Hyperammonemia with reduced ornithine, citrulline, arginine and proline: anew inborn error caused by a mutation in the gene encoding Delta(1)-pyrroline-5-carboxylate synthase

Delta (1)-pyrroline-5-carboxylate synthase (P5CS), a bifunctional ATP- and NADPH-dependent mitochondrial enzyme, catalyzes the reduction of glutamate to Delta (1)-pyrroline-5-carboxylate, a critical step in the biosynthesis o f proline, ornithine and arginine, Recently, we reported the cloning and ex pression of human and murine P5CS cDNAs, Previously, we showed that mammali an P5CS undergoes alternative splicing to generate two isoforms differing o nly by a 2 amino acid insert at the N-terminus of the gamma -glutamyl kinas e active site, The short isoform has high activity In the gut, where it par ticipates in arginine biosynthesis and is inhibited by ornithine, The long isoform, expressed in multiple tissues, is necessary for the synthesis of p roline from glutamate and is insensitive to ornithine, Here, we describe a newly recognized inborn error due to the deficiency of P5CS in two siblings with progressive neurodegeneration, joint laxity, skin hyperelasticity and bilateral subcapsular cataracts, Their metabolic phenotype includes hypera mmonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprol inemia. Both are homozygous for the missense mutation, R84Q, which alters a conserved residue in the! P5CS gamma -glutamyl kinase domain, R84Q is not present in 194 control chromosomes and dramatically reduces the activity of both P5CS isoforms when expressed in mammalian cells, Additionally, R84Q a ppears to destabilize the long isoform, This; is the first documented repor t of an inborn error of P5CS and suggests that this disorder should be cons idered in the differential diagnosis in patients with neurodegeneration and /or cataracts and connective tissue disease.