, with normal or moderately increased levels of the pyrimidine bases and the dihydropyrimidines, respectively. The deficiency of beta-ureidopropionase was confirmed by measuring all three enzymes of the pyrimidine degradation pathway. No activity of beta-ureidopropionase could be detected in a liver biopsy of the patient, while a normal activity of dihydropyrimidine dehydrogenase and dihydropyrimidinase was present. Thus, HPLC-tandem mass specrometry proved to be a powerful tool for the initial diagnosis of patients with deficiency of beta-ureidopropionase.
A mouse mutant with glutathionuria was discovered by screening for amino acidurias in the progeny of ethylnitrosourea-mutagenized mice. Total glutathione concentration was increased in both blood and urine but decreased in liver homogenates from affected mice. Glutathionuric mice exhibited lethargy, severe growth failure, shortened life spans and infertility. gamma-Glutamyl transpeptidase activity was deficient in kidney homogenates of glutathionuric mice. The glutathionuric phenotype in these mice is inherited as an autosomal recessive trait. This mouse mutant will be a useful animal model for the study of gamma-glutamyl transpeptidase physiology and glutathione metabolism.
Tenofovir disopril fumarate, a new nucleotide analogue against human immunodeficiency virus-1 (HIV-1), can induce hypophosphataemia, the mechanism of which is unclear. Moreover, a renal tubulopathy can occur in long-term treated patients, as observed in 2 HIV-1-infected patients after 12 months of tenofovir therapy, with polyuria-polydipsia, proteinuria, glycosuria and amino-aciduria, which resolved after discontinuation of tenofovir. The risk of renal tubulopathy symptoms in patients on long-term tenofovir therapy should be noted.
beta-Ureidopropionase deficiency is an inborn error of the pyrimidine degradation pathway, affecting the cleavage of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid. In this study, we report the elucidation of the genetic basis underlying a beta-ureidopropionase deficiency in four patients presenting with neurological abnormalities and strongly elevated levels of N-carbamyl-beta-alanine and N-carbamyl-beta-aminoisobutyric acid in plasma, cerebrospinal fluid and urine. No beta-ureidopropionase activity could be detected in a liver biopsy obtained from one of the patients, which reflected the complete absence of the beta-ureidopropionase protein. Analysis of the beta-ureidopropionase gene (UPB1) of these patients revealed the presence of two splice-site mutations (IVS1-2A>G and IVS8-1G>A) and one missense mutation (A85E). Heterologous expression of the mutant enzyme in Escherichia coli showed that the A85E mutation resulted in a mutant beta-ureidopropionase enzyme without residual activity. Our results demonstrate that the N-carbamyl-beta-amino aciduria in these patients is due to a deficiency of beta-ureidopropionase, which is caused by mutations in the UPB1 gene. Furthermore, an altered homeostasis of beta-aminoisobutyric acid and/or increased oxidative stress might contribute to some of the clinical abnormalities encountered in patients with a beta-ureidopropionase deficiency. An analysis of the presence of the two splice site mutations and the missense mutation in 95 controls identified one individual who proved to be heterozygous for the IVS8-1G>A mutation. Thus, a beta-ureidopropionase deficiency might not be as rare as is generally considered.
A patient with asymptomatic adult Fanconi syndrome with glycosuria, amino-aciduria, hypophosphatemia, and renal tubular acidosis was found to have hypouricemia (serum uric acid, 1.5-1.8 mg/100 ml) secondary to increased renal clearance of urate (urate clearance/glomerular filtration rate, 32 per cent). Increased urate clearance in this patient with multiple reabsorptive defects probably represents diminished urate reabsorption. Consistent with this, the uricosuric response to probenecid was diminished. Reabsorption of filtered urate appeared to be intact. Inhibition of urate secretion with pyrazinamide completely suppressed the uricosuria in this patient, suggesting that increased urate clearance was due to either enhanced secretion or diminished reabsorption of secreted urate. There was no direct evidence for increased urate secretion. The response of urate excretion to pharmacologic inhibitors of tubular transport of urate differs in various clinical states associated with hyperuricosuria. The responses may reflect different mechanisms of hyperuricosuria.
A 10-month-old boy was reported with the diagnosis of L-2 hydroxyglutaric aciduria. Amino acid chromatographic analysis revealed an 80-fold increase of hydroxyglutaric acid in the urine. Proton magnetic resonance (MR) spectroscopy of the brain obtained with the hybrid chemical shift imaging sequence (repetition time = 1,500 milliseconds, echo time = 40 milliseconds) revealed prominent peaks resonating at 2.50 ppm, which were attributable to L-2 hydroxyglutaric acid. Diffusion MR imaging was obtained using the echo-planar trace sequence (repetition time = 5,700 milliseconds, echo time = 139 milliseconds). Two different diffusion patterns were evident: a restricted diffusion pattern in the globi pallidi and an increased diffusion pattern in the white matter.
In a Chinese family with hereditary pancreatitis, two members are proven to have chronic pancreatitis. The propositus, a 31-year-old man, had epigastric pain since the age of 18. Multiple calcifications in the region of the pancreas were seen on plain film of the abdomen, ultrasonography, computed tomography, and endoscopic retrograde pancreatography. Pancreatolithotomy and side-to-side pancreatojejunostomy gave symptomatic improvement. His 60-year-old mother also had pancreatic calcifications in addition to diabetes. Known causes of secondary pancreatitis, such as hyperlipidemia, hyperparathyroidism, and amino aciduria, were ruled out in both patients.
An autosomal recessive disorder characterized by lamellar ichthyosis, an usual structural defect of the scalp hairs and amino aciduria occurred in two siblings in a South Indian family in Madras. In addition the female sibling was physically and mentally retarded. The disorder differs from typical Netherton's syndrome in several ways. The hair abnormality specific for this disorder appears to be splitting of the shaft. The possible mechanism of production of the split hairs is discussed.
Mental retardation in combination with proteinuria and a slight hyperlipoproteinemia was found in three brothers. The increased urinary protein excretion was dominated by albumin and the low molecular weight proteins retinol-binding protein (RBP) and beta2-microglobulin, indicating the presence of proximal tubular dysfunction. However, there was no glucosuria, phosphaturia or amino aciduria and the renal concentrating and acidification capacities were normal. A kidney biopsy in one of the patients revealed morphologic evidence of glomerular damage but a normal tubular structure. A mild hyper-beta-lipoproteinemia was found in the patients but not in their healthy siblings. The cause of this syndrome, hitherto not described, is unknown.
Two cases of neonatal renal tubular dysfunction and metabolic acidosis due to maternal sniffing of a product containing toluene are reported. Both mothers had been sniffing regularly throughout their pregnancies. The infants were dysmature and had some dysmorphic features. They had hyperchloraemic acidosis and exhibited amino-aciduria. The metabolic changes were however transient. It is suggested that the sniffing of toluene containing solvents during pregnancy may change membrane permeability in both the proximal as well as distal renal tubules and may also enhance liver enzyme activity in the foetus.
A 35-year-old-man presented with nephrotic syndrome due to mesangiocapillary glomerulonephritis; he later developed a potassium-losing state, generalized amino aciduria and glycosuria. Clinical and biochemical improvement occurred after steroid therapy. The possible pathophysiological mechanisms are discussed.
An unusual case of acute renal failure is reported following accidental cutaneous absorption of phenol and exposure to dichloromethane. Renal function during the onset of the nephrotoxic episode and the subsequent recovery period was monitored using a combination of standard clinical biochemical techniques and high resolution 1H-NMR urinalysis. The initial urine biochemical patterns (up to 2 weeks following exposure) showed amino aciduria, glycosuria and lactic aciduria consistent with renal cortical necrosis. There followed a period of polyuria revealing a biochemical pattern (succinic aciduria, dimethylaminuria and N,N-dimethylglycinuria) consistent with renal papillary damage. Haemodialysis was required for a period of 3 weeks and the patient was discharged 42 days after admission to hospital when renal function was normal by standard clinical chemistry criteria (urea, potassium, sodium, creatinine, calcium, phosphate, urine glucose and protein). 1H-NMR spectroscopic urinalysis revealed residual renal biochemical abnormalities consistent with renal papillary damage that were not detected by conventional analytical techniques. One year after the incident the patient is still polyuric, passing up to 3 l of urine a day.