Molecular genetics of inborn errors of metabolism: the case of hereditary fructose intolerance and hyperphenylalaninemia

HFI is a widespread condition but its world wide incidence rate remains unknown due to difficulty of HFI diagnosis. According to published data, the incidence rate varies quite widely among different ethnic groups (UK, 1 in 22,000; Central Europe, 1 in 26,100; Polish, 1 in 31,000). Furthermore, numerous reports of self-diagnosis in adulthood, inadvertent deaths to undiagnosed subjects, homozygous-heterozygous marriages, and the increasing influence on Italian population of migration flow coming from est Europe and Africa continent all indicate that the incidence rate could be higher. A wide newborn screening program is then the starting point to define the real frequency of HFI in Italy and to focus the most popular mutations in the Aldolase B gene. HPA patients can be differently treated: classical PKU patients with Phe-low diet, BH4 deficiency patients with a combined therapy with -Dopa/Carbidopa/5-hydroxytryptophan plus BH4; finally, patients affected by BH4-responsive PAH deficiency with BH4 alone. Thus, early detection of each group of patients has significant implications for the development of a customize therapeutic protocol. To this aim, this study will propose to expand the molecular screening to the genes involved in the metabolism of BH4. In addition, the molecular HPA screening will define a panel related to carriers and calculate the residual risk of being a HPA carrier.