New phenotype associated with phosphoribosyl pyrophosphate synthetase 1 deficiency

Posted by & filed under Exome sequencing, Part 11: PURINES AND PYRIMIDINES.

Al-Maawali A et al. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders. European Journal of Human Genetics (2015) 23, 310–316.


Phosphoribosyl pyrophosphate synthetase 1 (PRS-1) catalyses the first step of purine synthesis, and several X-linked disorders have been associated with both its deficiency (Arts syndrome, Charcot-Marie-Tooth disease type 5, and X-linked non-syndromic sensorineural deafness) and its superactivity (associated with gouty arthritis and uric acid lithiasis and, in severe forms, with sensorineural deafness, hypotonia and ataxia).

In this study, the authors use whole exome sequencing to identify a loss-of-function mutation in PRPS1, resulting in PRS-1 enzyme deficiency, as a cause of a novel phenotype in two brothers, consisting of intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadriparesis, macular coloboma-like lesions with retinal dystrophy, severe short stature, diabetes insipidus, and white matter abnormalities.  Nucleotide analysis showed nucleotide depletion (and particularly GTP depletion) as a possible pathophysiological mechanism.

Interestingly, both patients had been found to have an elevated maternal serum AFP; also, one patient had orotic aciduria (orotic acid was not measured in the other). The authors hypothesize that the latter finding could be due to the fact that phosphoribosyl pyrophosphate is necessary for the conversion of orotic acid to orotate monophosphate (by orotate phosphoribosyltransferase) during pyrimidine de novo synthesis.

This study expands the clinical spectrum of PRS-1 deficiency, as well as adding to the differential diagnosis of high maternal serum AFP during pregnancy and to that of orotic aciduria – with the caveat, of course, that until a similar phenotype is found with PRS-1 deficiency in an unrelated patient, the possibility that some of the clinical or biochemical features could be due to a different cause cannot be completely ruled out.


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