{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:00:51Z","timestamp":1784905251634,"version":"3.55.0"},"reference-count":41,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T00:00:00Z","timestamp":1784851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Apulia and neighbouring Southern Italian regions present a complex genetic stratification shaped by historical migrations. Phenylketonuria (PKU), caused by PAH mutations, serves as an excellent model for molecular epidemiology. This study maps the geographical distribution of PAH variants in a large Southern Italian cohort, evaluating their correlation with clinical phenotypes and long-term Body Mass Index (BMI). Methods: A retrospective cohort study was conducted on 344 patients followed for at least 10 years. Genetic characterization evolved from Sanger to Next-Generation Sequencing, and patients were stratified into micro-geographic clusters. Results: The genetic landscape was dominated by three ancestral variants (c.1208C&gt;T, c.1066-11G&gt;A, c.898G&gt;T), accounting for 58% of the allelic pool. Significant micro-geographic polarization was observed: c.1222C&gt;T clustered in Central\u2013Northern Apulia, mirroring historical Norman-Swabian migration, whereas c.441+5G&gt;T enriched in Southern Apulia. At final follow-up, classic PKU adult patients exhibited a four-fold increased risk of obesity (p &lt; 0.05), driven by severe null alleles that necessitate a lifelong dependency on engineered low-protein foods. Conclusions: PAH mutational stratification serves as a contemporary reflection of historical migratory maps. Incorporating regional and genotypic mapping provides a precision medicine framework to anticipate phenotype severity, optimize therapeutic management, and tailor long-term obesity risk monitoring.<\/jats:p>","DOI":"10.3390\/genes17080861","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T13:53:26Z","timestamp":1784901206000},"page":"861","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mediterranean PAH Stratification in Phenylketonuria: Tracing Historical Maps to Point Toward Clinical Phenotype and Obesity Risk"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8823-8061","authenticated-orcid":false,"given":"Albina","family":"Tummolo","sequence":"first","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Tabaku","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Meneleo","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1816-548X","authenticated-orcid":false,"given":"Ciro Leonardo","family":"Pierri","sequence":"additional","affiliation":[{"name":"Department of Pharmacy-Pharmaceutical Sciences, University of Bari \u201cAldo Moro\u201d, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7273-4263","authenticated-orcid":false,"given":"Anna","family":"De Grassi","sequence":"additional","affiliation":[{"name":"Department of Biosciences, Biotechnologies and Environment, University of Bari \u201cAldo Moro\u201d, Via E. Orabona 4, 70125 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vito","family":"Di Tullio","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Paterno","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"De Giovanni","sequence":"additional","affiliation":[{"name":"Department of Inherited Metabolic Disorders and Clinical Genetics, Children Hospital Giovanni XXIII, Azienda Ospedaliero-Universitaria Consorziale, 70126 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Sarno, S., Boattini, A., Carta, M., Ferri, G., Al\u00f9, M., Yao, D.Y., Ciani, G., Pettener, D., and Luiselli, D. (2014). An ancient Mediterranean melting pot: Investigating the uniparental genetic structure and population history of Sicily and Southern Italy. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096074"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/j.1469-1809.1993.tb00894.x","article-title":"Barriers to gene flow estimated by surname distribution in Italy","volume":"57","author":"Zei","year":"1993","journal-title":"Ann. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"eaaw3492","DOI":"10.1126\/sciadv.aaw3492","article-title":"Population structure of modern-day Italians reveals patterns of ancient and archaic ancestries in Southern Europe","volume":"5","author":"Raveane","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1056","DOI":"10.1038\/ejhg.2015.233","article-title":"The Italian genome reflects the history of Europe and the Mediterranean basin","volume":"24","author":"Fiorito","year":"2016","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/humu.20526","article-title":"The PAH gene, phenylketonuria, and a paradigm shift","volume":"28","author":"Scriver","year":"2007","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1002\/humu.9115","article-title":"The molecular basis of phenylalanine hydroxylase deficiency in Croatia","volume":"21","author":"Zschocke","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1093\/hmg\/2.10.1703","article-title":"Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: Implications for diagnosis of hyperphenylalaninemia in southern Europe","volume":"2","author":"Guldberg","year":"1993","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.ajhg.2020.06.006","article-title":"The genetic landscape and epidemiology of phenylketonuria","volume":"107","author":"Hillert","year":"2020","journal-title":"Am. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1159\/000484763","article-title":"Relationship between mutation genotype and biochemical phenotype in a heterogeneous Spanish phenylketonuria population","volume":"5","author":"Desviat","year":"1997","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/S0140-6736(53)90473-5","article-title":"Influence of phenylalanine intake on phenylketonuria","volume":"265","author":"Bickel","year":"1953","journal-title":"Lancet"},{"key":"ref_11","first-page":"1355","article-title":"Multiple origins for phenylketonuria in Europe","volume":"51","author":"Eisensmith","year":"1992","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/humu.10205","article-title":"A role for overdominant selection in phenylketonuria? Evidence from molecular data","volume":"21","author":"Krawczak","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Ilgaz, F., Pinto, A., G\u00f6kmen-\u00d6zel, H., Rocha, J.C., van Dam, E., Ahring, K., B\u00e9langer-Quintana, A., Dokoupil, K., Karabulut, E., and MacDonald, A. (2019). Long-term growth in phenylketonuria: A systematic review and meta-analysis. Nutrients, 11.","DOI":"10.3390\/nu11092070"},{"key":"ref_14","first-page":"e454","article-title":"Dietary management practices in phenylketonuria: Results of an Italian multicentric survey and comparison with the European guidelines","volume":"1","author":"Giorda","year":"2024","journal-title":"J. Innate Metab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109125","DOI":"10.1016\/j.ymgme.2025.109125","article-title":"European guidelines on diagnosis and treatment of phenylketonuria: First revision","volume":"145","author":"MacDonald","year":"2025","journal-title":"Mol. Genet. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Gundorova, P., Stepanova, A.A., Kuznetsova, I.A., Kutsev, S.I., and Polyakov, A.V. (2019). Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0211048"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.ymgme.2012.10.006","article-title":"Dietary treatment in phenylketonuria does not lead to increased risk of obesity or metabolic syndrome","volume":"107","author":"Rocha","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s13023-025-03686-4","article-title":"The relationship between adult phenylketonuria and the cardiovascular system\u2014Insights into mechanisms and risks","volume":"20","author":"Trefz","year":"2025","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s40246-022-00397-w","article-title":"Identification of phenylketonuria patient genotypes using single-gene full-length sequencing","volume":"16","author":"Gao","year":"2022","journal-title":"Hum. Genom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1038\/gim.2013.157","article-title":"Phenylalanine hydroxylase deficiency: Diagnosis and management guideline","volume":"16","author":"Vockley","year":"2014","journal-title":"Genet. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/jimd.12173","article-title":"The first European guidelines on phenylketonuria: Usefulness and implications for BH4 responsiveness testing","volume":"43","author":"Evers","year":"2020","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ymgme.2009.09.005","article-title":"Management of phenylketonuria in Europe: Survey results from 19 countries","volume":"99","author":"Blau","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1086\/301920","article-title":"A European multicenter study of phenylalanine hydroxylase deficiency: Classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype","volume":"63","author":"Guldberg","year":"1998","journal-title":"Am. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/j.1469-1809.2006.00328.x","article-title":"Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: A 96% detection rate with ten novel mutations","volume":"71","author":"Daniele","year":"2007","journal-title":"Ann. Hum. Genet."},{"key":"ref_25","first-page":"851","article-title":"Genetic history of phenylketonuria mutations in Italy","volume":"55","author":"Dianzani","year":"1994","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1016\/j.clinbiochem.2013.06.009","article-title":"Mutation analysis in hyperphenylalaninemia patients from South Italy","volume":"46","author":"Trunzo","year":"2013","journal-title":"Clin. Biochem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1017\/S0007114511000298","article-title":"Adjusting diet with sapropterin in phenylketonuria: What factors should be considered?","volume":"106","author":"MacDonald","year":"2011","journal-title":"Br. J. Nutr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1186\/s13023-021-01968-1","article-title":"Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at <4 years of age with phenylketonuria: Results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial","volume":"16","author":"Muntau","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1417","DOI":"10.1016\/S0140-6736(10)60961-0","article-title":"Phenylketonuria","volume":"376","author":"Blau","year":"2010","journal-title":"Lancet"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S79","DOI":"10.1042\/bst026s079","article-title":"Mutational spectrum of phenylketonuria in Ireland","volume":"26","author":"Mayne","year":"1998","journal-title":"Biochem Soc. Trans."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1038\/ijo.2008.161","article-title":"Thrifty genes for obesity, an attractive but flawed idea, and an alternative perspective: The \u2019drifty gene\u2019 hypothesis","volume":"32","author":"Speakman","year":"2008","journal-title":"Int. J. Obes."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1111\/j.1753-4887.1997.tb01578.x","article-title":"Healthy traditional Mediterranean diet: An expression of culture, history, and lifestyle","volume":"55","author":"Trichopoulou","year":"1997","journal-title":"Nutr. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.earlhumdev.2004.10.003","article-title":"The fetal, neonatal, and infant environments-the long-term consequences for disease risk","volume":"81","author":"Gluckman","year":"2005","journal-title":"Early Hum. Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41576-021-00414-z","article-title":"The genetics of obesity: From discovery to biology","volume":"23","author":"Loos","year":"2022","journal-title":"Nat. Rev. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1126\/science.1172257","article-title":"The genetic structure and history of Africans and African Americans","volume":"324","author":"Tishkoff","year":"2009","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s13023-019-1188-0","article-title":"The cardiovascular phenotype of adult patients with phenylketonuria","volume":"14","author":"Azabdaftari","year":"2019","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s13023-015-0378-7","article-title":"Special low protein foods for phenylketonuria: Availability in Europe and an examination of their nutritional profile","volume":"10","author":"Pena","year":"2015","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"892","DOI":"10.3390\/pediatric16040076","article-title":"Growth parameters and prevalence of obesity in PKU patients and peers: Is this the right comparison?","volume":"16","author":"Paterno","year":"2024","journal-title":"Pediatr. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.medcli.2022.09.025","article-title":"The correlation of lipid profile and waist circumference with phenylalanine levels in adult patients with classical phenylketonuria","volume":"160","year":"2023","journal-title":"Med. Clin."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Consentino, M.C., La Spina, L., Meli, C., Messina, M., Lo Bianco, M., Sapuppo, A., Pappalardo, M.G., Iacobacci, R., Arena, A., and Vecchio, M. (2025). Genotype\u2013Phenotype Correlation in a Large Cohort of Eastern Sicilian Patients Affected by Phenylketonuria: Newborn Screening Program, Clinical Features, and Follow-Up. Nutrients, 17.","DOI":"10.3390\/nu17030379"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s40246-026-00936-9","article-title":"Genotype\u2013phenotype correlations in phenylketonuria: PAH variants and BH4 responsiveness for treatment design","volume":"20","author":"Karaca","year":"2026","journal-title":"Hum. Genom."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/861\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T14:01:56Z","timestamp":1784901716000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/861"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,24]]},"references-count":41,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080861"],"URL":"https:\/\/doi.org\/10.3390\/genes17080861","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,24]]}}}