Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision

Abstract

In 2012, we published guidelines summarizing and evaluating late 2011 evidence for diagnosis and therapy of urea cycle disorders (UCDs). With 1:35 000 estimated incidence, UCDs cause hyperammonemia of neonatal (~50%) or late onset that can lead to intellectual disability or death, even while effective therapies do exist. In the 7 years increased awareness among health professionals and patient families. However, underrecognition and delayed diagnosis of UCDs still appear widespread. It was therefore necessary to revise the original guidelines to ensure an up-to-date frame of reference for professionals and patients as well as for awareness campaigns. This was accomplished by keeping the original spirit of providing a trans-European consensus based on robust evidence (scored with GRADE methodology), involving professionals on UCDs from nine countries in preparing this consensus. We believe this revised guideline, which has been reviewed by several societies that are involved in the management of UCDs, will have a positive impact on the outcomes of patients by establishing common standards, and spreading and harmonizing good practices. It may also promote the identification of knowledge voids to be filled by future research.

Chronic liver involvement in urea cycle disorders

“…Late‐onset patients may present at any age after the neonatal period with variable acute or chronic symptoms. Clinical symptoms are often nonspecific, but in most patients neurological signs prevail followed by psychiatric and hepatic‐digestive manifestations …”

Improvement of diagnostic yield in carbamoylphosphate synthetase 1 (CPS1) molecular genetic investigation by RNA sequencing

“…CPS1D is a rare metabolic condition with a nonspecific biochemical profile thus requiring additional tests. 5 Nowadays, confirmation of the disease is usually done by molecular genetic investigation that led to the reporting of more than 230 CPS1 mutations underlining the genetic heterogeneity at this locus. [7][8][9][10][11][12][13][14] In recent years, NGS became the preferred method for CPS1 molecular genetic investigation either as part of (often custom-made) gene panels or of whole exome or genome sequencing.…”

“…Diagnosis of CPS1D is based on a biochemical profile with increased plasma ammonia, decreased plasma citrulline, and a normal or low orotic acid in urine. Confirmation of the diagnosis requires either enzyme analysis in liver or small intestinal tissue or, recommended as method of choice, molecular genetic investigation …”

“…Confirmation of the diagnosis requires either enzyme analysis in liver or small intestinal tissue or, recommended as method of choice, molecular genetic investigation. 5,6 More than 230 CPS1 mutations are currently reported. [7][8][9][10][11][12][13][14][15] Molecular genetic investigation for CPS1D can use different methods: exon per exon sequencing (direct Sanger sequencing), next generation sequencing (NGS) as part of a (often custom-made) gene panel or whole exome or whole genome sequencing with or without the analysis of copy number variation (CNV), and RNA analysis.…”

Metabolic Disorders Presenting with Seizures in the Neonatal Period

“…They are inherited in an autosomal recessive pattern, with the exception of ornithine transcarbamylase deficiency, which is X-linked. Neonatal presentation is described in approximately half of cases, 31 and is often severe. The classic onset is characterized by acute to subacute progressive encephalopathy, poor feeding, emesis, temperature instability, and hyperventilation with subsequent metabolic alkalosis (►Table 1).…”