Cross-sectional multicenter study of patients with urea cycle disorders in the United States

Abstract

Inherited urea cycle disorders comprise eight disorders (UCD), each caused by a deficiency of one of the protein that is essential for ureagenesis. We report on a cross sectional investigation to determine clinical and laboratory characteristics of patients with UCD in the United States. The data used for the analysis was collected at the time of enrollment of individuals with inherited UCD into a longitudinal observation study. The study has been conducted by the Urea Cycle Disorders Consortium (UCDC) within the Rare Diseases Clinical Research Network (RDCRN) funded by the National Institutes of Health. One hundred eighty three patients were enrolled into the study. Ornithine transcarbamylase (OTC) deficiency was the most frequent disorder (55%), followed by argininosuccinic aciduria (17%) and citrullinemia (11%). 79% of the participants were white (16% Latinos), and 6% were African American. Intellectual and developmental disabilities were reported in 39% with learning disabilities (35%) and half had abnormal neurological examination. 63% were on a protein restricted diet, 37% were on Na-phenylbutyrate and 5% were on Na-benzoate. 45% of OTC deficient patients were on L-citrulline, while most patients with citrullinemia (58%) and argininosuccinic (79%) were on L-arginine. Plasma levels of branched-chain amino acids were reduced in patients treated with ammonia scavenger drugs. Plasma glutamine levels were higher in proximal UCD disorders and in the neonatal type disease. The RDCRN allows comprehensive analyses of rare inherited UCD, their frequencies and current medical practices.

Switch from Sodium Phenylbutyrate to Glycerol Phenylbutyrate Improved Metabolic Stability in an Adolescent with Ornithine Transcarbamylase Deficiency

“…Hyperammonemia-related neurological injuries range from lethal cerebral edema to mild or subclinical cognitive impairment, depending on the severity of the defect (Gropman et al 2008), with the most severely affected patients typically presenting early in life (Brusilow and Maestri 1996;Summar et al 2008;Tuchman et al 2008). Ornithine transcarbamylase (OTC) deficiency is the most common UCD, accounting for slightly more than half of all UCD cases (Summar et al 2008;Tuchman et al 2008;Batshaw et al 2014).…”

Two Hypomorphic Alleles of Mouse Ass1 as a New Animal Model of Citrullinemia Type I and Other Hyperammonemic Syndromes

“…4 Two recent studies determined that CTLN1 accounts for 14% to 27% of all reported UCDs. 15,16 Clinical symptoms of neonatal CTLN1 include delayed mental and physical development, irritability, recurrent vomiting, and lethargy. 9,17 Biochemically, CTLN1 is characterized by elevated plasma and urine concentrations of ammonia, citrulline, glutamine, and orotic acid, together with arginine deficiency.…”

Argininosuccinic aciduria: from a monogenic to a complex disorder

“…[11][12][13][14][15][16] Even subjects with milder forms of ASA who are diagnosed early in life by newborn screens can develop neurocognitive deficiencies, attention deficit/hyperactivity disorder, developmental disability, and seizures despite early treatment intervention. [17][18][19] Supporting this notion, hepatic disease and hypertension have been reported in patients with ASA who have good metabolic control. 13,15,[20][21][22] These data suggest that the complex phenotype observed in ASA involves mechanisms beyond the blockade in ureagenesis and that ASA could serve as an example of a complex IEM in which disease phenotype extends beyond the loss of the enzymatic function of ASL.…”