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.