The management of transitional care of patients affected by phenylketonuria in Italy: Review and expert opinion

Phenylketonuria (PKU) is a metabolic inherited disorder in which transition from infancy to adult care is particularly difficult and not sufficiently regulated. According to the scientific literature, only few medical centers offer healthcare assistance for adult patients with PKU that are therefore still treated in pediatric settings. This generates psychological, emotional, and organizational discomfort among patients, leading them to discontinue the follow-up. European guidelines and national consensus documents underline this unmet need and the lack of practical recommendations for a structured transitional pathway in PKU. The aim of this review and expert opinion is to propose good practices for managing the transition period of PKU patients, based on the literature and the experience of a panel of Italian experts in PKU. The consensus of the experts was obtained through the administration of three rounds of surveys and one structured interview. The result is the first proposal of a pathway for an efficient transition of PKU patients. Key steps of the proposed pathway are the "a priori" planning involving the pediatric and adult teams, the acceptance of the patient and his/her family to the process, the preliminary definition of appropriate spaces in the structure, the organization of meetings with the joint team, and the appointment of a transition coordinator. For the first time, the involvement of decision makers and patient associations is proposed

New approach in the diagnosis and therapy of hyperphenylalaninemia

Background. Phenylketonuria is the most prevalent inborn error of aminoacid metabolism. Is an autosomal recessive disorder. It results from mutations in the phenylalanine hydroxilase (PAH) gene. Phenotypes can vary from mild hyperphenylalaninemia to a severe phenylketonuria wich, if untreated, results in severe mental retardation. Thanks to neonatal screening programmes, early detection and promp dietetic intervention (phenylalanine restricted diet lifelong) has allowed to avoid neurocognitive complications. Recently, a new therapy is become widely used: the oral supplementation with the PAH cofactor (BH4), wich can alleviate the diet burden. Genotype-phenotype correlation is a reliable tool to predict metabolic phenotype in order to establish a better tailored diet and to assess the potential responsiveness to BH4 therapy. Aim Molecular analysis of the PAH gene, evaluation of genotype-phenotype correlation and prediction of BH4 responsiveness in a group of HPA patients living in Emilia Romagna. Patients and methods. We studied 48 patients affected by PAH deficiency in regular follow-up to our Metabolic Centre. We performed the molecular analysis of these patients using genomic DNA extracted from peripheral blood samples Results. We obtained a full genotipic characterization of 46 patients. We found 87 mutant alleles and 35 different mutations, being the most frequent IVS10-11 G>A (19.3%), R261Q (9.1%), R158Q (9.1%), R408Q (6.8%) and A403V (5.7%), including 2 new ones (L287, N223Y) ever described previously. Notably, we found 15 mutations already identified in BH4-responsive patients, according to the literature. We found 42 different genotipic combinations, most of them in single patients and involving a BH4-responsive mutation. Conclusion. BH4 responsiveness is shown by a consistent number of PAH deficient hyperphenylalaninemic patients. This treatment, combined with a less restricted diet or as monotherapy, can reduce nutritional complications and improve the quality of life of these patients

Thyroid Enlargement from Newborn to Adolescent

A thyroid enlargement , i.e., a goiter , may be due to many causes both congenital and acquired and could be detected at any age during childhood and adolescence. Goiters can be diffuse or nodular and associated with normal or altered thyroid function. The thyroid enlargement may be caused by increased TSH secretion acting as growth factor, by TSH receptor stimulating antibodies or by a TSH-independent process, such as infl ammation or neoplastic or infi ltrative disease. The relative frequency of the various forms varies according to the ag

Copy number determination of hypothyroidism genes by MLPA analysis in patients with hypothyroidism and thyroid hypoplasia

Background: Genetic hypothyroidism presents a heterogeneous genetic inheritance: single allele mutation in genes with recessive pattern (pseudodominance), digenic inheritance and one phenotype/one mutation association were all observed, in particular in case of mild or complex phenotypes. Therefore it is necessary to screen multiple genes in order to identify the genetic defect and to help clinical management of these patients and families. Objective and hypotheses:TSH receptor gene (TSHR) is the more frequent mutated gene in genetic hypothyroidism, so this represent the first target to be tested. If THSR gene sequence is normal, copy number determination of TSHR exons may be performed by MLPA analysis, together with other hypothyroidism genes. If hypothyroidism genes have normal dosage, their complete sequencing may be considerate. Methods: From a large series of patients with hypothyroidism already screened for point mutation in TSHR gene by sequencing, we selected 22 patients with thyroid hypoplasia. 9 pts. presented congenital hypothyroidism and were positive at neonatal screening, 13 pts. were diagnosed as subclinical hypothyroidism (TSH>4.2 mU/liter) after neonatal period. To complete the search of causative mutations we performed copy number determination on genomic DNA from peripheral blood by MLPA analysis, with probes for TSHR gene and PAX8, TPO, FOXE1 and NKX2.1 genes. Results: A deletion of TSHR gene exon 1 was identified in one allele in a patient, he was 6 yrs. old at first evaluation and presented TSH level up to normal range in more than two tests. Conclusions: Our results confirmed the primary role of TSHR gene mutations in hypothyroidism and the necessity of copy number determination of hypothyroidism genes in diagnostic steps. We intend to extend the MLPA analysis in all the patients with suspected genetic hypothyroidism, and to proceed with PAX8 gene sequencing in negative cases to improve the mutation detection of this heterogeneous diseas

Clinical relevance of short-chain acyl-CoA dehydrogenase (SCAD) deficiency: Exploring the role of new variants including the first SCAD-disease-causing allele carrying a synonymous mutation

AbstractShort-chain acyl-coA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of mitochondrial fatty acid oxidation caused by ACADS gene alterations. SCADD is a heterogeneous condition, sometimes considered to be solely a biochemical condition given that it has been associated with variable clinical phenotypes ranging from no symptoms or signs to metabolic decompensation occurring early in life.A reason for this variability is due to SCAD alterations, such as the common p.Gly209Ser, that confer a disease susceptibility state but require a complex multifactorial/polygenic condition to manifest clinically.Our study focuses on 12 SCADD patients carrying 11 new ACADS variants, with the purpose of defining genotype–phenotype correlations based on clinical data, metabolite evaluation, molecular analyses, and in silico functional analyses.Interestingly, we identified a synonymous variant, c.765G>T (p.Gly255Gly) that influences ACADS mRNA splicing accuracy. mRNA characterisation demonstrated that this variant leads to an aberrant splicing product, harbouring a premature stop codon.Molecular analysis and in silico tools are able to characterise ACADS variants, identifying the severe mutations and consequently indicating which patients could benefit from a long term follow- up. We also emphasise that synonymous mutations can be relevant features and potentially associated with SCADD