Transition to glycerol phenylbutyrate for the management of urea cycle disorders: clinical experiences.

BACKGROUND: Urea cycle disorders (UCDs) are a group of rare inborn diseases caused by a deficiency in one of the six enzymes or one of the two transporters involved in the urea cycle. The most common biochemical feature is elevated blood ammonia levels, which can be toxic at high levels, especially to the brain and may manifest as encephalopathy if left untreated. Glycerol phenylbutyrate (GPB) is currently approved for use in the USA and Europe for patients of all ages with UCD who cannot be managed with protein restriction and/or amino acid supplementation alone. This article presents the author's experience in different exemplary settings and depicts the most efficient management of UCDs with GPB. CASE PRESENTATION: Six patient histories are described. 4 had OCT, one citrullinemia, and one argininosuccinic aciduria. Treatment with GPB was started between 2 days and 14 years of age. Before GPB, one patient had not been treated, 4 had received sodium phenylbutyrate (NaPB), and one Na benzoate. CONCLUSIONS: Overall, treatment with GPB was followed by a relevant metabolic improvement, resulting in better therapeutic compliance, reduced hospitalization, and improved quality of life.

Clinical profile and outcome of cardiomyopathies in infants and children seen at a tertiary centre.

INTRODUCTION: Due to their rare prevalence and marked heterogeneity, pediatric cardiomyopathies (CMPs) are little known and scarcely reported. We report the etiology, clinical profile and outcome of a consecutive cohort of children diagnosed with CMP and followed at Meyer Children's Hospital over a decade. PATIENTS AND METHODS: We retrospectively reviewed patients consecutively referred from May 2008 to May 2019 for pediatric onset CMP (<18 years). Heart disease caused by arrhythmic disorders, toxic agents, rheumatic conditions and maternal disease were excluded. RESULTS: We enrolled 110 patients (65 males), diagnosed at a median age of 27 [4-134] months; 35% had an infant onset (<1 year of age). A positive family history was more often associated with childhood-onset (38.8%). Hypertrophic cardiomyopathy (HCM; 48 patients) was the most frequent phenotype, followed by dilated cardiomyopathy (DCM; 35 patients). While metabolic and idiopathic etiologies were preponderant in infants, metabolic and sarcomeric diseases were most frequent in the childhood-onset group. Major adverse cardiac events (MACE) occurred in 31.8% of patients, including hospitalization for acute heart failure in 25.5% of patients, most commonly due to DCM. Overall, the most severe outcomes were documented in patients with metabolic diseases. CONCLUSIONS: In a consecutive cohort of pediatric patients with CMP, those with infantile onset and with a metabolic etiology had the worst prognosis. Overall, MACE occurred in 41% of the entire population, most commonly associated with DCM, inborn errors of metabolism and genetic syndromes. Systematic NGS genetic testing was critical for etiological diagnosis and management.

The longitudinal biomonitoring of residents living near the waste incinerator of Turin: Polycyclic Aromatic Hydrocarbon metabolites after three years from the plant start-up.

The waste-to-energy (WTE) incinerator plant located in the Turin area (Italy) started to recover energy from the combustion of municipal solid waste in 2013. A health surveillance program was implemented to evaluate the potential health effects on the population living near the plant. This program included a longitudinal biomonitoring to evaluate temporal changes of some environmental pollutants, including polycyclic aromatic hydrocarbons (PAHs), in residents living in areas near the Turin incinerator (exposed group, E) compared to those observed in subjects living far from the plant (not exposed group, NE). Ten monohydroxy-PAHs (OH-PAHs), consisting in the principal metabolites of naphthalene, fluorine, phenanthrene, and pyrene, were analyzed in urines collected from the E and NE subjects after one (T1) and three years (T2) of plant activity and compared with those determined in the same cohort established before the plant start-up (T0). Spearman correlation analysis was undertaken to explore possible associations between OH-PAHs and personal characteristics, lifestyle variables, and dietary habits. A linear mixed model (LMM) approach was applied to determine temporal trends of OH-PAHs observed in the E and NE subjects and to evaluate possible differences in trend between the two groups. Temporal trends of OH-PAHs determined by LMM analysis demonstrated that, at all times, the E group had concentrations lower than those assessed in the NE group, all other conditions being equal. Moreover, no increase in OH-PAH concentrations was observed at T1 and T2 either in E or in NE group. Significant positive correlations were found between all OH-PAHs and smoking habits. Regarding variables associated to outdoor PAH exposure, residence near high traffic roads and daily time in traffic road was positively correlated with 1-hydroxynaphthalene and 1-hydroxypyrene, respectively. In conclusion, no impact of the WTE plant on exposure to PAHs was observed on the population living near the plant.

Long-term use of carglumic acid in methylmalonic aciduria, propionic aciduria and isovaleric aciduria in Italy: a qualitative survey.

OBJECTIVE: Organic acidurias (OAs) are a group of rare metabolic disorders that disrupt the regular amino acid metabolism. OAs are characterized by recurrent episodes of acidemia, ketonuria and hyperammonemia which can result in brain/liver damage and renal failure, and despite the life-long protein-restricted diet, impaired growth and long-term complications can occur. Consequently, a long-term management of OAs patients is required, aimed principally at reducing the frequency and duration of metabolic decompensation/hyperammonemia episodes. Nevertheless, unlike the acute phase, evidence on the chronic management of OAs patients is less consolidated. SUBJECTS AND METHODS: To expand the knowledge on this field, 13 Italian referral centers for the management of OAs were involved in a survey focused on the long-term use of carglumic acid (Carbaglu®, Recordati Rare Diseases). RESULTS: Participating centers reported a reduction between 69% and 81% in the annual number of metabolic decompensations with the chronic use of carglumic acid and an improvement in protein intake. Most centers reported no difficulty using carglumic acid as a long-term therapy, along with a great compliance. CONCLUSIONS: Taken together, obtained data align with the available literature and support a positive clinical experience with the long-term carglumic acid administration. Additional studies aimed at better defining a proper dosage for the chronic administration of carglumic acid and the clinical and biochemical characteristics of patients treated chronically are needed. In addition, the potential impact of this treatment regimen on the neurological development and growth of patients should be elucidated.

Case Report: Zellweger Syndrome and Humoral Immunodeficiency: The Relevance of Newborn Screening for Primary Immunodeficiency.

Background: Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs). Case Presentation: We report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected. Conclusion: In this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.

Biomonitoring of the adult population living near the waste incinerator of Turin: Serum concentrations of PCDDs, PCDFs, and PCBs after three years from the plant start-up.

In September 2013 a waste-to-energy (WTE) incinerator located in the Turin area (Piedmont, Northern Italy) started to produce energy by the incineration of municipal solid wastes. The plant, one of the largest WTE incinerator in Europe, burns up to 490,000 tons of waste per year. A health surveillance program was implemented in order to evaluate the potential health effects on the population living near the plant. This program included a biomonitoring study aimed at assessing levels of several environmental contaminants including, among others, PCDDs, PCDFs, and PCBs. Before the WTE incinerator start-up (T0), a group of 85 subjects (41 "exposed" and 44 "not exposed" subjects) was randomly selected for enrollment by the local health units among individuals aged 36-50 years who had been living in the same area for at least five years prior to the study. Subjects were balanced by exposure area, sex and five-year age classes. As from the study design, the same cohort was re-evaluated after three years of incinerator activity (T2). A parallel study was conducted on a group of 12 farmers living and/or working in farms located in an area in the range of 5 km around the incinerator. Results of this study did not evidence any impact of the WTE plant on human exposure to PCDDs, PCDFs, and PCBs. In fact, no significant differences were found in the concentrations of PCDDs + PCDFs, DL-PCBs, and NDL-PCBs measured in the population group residing near the plant after three years of activity (T2) with respect to the control group. A significant decrease of serum concentrations of all the analytes was observed at T2 in both groups compared to T0. Serum concentrations of PCDDs, PCDFs, and PCBs in the group of farmers were higher than those observed in the adult population under study.

Neuroimaging Changes in Menkes Disease, Part 2.

This is the second part of a retrospective and review MR imaging study aiming to define the frequency rate, timing, imaging features, and evolution of gray matter changes in Menkes disease, a rare multisystem X-linked disorder of copper metabolism characterized by early, severe, and progressive neurologic involvement. According to our analysis, neurodegenerative changes and focal basal ganglia lesions already appear in the early phases of the disease. Subdural collections are less common than generally thought; however, their presence remains important because they might challenge the differential diagnosis with child abuse and might precipitate the clinical deterioration. Anecdotal findings in our large sample seem to provide interesting clues about the protean mechanisms of brain injury in this rare disease and further highlight the broad spectrum of MR imaging findings that might be expected while imaging a child with the suspicion of or a known diagnosis of Menkes disease.

Neuroimaging Changes in Menkes Disease, Part 1.

Menkes disease is a rare multisystem X-linked disorder of copper metabolism. Despite an early, severe, and progressive neurologic involvement, our knowledge of brain involvement remains unsatisfactory. The first part of this retrospective and review MR imaging study aims to define the frequency rate, timing, imaging features, and evolution of intracranial vascular and white matter changes. According to our analysis, striking but also poorly evolutive vascular abnormalities characterize the very early phases of disease. After the first months, myelination delay becomes evident, often in association with protean focal white matter lesions, some of which reveal an age-specific brain vulnerability. In later phases of the disease, concomitant progressive neurodegeneration might hinder the myelination progression. The currently enriched knowledge of neuroradiologic finding evolution provides valuable clues for early diagnosis, identifies possible MR imaging biomarkers of new treatment efficacy, and improves our comprehension of possible mechanisms of brain injury in Menkes disease.

Biophysical characterisation, antitumor activity and MOF encapsulation of a half-sandwich ruthenium(ii) mitoxantronato system.

The novel non-conventional metallodrug [(η6-p-cymene)2Ru2mitoxantronato]Cl2 (1) exhibits redox activity, DNA intercalation ability, cathepsin B and D inhibition and in vitro antitumor activity able to circumvent cisplatin resistance. Moreover, 1 can be successfully incorporated into MIL100(Fe) as a proof of concept of the feasibility of metal-organic frameworks as carriers of non-conventional drugs.

Birth weight for gestational age centiles for Italian neonates.

OBJECTIVE: To provide centiles for birth weight (BW) according to gestational age (GA) and sex for infants born in Italy. METHODS: We used records of the whole neonatal population of Tuscany, a region in Italy, from July 1991 to June 2002 as resulting from the database of the cystic fibrosis neonatal screening program (n=290129). We excluded as unlikely for GA those BW that were more than two interquartile ranges above the 75th centile or below the 25th centile for each GA and gender group. RESULTS: We present the 3rd, 10th, 25th, 50th, 75th, 90th and 97th centiles of BW for GA from the 24th to 43rd week of gestation for male and female Italian neonates, as both tables and smoothed curves. CONCLUSIONS: The large size of the examined population allows us to provide up-to-date, reliable BW for GA centiles for Italian newborns, especially for lower GAs.

Allergic bronchopulmonary aspergillosis in Italian cystic fibrosis patients: prevalence and percentage of positive tests in the employed diagnostic criteria.

The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in cystic fibrosis (CF) patients is difficult to determine because the data in the literature are not homogeneous or comparable. ABPA and CF have similar clinical symptoms which make diagnosis difficult and underestimate the real dimensions of the problem. We conducted an epidemiological study on 3089 Italian CF patients to determine the prevalence of ABPA in Italy and verify the percentage of positive tests in the employed diagnostic criteria. Our results indicate that the prevalence of ABPA in Italian CF patients is 6.18%, mainly in adolescents and young adults. ABPA is diagnosed using clinical symptoms (presence of episodic bronchial obstructions or typical radiographic features) and on the basis of other criteria which can only be partially fulfilled in paediatric patients. Among the diagnostic tests the most sensitive are the total IgE (84.5%), specific IgE anti-Aspergillus fumigatus (81.6%) and the prick test (68.3%). In the absence of clinical symptoms and gold standard diagnostic tests, serological positivity and/or the skin test are not sufficient evidence to confirm the presence of ABPA.

[Bacterial infections and resistance to antibiotics in cystic fibrosis]. / Infezioni batteriche e resistenza agli antibiotici nella fibrosi cistica.

Knowledge of the microbiology of pulmonary infections is critical for treatment of cystic fibrosis because sickness and mortality in this disease are mainly due to relapse occurring in the respiratory tract. The microbiology of pulmonary infections presents several singular aspects. Respiratory tract infections are caused by bacteria such as Staphylococcus aureus in the early years of life and Pseudomonas aeruginosa and Burkholderia cepacia thereafter. The patients, who are not immune compromised, are predisposed to chronic colonization and highly transmissible bacterial strains can cause cross-infections. Bacterial also develop resistance mechanisms which make them difficult to treat. Until recently the relationship between genetic defects and a predisposition to colonization was not noted, but recent studies have allowed us to form some interesting hypothesis. The present work analyzes the principal mechanisms of antibiotic resistance, with particular reference to classic cystic fibrosis pathogens, and looks at future prospects of respiratory tract infection treatment.

[Cerebral venous thrombosis in a child with iron deficiency anemia caused by food allergy]. / Trombosi venosa cerebrale in un bambino con anemia sideropenica da allergia alimentare.

Cerebral venous thrombosis is an infrequent cause of childhood stroke. It is reported most frequently in the setting of acute dehydration, cyanotic congenital heart disease, or the nephrotic syndrome and it is commonly found in patients with hereditary coagulation or immunologic disorders. Thrombotic tendencies may also occur in children with iron deficiency anemia. We describe a 11-months old boy with cerebral venous thrombosis likely attributable to dehydration and iron deficiency anemia by intestinal chronic blood loss, caused by food allergy.

[Clinical and physiopathological significance of pneumatocele in pulmonary pathology in children]. / Significato clinico e fisiopatologico dei pneumatoceli nella patologia polmonare del bambino.

Two cases of pneumatocele are reported. As our cases suggest and as the literature reports, the pneumatoceles are almost always benign lesions, whose resolution is only partially influenced by the therapy. On contrary their worrying radiological aspect and their long persistence can induce erroneously to think not efficacious the started therapy and therefore to change it. The etiology and the pathogenesis of pneumatocele are not completely clarified, even if various theory have been proposed.

[Efficacy of steroid therapy in a case of hepatic hemangioendothelioma in childhood]. / Efficacia della terapia steroidea in un caso di emangioendotelioma epatico in età pediatrica.

Multiple hepatic hemangioendothelioma are vascular lesions of the liver that generally appear in the infancy with hepatomegaly, high output congestive heart failure and cutaneous hemangiomas. Many plans for management (steroid, radiation, hepatic artery ligation, embolization, cyclophosphamide) have been proposed. We report a case in two months old boy of hepatic hemangioendothelioma with arteriovenous shunts and heart congestive failure, successfully treated with steroid.