Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The case of a 4 years old boy, hospitalized for an unexplained coma, is reported. He is the first child of a non-consanguin couple. The psychomotor development of this child was considered as normal up to the age of 18 months; then, a delay in language development, behaviour disorders with an important instability interrupted by episodes of somnolence, were observed. This child was treated for psychotic disorders. At the age of 3 and half, he had two episodes of seizures associated with fever. He was hospitalized for a 24 hours coma (4 years old). An hepatomegaly and a dry, brittle hair were then observed. Hyperammonemia was made obvious by a protein tolerance test. The diagnosis of argininosuccinate lyase (ASAL) deficiency was based on the increased levels of ASA in plasma and urine. The deficiency was proved by a fibroblast culture. With protein restriction, hepatomegaly disappeared, hair became normal, the behaviour disorders and the delay in language development was improved. However, some school difficulties persist. This case shows that an hereditary metabolic syndrome can be revealed by psychotic like symptoms in childhood.
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PMID:[Argininosuccinic aciduria. A new case revealed by psychiatric disorders]. 271 82

The presentation and 2 year treatment of a patient with argininosuccinic aciduria is reported. Erythrocyte argininosuccinate lyase activity was less than 2% of normal. Long-term management included protein restriction and arginine dietary supplementation. The child experienced three episodes of hyperammonaemia (greater than 100 microns), the first at birth, the second at 6.5 months and the third at 16 months. Neurological development deteriorated between 14 and 24 months. Hepatomegaly and biochemical hepatitis, a feature of this condition, was accompanied by enlarged mitochondria with tubular paracrystalline inclusions not previously recognized in this disorder.
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PMID:Argininosuccinic aciduria: long-term treatment with arginine. 311 34

Hepatomegaly is an important clinical finding in patients with argininosuccinic aciduria (a hereditary defect of the urea cycle enzyme, argininosuccinate lyase [argininosuccinase]). A severe degree of liver fibrosis, almost corresponding to cirrhosis, was observed in liver biopsy material obtained from a boy with this disorder. This observation is of interest in light of the fact that liver fibrosis or cirrhosis are hallmarks of many inheritable phenotypes, and especially of inborn errors of metabolism. Variable degrees of liver fibrosis are noted in other inborn defects of the urea cycle, eg, in ornithine transcarbamylase and carbamoylphosphate synthetase deficiencies. These findings appear to indicate that inheritable defects of urea synthesis may form a group of metabolic disorders prone to cause hepatic fibrosis, or even cirrhosis, as shown in our patient.
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PMID:Severe liver fibrosis in argininosuccinic aciduria. 375 45

The effects of sodium citrate supplementation to improve aspartic acid supply in a 5-year-old girl with argininosuccinate lyase deficiency were studied over a period of 5 years under constant and total parenteral nutrition. Daily increasing doses of sodium citrate (0-8 mmol/kg) were continuously infused i.v.. Her standard therapy with arginine hydrochloride (4 mmol/kg/day) and sodium benzoate (200 mg/kg/day) was continued. Serum citrulline concentrations were reduced by citrate supplementation (161.8-41.7 mumol/l). Correspondingly serum concentrations of argininosuccinate and its anhydrides rose (270-458 mumol/l), positively correlated with the doses of sodium citrate. Renal elimination of argininosuccinate did not change measurably. There was no improvement in plasma ammonia concentration, which remained between 88 and 136 mumol/l. A long-standing hepatomegaly did not improve. The patient developed a significant alkalosis with blood pH-values increasing up to 7.55. The alkalosis lead to a reduction in renal ammonium elimination by at least 5.3 mmol/kg per day; the portion of ammonium-nitrogen decreased from 54.2% to finally 9% of total urinary nitrogen. Nevertheless total urinary nitrogen elimination, as measured by pyrochemiluminescence, improved by 24.5% during the 5 days and rose from 2065 mg nitrogen/day to 2570 mg/day. This improvement could not be explained by the metabolites determined and corresponded with an increase in chemically undefined nitrogen excretion, which rose from 0% to 65.9% of total urinary nitrogen. Further investigations are necessary to elucidate the nature of these unexplained nitrogen-containing compounds. CONCLUSION. Sodium citrate supplementation improved renal nitrogen elimination in a patient with argininosuccinate lyase deficiency in the observation period of 5 days by up to 24.5%.
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PMID:Sodium citrate supplementation in inborn argininosuccinate lyase deficiency: a study in a 5-year-old patient under total parenteral nutrition. 858 5

A 4-month-old boy, with late-onset argininosuccinate lyase (ASL) deficiency with hepatomegaly, was treated by protein restricted diet and arginine supplementation; he was followed for 3 years. Hepatomegaly and mild liver dysfunction persisted without significant hyperammonemia. He maintained normal psychomotor development to the age of 12 months, but, at 3 years of age, his developmental status is in the borderline normal range. Liver biopsy performed at 12 months of age demonstrated swollen and pale hepatocytes with abnormal glycogen deposition and mild periportal fibrosis. A subsequent liver biopsy at 3 years of age showed progressive liver fibrosis in the periportal and central areas, which extended into the liver lobule. These findings suggest that liver impairment in ASL deficiency may advance without significant hyperammonemia and underline the importance of repeated liver biopsy in this disorder, even when the plasma ammonia level is well controlled.
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PMID:Progressive liver fibrosis in late-onset argininosuccinate lyase deficiency. 1237 Jul 74

Argininosuccinate lyase (ASL) deficiency (McKusick 207900) is a rare autosomal recessive disorder affecting the urea cycle. The cardinal symptom in the neonatal form is progressive hyperammonemia, which is often life-threatening. However, clinical symptoms in the late onset form are quite heterogeneous. As well as measurement of ASL activity, analysis of the ASL gene is necessary to clarify the genetic basis of various phenotypes. We report a patient with late onset argininosuccinate lyase deficiency (ASLD) who had hepatomegaly and mildly increased level of ammonia. By mutation analysis of the mRNA and genomic DNA from the patient's leukocytes, we identified a novel missense mutation 1395G>C in the homozygous state, which results in the exchange of a stop codon to tyrosine at amino acid position 465 (X465Y). This unique mutation causes an elongation of fifty amino acids in the C-terminal region of the ASL protein, and is likely related to a milder phenotype compared with previously reported mutations. In addition, this is the first report on mutation analysis in a Japanese ASLD patient.
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PMID:A novel stop codon mutation (X465Y) in the argininosuccinate lyase gene in a patient with argininosuccinic aciduria. 1251 96

Argininosuccinic aciduria (ASAuria) is an inborn error of metabolism caused by mutations in the argininosuccinate lyase (ASL) gene, which leads to the accumulation of argininosuccinic acid (ASA) in body fluids and severe hyperammonemia. A severe neonatal form and a milder late-onset variant are described. We report a novel ASL pseudogene located in the centromeric region of chromosome 7, 14 novel mutations in the ASL gene, and a novel intronic polymorphism found in a cohort of Italian patients. Our approach relied exclusively on genomic DNA analysis. We found seven missense mutations, two nonsense, three small insertions/deletions, and two splicing mutations. Only two patients harbored previously described mutations, and among the novel variants only two were present in more than one kindred. The pathogenicity of the splicing mutations was demonstrated by a functional splicing assay that employed a hybrid minigene. We also performed molecular modeling using the reported three-dimensional structure of ASL to predict the functional consequences of the missense mutations. There was no genotype-phenotype correlation. Patients with neonatal onset display developmental delay and seizures despite adequate metabolic control. Moreover, hepatomegaly, fibrosis, and abnormal liver function tests are common complications in these patients, but not in patients with the late infancy form. We stress the importance of mutation analysis in patients with ASAuria, to confirm the clinical diagnosis, and to perform DNA-based prenatal diagnosis in future pregnancies of these families.
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PMID:Argininosuccinate lyase deficiency: mutational spectrum in Italian patients and identification of a novel ASL pseudogene. 1732 97

Argininosuccinate lyase deficiency is a urea cycle disorder which can present in the neonatal period with hyperammonemic encephalopathy, or later in childhood with episodic vomiting, growth and developmental delay. Abnormal hair, hepatomegaly, and hepatic fibrosis are unique features of this disorder. Twelve patients with argininosuccinate lyase deficiency were ascertained between 4 and 6 weeks of age by urine amino acid screening. One infant in a previously identified family was diagnosed shortly after birth. Diagnosis was confirmed by enzyme assay in red blood cells and/or skin fibroblasts. At the time of last follow-up, patients had been followed for 13-33 years. All patients were asymptomatic at detection, 7 had slightly increased blood ammonia, and all were initially treated with low-protein diet. Utilization of (14)C-citrulline by intact skin fibroblasts measured by (14)C incorporation into macromolecules was 74-135% of the control mean for 7 of the 8 patients studied. Nine patients had normal development, 4 had learning disability, 6 had EEG abnormalities, 3 had seizure disorder. None had any episodes of hyperammonemic coma. None had hepatomegaly. Patients detected by screening had higher enzyme activity measured by the (14)C-citrulline incorporation assay than comparison groups of patients with neonatal-onset and with late-onset detected by clinical disease. The ability to utilize (14)C-citrulline by intact fibroblasts seems to correlate with clinical outcome and may have prognostic value. It is likely that early diagnosis and treatment contributed to the relatively mild clinical course of the study group.
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PMID:Argininosuccinate lyase deficiency: longterm outcome of 13 patients detected by newborn screening. 1963 76

BACKGROUNDLiver disease in urea cycle disorders (UCDs) ranges from hepatomegaly and chronic hepatocellular injury to cirrhosis and end-stage liver disease. However, the prevalence and underlying mechanisms are unclear.METHODSWe estimated the prevalence of chronic hepatocellular injury in UCDs using data from a multicenter, longitudinal, natural history study. We also used ultrasound with shear wave elastography and FibroTest to evaluate liver stiffness and markers of fibrosis in individuals with argininosuccinate lyase deficiency (ASLD), a disorder with high prevalence of elevated serum alanine aminotransferase (ALT). To understand the human observations, we evaluated the hepatic phenotype of the AslNeo/Neo mouse model of ASLD.RESULTSWe demonstrate a high prevalence of elevated ALT in ASLD (37%). Hyperammonemia and use of nitrogen-scavenging agents, 2 markers of disease severity, were significantly (P < 0.001 and P = 0.001, respectively) associated with elevated ALT in ASLD. In addition, ultrasound with shear wave elastography and FibroTest revealed increased echogenicity and liver stiffness, even in individuals with ASLD and normal aminotransferases. The AslNeo/Neo mice mimic the human disorder with hepatomegaly, elevated aminotransferases, and excessive hepatic glycogen noted before death (3-5 weeks of age). This excessive hepatic glycogen is associated with impaired hepatic glycogenolysis and decreased glycogen phosphorylase and is rescued with helper-dependent adenovirus expressing Asl using a liver-specific (ApoE) promoter.CONCLUSIONOur results link urea cycle dysfunction and impaired hepatic glucose metabolism and identify a mouse model of liver disease in the setting of urea cycle dysfunction.TRIAL REGISTRATIONThis study has been registered at ClinicalTrials.gov (NCT03721367, NCT00237315).FUNDINGFunding was provided by NIH, Burroughs Wellcome Fund, NUCDF, Genzyme/ACMG Foundation, and CPRIT.
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PMID:Chronic liver disease and impaired hepatic glycogen metabolism in argininosuccinate lyase deficiency. 3199 Jun 80