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Abstract: Carbamoyl Phosphate Synthetase 1 deficiency (CPS1D) is a rare autosomal recessive urea cycle disorder, potentially leading to lethal hyperammonemia. Based on the age of onset, there are two distinct phenotypes: neonatal and late form. The CPS1 enzyme, located in the mitochondrial matrix of hepatocytes and epithelial cells of intestinal mucosa, is encoded by the CPS1 gene. At present more than 220 clear-cut genetic lesions leading to CPS1D have been reported. As most of them are private mutations diagnosis is complicated. Here we report an overview of the main clinical findings and biochemical and molecular data of 13 CPS1D Italian patients. In two of them, one with the neonatal form and one with the late form, cadaveric auxiliary liver transplant was performed. Mutation analysis in these patients identified 17 genetic lesions, 9 of which were new confirming their “private” nature. Seven of the newly identified mutations were missense/nonsense changes. In order to study their protein level effects, we performed an in silico analysis whose results indicate that the amino acid substitutions occur at evolutionary conserved positions and affect residues necessary for enzyme stability or function. [Copyright &y& Elsevier]

Ornithine transcarbamylase deficiency (OTCD) is an X-linked urea cycle disorder due to a defect of the mithocondrial enzyme ornithine transcarbamylase (OTC). Genetic analysis in nine unrelated Italian patients affected by OTCD (one male patient and eight female manifesting carriers) led to the detection of three novel mutations and six previously reported mutations in the OTC gene. The analysis was performed by direct sequencing of OTC cDNA, OTC exons, and intron–exon boundaries and enzymatic restriction analysis on the patients'' genomic DNA and total RNA isolated from peripheral blood lymphocytes. In the male patient the new mutation S132P due to the nucleotide change c.394T>C was identified. In a manifesting carrier the nucleotide change c.292G>A that leads to the novel amino acid substitution E98K was identified; this mutation is close to the OTC protein''s carbamyl phospate binding site. In another manifesting carrier the OTC cDNA analysis revealed the normally spliced transcript and an aberrant transcript with an insertion of two nucleotides (c.77–78insAG). In the patient''s genomic DNA we identified a new transvertion IVS1−3C>G at the heterozygous state; this nucleotide change generates a new splice acceptor site in intron 1 that induces an RNA splicing defect. This insertion causes a frame shift in OTC cDNA ORF and leads to a premature stop codon. The previously described mutations N161S, R141Q, T178M, R92X, A208T, M268T were identified in the other six manifesting carriers. [Copyright &y& Elsevier]

The increased survival of urea cycle disorders (UCDs) patients has led the attention to clinical manifestations that characterize the long-term disease course. Acute and chronic liver disease have been anecdotally reported since the very first description of UCDs. However, a detailed analysis of long-term liver involvement in large patient cohorts is still needed. Chronic liver damage in UCDs has probably a multifactorial origin, but the specific underlying mechanisms of liver disease have not yet been well elucidated. In this study, we report on chronic liver involvement and on associated metabolic abnormalities in a large cohort of 102 UCD patients, followed by two reference centers in Italy. Chronic liver involvement was observed in over 60% of UCDs patients, and comparison between individual diseases showed a significant higher frequency in argininosuccinate lyase deficiency (ASLD) and in hyperornithinemia-hyperammonemia-homocitrullinemia (HHH) syndrome with elevation of transaminases and of gamma-GT in ASLD, and of alpha-fetoprotein in HHH syndrome. Also, consistent with a chronic hepatic dysfunction, ultrasound examination revealed more pronounced abnormalities in ASLD and in HHH syndrome, when compared to other UCDs. Our study highlights in a large UCDs patients' cohort that chronic liver disease is a common finding in UCDs, often with a distinct phenotype between different diseases. Furthers studies are needed to elucidate the specific involvement of different metabolic pathways in the pathogenesis of liver dysfunction in UCDs., (© 2019 SSIEM.)