Urea Cycle Defects Research Articles

Aminograms during Continuous Hemodiafiltration in the Treatment of Hyperammonemia Due to Ornithine Transcarbamylase Deficiency

Background. Hyperammonemia caused by ornithine transcarbamylase (OTC) deficiency can be properly managed by continuous arteriovenous hemodiafiltration (CAVHDF). Removal of amino acids (AA) during CAVHDF has not been thoroughly investigated. AA losses in patients with urea cycle defects due to ornithine transcarbamylase deficiency treated by CAVHDF were analyzed. Methods. Twelve neonates with elevated serum ammonia levels, confirmed through urine organic acid analysis and serum amino acid studies, were documented to have OTC deficiency. CAVHDF was administered in an attempt to lower serum ammonia concentration. Amino acid analysis of ultrafiltration and serum were performed by liquid chromatography. Results. Serum levels of leucine, isoleucine, methionine, phenylalanine, and tyrosine were significantly lower than acceptable in these patients. Glutamine was the only amino acid that increased significantly, which is clinically relevant to OTC enzyme deficiency. Although the mean serum concentrations of tyrosine and glutamine concentrations were lower in the dialysate, the serum and dialysate concentrations of other amino acids did not differ. Conclusion. CAVHDF may induce changes in amino acid metabolism and distribution as well. The requirement of aminogram monitor for amino acid supplementation in urea cycle defect patients is important.

Urea cycle defects: Changes of amino acid CSF/plasma-ratios

Urea cycle defects: Changes of amino acid CSF/plasma-ratios

Study of Inherited Metabolic Disorders in Singapore – 13 Years Experience

Recommended by the National Advisory Council of the Disabled, the Ministry of Health of Singapore supported a nationwide study of inherited metabolic disorders (IMDs). When the 5-year project ended, investigations were provided as a diagnostic service. This paper documents our 13-year experience. Patients with symptoms suggestive of an IMD were referred. Investigations on heparinised blood and/or urine included amino acid analysis using a Beckman 6300 Amino Acid Analyser, organic acids analysis using a Hewlett- Packard gas chromatography and mass spectrometry, mucopolysaccharides quantitative assay and high-resolution electrophoresis, sugars by thin-layer chromatography. Of the 3656 patients studied from 1992 to 2005, IMDs were found in 127 (77 males; 50 females; age range, 1 day to 56 years). Their ethnic distribution was: 55.1% Chinese, 19.7% Malays, 11.0% Indians, 11.0% other races and 3.2% unknown. IMD diagnosed comprised 41 (32.3%) organic acidurias, 34 (26.8%) amino acidaemias/acidurias, 14 (11.0%) urea cycle defects, 15 (11.8%) mucopolysaccharidoses, 6 (4.7%) carbohydrate disorders and 17 (13.4%) others. Twenty-three (18.1%) cases were diagnosed during the neonatal period and 36 (28.3%) after the age of 13. Positive detection rate was 3.5% and 48 IMDs were found. Significant proportion of cases had late-onset IMDs. Early identification of IMDs permits timely management, genetic counselling and prenatal diagnosis.

External Proficiency Testing Programmes in Laboratory Diagnoses of Inherited Metabolic Disorders

This paper shows the importance and value of external proficiency testing programmes in monitoring and improving a laboratory's diagnostic skills. It reviews and documents the wide variety of inherited metabolic disorders (IMDs) encountered in the programmes organised by the Human Genetics Society of Australasia and the College of American Pathologists. The programmes used actual patient specimens to assess a laboratory's ability to provide diagnoses based on laboratory tests results and brief clinical information. Participating laboratory was also required to suggest additional test(s) to confirm diagnoses. The results of diagnoses on 116 samples were reviewed. Altogether 49 IMDs were encountered, including 26 organic acidurias, 16 aminoacidurias, 3 urea cycle defects, 5 mucopolysaccharidoses, and 1 each of mucolipidosis and purine disorder. Our report for 21 of the 116 samples (18.1%) deviated from the actual diagnoses. Deviations from the final diagnoses were recorded along with the reasons for them. The main reasons for the deviations were: the lack of standards for recognising metabolites of pathognomonic significance, absence of characteristic metabolites in samples collected during treatment, the presence of misleading unusual metabolites, inadequate clinical information, and inability to perform additional tests due to insufficient specimens. The programmes provided a wide variety of IMDs, some of which we have yet to encounter in our patients. They also enabled us to learn about the varied biochemical manifestations at different stages of disease and the identity of previously unidentified metabolites. They enhanced our knowledge and experience and improved our diagnostic skills.

HYPERORNITHINEMIA, HYPERAMMONEMIA, HOMOCITRULLINEMIA (HHH) SYNDROME PRESENTING WITH SEVERE LIVER FAILURE

Hyperornithinemia, Hyperammonemia, Homocitrullinemia (HHH) syndrome is a rare autosomal recessive disorder of amino acid metabolism, which was first described by Shih et al in 1969. It has now been described in more than 50 patients. Patients present clinically with vomiting, lethargy, impaired growth and delayed developmental milestones. The characteristic neurological picture may include spastic gait, pyramidal tract signs, seizures and ataxia. As it is a urea cycle defect, patients will have elevated serum ammonia. The amino acid ornithine is elevated in the plasma and homocitrulline is elevated in the urine. The gene (ORNT1) for HHH syndrome has been identified and maps to 13q14. Different mutations in this gene have been reported. Liver involvement such as mild coagulopathy, hepatitis picture and acute liver failure responding to a protein restricted diet has been reported in HHH syndrome. Histopathology of the liver may show the typical picture of vacuolated hepatocytes filled with glycogen. Bizarre shapes and structures of the mitochondria are the usual findings by electron microscopy. We report a child who presented with severe coagulopathy and elevated liver transaminases. She was transferred to our centre for a possible liver transplant. A diagnosis of HHH syndrome was confirmed and the child was treated for her HHH syndrome. Complete recovery of the liver function was achieved. Once a protein restricted diet with adequate calories was started along with citrulline supplementation, the liver function including the elevated liver enzymes and coagulopathy dramatically returned to normal. To our knowledge, there are no reported cases in the literature of a patient who has HHH syndrome presenting with such severe liver failure. It is important to consider the diagnosis of HHH syndrome in patients presenting with liver failure and to treat them aggressively prior to considering liver transplantation.

Successful anticonvulsive therapy with D/L 3-hydroxybutyrate and ketogenic diet in a boy with agininosccinate lyase deficiency and status epileptics minor

Ketogenic Diet is indicated in pharmacoresistent epilepsy, but seems to be contraindicated in urea cycle defects, because metabolic changes are comparable to a fast. Alternatively, administration of 3-β-Hydroxybutyrate (BHB) is discussed. D/L BHB is successfully used in few patients with hypoketotic neurometabolic disorders like Glutaric aciduria type II.

Transmission of Donor Melanoma after OLT in a Teenager with Urea Cycle Defect – A Case Report

Transmission of Donor Melanoma after OLT in a Teenager with Urea Cycle Defect – A Case Report

Carbamyl phosphate synthase deficiency: Diagnosed during pregnancy in a 41-year-old

Carbamyl phosphate synthase deficiency (CPS) is a rare urea cycle defect. We present a case of a 41-year-old woman diagnosed with CPS deficiency during pregnancy. She is the oldest CPS-deficient patient, at diagnosis, reported to date and the first to be diagnosed during pregnancy. This case highlights the need for consideration of inborn errors of metabolism in adults presenting with unusual neurological and psychiatric conditions.

Renal replacement therapy in the treatment of confirmed or suspected inborn errors of metabolism

Analysis of mortality and risk factors for mortality in the use of renal replacement therapy to correct metabolic disturbances associated with confirmed or suspected inborn errors of metabolism. A retrospective review of an institutional review board-approved pediatric acute renal failure data base at the University of Michigan. Eighteen patients underwent 21 renal replacement therapy treatments for metabolic disturbances caused by urea cycle defects (n = 14), organic acidemias (n = 5), idiopathic hyperammonemia (n = 1), and Reye syndrome (n = 1). There were 14 boys (74%) and 4 girls (26%), with a mean age and weight of 56.2 +/- 71.0 months and 18.5 +/- 19.2 kg, respectively, at the initiation of renal replacement therapy. Overall treatment mortality rate was 57.2% (12 of 21 treatments), with 11 of the 18 patients (61.1%) dying before hospital discharge. Two-year follow-up on those patients demonstrated that 5 patients (71.4%) remained alive. Initial therapy with hemodialysis was associated with improved survival. Ten treatments (47.6%) required transition to another form of renal replacement therapy to maintain ongoing metabolic control, with a mean duration of 6.1 +/- 9.8 days. Time to renal replacement therapy >24 hours was associated with an increased risk of mortality, whereas a blood pressure >5th percentile for age at the initiation of therapy and the use of anticoagulation were associated with a decreased risk of mortality. Renal replacement therapy can correct the metabolic disturbances that accompany suspected or confirmed inborn errors of metabolism. Our experience demonstrates an approximately 60% mortality rate associated with renal replacement treatment, with more than 70% of survivors living longer than 2 years.

Fatal cerebral edema from late-onset ornithine transcarbamylase deficiency in a juvenile male patient receiving valproic acid

The aims of this report are to 1) present a rare case of fatal cerebral edema associated with late-onset ornithine transcarbamylase (OTC) deficiency in a juvenile male patient receiving valproic acid and 2) review the neuropathologic changes associated with the hyperammonemia. Case report. A community hospital and a tertiary pediatric critical care unit. Carbohydrate administration, intravenous nitrogen excretion cocktail, and high-flux hemodialysis. Despite aggressive therapy for presumed late-onset OTC deficiency, the patient rapidly developed fatal cerebral edema with tonsillar herniation. A liver biopsy confirmed OTC deficiency with approximately 3% of residual hepatic enzyme activity. Chromosomal analysis showed a normal male karyotype. A thorough molecular analysis of the coding region in the OTC gene Xp21.1 was completed, but mutations were not identified, suggesting an upstream or downstream abnormality. Severe brain swelling was evident on neuropathology, and histopathology showed Alzheimer type II astrocytes, neuronal cytoplasmic changes, and hypertrophy and eosinophilia of the small arterial walls. OTC deficiency is the most common urea cycle defect causing hyperammonemia. Late-onset presentations of OTC are infrequent, primarily affecting female patients. We present a rare case of a late-onset OTC deficiency in a juvenile male patient receiving valproic acid therapy who developed fatal cerebral edema. Valproic acid exacerbates acute elevations in ammonia and may contribute synergistically with ammonia to cerebral mitochondrial dysfunction.

Hepatocyte transplantation for liver‐based metabolic disorders

Hepatocyte transplantation is being investigated as an alternative to orthotopic liver transplantation in patients with liver-based metabolic disorders. The progress made in this field to date is reviewed. Protocols have been developed using collagenase perfusion to isolate human hepatocytes from unused donor liver tissue. Hepatocytes with a high viability can often be obtained and can be cryopreserved for later use, though with loss of function on thawing. For clinical use, hepatocytes must be prepared in clean GMP conditions with cells meeting criteria of function and lack of microbial contamination before patient use. Hepatocytes are infused intraportally into the patient's liver, where a proportion of cells will engraft and replace the deficient metabolic function without the need for major surgery. Twenty patients have now received hepatocyte transplantation, including eight children at King's College Hospital. There was a range of aetiologies of liver disease: familial hypercholesterolaemia, Crigler-Najjar syndrome type 1, urea cycle defects, infantile Refsum disease, glycogen storage disease type Ia, inherited factor VII deficiency and progressive familial intrahepatic cholestasis type 2. Clinical improvement and partial correction of the metabolic abnormality was observed in most cases. Considerable progress has been made in developing the technique, but hepatocyte transplantation is limited by the available supply of liver tissue. Hepatocytes derived from stem cells could provide alternative sources of cells in the future.

Childhood Functional Gastrointestinal Disorders: Neonate/Toddler

Recognizing the importance of childhood functional gastrointestinal disorders in understanding adult functional gastrointestinal disorders, and encouraging clinical and research interest, the Rome Coordinating Committee added a pediatric working team to Rome II in 1999. For Rome III, there was an increase from 1 to 2 pediatric working teams. This report summarizes the current consensus concerning functional disorders in infants and toddlers. Another report covers disorders diagnosed more often in school-aged children and adolescents. The symptoms from functional gastrointestinal disorders in children younger than 5 years depend on maturational factors in anatomy, gastrointestinal physiology, and intellectual and affective functioning. There has been little or no change for infant regurgitation, infant rumination syndrome, or infant dyschezia. Cyclic vomiting syndrome may be diagnosed after 2 rather than 3 episodes. The description of infant colic has been expanded, although there was consensus that infant colic does not reflect gastrointestinal malfunction. The greatest change was in functional constipation. Functional constipation and functional fecal retention in the 1999 report were merged into a single entity: functional constipation. Data-driven changes in diagnostic criteria for functional constipation appear to be less rigid and more inclusive than previous criteria.

Metabolic changes associated with hyperammonemia in patients with propionic acidemia

Propionic acidemia is an autosomal recessive disorder caused by deficiency of propionyl CoA carboxylase. Affected patients can develop severe hyperammonemia, whose causative mechanism is unknown. In this study, we monitored changes in metabolic parameters associated with hyperammonemia in patients with propionic acidemia. Levels of ammonia were correlated with plasma levels of individual amino acids and carnitine and with urinary organic acids. Significance of correlations was determined with analysis of variance. Hyperammonemia positively correlated with an increase in branched-chain amino acids (leucine and isoleucine) and a decrease in glutamine/glutamate and esterified carnitine. The urinary excretion of methylcitric acid, formed by the combination of propionic acid with oxaloacetate from the Krebs cycle, increased while that of citric acid decreased with hyperammonemia. These results suggest that in propionic acidemia, hyperammonemia is triggered by catabolism with the accumulation of propionic acid derivatives. The decrease of the plasma levels of glutamine/glutamate with hyperammonemia in patients with propionic acidemia indicates that the mechanism producing hyperammonemia differs from that in urea cycle defects. The increase in methylcitric acid and decline in citric acid urinary excretion suggest that hyperammonemia in propionic acidemia might be related to inability to maintain adequate levels of glutamine precursors through a dysfunctional Krebs cycle.

Model for end-stage liver disease (MELD) exception for unusual metabolic liver diseases

Metabolic liver disease is the underlying diagnosis in only a small proportion of patients who undergo liver transplantation (LT), but for these patients, LT is lifesaving. Patients with metabolic liver disease often do not present with typical findings of end-stage liver disease and require special consideration and scrutiny concerning the appropriateness and timing of LT. Liverbased metabolic disease is classified into 3 types: (1) disease that causes structural liver damage with liver failure or cirrhosis, (2) metabolic disease without structural liver damage that affects other organs (especially the central nervous system), and (3) metabolic disease with systemic deficiencies that are partially represented in the liver. There may be overlap in presentation, with some disease forms presenting either with or without structural liver disease. General considerations that affect review board decisions may include the relative contraindication of the use of living-related donor organs and the unpredictable metabolic course that may cause severe central nervous system complications in several of these disease states. Also, although many of these diseases present mostly in children, adolescents and adults previously managed medically are increasingly presenting for LT consideration when medical management becomes more difficult or complex as they mature.

Model for end-stage liver disease (MELD) exception guidelines

Model for end-stage liver disease (MELD) exception guidelines

Cirrhosis in an infant heterozygous for classical citrullinaemia

Classical citrullinaemia is caused by the inherited deficiency of argininosuccinate synthetase. Although varying degrees of liver involvement have been observed in urea cycle defects, including classical citrullinaemia, the co-existence of liver failure in a patient heterozygous for the disease has not been reported before. A female infant was investigated to find out the aetiology of early infantile liver failure. She was later found to be a heterozygote for the G390R mutation found in severe citrullinaemia patients. Classical citrullinaemia is a phenotypically heterogeneous disease, and observations for signs of its presence should be made even in heterozygotes.

Neonatal Screening by Tandem Mass Spectrometry

After completing this article, readers should be able to: 1. List the major categories of diseases detectable by expanded newborn screening. 2. Give examples of the benefits and limitations of screening by tandem mass spectrometry. 3. Describe the appropriate follow-up for an abnormal screening result. The screening of newborns for inherited metabolic disorders is a well-established public health activity, first implemented in the early 1960s for the presymptomatic identification of patients who have phenylketonuria (PKU). Since then, significant technological advances, most importantly the development of tandem mass spectrometry (MS/MS), have enabled the detection of an increasing number of metabolic disorders in newborn blood. This article reviews the basic technology of MS/MS and its application to newborn screening, with the aim of highlighting the benefits and pointing out some limitations of this powerful technology. Early screening for PKU used the bacterial inhibition assay of Guthrie, in which inhibition of bacterial growth on an agar medium, introduced by the addition of a phenylalanine analog, was overcome by the presence of dried blood discs containing high levels of phenylalanine (such as from a PKU patient). This approach later was adapted for the detection of leucine in patients who have maple syrup urine disease (MSUD), methionine in patients who have classic homocystinuria, and tyrosine in patients who have tyrosinemia. Over the years, other techniques have been implemented to screen for additional disorders, including congenital hypothyroidism, biotinidase deficiency, galactosemia, hemoglobinopathies, and congenital adrenal hyperplasia. The classic criteria used to determine whether a disorder is suitable for screening include: 1) the disorder is clinically and biochemically well defined, 2) it is associated with significant morbidity or mortality, 3) an effective treatment is available, and 4) there is a simple and safe screening test. (1) By the early 1990s, all states offered screening for at least PKU and congenital hypothyroidism, …

Hepatocyte transplantation for metabolic liver disease: UK experience

For end-stage liver disease and liver-based metabolic conditions the accepted treatment is liver transplantation. With developments in surgical techniques and immunosuppressive drug therapy the survival of patients and grafts is now good. In the conventional procedure the patient's whole liver is replaced with a liver obtained from a braindead or living donor. When the donor liver is too big it can be reduced to a compatible size; and, recently, split-liver procedures have been performed whereby the right lobe is transplanted into an adult and the smaller left lobe into a child,1 thus increasing the effective donor pool. Another important advance in surgical technique is the use of auxiliary liver transplantation for patients with acute liver failure and certain liver-based metabolic defects such as Crigler–Najjar syndrome type I, urea cycle defects, and familial hypercholesterolaemia. In this procedure, part of the patient's liver, often the left lobe, is replaced with part of a donor liver. In a patient with acute liver failure this leaves open the possibility of regeneration of the native liver, in which case immunosuppression can be stopped and the graft allowed to atrophy; and in a patient with a metabolic disorder the native liver will be available for future gene therapy. The results of auxiliary liver transplantation in man2 have supported observations in animals that small amounts of liver tissue can provide sufficient function to correct an underlying metabolic defect. This finding was a spur to work on hepatocyte transplantation for such disorders. The aim is to repopulate the liver with donor hepatocytes, injected either directly into the liver or into the spleen, from which they migrate to the liver. If the technique proves successful, hepatocyte transplantation offers several potential advantages. In terms of supply, there is the possibility of using cells from livers that are unsuitable for conventional transplantation because of steatosis or trauma. The patient does not have to undergo major surgery; moreover, in metabolic conditions the native liver provides a safety net in case of failure. One of the most important advantages is the availability of the liver as a target organ for gene therapy when this becomes a clinical reality. Experience of hepatocyte transplantation has been gained in patients with acute liver failure3,4 and metabolic liver diseases such as Crigler–Najjar syndrome type I,5 glycogen storage disease type 1a,6 and urea cycle defects.7 The background to this work has been described elsewhere.8–11 The current paper discusses the sources of hepatocytes, the isolation process, preclinical studies and clinical experience in the UK, especially in the treatment of liver-based inborn errors of metabolism.

Neonatal Hyperammonemia: The N-carbamoyl-L-glutamic Acid Test

In a prospective study, patients with a suspected urea cycle defect underwent oral N-carbamoyl-L-glutamic acid loading testing. In patients with subsequently confirmed N-acetylglutamate synthase deficiency, hyperammonemia normalized within 8 hours. This test may be useful in the early diagnosis of patients with suspected urea cycle disorders.

Urea cycle defects: Management and outcome

This paper reviews the clinical presentation of 217 patients with urea cycle defects, including 121 patients with neonatal-onset forms and 96 patients with late-onset forms. Long-term outcome of these patients is also reported with the severity of the neonatal forms of these disorders, mostly for ornithine carbamoyltransferase-deficient males. Patients with late-onset forms may present at any age and carry a 28% mortality rate and a subsequent risk of subsequent disabilities.