Low bone mineralization in phenylketonuria may be due to undiagnosed metabolic acidosis.

Background: Dietary intervention is to date the mainstay treatment to prevent toxic phenylalanine (Phe) accumulation in PKU patients. Despite success preventing central nervous system damage, there is increasing evidence of possible other unfavorable outcomes affecting other systems, e.g. kidney and bone; underlying mechanisms are yet to be fully elucidated. Methods: This observational, cross-sectional and descriptive study investigated 20 adult with PKU evaluating biochemical parameters, BMD measurements and extrapolating data from 3-days food records and protein substitutes (PS) and special low protein foods (SLPF) composition. Results: Blood gas venous analysis (VBG) indices were indicative of metabolic acidosis in 60% of PKU patients and VBG pH significantly correlated with BMD's Z-score (p-value = 0.022) even if its overall mean was in range (-1.29). Low bone mineral density for chronological age (Z-score < - 2.0) was found in 4 patients (20%). Indices of kidney function were not impaired. All used PS had a moderate excess of acidity, while SLPF were alkalizing and type/variety of consumed vegetables did not determine significant changes in acid-base equilibrium. Total intakes of potassium and magnesium were lower than expected. Discussion: PKU patients seem to be at risk of metabolic acidosis, directly linked to possible low bone mineralization. This may be related to the acidic composition of PS, potentially capable of acidifying the entire diet. Reported low intakes of potassium and magnesium may be relevant to these observations. Further studies are needed to better address these topics.

Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy.

BACKGROUND: Hyperphenylalaninemias (HPA) are due to several gene mutations, of which the PAH gene is the most frequently involved. Prevalence and incidence of disease vary between populations, with genotype/phenotype correlations not always capable to correctly predict disease severity. The aim of this study was to give an overview of PAH mutations among one of the largest cohort of patients among Europe, born in Lombardy (Italy) starting from late 1970 s and including over a 60 years of activity; furthermore, to evaluate and discuss identified genotype/phenotype correlations and related reliability. PATIENTS/METHODS: Eight hundred and twenty-six HPA patients in current follow-up at the San Paolo Hospital in Milan (Italy) were retrospectively reviewed, including molecular results and allelic phenotype and genotype values (attributed on the basis of the APV/GPV system) to verify genotype-phenotype correlations. RESULTS: A total of 166 different PAH variants were reviewed; of those, seven variants were identified as not previously described in literature. Most frequently reported variant was p.Ala403Val, followed by p.Arg261Gln, p.Val245Ala, IVS10-11 g>a, p.Tyr414Cys and p.Leu48Ser. Phenotype prediction, based on APV/GPV, matched the actual phenotype in most cases, but not always. CONCLUSION/DISCUSSION: The cohort of patients included in this study constitute a representative sample of the HPA population worldwide. Studies on this sample may allow to improve clinical and genetic evaluation performances for affected patients, consequently to develop personalized medicine interventions and provide more precise indications on the correct treatment approach based on the accumulated evidence, also in light of a prognostically reliable but not always conclusive APV/GPV system.

Breastfeeding in Phenylketonuria: Changing Modalities, Changing Perspectives.

Phenylketonuria (PKU) management aims to control phenylalanine (Phe) intakes. In newborns and infants this implies possible titration of Human milk (HM) with supplementation of Phe-free formula. HM benefits, better if prolonged, are well known in healthy populations, suggesting it may be used in PKU patients. Despite that, the current literature does not define recommendations on how best perform it in such a population. The main purpose of this study was to evaluate nutrition approaches in newborns and infants affected by PKU and to define if differences can influence the duration of breastfeeding. Data from 42 PKU infants were reviewed. Of these, 67% were breastfed with the use of three different approaches. The type of approach used impacted the duration of breastfeeding, which was longer when using a pre-measured amount of Phe-free formula administered prior to HM. This is the first study to suggest a specific method for breastfeeding in PKU. Considering widely known breastfeeding benefits, both for patients and their mothers, our data should encourage adequate awareness on how to choose correct breastfeeding modalities.

Caregivers' Intention to Vaccinate Their Children Under 12 Years of Age Against COVID-19: A Cross-Sectional Multi-Center Study in Milan, Italy.

The impact of Coronavirus disease 2019 (COVID-19) on the pediatric population is increasingly recognized. A widespread vaccination in childhood would provide benefits for children and might help ending the pandemic by enhancing community protection. Following recent approval by the European Medicines Agency (EMA) of Comirnaty (Pfizer-BioNTech) for children aged 5-11 years, we aimed to investigate caregivers' intention to vaccinate their children <12 years of age against COVID-19. A structured questionnaire was administered to caregivers of children aged <12 years visiting the Emergency Department or the outpatient clinics in three major hospitals of Milan, Italy, from 20 September to 17 October 2021. A total of 612 caregivers were invited to participate and 604 accepted (response rate >98%). Three questionnaires were excluded due to compiling errors and 601 were included in the analysis. A total of 311 (51.7%) caregivers stated they would have their child vaccinated, 138 (23%) would refuse to vaccinate their child and 152 (25.3%) were unsure. The intention to vaccinate the child was higher in caregivers vaccinated against COVID-19, in those with a bachelor's degree or higher level of education, and in those with friends/acquaintances who became ill or died due to COVID-19. This study shows that increasing efforts are necessary to provide evidence-based tailored information to caregivers and to promote vaccination in this pediatric age group.

L-alanine supplementation in Pompe disease (IOPD): a potential therapeutic implementation for patients on ERT? A case report.

BACKGROUND: Pompe disease (PD) is a disorder of glycogen metabolism conditioning a progressive and life conditioning myopathy. Enzyme replacement therapy (ERT) is currently the best treatment option for PD, but is not resolutive. While other potential therapeutic approaches have been reported before, these have never been tried as co- treatments. L-alanine oral supplementation (LAOS) has been proven to reduce muscle breakdown: we hereby report the first case of supplementation on a PD patient on ERT. CASE PRESENTATION: F. is a 9 y.o. infantile onset Pompe Disease (IOPD) girl ERT-treated since age 1 developing a progressive myopathy. We started her on LAOS and performed assessments at baseline, 6 and 9 months. At baseline, F.'s weight, height and BMI were within normal ranges, while body composition showed low fat mass -FM and high resting energy expenditure-REE levels. After LAOS, a progressive FM increase and REE reduction could be observed both at 6 and 9 months. CONCLUSIONS: ERT is not curative for PD patients thus additional treatments could be considered to improve outcomes. Our patient showed physical signs of inability to accumulate energy when exclusively on ERT, while FM increase and REE reduction occurred when supplemented with LAOS, likely reflecting anabolic pathways' implementation. This is the first case reporting potential LAOS benefits in PD-on ERT patients. Longitudinal case control studies are yet needed to evaluate possible efficacy of combined LAOS And ERT treatment in PD patients.

PMM2-CDG and nephrotic syndrome: A case report.

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, characterized by a defect in the protein glycosylation process. Enzymes involved in this metabolic mechanism have ubiquitous distribution; thus, their alteration can cause systemic involvement and considerable phenotypic variability. Nephrotic syndrome (NS) is a clinical condition characterized by edema, hypoalbuminemia, hyperlipidemia, and proteinuria. We hereby report the case of a girl with central hypotonia, epilepsy, and severe psychomotor delay diagnosed with phosphomannomutase 2 deficiency (PMM2-CDG) after presenting with nephrotic syndrome at age 4 years.

Telehealth and COVID-19: Empowering Standards of Management for Patients Affected by Phenylketonuria and Hyperphenylalaninemia.

Phenylketonuria (PKU) and Hyperphenylalaninemia (HPA) are inborn errors of metabolism (IEM) due to mutations in the PAH gene resulting in increased blood phenylalanine (Phe) concentrations. Depending on the Phe levels, a lifelong dietary intervention may be needed. During the COVID-19 pandemic, finding new strategies to ensure follow-up and metabolic control for such patients became mandatory and telehealth was identified as the most eligible tool to provide care and assistance beyond barriers. The aim of this study was to evaluate how telehealth use may have impacted disease follow-ups. Seven hundred and fifty-five patients affected by PKU/HPA in follow-ups at the Clinical Department of Pediatrics (San Paolo Hospital, ASST Santi Paolo e Carlo, University of Milan, Italy) were included in this study. The data regarding the used telehealth model, type of performed consultations and patients' perspectives were retrospectively collected and analyzed after a one-year experience of implemented follow-ups. The results demonstrated that telehealth seemed to be a useful tool to improve the adherence to treatment and that it could guarantee continuous assistance and care beyond the surrounding epidemiological status. Patients expressed great satisfaction with the offered services and requested that they were implemented in standards of care on a long-term basis. Our results suggested the implementation of telehealth in the management guidelines for PKU/HPA patients.

PKU and COVID19: How the pandemic changed metabolic control.

BACKGROUND: COVID19 pandemic urged the need to take severe measures for reducing the epidemic spread. Lockdowns were imposed throughout countries and even Inborn errors of metabolism (IEMs) affected patients had to face it and adapt, with management strategies changes coming along. Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism causing, when not treated, blood Phe increases and consequent central nervous system (CNS) damage. Dietary intervention is the main recognized treatment and must be maintained long-life, however adherence is often suboptimal in adulthood. Aim of this study was to evaluate whether and how the pandemic had impacted PKUs metabolic control and what factors may have played a role as potential modifiers. METHODS: Patients ≥4 yo and in follow-up at our Metabolic Clinic were enrolled in this study, divided into subgroups according to age (GROUP A < 12 yo; GROUP B ≥ 12 yo). Videoconsults were conducted on a minimum monthly basis and collected DBS were studied and compared to previous year same time-period in order to evaluate possible changes. RESULTS: 39% of patients (n = 121) increased the number of performed DBS. "Non-compliant" patients were reduced (11-3%) with a - 14% of patients with mean Phe levels >600 umol/l and a - 8% of patients with 100% DBS above same level. GROUP A maintained substantially unchanged metabolic control among two analyzed time-periods. On the contrary, GROUP B demonstrated significant reductions in mean blood Phe concentrations (p < 0.0001) during the pandemic (mean 454 umol/l, SD ± 252, vs. 556.4 umol/l, SD ± 301). DISCUSSION: COVID19 pandemic strongly impacted people's life with lifestyle habits changing consistently. PKU patients had to adapt their dietary restrictions to the new environment they were exposed to and, if younger patients could have been less exposed (meals strictly according to diet plan independently from setting), adolescent and adults strongly reflected the obligation to stay home by showing better metabolic control. Multiple factors could have played a role in that and the availability of teleconsultancy may have contributed allowing easier connections, but our data demonstrate how the pandemic and the environment can strongly impact PKUs adherence to treatment and how removing distance barriers can ameliorate and optimize metabolic compliance.

Psychological wellbeing in parents of children with phenylketonuria and association with treatment adherence.

BACKGROUND: Phenylketonuria (PKU) is a rare metabolic disorder that leads to severe neurological abnormalities unless early treated with a strict phenylalanine (Phe)-restricted diet. The parents' involvement in PKU management is crucial and could lead to psychological distress; however, few studies have explored the parents' psychological wellbeing. The study aimed to: 1) evaluate the presence of psychological distress and impaired quality of life among parents of children with PKU, assessing the impact of the diagnosis and the impact of the treatment management; 2) explore the associations between parents' psychological outcomes and their children's blood-Phe levels. METHODS: One hundred thirty-eight parents of patients with PKU (who need a Phe-restricted diet) and with a mild form (mild hyperphenylalaninemia-MHP, with no diet indication) filled-out self-report psychological questionnaires; Phe-levels of children with PKU were retrieved. RESULTS: Parents of children with PKU did not report higher levels of psychological distress neither compared with the normative scores nor with parents of children with MHP. Optimal Phe-levels were associated with a higher number of parents' depressive complaints, with a lower tendency to express anger feelings, with a lower social functioning, and a higher mental health. CONCLUSIONS: Parents of children with PKU showed a good psychological adaptation to their children's disease and treatment. Findings highlighted associations between parents' psychological wellbeing and their children's adherence to diet. Interestingly, an optimal adherence to the diet of their children was associated with parental low social functioning, a higher tendency to control the anger expression, and greater somatic depressive symptoms.

Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth.

BACKGROUND: Pyruvoyl Tetrahydropterin Synthase (PTPS) Deficiency is the most common form of BH4 deficiency resulting in hyperphenylalaninemia. It can have variable clinical severity and there is limited information on the clinical presentation, natural history and effectiveness of newborn screening for this condition. METHODS: Retrospective data (growth and clinical parameters, biochemical and genetic testing results, treatment) were collected from 19 patients with PTPS deficiency in different centers, to evaluate biochemical and clinical outcomes. Descriptive statistics was used for qualitative variables, while linear regression analysis was used to correlate quantitative variables. RESULTS: Patients with PTPS deficiency had an increased incidence of prematurity (4/18) with an average gestational age only mildly reduced (37.8 ± 2.4 weeks) and low birth weight (-1.14 ± 0.97 SD below that predicted for gestational age). With time, weight and height approached normal. VALUES: All patients were identified by newborn screening for an elevated phenylalanine level. However, phenylalanine levels were normal in two whose testing was performed at or before 24 h of age. Sapropterin dihydrochloride treatment normalized phenylalanine levels. Molecular testing identified novel variants in the PTS gene, some of which present in more than one affected family. The neurotransmitter derivatives 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) in the CSF were decreased in most cases except in 2 families with the peripheral form of PTPS deficiency. With time, HVA and 5HIAA became abnormally low in two of these patients requiring therapy. Prolactin (whose secretion is inhibited by dopamine) levels were elevated in several patients with PTPS deficiency and inversely correlated with the z-scores for height (p < 0.01) and weight (p < 0.05). Most patients with PTPS deficiency had delayed development early in life, improving around school age with IQs mostly in the normal range, with a small decline in older individuals. From a neurological standpoint, most patients had normal brain MRI and minor EEG anomalies, although some had persistent neurological symptoms. DISCUSSION: Patients with PTPS deficiency have not only an increased incidence of prematurity, but also decreased birth weight when corrected for gestational age. Hyperphenylalaninemia can be absent in the first day of life. Therapy with sapropterin dihydrochloride normalizes phenylalanine levels and neurotransmitter precursors can improve CSF neurotransmitter metabolites levels. Insufficient dopaminergic stimulation (as seen from elevated prolactin) might result in decreased height in patients with PTPS deficiency. Despite early delays in development, many patients can achieve independence in adult life, with usually normal neuroimaging and EEG.

PIGW-related glycosylphosphatidylinositol deficiency: Description of a new patient and review of the literature.

Inherited glycosylphosphatidylinositol (GPI) deficiencies are a group of clinically and genetically heterogeneous conditions belonging to the congenital disorders of glycosylation. PIGW is involved in GPI biosynthesis and modification, and biallelic pathogenic variants in this gene cause autosomal recessive GPI biosynthesis defect 11. Only five patients and two fetuses have been reported in the literature thus far. Here we describe a new patient with a novel homozygous missense variant in PIGW, who presented with hypotonia, severe intellectual disability, early-onset epileptic seizures, brain abnormalities, nystagmus, hand stereotypies, recurrent respiratory infections, distinctive facial features, and hyperphosphatasia. Our report expands the phenotype of GPI biosynthesis defect 11 to include stereotypies and recurrent respiratory infections. A detailed and long-term analysis of the electroclinical characteristics and review of the literature suggest that early-onset epileptic seizures are a key manifestation of GPI biosynthesis defect 11. West syndrome and focal-onset epileptic seizures are the most common seizure types, and the fronto-temporal regions may be the most frequently involved areas in these patients.

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.

Psychological and psychosocial implications for parenting a child with phenylketonuria: a systematic review.

INTRODUCTION: Since phenylketonuria (PKU) appears to have specificities that might challenge the parents' adaptation and well-being, the present review aimed to evaluate the impact of parenting a child with PKU on parents' psychological and psychosocial functioning. EVIDENCE ACQUISITION: A systematic electronic search was conducted using PubMED, Scopus, Embase, PsychInfo, Google Scholar and Cochrane Database to identify studies exploring psychological and psychosocial issues of parents of PKU children. The search retrieved 427 articles to review against inclusion criteria; a total of 17 studies were included in the review. Results were summarized qualitatively. EVIDENCE SYNTHESIS: Findings revealed a complex pattern of interrelated factors both on parental psychological wellbeing and psychosocial functioning. In particular, crucial for parents' adjustment to child PKU are the diagnosis resolution and the perceived social support; parents showed good coping strategies and quality of life; while, with regard to mental health, the studies reviewed showed inconsistent results, thus pointed out a moderate level of distress. The review examines patterns of results across studies and discusses methodological heterogeneities and problems related to different or inconsistent findings. CONCLUSIONS: Parenting a child with PKU had direct implications on the diagnosis resolution, the parents mental health and the disease management. Findings could help healthcare professionals to identify situations at risk for psychological maladjustments both in parents and in children, as the unresolved diagnosis or a tendency toward the social isolation. Results highlighted the necessity of a multidisciplinary caring approach for the family, with a particular focus on critical moments such diagnosis or developmental transitions.

Predictability and inconsistencies in the cognitive outcome of early treated PKU patients.

Long-term cognitive outcome and treatment of adult early treated (ET)PKU patients is a main issue in PKU research. We questioned whether the intellectual development of ETPKU patients is stable and to what extent its variation may be predicted by the quality of metabolic control. The aims of the present longitudinal retrospective study were to assess in young adult ETPKU patients: i) the relationship between IQ and metabolic control during the first two decades of life; and ii) the intra- and interindividual variability in the developmental trajectory which cannot be predicted by the disease's biomarkers. We collected biochemical data from 65 ETPKU patients (diagnostic blood Phe > 360 µmol/l) who were assessed twice for IQ (Wechsler Intelligence Scale) during their lifetime (mean age: 10.2 and 19.6 years, respectively). Results show that in ETPKU patients IQ over the second decade of life remained stable in about half of the patients (51%); while the rest experienced a gain (7 to 15 points) or loss (7 to 28 points) in IQ scores (23 and 26% respectively) whatever the quality of metabolic control was. The main factor affecting the second IQ was the value of the first IQ (p < 0.000) whose effect overruled that of the markers of metabolic control. Looking at the developmental trajectory of our ETPKU patients, the present study disclosed a remarkable interindividual variability in their cognitive outcome and also an inconsistent linkage between cognitive performances and biochemical control, thus supporting the hypothesis of an individual resilience or vulnerability to Phe in young adult ETPKU.

Work activity and phenylalanine levels in a population of young adults with classic PKU.

BACKGROUND: Phenylketonuria (PKU) is an inborn error of metabolism characterized by increased blood concentrations of phenylalanine (Phe). OBJECTIVES: The aim of the present study was to assess the association between the metabolic compliance of adult patients affected by classic PKU and the characteristics of their present and past occupations. METHODS: The study population consisted of working adults, affected by classic PKU, and following a dietary treatment. Univariate linear-mixed models and multivariate analysis were applied to assess the association between Phe blood levels and individual covariates: age, sex, time at diagnosis, educational level and work characteristics. RESULTS: A linear relationship was found with age (an average annual increase of 30.56 µMol/L (C.I. 95%: 7.53; 53.60) in the mean Phe blood levels). Full-time work appeared to be associated with a worse metabolic compliance when compared to part-time work (mean Phe blood levels >281.11 µMol/L). Shift work was related to a worse metabolic compliance, with mean Phe plasmatic levels >356.73 µMol/L. CONCLUSIONS: Our data suggests that work may influence the metabolic compliance in adults with PKU. In particular, a part-time employment could allow for a better metabolic compliance, while daily work should be preferred to shift work.

Cerumen: A fundamental but neglected problem by pediatricians.

OBJECTIVES: Under physiological conditions, cerumen (Ce) is regularly extruded from the ear canal by a self-cleaning mechanism. Failure of this mechanism leads to excessive accumulation or impaction of Ce. Limited data are available concerning the prevalence of cerumen in healthy and sick infants and children. We assessed the prevalence of Ce in a large population of infants and children and compared the Ce removal attitudes of paediatricians (PEDs) and otorhinolaryngologists (ENTs). METHODS: Children seen in November 2014 for acute respiratory infections, including suspected acute otitis media, or well-being visits, were enrolled. The following data were recorded: presence, laterality, and amount of Ce; presenting complaints and final diagnosis; attempt to remove Ce during the visit; and type of physician. RESULTS: Among 819 children aged 1 month to 12 years, Ce was present in 594 (72.5%), of whom 478 (80.5%) had bilateral Ce, and 261 (43.9%) had Ce in a relevant amount (cerumen obstructing at least 50% of the ear canal). Presence of Ce was more common in younger and in African or Asian children. PEDs were less likely to remove cerumen than ENTs (28.8% vs 91.0%, p < 0.001) irrespective of age, gender, race and reason for visit. Ce was removed by PEDs in less than one-third of sick children with a final diagnosis of acute otitis media (AOM) (31.6%) compared with almost all the children by ENTs (95.6%, p < 0.001). CONCLUSION: Ce is highly prevalent in healthy and sick children but is quite neglected by PEDs. Educational programs to reinforce the importance of Ce removal and to improve the techniques for removal in case of suspected AOM should be implemented and rigorously evaluated in order to avoid incorrect diagnosis and erroneous treatments.

Randomized controlled trial of a protein substitute with prolonged release on the protein status of children with phenylketonuria.

OBJECTIVE: To examine whether a phenylalanine-free protein substitute with prolonged release may be beneficial to the protein status of children with phenylketonuria (PKU) compared to conventional substitutes. METHODS: Sixty children with PKU, 7 to 16 years of age, were randomly allocated to receive either a prolonged-release (test) or the current conventional protein substitute for 30 days. Subjects were additionally sex and age matched with 60 subjects with mild hyperphenylalaninemia and 60 unaffected subjects. The protein status in children with PKU was assessed by albumin, transthyretin, and retinol-binding protein (RBP), and changes throughout the trial period were the primary outcome measures. RESULTS: Children with PKU did not differ in anthropometry from children with mild hyperphenylalaninemia or unaffected children but they ingested lower amounts of proteins (p < 0.01). No differences occurred throughout the trial between or within children with PKU who received the test or conventional substitute for macronutrient intake. Albumin and RBP concentrations were within the age-specific reference range for all children. The rate of protein insufficiency (transthyretin concentration less than 20 mg/dL) did not differ statistically between children receiving test or conventional substitute (recruitment 51.8% vs 53.6%; end of the trial 44.4% vs 50.0%) but mean transthyretin recovered over 20 mg/dL in children who received the test substitute, increasing from 19.1 to 20.7 mg/dL (mean change, 1.6 mg/dL; 95% confidence interval 0.4 to 2.8 mg/dL). In children receiving conventional substitute mean transthyretin changed from 19.0 to 19.2 mg/dL (0.2; -0.2 to 0.6) mg/dL. CONCLUSIONS: Protein substitutes with prolonged release might be beneficial to protein status in children with phenylketonuria.

Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling.

The type I interferon system is integral to human antiviral immunity. However, inappropriate stimulation or defective negative regulation of this system can lead to inflammatory disease. We sought to determine the molecular basis of genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome and of other undefined neurological and immunological phenotypes also demonstrating an upregulated type I interferon response. We found that heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state. Cellular and biochemical assays indicate that these mutations confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseline and ligand-induced interferon signaling. Our results demonstrate that aberrant sensing of nucleic acids can cause immune upregulation.

Preliminary data on immunogenicity, safety and tolerability of trivalent inactivated influenza vaccine in children with inborn errors of metabolism at risk of decompensation.

In order to evaluate the immunogenicity, safety and tolerability of influenza vaccination in children with inborn errors of metabolism (IEMs), we enrolled 20 patients with IEMs at risk of decompensation (14 males; mean age±SD, 8.5±3.9years) and 20 healthy age- and gender-matched controls. Four weeks after vaccination, seroconversion rates were 75-85% and seroprotection rates 85-95%, with high geometric mean titers (GMTs) of all three influenza antigen strains in both groups. Three months after vaccination, most of the subjects remained seroconverted with high seroprotection rates and high GMTs for all the three influenza strains. Safety and tolerability were also very good, with no differences between the groups.

Fabry disease presenting with sudden hearing loss and otosclerosis: a case report.

INTRODUCTION: Fabry disease is an X-linked lysosomal storage disorder resulting in a multiple-system disorder with a wide spectrum of physical signs and symptoms, predominantly affecting the central and peripheral nervous systems, skin, heart, kidneys, and eyes. CASE PRESENTATION: We describe the case of a 26-year-old European Caucasian man who had Fabry disease and who presented with episodic sudden unilateral hearing loss and was treated with glucocorticoids, pentoxifylline, hyperbaric oxygen, and fluoride because of concomitant audiometric evidence of otosclerosis. This case demonstrates the partial and transient beneficial effect of standard treatment for sudden hearing loss not related to Fabry disease and analyzes the possible connection between typical Fabry disease inner-ear lesions and otosclerosis. Whereas hearing loss has been described in connection with Fabry disease, otosclerosis-associated hearing loss in Fabry disease has not yet been described. CONCLUSIONS: Although progressive hearing loss in patients with Fabry disease seems to be influenced by replacement therapy, few data concerning treatment of sudden hearing loss are available. The lack of literature concerning the pathogenesis of the otological involvement in Fabry disease makes it impossible to identify a connection between the latter and otosclerosis. Therefore, this report may help to reinforce the importance of a thorough evaluation of hearing in patients with Fabry disease and may be of help with therapeutic decision-making.