Hypoxanthine-guanine phosphoribosyltransferase deficiency (HPRT-d): cascade genetic screening in an affected family with HPRT1 c.584A> C mutation

Abstract

Abstract: 

The hypoxanthine-guanine phosphoribosyltransferase deficiency (HPRT-d) is an inborn error in purine metabolism with X-linked inheritance responsible for Lesch-Nyhan disease (LND) and its attenuated variants (LNV). LND shows a totally enzymatic deficiency and it`s characterized by hyperuricemia, self-mutilation, neurodevelopmental delay, intellectual disability, etc. LNV show partial enzymatic deficiency resulting in hyperuricemia, gout, nephrolithiasis, renal failure and variable neurological compromise; these variants are considered to be underdiagnosed because they are misclassified as gout or hyperuricemic syndrome. Early diagnosis in hemizygous males is crucial to promptly start treatment with allopurinol in order to prevent severe kidney damage. Carrier identification is required to provide genetic counselling. Both presentations of the disease were diagnosed in our centre. This study was aimed to realize a cascade genetic screening to members of a family with a confirmed diagnosis of HPRT-d (LNV) and HPRT1 c.584A> C mutation. The study was performed in subjects with different degrees of kinship with a common 5 generations ancestor. This family originating from La Calera and Saldan has the antecedents of LNV cases with the HPRT1 c.584A> C mutation. Eight women and eight men were included; informed consent was obtained prior to blood extraction and genetic study. Identification of the HPRT1 c.584A> C mutation was carried out by PCR and restriction enzyme digestion to establish the genotype. Seven females were carriers and six males were hemizygous. Respect to positive cases, it was corroborated that 4 males had some symptoms related to hyperuricemia and 2 minors (aged 1 week and 1 year) without symptoms but with hyperuricemia subsequently confirmed. Although LND and its variants are rare diseases, they should be considered in the differential diagnosis of hyperuricemia. Cascade genetic screening in this family allowed us to make an early diagnosis of affected males and to establish treatment with allopurinol in order to prevent gouty manifestations and kidney failure. In women, the importance of identifying carriers for X-linked diseases is essential to provide genetic counselling in family planning.