Hyperammonemia with reduced ornithine, citrulline, arginine and proline: a new inborn error caused by a mutation in the gene encoding Delta1-pyrroline-5-carboxylate synthase

Abstract

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 of proline, ornithine and arginine. Recently, we reported the cloning and expression of human and murine P5CS cDNAs. Previously, we showed that mammalian P5CS undergoes alternative splicing to generate two isoforms differing only by a 2 amino acid insert at the N-terminus of the gamma-glutamyl kinase active site. The short isoform has high activity in the gut, where it participates in arginine biosynthesis and is inhibited by ornithine. The long isoform, expressed in multiple tissues, is necessary for the synthesis of proline 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 hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia. 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 appears to destabilize the long isoform. This is the first documented report of an inborn error of P5CS and suggests that this disorder should be considered in the differential diagnosis in patients with neurodegeneration and/or cataracts and connective tissue disease.

Severe congenital cutis laxa with cardiovascular manifestations due to homozygous deletions in ALDH18A1

“…Although the etiology of the severe neurocutaneous disorder in the family originally described by de Barsy remains unknown it was shown that de Barsy-like disorders can be due to mutations either in PYCR1 or ALDH18A1 [11,12,14,15]. In our patients, we found clinical features like facial dysmorphism, hypotonia, adducted thumbs and cutis laxa, which are frequently found in progeroid cutis laxa syndromes.…”

Leigh-Like Syndrome Due to Homoplasmic m.8993T>G Variant with Hypocitrullinemia and Unusual Biochemical Features Suggestive of Multiple Carboxylase Deficiency (MCD)

“…Post-mortem genetic testing identified the m.8993T>G variant in the liver, muscle and blood with variant loads of 82-87% (Henriques et al 2012). Persistent hypocitrullinemia has been described in other mitochondrial disorders including Pearson syndrome (Ribes et al 1993), Leigh syndrome caused by isolated complex I deficiency (Debray et al 2010), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) (Naini et al 2005), mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease (Bindoff 2006), and with secondary mitochondrial respiratory chain dysfunction caused by organic acidemias (Atkuri et al 2009) and deficiency of mitochondrial pyrroline-5-carboxylate synthetase (P5CS) (Baumgartner et al 2000). In a small series of 16 Leigh syndrome patients, sensitivity and specificity of hypocitrullinemia as a marker for the m.8993T>G variant were reported to be 66% and 85%, respectively (Debray et al 2010).…”

Clinical and biochemical features guiding the diagnostics in neurometabolic cutis laxa

“…21,22,38,42,43 The two patients, presented by Baumgartner et al, 22 showed low ornithine, arginine, citrulline and proline. Except for low ornithine levels in two of the patients described by Bicknell et al, 21 no amino-acid profile abnormalities have been described in the other patients.…”

“…18 The similar and metabolically related P5CS deficiency (P5CSD) is caused by mutations in ALDH18A1. 21,22 Patients with DBS, or ARCL3, have CL, growth retardation, corneal clouding, athetoid movements and developmental delay. 23 Some children with a clinical diagnosis of DBS also carry mutations in the PYCR1 or ALDH18A1 genes.…”