Identification of Urine Organic Acids for the Detection of Inborn Errors of Metabolism Using Urease and Gas Chromatography-Mass Spectrometry (GC/MS).

A patient suspected of an inborn error of metabolism will commonly have urine organic acid analysis performed as part of their workup. The traditional urine organic acid method involves extraction of the acidic fraction from urine samples using an organic solvent, derivatization of extracted compounds, and identification using gas chromatography-mass spectrometry (GC/MS). Unfortunately, the extraction step results in the loss of many neutral and positively charged compounds which may be of interest to metabolic physicians and biochemical geneticists.

Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome.

Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS.

Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B.

Riboflavin, or vitamin B2, is a precursor to flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) molecules, required in biological oxidation-reduction reactions. We previously reported a case of a newborn female who had clinical and biochemical features of multiple acyl-CoA dehydrogenation deficiency (MADD), which was corrected by riboflavin supplementation. The mother was then found to be persistently riboflavin deficient, suggesting that a possible genetic defect in riboflavin transport in the mother was the cause of the transient MADD seen in the infant.

Identification of urine organic acids for the detection of inborn errors of metabolism using urease and gas chromatography-mass spectrometry (GC-MS).

A patient suspected of an inborn error of metabolism will commonly have urine organic acid analysis performed as part of their workup. The traditional urine organic acid method involves extraction of the acidic fraction from urine samples using an organic solvent, derivatization of extracted compounds, and identification using gas chromatography-mass spectrometry (GC-MS). Unfortunately, the extraction step results in the loss of many neutral and positively charged compounds, which may be of interest to metabolic physicians and biochemical geneticists.

National academy of clinical biochemistry laboratory medicine practice guidelines: follow-up testing for metabolic disease identified by expanded newborn screening using tandem mass spectrometry; executive summary.

Background: Almost all newborns in the US are screened at birth for multiple inborn errors of metabolism using tandem mass spectrometry. Screening tests are designed to be sufficiently sensitive so that cases are not missed. The NACB recognized a need for standard guidelines for laboratory confirmation of a positive newborn screen such that all babies would benefit from equal and optimal follow-up by confirmatory testing.

Creating genetics-based infusion centers: a case study of two models.

In 1993, the first effective enzyme replacement therapy for a genetic disease, Ceredase (Genzyme Corporation, Cambridge, MA), was approved for use in patients with Gaucher disease. Over the next 13 years, enzyme replacement therapy became clinically available for the treatment of Fabry disease, mucopolysaccharidosis Type I, mucopolysaccharidosis Type II, mucopolysaccharidosis Type VI, and glycogen storage disease Type II. The development of enzyme replacement therapy to treat lysosomal storage diseases has resulted in an increasing number of genetic patients undergoing weekly or biweekly intravenous enzyme replacement therapy and an expanded role of the genetics team to include comprehensive care involving therapeutic intervention for lysosomal storage diseases.

Rescue from neonatal death in the murine model of hereditary tyrosinemia by glutathione monoethylester and vitamin C treatment.

Hereditary tyrosinemia type 1 (HT1) is a recessive disease caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH) that catalyzes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. In mice models of HT1, FAH deficiency causes death within the first 24h after birth. Administration of 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC) prevents neonatal death in HT1 mice, ameliorates the HT1 phenotype but does not prevent development of hepatocellular carcinoma later on.

Survival after treatment with phenylacetate and benzoate for urea-cycle disorders.

Background: The combination of intravenous sodium phenylacetate and sodium benzoate has been shown to lower plasma ammonium levels and improve survival in small cohorts of patients with historically lethal urea-cycle enzyme defects.

Methods: We report the results of a 25-year, open-label, uncontrolled study of sodium phenylacetate and sodium benzoate therapy (Ammonul, Ucyclyd Pharma) in 299 patients with urea-cycle disorders in whom there were 1181 episodes of acute hyperammonemia.

Results: Overall survival was 84% (250 of 299 patients).

Newborn screening for medium-chain acyl-CoA dehydrogenase deficiency: a global perspective.

As judged by tandem mass spectrometry blood spot screening, the incidence of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is 1:14 600 (CI 95%: 1:13 500-1:15 900) in almost 8.2 million newborns worldwide and is 2- to-3 fold higher than that identified in the same populations after clinical presentation. In mass-screened newborn populations, the 985A>G (K329E) mutation accounts for 54-90% of disease alleles, with homozygotes representing about 47-80% of MCAD deficiency cases.

Urea cycle disorders: clinical presentation outside the newborn period.

Although most commonly associated with infancy, the majority of individuals with urea cycle disorders (UCDs) present outside the neonatal period, frequently in childhood. Signs and symptoms are often vague, but recurrent; fulminant presentations associated with acute illness are also common. A disorder of urea cycle metabolism should be considered in children who have recurrent symptoms, especially neurologic abnormalities associated with periods of decompensation.

Genetic counseling issues in urea cycle disorders.

The goal of counseling families that have a urea cycle disorder (UCD) is to facilitate the process of scientific understanding, emotional acceptance, and decision-making in a nondirective way. A proper understanding of the genes involved, inheritance patterns, available testing, and complicating factors is critical to serving the families' needs. This article summarizes the needed information, in particular describing the complexities of prenatal testing and counseling issues for each UCD.

Nutritional management of urea cycle disorders.

Nutritional management of patients who have urea cycle disorders is one of the most challenging tasks in clinical nutrition. The degree to which protein intake should be restricted in urea cycle disorders requires complex calculations which depend on many variables such as specific enzyme defect, age-related growth rate, current health status, level of physical activity, amount of free amino acids administered, energy intake, residual urea cycle function, family lifestyle, use of nitrogen-scavenging medications, and the patient's eating behaviors. This paper presents two case histories and a series of recommendations outlining the nutrition management of urea cycle disorders.

Considerations in the difficult-to-manage urea cycle disorder patient.

Today, patients with urea cycle disorder (UCD) may survive well beyond infancy. The goal of keeping them in consistent nitrogen balance can be undermined by changing metabolic needs throughout various stages of life, resulting in hyperammonemia in the short term, and poor growth and development in the long term. The specific UCD genotype can affect the risk of metabolic destabilization and management difficulties, as can variable protein tolerance secondary to changing growth demands, biochemical complications, and environmental influences.

Unmasked adult-onset urea cycle disorders in the critical care setting.

Most often, urea cycle disorders have been described as acute onset hyperammonemia in the newborn period; however, there is a growing awareness that urea cycle disorders can present at almost any age, frequently in the critical care setting. This article presents three cases of adult-onset hyperammonemia caused by inherited defects in nitrogen processing in the urea cycle, and reviews the diagnosis, management, and pathophysiology of adult-onset urea cycle disorders. Individuals who have milder molecular urea cycle defects can lead a relatively normal life until a severe environmental stress triggers a hyperammonemic crisis.

Ascorbate decreases Fabry cerebral hyperperfusion suggesting a reactive oxygen species abnormality: an arterial spin tagging study.

Purpose: To test the hypothesis that reactive oxygen species contribute to the cerebral hyperperfusion in Fabry disease.

Material And Methods: We examined the effect of intravenous injection of ascorbate on cerebral blood flow (CBF) using magnetic resonance arterial spin tagging. Nineteen patients with Fabry disease and 15 control subjects were studied as part of a randomized double-blind placebo-controlled trial of enzyme replacement therapy (ERT).

The call from the newborn screening laboratory: frustration in the afternoon.

Newborn screening programs in the United States are evolving in concert with technologic advances in analytic chemistry and medicine. Many more disorders are being identified on dried filter paper blood spots without fundamentally altering the basic principles first put forward in the 1960s. Some disorders have been added without researchers knowing if there is a true benefit to early diagnosis and treatment; some disorders currently being detected will merit little or no follow-up in the future.

Genitopatellar syndrome: expanding the phenotype.

Genitopatellar syndrome is a recently described disorder with characteristic facies, genital anomalies, absent patella, flexion contractures, microcephaly, renal anomalies, and mental retardation. The presence of affected siblings in two of the original families suggests autosomal recessive inheritance. We report a new patient that exhibits all of these cardinal features and is also the second case to have additional, more severe findings including a congenital heart defect, anal anomalies, and features of an ectodermal dysplasia, thus expanding the phenotype to include these manifestations.

Evaluation of liver fatty acid oxidation in the leptin-deficient obese mouse.

We hypothesized that liver fatty acid oxidation (FAO) is compromised in the leptin-deficient obese (Lep(ob)/Lep(ob)) mouse model, and that this would be further challenged when these mice were fed a high-fat diet. Obese mice had a 3.8-fold increased body fat content and a 9-fold increased liver fat content as compared to control mice when both groups were fed a low-fat diet.