Search Results (7)

Background/Objectives. Maternal phenylketonuria syndrome (MPKUS) is the most serious pregnancy complication of women with phenylketonuria (PKU). High phenylalanine (Phe) levels are indeed embryotoxic for the fetus. A low-Phe diet started before conception and maintained throughout pregnancy ensures optimal blood Phe concentrations (120–360 μmol/L) and pregnancy outcome. Women with unplanned pregnancies are at higher risk of MPKUS and require a rapid and sustained reduction of blood Phe. In this retrospective study, we evaluated the effects of dietary intervention on Phe levels and on the clinical parameters of offspring at birth in a group of patients with PKU. We also describe the fetal outcome of unplanned and untreated mothers with PKU. Methods. The cohort consisted of 13 patients for a total of 22 pregnancies: 16 successful pregnancies and 6 abortions. Pregnancies were divided into three groups: “Planned Pregnancies, PP (n = 5)”, “Unplanned Pregnancies, UP (n = 6)”, and “Unplanned and untreated Pregnancies UT (n = 5)”. Results. Women in the UP group showed higher levels of Phe than women in the PP group, especially during the first trimester. The offspring of the UP group showed no congenital malformations but lower median auxologic parameters at birth compared to those from the PP group, although these were not significantly different. The women in the UT group received the diagnosis of PKU after the birth of offspring with MPKUS. Conclusions. A low-Phe diet is critical to prevent MPKUS, especially when started before conception or no later than the 10th week of gestation. Intensive effort is necessary to avoid unplanned pregnancies and to identify undiagnosed women with PKU at risk of MPKUS. Full article

A comprehensive evaluation of obstructive sleep apnoea (OSA) may allow for the development of more efficient management of Down syndrome (DS). We aimed to evaluate the effect of a multidisciplinary approach to DS with OSA. A total of 48 DS children aged 4–12 years were prospectively investigated with nasal endoscopy, orthodontic examination, and overnight polygraphy (PG); the Italian Child Sleep Habits Questionnaire (CSHQ-IT) was filled out by the mothers. The total CSHQ-IT score was 63 (96% of children reporting sleep problems). The major ear, nose, and throat characteristics were enlarged palatine tonsils (62%), adenoid tonsils (85%), and chronic rhinosinusitis (85%). DS children showed orthognathic profile in 68% of cases, class I relationship in 63%, and cross-bite in 51%. PG revealed OSA in 67% of cases (37% mild, 63% moderate–severe). The oxygen desaturation index (ODI) was higher in the group with OSA (5.2) than with non-OSA (1.3; p < 0.001). The ODI was higher (p = 0.001) and SpO2 lower (p = 0.03) in children with moderate–severe OSA than with mild OSA. The apnoea–hypopnea index (AHI) and percentage time with SpO2 < 90% were higher in DS children with grade III than with grade I or II adenoids (5 vs. 1, p = 0.04, and 1.2 vs. 0.1, p = 0.01, respectively). No significant correlations were found between PG and the total CSHQ-IT score or orthodontic data. However, children showing associated cross-bite, grade III adenoids and size 3 or 4 palatine tonsils showed higher AHI and ODI than those without (p = 0.01 and p = 0.04, respectively). A coordinated multidisciplinary approach with overnight PG is a valuable tool when developing diagnostic protocols for OSA in DS. Full article

The mainstay of phenylketonuria treatment is a low protein diet, supplemented with phenylalanine (Phe)-free protein substitutes and micronutrients. Adhering to this diet is challenging, and even patients with good metabolic control who follow the dietary prescriptions in everyday life ignore the recommendations occasionally. The present study explores the ability of slow-release large neutral amino acids (srLNAAs) to prevent Phe increase following a Phe dietary load. Fourteen phenylketonuric patients aged ≥13 years were enrolled in a 6-week protocol. Oral acute Phe loads of 250 and 500 mg were added to the evening meal together with srLNAAs (0.5 gr/kg). Phe and tyrosine were dosed before dinner, 2h-after dinner, and after the overnight fast. After oral Phe loads, mean plasma Phe remained stable and below 600 µmol/L. No Phe peaks were registered. Tyrosine levels significantly increased, and Phe/Tyrosine ratio decreased. No adverse events were registered. In conclusion, a single oral administration of srLNAAs at the dose of 0.5 gr/kg is effective in maintaining stable plasma Phe during acute oral loads with Phe-containing food and may be added to the dietetic scheme in situations in which patients with generally good adherence to diet foresee a higher than prescribed Phe intake due to their commitments. Full article

Down syndrome (DS) is a major genetic cause of intellectual disability. DS pathogenesis has not been fully elucidated, and no specific pharmacological therapy is available. DYRK1A overexpression, oxidative stress and mitochondrial dysfunction were described in trisomy 21. Epigallocatechin-3-gallate (EGCG) is a multimodal nutraceutical with antioxidant properties. EGCG inhibits DYRK1A overexpression and corrects DS mitochondrial dysfunction in vitro. The present study explores safety profiles in DS children aged 1–8 years treated with EGCG (10 mg/kg/die, suspended in omega-3, per os, in fasting conditions, for 6 months) and EGCG efficacy in restoring mitochondrial complex I and F₀F₁-ATP synthase (complex V) deficiency, assessed on PBMCs. The Griffiths Mental Developmental Scales—Extended Revised (GMDS-ER) was used for developmental profiling. Results show that decaffeinated EGCG (>90%) plus omega-3 is safe in DS children and effective in reverting the deficit of mitochondrial complex I and V activities. Decline of plasma folates was observed in 21% of EGCG-treated patients and should be carefully monitored. GMDS-ER scores did not show differences between the treated group compared to the DS control group. In conclusion, EGCG plus omega-3 can be safely administered under medical supervision in DS children aged 1–8 years to normalize mitochondria respiratory chain complex activities, while results on the improvement of developmental performance are still inconclusive. Full article

Phenylketonuria is an inborn error of phenylalanine (Phe) metabolism diagnosed by newborn screening and treated early with diet. Although diet prevents intellectual disability, patients often show impairment of executive functions, working memory, sustained attention, and cognitive flexibility. Large neutral amino acids (LNAAs) have been proposed as a dietary supplement for PKU adults. Few studies show that LNAAs may help in improving metabolic control as well as cognitive functions. In this study, 10 adult PKU patients with poor metabolic control were treated for 12 months with LNAAs (MovisCom, 0.8–1 g/kg/day) and underwent Phe and Tyrosine (Tyr) monitoring monthly. Neuropsychological assessment was performed at T0, T+3, and T+12 months by using the American Psychological General Well-Being Index, the Wisconsin Card Sorting Test, the Test of Attentional Performance, and the 9-Hole Peg Test. No change in plasma Phe levels was observed during LNAAs supplementation, while Tyr levels significantly improved during LNAAs supplementation (p = 0.03). Psychometric tests showed an improvement of distress and well-being rates, of executive functions, attention, and vigilance, whereas no difference was noted regarding hand dexterity. This study adds evidence of the advantage of LNAAs supplementation in improving cognitive functions and well-being in patients with PKU with poor metabolic control. Full article

The aim of this study was to assess the prevalence and type of congenital heart disease (CHD) and the associated mutation spectrum in a large series of patients with neurofibromatosis type 1 (NF1), and correlate the mutation type with the presence and subgroups of cardiac defects. The study cohort included 493 individuals with molecularly confirmed diagnosis of NF1 for whom cardiac evaluation data were available. CHD was reported in 62/493 (12.6%) patients. Among these patients, 23/62 (37.1%) had pulmonary valve stenosis/dysplasia, 20/62 (32.3%) had mitral valve anomalies, and 10/62 (16.1%) had septal defects. Other defects occurred as rare events. In this NF1 subcohort, three subjects carried a whole-gene deletion, while 59 were heterozygous for an intragenic mutation. A significantly increased prevalence of non-truncating intragenic mutations was either observed in individuals with CHD (22/59, 37.3%) or with pulmonary valve stenosis (13/20, 65.0%), when compared to individuals without CHD (89/420, 21.2%) (p = 0.038) or pulmonary valve stenosis (98/459, 21.4%) (p = 0.002). Similarly, patients with non-truncating NF1 mutations displayed two- and six-fold higher risk of developing CHD (odds ratio = 1.9713, 95% confidence interval (CI): 1.1162–3.4814, p = 0.0193) and pulmonary valve stenosis (odds ratio = 6.8411, 95% CI: 2.6574–17.6114, p = 0.0001), respectively. Noteworthy, all but one patient (19/20, 95.0%) with pulmonary valve stenosis, and 18/35 (51.4%) patients with other CHDs displayed Noonan syndrome (NS)-like features. Present data confirm the significant frequency of CHD in patients with NF1, and provide further evidence for a higher than expected prevalence of NF1 in-frame variants and NS-like characteristics in NF1 patients with CHD, particularly with pulmonary valve stenosis. Full article

Phenylketonuria (PKU) was the first inherited metabolic disease in which dietary treatment was found to prevent the disease’s clinical features. Treatment of phenylketonuria remains difficult due to progressive decrease in adherence to diet and the presence of neurocognitive defects despite therapy. This review aims to summarize the current literature on new treatment strategies. Additions to treatment include new, more palatable foods based on glycomacropeptide that contains very limited amount of aromatic amino acids, the administration of large neutral amino acids to prevent phenylalanine entry into the brain or tetrahydropterina cofactor capable of increasing residual activity of phenylalanine hydroxylase. Moreover, human trials have recently been performed with subcutaneous administration of phenylalanine ammonia-lyase, and further efforts are underway to develop an oral therapy containing phenylanine ammonia-lyase. Gene therapy also seems to be a promising approach in the near future. Full article