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.

Ultrastructural and Immunohistochemical Diagnosis of a Neonatal Herpes Simplex Virus Infection Presenting as Fulminant Hepatitis: A Case Report.

TORCH (Toxoplasmosis, Rubella, Cytomegalovirus, Herpes Simplex Virus and Syphilis) infections are a major cause of intrauterine and perinatal infections with associated morbidity and mortality. Neonatal Herpes Simplex Virus infection caused by an enveloped, double-stranded DNA virus of the Herpesviridae family is devastating and fatal. Herpes Viruses are not hepatotropic but may rarely cause hepatitis. Most cases of HSV hepatitis rapidly progress to fulminant hepatic failure and often fatal before the diagnosis or transplantation. Nowadays, despite the availability of antiviral treatment (acyclovir), the outcome remains poor because of late identification of hepatic Herpes Simplex Virus (HSV) infection. We report a male neonate suspected with a metabolic/mitochondrial disease and multi-organ involvement but who developed a fulminant hepatic failure and disseminated coagulopathy secondary to HSV type 1 (HSV-1) infection. The postmortem diagnosis was performed demonstrating HSV-1 in liver tissue by transmission electron microscopy and by retrospective detection of HSV specific antigens by immunohistochemistry.

Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy, according to genetic background.

BACKGROUND AND AIMS: Phenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. METHODS AND RESULTS: A total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype. Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. CONCLUSIONS: Several factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.

Carnitine longitudinal pattern in preterm infants <1800 g body weight: a case-control study.

BACKGROUND: The aim of this study is to investigate free carnitine (C0) and total acylcarnitine levels (AC) in preterm infants with BW < 1800 g and the relationship with neonatal and perinatal factors. METHODS: Ninety-three thousand two hundred and ninety-three newborns were screened between 2011 and 2013. Dried blood samples (DBS) were collected at 48-72 h, 14, and 30 days of age. We studied 92 consecutive preterm (BW < 1800 g) infants with low carnitine levels at 30 days of life (Group 1). As controls, we included the first 92 cases (BW < 1800 g) with normal carnitine levels (Group 2) and another 92 at or near-term newborns with BW > 1800 g (Group 3). RESULTS: Compared to 48-72 h levels, C0 and AC decreased at 14 and 30 days of life in Groups 1 and 2 (p < 0.001). In Group 2, the percentage of children with carnitine-free parenteral nutrition (PN) and BW < 1000 g was lower than in Group 1 (p < 0.001). Only in Group 2 did C0 increase at 30 days (p < 0.001). The multivariate regression analysis confirmed the influence of body weight and type of nutrition on C0 and AC. CONCLUSION: Body weight and type of nutrition influenced the carnitine longitudinal pattern.

Comparison between liquid and tablet formulations of levothyroxine in the initial treatment of congenital hypothyroidism.

OBJECTIVE: To evaluate the effects of liquid (drops) and tablet formulations of levothyroxine in homogeneous groups of infants with congenital hypothyroidism (CH) as diagnosed through neonatal screening. STUDY DESIGN: Forty-two consecutive infants with CH were subdivided into 2 groups consisting of infants with the severe or the moderate/mild form. For each form, the infants with CH were randomly assigned to receive liquid (group 1) or tablet (group 2) formulation. In all patients, thyroid function tests were performed before the beginning of therapy and at 15 and 30 days and at 3 and 6 months after the beginning of therapy. RESULTS: In the severe form, after 15 days of treatment, serum thyrotropin (TSH) levels became normal in 8 of 9 patients in group 1 and in 5 of 9 patients in group 2; serum free triiodothyronine (fT3) levels were significantly higher in group 1 than in group 2; and serum fT4 levels were higher than the upper limit of the normal range in all patients in both groups. During the follow-up, there were significantly more patients with suppressed TSH concentrations in group 1 than in group 2. In the moderate/mild form, the patients of group 1 and group 2 showed median values of TSH, fT3, and fT4 that were not significantly different. No clinical or electrocardiographic signs of heart disease were found. There were no significant differences in the developmental quotient between group 1 and group 2 patients with severe and moderate/mild CH. CONCLUSIONS: Our data seem to indicate that there is not complete bioequivalence between drops and tablets, especially in infants with severe CH.

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.

Short-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.

Psychological and behavioural aspects in children and adolescents with congenital hypothyroidism diagnosed by neonatal screening: comparison between parents' and children's perceptions.

OBJECTIVE: To compare the psychological adjustment and behaviour of congenital hypothyroidism (CH) children and their parents with a control group. STUDY DESIGN: A cross-sectional study was carried out with 84 CH subjects diagnosed by neonatal screening (range 2.7-18.6 years), subdivided into four age groups: group 1 (2-5 years); group 2 (6-10 years); group 3 (11-13 years); and group 4 (14-18 years) and was compared with an age-matched control group. Patients were assessed using two questionnaires: Child Behaviour Checklist for parents and Youth Self-Report for children over 11 years of age. RESULTS: In groups 1, 3 and 4, total score (TS), internalising score (IS=problems within the self) and externalising score (ES=conflicts with other people) as reported by parents were not significantly different in CH patients and in controls. In group 2, parents of CH children showed values of TS (P<0.05), IS (P<0.05), ES (P<0.05) and scores on other scales significantly higher than controls. In self-reports of groups 3 and 4, the behavioural scales were not significantly different in CH patients and in controls. CONCLUSIONS: Paediatricians should be informed about the increased risk of the development of behavioural problems at primary school age in CH patients. At this age special attention should be paid to parental worries and anxiety. However, it can be reassuring for the patients and parents to know that the problems may be related to CH, and that they may spontaneously disappear.