Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: Expanding the spectrum of PRPS1-related disorders

Almundher Al-Maawali, Lucie Dupuis, Susan Blaser, Elise Heon, Mark Tarnopolsky, Fathiya Al-Murshedi, Christian R. Marshall, Tara Paton, Stephen W. Scherer, Jeroen Roelofsen, André B P Van Kuilenburg, Roberto Mendoza-Londono*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders.

Original languageEnglish
Pages (from-to)310-316
Number of pages7
JournalEuropean Journal of Human Genetics
Volume23
Issue number3
DOIs
Publication statusPublished - Mar 1 2015

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

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