title: Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders.
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.
authors: 1] Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada [2] Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
authors: Almundher
authors: A
authors: Al-Maawali
authors: Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
authors: Lucie
authors: L
authors: Dupuis
authors: Diagnostic Imaging, Division of Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors: Susan
authors: S
authors: Blaser
authors: Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors: Elise
authors: E
authors: Heon
authors: Departments of Pediatrics and Medicine, Division of Neuromuscular and Neurometabolic Disease, McMaster University, Toronto, ON, Canada.
authors: Mark
authors: M
authors: Tarnopolsky
authors: Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Sultan Qaboos University, Muscat, Oman.
authors: Fathiya
authors: F
authors: Al-Murshedi
authors: 1] The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada [2] Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada.
authors: Christian R
authors: CR
authors: Marshall
authors: 1] The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada [2] Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada.
authors: Tara
authors: T
authors: Paton
authors: 1] The Centre for Applied Genomics and Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada [2] Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, ON, Canada.
authors: Stephen W
authors: SW
authors: Scherer
authors: Labratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors: Jeroen
authors: J
authors: Roelofsen
authors: Labratory of Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands.
authors: André B P
authors: AB
authors: van Kuilenburg
authors: Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
authors: Roberto
authors: R
authors: Mendoza-Londono
mesh_terms: D001921:Brain / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D003919:Diabetes Insipidus / Q000175:diagnosis / Q000235:genetics*; D004562:Electrocardiography; D059472:Exome; D019066:Facies; D005317:Fetal Growth Retardation / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D058499:Retinal Dystrophies / Q000175:diagnosis / Q000235:genetics*; D012268:Ribose-Phosphate Pyrophosphokinase / Q000235:genetics*; D013577:Syndrome
chemical_list: C510474:PRPS1 protein, human; D012268:Ribose-Phosphate Pyrophosphokinase