Phosphoribosylpyrophosphate Synthetase Deficiency

Clinical characteristics: Phosphoribosylpyrophosphate synthetase (PRS) deficiency, an X-linked disorder, is a phenotypic continuum comprising three disorders previously thought to be clinically distinct: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). In affected males, the PRS deficiency phenotypic spectrum ranges from severe congenital profound sensorineural hearing loss, intellectual disability, delayed motor development, and progressive ophthalmologic involvement (retinal dystrophy and optic atrophy) to normal cognitive abilities and relatively later-onset, somewhat milder manifestations, such as mild sensorineural hearing loss, peripheral neuropathy, and gait ataxia.

Heterozygous females can show isolated and/or milder manifestations in the PRS deficiency spectrum. To date, 40 families with PRS deficiency have been reported.

Diagnosis/testing: The diagnosis of PRS deficiency is established in a male proband with suggestive findings and a hemizygous pathogenic variant in PRPS1 identified by molecular genetic testing. The diagnosis of PRS deficiency is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in PRPS1 identified by molecular genetic testing.

Management: Treatment of manifestations: There is no cure for PRS deficiency. Supportive care to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in neurology, physiatry, physical therapy, occupational therapy, audiology, otolaryngology, ophthalmology and low vision services, education, and medical genetics.

Surveillance: Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations involves scheduled follow up with the treating specialists.

Genetic counseling: PRS deficiency is inherited in an X-linked manner. If the mother of the proband has a PRPS1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%; if the father of the proband has a PRPS1 pathogenic variant, he will transmit it to all his daughters and none of his sons. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a PRPS1 pathogenic variant. Once the PRPS1 pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible.