Individual and Family Determinants for Quality of Life in Parents of Children with Inborn Errors of Metabolism Requiring a Restricted Diet: A Multilevel Analysis Approach.

OBJECTIVE: The objective of this study was to compare the quality of life (QoL) for parents of children with inborn errors of metabolism (IEMs) requiring a restricted diet with French population norms and investigate parental QoL determinants. STUDY DESIGN: This cross-sectional study included mothers and/or fathers of children < 18 years of age affected by IEMs requiring a restricted diet (except phenylketonuria) from January 2015 to December 2017. Parents' QoL was assessed using the World Health Organization Quality of Life BREF questionnaire and compared with age- and sex-matched reference values from the French general population. Linear mixed models were used to examine the effects of demographic, socioeconomic, disease-related, and psychocognitive factors on parental QoL, according to a 2-level regression model considering individuals (parents) nested within families. RESULTS: Of the 1156 parents invited to participate, 785 (68%) were included. Compared with the general population, parents of children with IEMs requiring a restricted diet reported a lower QoL in physical and social relationship domains but a higher QoL in the psychological domain. In the multivariate analysis, characteristics associated with poorer parental QoL included both parent-related factors (being a father, older age, more educated parent, nonworking parent, greater anxiety, seeking more social support, and using less positive thinking and problem-solving coping strategies) and family-related factors (disease complications, increased number of hospital medical providers, child's younger age, single-parent family, and lower family material wealth). CONCLUSION: Parents of children with IEMs requiring a restricted diet reported poorer QoL in physical and social relationship domains than population norms. Psychocognitive factors, beyond disease-specific and family-related characteristics, were the most important determinants influencing parental QoL and may represent essential aspects for interventions. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02552784.

Fifty years of research on mitochondrial fatty acid oxidation disorders: The remaining challenges.

Since the identification of the first disorder of mitochondrial fatty acid oxidation defects (FAOD) in 1973, more than 20 defects have been identified. Although there are some differences, most FAOD have similar clinical signs, which are mainly due to energy depletion and toxicity of accumulated metabolites. However, some of them have an unusual clinical phenotype or specific clinical signs. This manuscript focuses on what we have learnt so far on the pathophysiology of these disorders, which present with clinical signs that are not typical of categorical FAOD. It also highlights that some disorders have not yet been identified and tries to make assumptions to explain why. It also deals with new treatments under consideration in FAOD, including triheptanoin and similar anaplerotic substrates, ketone body treatments, RNA and gene therapy approaches. Finally, it suggests challenges for the diagnosis of FAOD in the coming years, both for symptomatic patients and for those diagnosed through newborn screening. The ultimate goal would be to identify all the patients born with FAOD and ensure for them the best possible quality of life.

Long-term follow-up of 64 children with classical infantile-onset Pompe disease since 2004: A French real-life observational study.

BACKGROUND: Classical infantile-onset Pompe disease (IOPD) is the most severe form of Pompe disease. Enzyme replacement therapy (ERT) has significantly increased survival but only a few studies have reported long-term outcomes. METHODS: We retrospectively analyzed the outcomes of classical IOPD patients diagnosed in France between 2004 and 2020. RESULTS: Sixty-four patients were identified. At diagnosis (median age 4 months) all patients had cardiomyopathy and most had severe hypotonia (57 of 62 patients, 92%). ERT was initiated in 50 (78%) patients and stopped later due to being ineffective in 10 (21%). Thirty-seven (58%) patients died during follow-up, including all untreated and discontinued ERT patients, and 13 additional patients. Mortality was higher during the first 3 years of life and after the age of 12 years. Persistence of cardiomyopathy during follow-up and/or the presence of heart failure were highly associated with an increased risk of death. In contrast, cross-reactive immunologic material (CRIM)-negative status (n = 16, 26%) was unrelated to increased mortality, presumably because immunomodulation protocols prevent the emergence of high antibody titers to ERT. Besides survival, decreased ERT efficacy appeared after the age of 6 years, with a progressive decline in motor and pulmonary functions for most survivors. CONCLUSIONS: This study reports the long-term follow-up of one of the largest cohorts of classical IOPD patients and demonstrates high long-term mortality and morbidity rates with a secondary decline in muscular and respiratory functions. This decreased efficacy seems to be multifactorial, highlighting the importance of developing new therapeutic approaches targeting various aspects of pathogenesis.

Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency.

INTRODUCTION: This study aims to define the phenotypic and molecular spectrum of the two clinical forms of ß-galactosidase (ß-GAL) deficiency, GM1-gangliosidosis and mucopolysaccharidosis IVB (Morquio disease type B, MPSIVB). METHODS: Clinical and genetic data of 52 probands, 47 patients with GM1-gangliosidosis and 5 patients with MPSIVB were analysed. RESULTS: The clinical presentations in patients with GM1-gangliosidosis are consistent with a phenotypic continuum ranging from a severe antenatal form with hydrops fetalis to an adult form with an extrapyramidal syndrome. Molecular studies evidenced 47 variants located throughout the sequence of the GLB1 gene, in all exons except 7, 11 and 12. Eighteen novel variants (15 substitutions and 3 deletions) were identified. Several variants were linked specifically to early-onset GM1-gangliosidosis, late-onset GM1-gangliosidosis or MPSIVB phenotypes. This integrative molecular and clinical stratification suggests a variant-driven patient assignment to a given clinical and severity group. CONCLUSION: This study reports one of the largest series of b-GAL deficiency with an integrative patient stratification combining molecular and clinical features. This work contributes to expand the community knowledge regarding the molecular and clinical landscapes of b-GAL deficiency for a better patient management.

Determinants of Quality of Life in Children with Inborn Errors of Metabolism Receiving a Restricted Diet.

OBJECTIVE: To investigate the determinants of quality of life (QoL) in children with inborn errors of metabolism with restricted diet (IEMRDs) using a single theory-based multidimensional model. STUDY DESIGN: In this multicenter cross-sectional study, data from children aged 8-17 years with IEMRDs (except phenylketonuria) and their parents were collected from January 2015 to December 2017. Measurements included a child's self-reported QoL, self-rated behavioral problems and anxiety, and parental anxiety. Based on hypotheses from a literature-built theoretical model linking demographic, clinical, family environment, and psychosocial characteristics to QoL either directly or indirectly, associations of these factors with a child's self-rated QoL were examined using a structural equation modeling approach. RESULTS: A total of 312 children (mean [SD] age, 12.2 [2.6] years; 51% boys [n = 160]) were included. Higher levels of trait anxiety and behavioral problems in children were the most important factors associated with poorer QoL (standardized path coefficients, -0.71 and -0.23, respectively). In addition, higher parent trait anxiety, younger age at diagnosis, and a disease requiring an emergency diet were associated with poorer QoL in these children. The final model fit the data closely according to conventional goodness-of-fit statistics and explained 86% of the QoL variance. CONCLUSIONS: Psychosocial factors appear to be major determinants of QoL impairment in children with IEMRDs. These factors should be addressed in clinical practice as part of the global treatment plan for a child with IEMRD. Future studies based on a longitudinal design should consider coping strategies when exploring potential predictive factors of QoL.

Very long-term outcomes in 23 patients with cblA type methylmalonic acidemia.

OBJECTIVES: To present the very long-term follow up of patients with cobalamin A (cblA) deficiency. METHODS: A retrospective case series of adult (>16 years) patients with molecular or enzymatic diagnosis of cblA deficiency. RESULTS: We included 23 patients (mean age: 27 ± 7.6 years; mean follow-up: 24.9 ± 7.6 years). Disease onset was mostly pediatric (78% < 1 year, median = 4 months) with acute neurologic deterioration (65%). Eight patients presented with chronic symptoms, and one had an adult-onset mild cblA deficiency. Most of the patients (61%) were initially classified as vitamin B12-unresponsive methylmalonic aciduria (MMA); in vitro B12 responsiveness was subsequently found in all the tested patients (n = 13). Initial management consisted of protein restriction (57%), B12 (17%), or both (26%). The main long-term problems were intellectual disability (39%) and renal failure (30%). However, 56.5% of the patients were living independently. Intellectual disability was equally distributed among the initial treatment groups, while renal failure (moderate and beginning at the age of 38 years) was present in only one out of seven patients initially treated with B12. CONCLUSIONS: We provide a detailed picture of the long-term outcome of a series of adult cblA patients, mostly diagnosed before the enzymatic and molecular era. We confirm that about 35% of the patients do not present acutely, underlining the importance of measuring MMA in any case of unexplained chronic renal failure, intellectual disability, or growth delay. In addition, we describe a patient with a milder adult-onset form. Early B12 supplementation seems to protect from severe renal insufficiency.

Health Status of French Young Patients with Inborn Errors of Metabolism with Lifelong Restricted Diet.

OBJECTIVE: To describe the health status of young patients affected by inborn errors of metabolism that require adherence to a restricted diet (IEMRDs) and to describe and compare their self- and proxy (parent)-reported quality of life (QoL) with reference values. STUDY DESIGN: A cross-sectional study was conducted in 2015-2017 in patients affected by IEMRDs (except phenylketonuria) younger than 18 years. Data collection was based on medical records, clinical examinations, parents' and children's interviews, and self-reported questionnaires. Measurements included clinical and healthcare data, child and family environment data, and self- and proxy (parent)-reported QoL. RESULTS: Of the 633 eligible participants, 578 were recruited (50.3% boys; mean age: 8.7 years); their anthropometric status did not differ from the general population. Approximately one-half of them had at least 1 complication of the disease. Their self-reported global QoL did not differ from that of the general population. However, relations with friends and leisure activities QoL domains were negatively impacted, whereas relations with medical staff, relations with parents, and self-esteem QoL domains were positively impacted. Their proxy (parent)-reported QoL was negatively impacted. CONCLUSIONS: Young patients affected by IEMRDs present a high rate of clinical complications. Although their proxy (parent)-reported QoL was negatively impacted, their self-reported QoL was variably impacted (both positively and negatively). These results may inform counseling for those who care for affected patients and their families.

Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients.

Fabry disease (FD), a rare X-linked disease, can be treated with bi-monthly infusion of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A (AGAL-A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12-15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.

Novel patient missense mutations in the HSD17B10 gene affect dehydrogenase and mitochondrial tRNA modification functions of the encoded protein.

MRPP2 (also known as HSD10/SDR5C1) is a multifunctional protein that harbours both catalytic and non-catalytic functions. The protein belongs to the short-chain dehydrogenase/reductases (SDR) family and is involved in the catabolism of isoleucine in vivo and steroid metabolism in vitro. MRPP2 also moonlights in a complex with the MRPP1 (also known as TRMT10C) protein for N1-methylation of purines at position 9 of mitochondrial tRNA, and in a complex with MRPP1 and MRPP3 (also known as PRORP) proteins for 5'-end processing of mitochondrial precursor tRNA. Inherited mutations in the HSD17B10 gene encoding MRPP2 protein lead to a childhood disorder characterised by progressive neurodegeneration, cardiomyopathy or both. Here we report two patients with novel missense mutations in the HSD17B10 gene (c.34G>C and c.526G>A), resulting in the p.V12L and p.V176M substitutions. Val12 and Val176 are highly conserved residues located at different regions of the MRPP2 structure. Recombinant mutant proteins were expressed and characterised biochemically to investigate their effects towards the functions of MRPP2 and associated complexes in vitro. Both mutant proteins showed significant reduction in the dehydrogenase, methyltransferase and tRNA processing activities compared to wildtype, associated with reduced stability for protein with p.V12L, whereas the protein carrying p.V176M showed impaired kinetics and complex formation. This study therefore identified two distinctive molecular mechanisms to explain the biochemical defects for the novel missense patient mutations.

Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis.

BACKGROUND: Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects ketone body and isoleucine catabolism. Neurological impairment may occur secondary to ketoacidotic episodes. However, we observed neuromotor abnormalities without ketoacidotic events in two T2-deficient families. We hypothesized that the neurological signs were related to the genetic defect and may occur independently of ketoacidotic episodes. We therefore conducted a retrospective review on a French T2-deficient patient series searching for neuromotor impairment. METHODS: In total, 26 cases were retrospectively analysed for clinical, biological and neuroimaging data. RESULTS: Neurological findings were observed for 6/26 (23%) patients. Among these, two had never experienced ketoacidotic episodes, though they developed extrapyramidal signs with putamen involvement. Two of the other four patients developed neurological abnormalities before the first ketoacidotic crisis, with putamen involvement in one case. The third patient developed extrapyramidal symptoms more than 10 years after the initial decompensation with globus pallidus involvement. The last patient developed extrapyramidal signs immediately after a severe ketoacidotic crisis with putaminal lesions. CONCLUSIONS: Most T2-deficient patients achieved normal neurodevelopment. However, on account of the role of T2 in isoleucine catabolism, these patients are potentially exposed to accumulation of toxic isoleucine-derived metabolites, which may contribute to neurological impairment. Our findings confirm previous observations that neurological symptoms in T2 deficiency may occur unrelated to ketoacidosis. The role of protein restriction as a preventive measure against neurological symptoms could not be established in this study and deserves further evaluation. Long-term follow-up data on children diagnosed by newborn screening may clarify the pathogenesis of this neurometabolic association.

Maternal phenylketonuria: low phenylalaninemia might increase the risk of intra uterine growth retardation.

BACKGROUND: Malformations and mental retardation in the offspring of women with Phenylketonuria (PKU) can be prevented by maintaining maternal blood Phenylalanine (PHE) within a target range (120-300 µmol/L) through a PHE-restricted diet. In a former French study, a high and unexpected proportion of intra uterine growth retardation (IUGR) has been reported. Guidelines have been proposed to all French centres caring for maternal PKU since 2002. OBJECTIVE: To confirm IUGR and investigate its causes. The other goals were to assess the follow-up of these pregnancies based on the new guidelines and the pertinence of these recommendations. DESIGN: Clinical, biological and ultrasound data of all pregnancies in PKU women in France, from 2002 to 2007 were retrospectively analyzed. RESULTS: Data from 115 pregnancies in 86 women with PKU were collected. Ninety percent of women had been informed of the risk of maternal PKU in the absence of a strict diet during pregnancy, 88 % of women had started a diet before conception, and 45 % of infants were born small for gestational age (birth length and/or weight ≤-2 SD). PHE intakes were lower in the group with IUGR from the fifth to the eighth month of pregnancy and duration of time spent at <120 µmol/L during pregnancy was associated with a higher risk of IUGR. CONCLUSION: Hyperphenylalaninemia (HPA) is not the only risk factor for IUGR; PHE lower than 120 µmol/L could also be associated with the IUGR occurrence. Even if the monitoring of these pregnancies has been improved since the initiation of guidelines, we would like to stress on the importance of the dietary aspect of the disease.

Evaluation of miglustat treatment in patients with type III mucopolysaccharidosis: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and safety of oral miglustat treatment in patients with mucopolysaccharidosis type III. The primary outcome was efficacy with improvement or stabilization in at least two domains of Vineland Adaptative Behavior Scales at 6 months. The secondary outcome measured the evolution of other cognitive tests at 12 months. The safety and tolerability were assessed throughout the study. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled, monocenter, institutional, phase IIb to III study. In case of efficacy at 6 months, the study would go on for another 6 months on an open design with all patients receiving miglustat. In the absence of efficacy at 6 months, the trial had to be continued for 6 more months with the initial design. RESULTS: After 6 months, efficacy was not superior in patients with miglustat. The independent review board confirmed continuing the study until 12 months. CONCLUSION: Miglustat treatment was not associated with any improvement/stabilization in behavior problems in patients with mucopolysaccharidosis type III. Miglustat has an acceptable safety profile. However, the study has confirmed that miglustat is able to pass through the blood-brain barrier without significantly decreasing ganglioside levels.

Tyrosinemia type 1 in pediatric nephrology: Not always straightforward.

The main clinical features of tyrosinemia type 1 usually appear in the first months of life, including fever, diarrhea, vomiting, liver involvement, growth failure, and renal proximal tubulopathy with subsequent hypophosphatemic rickets. An early diagnosis is crucial in order to provide specific management and to prevent complications. Here, we report on two cases referred primarily to pediatric nephrologists for the diagnosis of "neonatal tubulopathy" and management of "X-linked hypophosphatemia (XLH)," respectively. Our aim is to emphasize that (1) even a mixed tubulopathy can reveal tyrosinemia, and (2) tyrosinemia is a classic differential diagnosis of XLH that should not be forgotten, especially in the era of the anti-FGF23 burosumab.

Neurological manifestations in adults with phenylketonuria: new cases and review of the literature.

OBJECTIVE: Phenylketonuria (PKU) is a rare autosomal recessive disease characterised by high plasma phenylalanine levels inducing, if untreated, serious neurological manifestations in children but also, rarely, in adults who stopped their diet. The objective of the study was to describe the neurological manifestations observed in adults with PKU. METHODS: We analysed cases reported in French reference centres for inborn errors of metabolism and cases already reported in the literature. RESULTS: We report 8 new cases of neurological manifestations and 22 cases in the literature, which occurred in adult PKU patients, associated with chronic or rapid increase of phenylalanine levels, mostly when strict low-phenylalanine diet was stopped early in life. Neurological symptoms consisted in cerebellar ataxia, tremor, brisk reflexes, visual loss, sensory manifestations, and/or headaches. Visual loss was more frequent in the new cases (4/8) of the present series than in the literature (4/22). These neurological complications were associated with leucopathy on brain magnetic resonance imaging (27/29). The start of a low-phenylalanine diet improved or fully reversed neurological manifestations, even in patients with late diagnosis during adulthood. CONCLUSION: Neurological manifestations can complicate PKU in adult patients with elevated phenylalanine levels, after long or short period of diet discontinuation. Neurologists should be aware of this diagnosis, and measure phenylalaninemia in case of neurological symptoms associated with non-specific leucopathy on brain MRI. PKU patients should be systematically encouraged to continue their diet and their medical follow-up to avoid neurological complications.

Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study.

BACKGROUND: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus. METHODS: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among populations using Wright's fixation index (Fst). To estimate the molecular evolutionary history of the PAH gene, we performed phylogenetic and evolutionary analyses using whole-genome and exome-sequencing data from healthy individuals and non-PKU patients, respectively. Finally, we used exome-wide association study to decipher potential genetic loci associated with population divergence on PAH. FINDINGS: The study included 696 patients and revealed 132 pathogenic PAH variants. Three geographical areas showed significant enrichment for a pathogenic PAH variant: North of France (p.Arg243Leu), North-West of France (p.Leu348Val), and Mediterranean coast (p.Ala403Val). One PAH variant (p.Glu280Gln) was significantly enriched among North-Africans (OR = 23·23; 95% CI: 9·75-55·38). PAH variants exhibiting a strong genetic differentiation were significantly enriched in the 'Biopterin_H' domain (OR = 6·45; 95% CI: 1·99-20·84), suggesting a balancing selection pressure on the biopterin function of PAH. Phylogenetic and timetree analyses were consistent with population differentiation events on European-, African-, and Asian-ancestry populations. The five PAH variants most strongly associated with a high selection pressure were phylogenetically close and were located within the biopterin domain coding region of PAH or in its vicinity. Among the non-PAH loci potentially associated with population divergence, two reached exome-wide significance: SSPO (SCO-spondin) and DBH (dopamine beta-hydroxylase), involved in neuroprotection and metabolic adaptation, respectively. INTERPRETATION: Our data provide evidence on the combination of evolutionary and adaptive events in populations with distinct ancestries, which may explain the overdominance of some genetic variants on PAH. FUNDING: French National Institute of Health and Medical Research (INSERM) UMR_S 1256.

Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years.

OBJECTIVE: To evaluate the effect of bone marrow transplantation in children with Hunter syndrome. STUDY DESIGN: Eight boys received a bone marrow graft between the ages of 3 and 16 years from 1990 to 2000. In 6 cases, the donor was a sibling with identical HLA status, in 1 case an unrelated donor with HLA-compatible, and in 1 case a mismatched unrelated donor. A complete multidisciplinary evaluation was performed yearly. RESULTS: Successful engraftment was achieved in all patients, with the proportion of donor cells reaching > or =95% 1 month after transplantation in all patients. Patients have been followed from between 7 and 17 years and all are still alive, except for 1 boy who died at the age of 10 from unrelated causes. Cardiovascular abnormalities stabilized in all patients, hepatosplenomegaly resolved, and joint stiffness improved, Perceptual hearing defects remained stable, and transmission hearing defects improved. Only 1 child required subsequent surgery to correct kyphosis. Neuropsychological outcome was variable and appeared to be related to the severity of the syndrome. CONCLUSIONS: Bone marrow transplantation is effective on the no neuropsychological symptoms of Hunter disease.

A rare late progression form of Sly syndrome mucopolysaccharidosis.

Mucopolysaccharidoses VII, or Sly syndrome, is linked to mutations in the beta-glucuronidase encoding gene. Sly syndrome is a rare condition and presentation is highly variable, ranging from a prenatal form with severe, lethal fetal hydrops to more benign adolescent or adult forms with simple thoracic kyphosis. Molecular diagnosis of this adult male patient identified two missense mutations in the GUSB gene that led to a deficiency in beta-glucuronidase catalytic activity and the resulting accumulation of chondroitin sulfate glycosaminoglycans. During childhood, bilateral inguinal hernia was repaired at 1 year of age and gait abnormalities were noted, leading to a bilateral femoral varization osteotomy due to a bilateral coxa valga with hip subluxation at the age of 7.5. The patient suffered regular upper respiratory infections and required numerous orthopedic surgeries. Despite learning difficulties with visual and hearing deficits, the patient worked full-time and undertook regular leisure activities. At 33 years of age, the patient's health deteriorated; a hip replacement and glaucoma leading to reductions in his visual field limited his capacity to travel independently. The patient was hospitalized at 51. Although he remained self-sufficient for taking meals, he needed help with many daily activities. Following a period marked by major asthenia with a general loss of autonomy, the patient died at 52 years of age. With the advent of new enzyme replacement therapies, this medical history of this rare untreated attenuated patient may provide benchmarks to judge the efficacy of treatment in future patients.

Treatment needs and expectations for Fabry disease in France: development of a new Patient Needs Questionnaire.

BACKGROUND: Fabry disease (FD) is a rare, X-linked, inherited lysosomal disease caused by absent or reduced α-galactosidase A activity. Due to the heterogeneity of disease presentation and progression, generic patient-reported outcome (PRO) tools do not provide accurate insight into patients' daily lives and impact of disease specific treatments. Also, the French National Health Authority, (HAS) actively encourages a patient-centric approach to improve the quality of care throughout the patient journey. In response to this initiative, we aimed to develop and validate a specific, self-reported, Patient Needs Questionnaire for people living with Fabry disease to appraise patient needs and expectations towards their treatment (PNQ Fabry). This endeavour was led with the help of French patient associations (APMF & VML) and dedicated expert centres. PNQ Fabry was developed according to the FDA/EMA methodologies and best practices for the development of PRO tools in rare diseases. Our approach comprised of three steps, as follows: concept elicitation and item generation, item reduction, and final validation of the questionnaire through a two-stage survey. RESULTS: Intrinsic and extrinsic reliability was established, using a validated benchmark questionnaire. With the invaluable help of patient associations, we recruited a satisfactory population in this rare disease setting, to ensure robust participation to validate our PNQ (final number of questionnaires: 76). At the end of the process, a 26-item patient-reported questionnaire was obtained with excellent psychometric properties, exhibiting very satisfactory measurement outcomes for reliability and validity. The results of this initiative demonstrate that the PNQ Fabry is accurate, suitable and tailored to FD patients, as it addresses themes identified during patient interviews, that were further validated through statistical analyses of quantitative surveys. An ongoing phase IV study is using this tool. CONCLUSION: We believe the PNQ Fabry will be a reliable and insightful tool in clinical practice, to improve patient management in FD.

Influenza burden in febrile infants and young children in a pediatric emergency department.

BACKGROUND: In France, epidemiologic data in children in ambulatory settings are scarce. We aimed to measure the burden of influenza in young children. METHODS: Febrile children younger than 36 months were consecutively recruited in a pediatric emergency department during the 2002 epidemic peak. Virology analysis and follow-up were systematic. RESULTS: During calendar weeks 3 to 6, 2002, 575 children were recruited; 49% were positive: A/H3N2 in 44% and B in 5%. Prevalence rate was 57% in 12- to 35-month-old children and 39% in infants younger than 12 months. The main clinical pictures were nonrespiratory in one third of them. One of 8 patients had a complication. One of 10 patients was hospitalized, and the estimated specific hospitalization rate for the study period was 237 of 100,000 in the general population among infants younger than 12 months. Forty-two percent of children (n = 110) were prescribed antibiotics and at least 34% of them were inappropriate (n = 89). Median length of disease was 8 days, and 25% of the children had not fully recovered by day 11. Only one child had been previously vaccinated of 65 with chronic conditions. Both epidemic strains were covered by the vaccine. CONCLUSIONS: Health outcomes showed that influenza disease burden in young French children is similar to that observed in North America. An active vaccination strategy would have strongly reduced the burden of influenza and lowered antibiotic use. Continuous efforts are needed to reach requirements of our influenza vaccination policy.