title: Early neurological phenotype in 4 children with biallelic PRODH mutations.
abstract: Hyperprolinemia type I (HPI) results from a deficiency of proline oxidase (POX), involved in the first step in the conversion of proline to glutamate. Diverse phenotypes were described in patients with HPI, prior to the identification of the POX gene (PRODH): whereas various patients were asymptomatic, others had neurological and extraneurological defects. The PRODH gene is located in the region deleted in velocardiofacial syndrome (VCFS). Heterozygous and homozygous mutations have been identified in patients with variable hyperprolinemia and various features (patients with schizophrenia, chromosome 22q11 microdeletions and/or neurological defects). A functional study has divided the PRODH missense mutations into three groups: those leading to mild, moderate, or severe reduction of POX activity. In this study, we report four unrelated children with HPI and a homogeneous severe neurological phenotype. We identified biallelic abnormalities in PRODH in these patients that led to severe reduction of POX activity. These included missense and non-sense mutations, deletions of PRODH and a 22q11 microdeletion. Four other children have been reported with severe biallelic PRODH mutations. The phenotype of these eight patients associates early psychomotor development delay with predominant cognitive defects, autistic features and epilepsy. Their values of hyperprolinemia ranged from 400 to 2200 micromol/L. Patients with biallelic PRODH alterations resulting in severely impaired POX activity had an early onset and severe neurological features. Thus, children with this phenotype and those with a microdeletion in chromosome 22q11, especially those with mental retardation and autistic features, should be tested for hyperprolinemia. Hyperprolinemic patients should be screened for PRODH mutations.
authors.affiliation: AP-HP, Service de neuropédiatrie, Hôpital Armand Trousseau, Paris, France. alexandra.afenjar@trs.aphp.fr
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Moutard
authors.forename: Diane
authors.initials: D
authors.lastname: Doummar
authors.forename: Agnés
authors.initials: A
authors.lastname: Guët
authors.forename: Daniel
authors.initials: D
authors.lastname: Rabier
authors.forename: Anne-Isabelle
authors.initials: AI
authors.lastname: Vermersch
authors.forename: Cyril
authors.initials: C
authors.lastname: Mignot
authors.forename: Lydie
authors.initials: L
authors.lastname: Burglen
authors.forename: Delphine
authors.initials: D
authors.lastname: Heron
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Thioulouse
authors.forename: Thierry Billette
authors.initials: TB
authors.lastname: de Villemeur
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.forename: Diana
authors.initials: D
authors.lastname: Rodriguez
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006966:Hyperprolactinemia / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010641:Phenotype; D011394:Proline Oxidase / Q000172:deficiency* / Q000235:genetics*
chemical_list: D011394:Proline Oxidase