Publications by authors named "François Feillet"

98 Publications

Expanding the phenotype of X-linked SSR4-CDG: Connective tissue implications.

Hum Mutat 2021 Feb 21;42(2):142-149. Epub 2020 Dec 21.

Unit-703 Center for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, Madrid, Spain.

Signal sequence receptor protein 4 (SSR4) is a subunit of the translocon-associated protein complex, which participates in the translocation of proteins across the endoplasmic reticulum membrane, enhancing the efficiency of N-linked glycosylation. Pathogenic variants in SSR4 cause a congenital disorder of glycosylation: SSR4-congenital disorders of glycosylation (CDG). We describe three SSR4-CDG boys and review the previously reported. All subjects presented with hypotonia, failure to thrive, developmental delay, and dysmorphic traits and showed a type 1 serum sialotransferrin profile, facilitating the diagnosis. Genetic confirmation of this X-linked CDG revealed one de novo hemizygous deletion, one maternally inherited deletion, and one de novo nonsense mutation of SSR4. The present subjects highlight the similarities with a connective tissue disorder (redundant skin, joint laxity, blue sclerae, and vascular tortuosity). The connective tissue problems are relevant, and require preventive rehabilitation measures. As an X-linked disorder, genetic counseling is essential.
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http://dx.doi.org/10.1002/humu.24151DOI Listing
February 2021

Religious dietary rules and their potential nutritional and health consequences.

Int J Epidemiol 2021 Mar;50(1):12-26

Pediatric Gastroenterology Department, Necker Enfants-Malades Hospital, Paris Descartes University, Paris, France.

Background: The vast majority of the world population declares affiliation to a religion, predominantly Christianity and Islam. Many religions have special dietary rules, which may be more or less strictly adhered to.

Methods: Religious food rules were collected from holy books and religious websites as well as their translation into dietary practices. The literature was searched for potential associations between these rules and potential nutritional consequences.

Results: Jewish, Islamic and Indian religions support prolonged breastfeeding. Religious avoidance of alcohol is probably beneficial to health. When strictly applied, a few rules may lead to nutritional inadequacies, mainly in populations living in unfavourable socio-economic or environmental conditions. In Jewish and Muslim observants, animal slaughtering procedures may increase the risk of iron deficiency. Jews may be at risk of excess sodium intake related to home-prepared foods. A vegan diet, as observed by some believers, often by drifting from original precepts, or by some Hindus or Buddhists, may result in vitamin B12, calcium, iron, zinc, selenium and n-3 fatty acids deficiencies.

Conclusion: When implemented in accordance with the rules, most religious food precepts are not detrimental to health, as suggested by the fact that they have more or less been followed for millennia. Nevertheless, some practices may lead to nutritional inadequacies, such as iron, calcium, vitamin D and vitamin B12 deficiencies. Patients with low socio-economic status, children and women of childbearing age are of particular risk of such deficiencies. Being aware of them should help health professionals to take an individualized approach to decide whether to supplement or not.
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http://dx.doi.org/10.1093/ije/dyaa182DOI Listing
March 2021

Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency.

J Inherit Metab Dis 2021 Jan 1;44(1):178-192. Epub 2020 Dec 1.

Department of Pediatrics Emma Children's Hospital, Amsterdam University Medical Centre, Amsterdam, The Netherlands.

Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
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http://dx.doi.org/10.1002/jimd.12332DOI Listing
January 2021

Clinical and molecular characterization of adult patients with late-onset MTHFR deficiency.

J Inherit Metab Dis 2020 Oct 22. Epub 2020 Oct 22.

APHP, La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
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http://dx.doi.org/10.1002/jimd.12323DOI Listing
October 2020

Clinical and biological characterization of 20 patients with TANGO2 deficiency indicates novel triggers of metabolic crises and no primary energetic defect.

J Inherit Metab Dis 2021 Mar 28;44(2):415-425. Epub 2020 Sep 28.

Inserm U1151, Institut Necker Enfants-Malades, Paris, France.

TANGO2 disease is a severe inherited disorder associating multiple symptoms such as metabolic crises, encephalopathy, cardiac arrhythmias, and hypothyroidism. The mechanism of action of TANGO2 is currently unknown. Here, we describe a cohort of 20 French patients bearing mutations in the TANGO2 gene. We found that the main clinical presentation was the association of neurodevelopmental delay (n = 17), acute metabolic crises (n = 17) and hypothyroidism (n = 12), with a large intrafamilial clinical variability. Metabolic crises included rhabdomyolysis (15/17), neurological symptoms (14/17), and cardiac features (12/17; long QT (n = 10), Brugada pattern (n = 2), cardiac arrhythmia (n = 6)) that required intensive care. We show previously uncharacterized triggers of metabolic crises in TANGO2 patients, such as some anesthetics and possibly l-carnitine. Unexpectedly, plasma acylcarnitines, plasma FGF-21, muscle histology, and mitochondrial spectrometry were mostly normal. Moreover, in patients' primary myoblasts, palmitate and glutamine oxidation rates, and the mitochondrial network were also normal. Finally, we found variable mitochondrial respiration and defective clearance of oxidized DNA upon cycles of starvation and refeeding. We conclude that TANGO2 disease is a life-threatening disease that needs specific cardiac management and anesthesia protocol. Mechanistically, TANGO2 disease is unlikely to originate from a primary mitochondrial defect. Rather, we suggest that mitochondrial defects are secondary to strong extrinsic triggers in TANGO2 deficient patients.
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http://dx.doi.org/10.1002/jimd.12314DOI Listing
March 2021

Pollutants in Breast Milk: A Public Health Perspective - A Commentary of the Nutrition Committee of the French Society of Pediatrics.

J Pediatr Gastroenterol Nutr 2021 Mar;72(3):343-346

Université de Paris, Assistance Publique Hôpitaux de Paris, Paris.

Abstract: Pregnant and lactating women are continuously and ubiquitously exposed to numerous environmental pollutants from various sources including air, food, water, and occupational and household environments. The available evidence shows that pollutants are present in human milk and one of the emerging questions is what happens when the nursing infant is involuntarily exposed to contaminants through breastfeeding.The available literature does not currently provide a conclusive evidence of any consistent or clinically relevant health consequences in infants exposed to environment chemicals through breast milk. The available data strongly suggest that the benefits of breastfeeding outweigh the potential harmful effects of pollutants contained in human milk. The committee of nutrition of the French Pediatric Society strongly supports breastfeeding but also calls for public health actions to reduce the overall contamination level in the environment, to continue promoting breastfeeding, and to support research in this area.
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http://dx.doi.org/10.1097/MPG.0000000000002928DOI Listing
March 2021

[Phenylketonuria, from diet to gene therapy].

Med Sci (Paris) 2020 Aug-Sep;36(8-9):725-734. Epub 2020 Aug 21.

Centre de référence des maladies métaboliques, Service de pédiatrie, CHRU de Nancy, 54000 Nancy, France - Inserm UMR_S 1256 (NGERE, Nutrition Génétique et Exposition aux Risques Environnementaux), Faculté de médecine de Nancy, Université de Lorraine, 54000 Nancy, France.

The prognosis for phenylketonuria (PKU) has been improved by neonatal screening and dietary management via a low-phenylalanine diet. This treatment must be followed throughout life, which induces severe compliance problems. Drug treatment with sapropterin (or BH4) has come to help a reduced percentage of patients who respond to this drug. A subcutaneous enzyme therapy is available in the USA and has obtained European marketing authorization, but generates significant side effects, which limits its effectiveness. New therapeutic options for PKU are currently being developed, in particular gene therapy. The purpose of this article is to take stock of the pathophysiology and the various new therapeutic modalities currently in development.
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http://dx.doi.org/10.1051/medsci/2020127DOI Listing
October 2020

The Genetic Landscape and Epidemiology of Phenylketonuria.

Am J Hum Genet 2020 08 14;107(2):234-250. Epub 2020 Jul 14.

Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, Clinic I, University Hospital Heidelberg, 69120 Heidelberg, Germany; Division of Metabolism, University Children's Hospital, 8032 Zürich, Switzerland. Electronic address:

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413859PMC
August 2020

Prolonged 25-OH Vitamin D Deficiency Does Not Impair Bone Mineral Density in Adult Patients With Vitamin D 25-Hydroxylase Deficiency (CYP2R1).

Calcif Tissue Int 2020 08 19;107(2):191-194. Epub 2020 May 19.

Reference Center for Inborn Errors of Metabolism, Pediatric Unit, University Hospital of Nancy, Nancy, France.

Vitamin D-dependent rickets type 1B (VDDR1B) is an autosomal semidominant genetic disorder caused by a deficiency in CYP2R1, which encodes vitamin D 25-hydroxylase, an enzyme that plays a crucial role in the conversion of vitamin D to 25-dihydroxyvitamin D. VDDR1B is a severe form of rickets that occurs during infancy and which is responsive to 25-OH vitamin D supplementation. We studied three adult patients from a multi-consanguineous family with VDDR1B. They have been diagnosed with pseudo-nutritional rickets and treated during their adolescence with 25-OH vitamin D. These patients stopped their treatments at the end of adolescence and were contacted 14 to 17 years later when VDDR1B diagnosis was carried out in their niece and nephews. These three patients had undetectable 25-OH vitamin D, but normal levels of plasma 1-25(OH) vitamin D. All patients had a hip bone mineral density and a normal vertebral despite osteoarthritis degenerative lesions which may impact BMD evaluation. These findings show that vitamin D supplementation has a questionable effect, if any, for osteoporosis prevention in adulthood in contrast to its crucial importance during infancy and adolescence.
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http://dx.doi.org/10.1007/s00223-020-00704-4DOI Listing
August 2020

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

J Pediatr 2020 05 4;220:184-192.e6. Epub 2020 Mar 4.

Department of Epidemiology and Health Economics, AP-HM/EA 3279 CEReSS (Centre d'Etude et de Recherche sur les Services de Santé et la Qualité de vie), Aix-Marseille Univ, Marseille, France.

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.
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http://dx.doi.org/10.1016/j.jpeds.2020.01.059DOI Listing
May 2020

Analysis of fibroblasts from patients with cblC and cblG genetic defects of cobalamin metabolism reveals global dysregulation of alternative splicing.

Hum Mol Genet 2020 Jul;29(12):1969-1985

Inserm UMRS 1256 NGERE - Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy F-54000, France.

Vitamin B12 or cobalamin (Cbl) metabolism can be affected by genetic defects leading to defective activity of either methylmalonyl-CoA mutase or methionine synthase or both enzymes. Patients usually present with a wide spectrum of pathologies suggesting that various cellular processes could be affected by modifications in gene expression. We have previously demonstrated that these genetic defects are associated with subcellular mislocalization of RNA-binding proteins (RBP) and subsequent altered nucleo-cytoplasmic shuttling of mRNAs. In order to characterize the possible changes of gene expression in these diseases, we have investigated global gene expression in fibroblasts from patients with cblC and cblG inherited disorders by RNA-seq. The most differentially expressed genes are strongly associated with developmental processes, neurological, ophthalmologic and cardiovascular diseases. These associations are consistent with the clinical presentation of cblC and cblG disorders. Multivariate analysis of transcript processing revaled splicing alterations that led to dramatic changes in cytoskeleton organization, response to stress, methylation of macromolecules and RNA binding. The RNA motifs associated with this differential splicing reflected a potential role of RBP such as HuR and HNRNPL. Proteomic analysis confirmed that mRNA processing was significantly disturbed. This study reports a dramatic alteration of gene expression in fibroblasts of patients with cblC and cblG disorders, which resulted partly from disturbed function of RBP. These data suggest to evaluate the rescue of the mislocalization of RBP as a potential strategy in the treatment of severe cases who are resistant to classical treatments with co-enzyme supplements.
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http://dx.doi.org/10.1093/hmg/ddaa027DOI Listing
July 2020

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

EBioMedicine 2020 Jan 7;51:102623. Epub 2020 Jan 7.

University of Lorraine, INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, Nancy, France; Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, University Hospital of Nancy, Nancy, France; Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, Nancy F-54000, France.

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.
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http://dx.doi.org/10.1016/j.ebiom.2019.102623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000351PMC
January 2020

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

Hum Mutat 2020 04 14;41(4):837-849. Epub 2020 Jan 14.

Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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http://dx.doi.org/10.1002/humu.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457149PMC
April 2020

Dietary practices in methylmalonic acidaemia: a European survey.

J Pediatr Endocrinol Metab 2020 Jan;33(1):147-155

Birmingham Women's and Children's Hospital, Birmingham, UK.

Background The dietary management of methylmalonic acidaemia (MMA) is a low-protein diet providing sufficient energy to avoid catabolism and to limit production of methylmalonic acid. The goal is to achieve normal growth, good nutritional status and the maintenance of metabolic stability. Aim To describe the dietary management of patients with MMA across Europe. Methods A cross-sectional questionnaire was sent to European colleagues managing inherited metabolic disorders (IMDs) (n=53) with 27 questions about the nutritional management of organic acidaemias. Data were analysed by different age ranges (0-6 months; 7-12 months; 1-10 years; 11-16 years; >16 years). Results Questionnaires were returned from 53 centres. Twenty-five centres cared for 80 patients with MMA vitamin B12 responsive (MMAB12r) and 43 centres managed 215 patients with MMA vitamin B12 non-responsive (MMAB12nr). For MMAB12r patients, 44% of centres (n=11/25) prescribed natural protein below the World Health Organization/Food and Agriculture Organization/United Nations University (WHO/FAO/UNU) 2007 safe levels of protein intake in at least one age range. Precursor-free amino acids (PFAA) were prescribed by 40% of centres (10/25) caring for 36% (29/80) of all the patients. For MMAB12nr patients, 72% of centres (n=31/43) prescribed natural protein below the safe levels of protein intake (WHO/FAO/UNU 2007) in at least one age range. PFAA were prescribed by 77% of centres (n=33/43) managing 81% (n=174/215) of patients. In MMAB12nr patients, 90 (42%) required tube feeding: 25 via a nasogastric tube and 65 via a gastrostomy. Conclusions A high percentage of centres used PFAA in MMA patients together with a protein prescription that provided less than the safe levels of natural protein intake. However, there was inconsistent practices across Europe. Long-term efficacy studies are needed to study patient outcome when using PFAA with different severities of natural protein restrictions in patients with MMA to guide future practice.
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http://dx.doi.org/10.1515/jpem-2019-0277DOI Listing
January 2020

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

Genet Med 2020 03 25;22(3):610-621. Epub 2019 Nov 25.

Division of Neuropediatrics and Pediatric Metabolic Medicine, Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis.

Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods.

Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH).

Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.
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http://dx.doi.org/10.1038/s41436-019-0698-4DOI Listing
March 2020

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

J Neurol 2020 Feb 7;267(2):531-542. Epub 2019 Nov 7.

Hospices Civils de Lyon, Hôpital Neurologique Pierre Wertheimer, Neurologie C, 69677, Bron Cedex, France.

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.
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http://dx.doi.org/10.1007/s00415-019-09608-2DOI Listing
February 2020

SIRT1 activation rescues the mislocalization of RNA-binding proteins and cognitive defects induced by inherited cobalamin disorders.

Metabolism 2019 12 28;101:153992. Epub 2019 Oct 28.

Université de Lorraine, Inserm, UMRS 1256, NGERE - Nutrition, Genetics, and Environmental Risk Exposure, F-54000 Nancy, France; Université de Lorraine, CHRU-Nancy, National Center of Inborn Errors of Metabolism, F-54000 Nancy, France. Electronic address:

Background: The molecular consequences of inborn errors of vitamin B12 or cobalamin metabolism are far from being understood. Moreover, innovative therapeutic strategies are needed for the treatment of neurological outcomes that are usually resistant to conventional treatments. Our previous findings suggest a link between SIRT1, cellular stress and RNA binding proteins (RBP) mislocalization in the pathological mechanisms triggered by impaired vitamin B12 metabolism.

Objectives And Methods: The goal of this study was to investigate the effects of the pharmacological activation of SIRT1 using SRT1720 on the molecular mechanisms triggered by impaired methionine synthase activity. Experiments were performed in vitro with fibroblasts from patients with the cblG and cblC inherited defects of vitamin B12 metabolism and in vivo with an original transgenic mouse model of methionine synthase deficiency specific to neuronal cells. Subcellular localization of the RBPs HuR, HnRNPA1, RBM10, SRSF1 and Y14 was investigated by immunostaining and confocal microscopy in patient fibroblasts. RBPs methylation and phosphorylation were studied by co-immunoprecipitation and proximity ligation assay. Cognitive performance of the transgenic mice treated with SRT1720 was measured with an aquatic maze.

Results: Patient fibroblasts with cblC and cblG defects of vitamin B12 metabolism presented with endoplasmic reticulum stress, altered methylation, phosphorylation and subcellular localization of HuR, HnRNPA1 and RBM10, global mRNA mislocalization and increased HnRNPA1-dependent skipping of IRF3 exons. Incubation of fibroblasts with cobalamin, S-adenosyl methionine and okadaic acid rescued the localization of the RBPs and mRNA. The SIRT1 activating compound SRT1720 inhibited ER stress and rescued RBP and mRNA mislocalization and IRF3 splicing. Treatment with this SIRT1 agonist prevented all these hallmarks in patient fibroblasts but it also improved the deficient hippocampo-dependent learning ability of methionine synthase conditional knock-out mice.

Conclusions: By unraveling the molecular mechanisms triggered by inborn errors of cbl metabolism associating ER stress, RBP mislocalization and mRNA trafficking, our study opens novel therapeutic perspectives for the treatment of inborn errors of vitamin B12 metabolism.
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http://dx.doi.org/10.1016/j.metabol.2019.153992DOI Listing
December 2019

Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis.

J Hum Genet 2020 Jan 23;65(2):91-98. Epub 2019 Oct 23.

INSERM UMR_S 1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure and Reference Centre for Inherited Metabolic Diseases (ORPHA67872), University Hospital of Nancy and Faculty of Medicine of Nancy, University of Lorraine, Nancy, France.

Hereditary spastic paraplegias (HSPs) are characterized by lower extremity spasticity and weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errors of metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weakness occurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weakness and the metabolic changes, including hyperhomocysteinemia and decreased activity of both N(5,10)methylenetetrahydrofolate reductase (MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spastic paraparesis phenotype with combined metabolic, muscular, and neurological components.
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http://dx.doi.org/10.1038/s10038-019-0689-yDOI Listing
January 2020

Bone mineral density is within normal range in most adult phenylketonuria patients.

J Inherit Metab Dis 2020 03 6;43(2):251-258. Epub 2020 Feb 6.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC - Location AMC, Amsterdam, The Netherlands.

Low bone mineral density (BMD) as a risk factor for fractures has been a long-standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual-energy X-ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18-46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z-score <-2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35-40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.
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http://dx.doi.org/10.1002/jimd.12177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078943PMC
March 2020

Mineral and vitamin intake of infants and young children: the Nutri-Bébé 2013 survey.

Eur J Nutr 2020 Sep 25;59(6):2463-2480. Epub 2019 Sep 25.

INSERM 1256, Lorraine University, 54000, Nancy, France.

Purpose: Minerals and vitamins are essential for optimal growth and development, particularly during the first years of life. Therefore, regularly evaluating their intake makes sense. For this purpose, we report the data from the Nutri-Bébé 2013 survey in comparison with the European Food Safety Authority Adequate Intake (AI), or Average Requirement, (AR) according to age.

Methods: This observational, nationally representative, cross-sectional survey was conducted in 1035 non-breastfed French children aged 0.5-35 months. Dietary intake was recorded using a food diary on three non-consecutive days, framed by two face-to-face interviews.

Results: The intake of zinc, magnesium and water-soluble vitamins most of the time met the recommendations. From the first weeks of life, sodium intake exceeded the AI, with a maximum median intake of 1137 mg/day after the age of 30 months. However, it has decreased since 2005. Calcium median intake often exceeded the AI or AR, reaching a maximum of 780 mg/day between 18 and 23 months. Median vitamin A intake always exceeded the AI or AR but exceeded the recommended upper limit in only a few cases. After 2 years, median iron intake was clearly below the AR, i.e. lower than 6.0 mg/day. Dietary vitamin D intake was below the AI, thereby justifying adequate supplementation. Vitamin E intake was below the AI in 50-75% of toddlers.

Conclusion: This survey highlights excessive sodium intake as well as a shortfall of iron, vitamin D, and vitamin E intakes. The potential consequences of these discrepancies with respect to health outcomes remain to be assessed.
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http://dx.doi.org/10.1007/s00394-019-02093-3DOI Listing
September 2020

The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency.

Genet Med 2020 01 29;22(1):199-209. Epub 2019 Aug 29.

Metabolic Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Purpose: Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantile-onset encephalomyopathic MDDS. Here we describe the natural history of this disease.

Methods: Multinational series of new genetically confirmed cases from six pediatric centers.

Results: Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalized weakness, and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anemia (13%). Laboratory features included elevated lactate (blood, cerebrospinal fluid (CSF), urine, magnetic resonance (MR), spectroscopy), ragged-red and cytochrome c oxidase-deficient fibers, lipid myopathy, and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year.

Conclusions: Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.
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http://dx.doi.org/10.1038/s41436-019-0613-zDOI Listing
January 2020

Deciphering exome sequencing data: Bringing mitochondrial DNA variants to light.

Hum Mutat 2019 12 26;40(12):2430-2443. Epub 2019 Aug 26.

INSERM-University of Burgundy-Franche Comté, UMR1231 GAD, Dijon, France.

The expanding use of exome sequencing (ES) in diagnosis generates a huge amount of data, including untargeted mitochondrial DNA (mtDNA) sequences. We developed a strategy to deeply study ES data, focusing on the mtDNA genome on a large unspecific cohort to increase diagnostic yield. A targeted bioinformatics pipeline assembled mitochondrial genome from ES data to detect pathogenic mtDNA variants in parallel with the "in-house" nuclear exome pipeline. mtDNA data coming from off-target sequences (indirect sequencing) were extracted from the BAM files in 928 individuals with developmental and/or neurological anomalies. The mtDNA variants were filtered out based on database information, cohort frequencies, haplogroups and protein consequences. Two homoplasmic pathogenic variants (m.9035T>C and m.11778G>A) were identified in 2 out of 928 unrelated individuals (0.2%): the m.9035T>C (MT-ATP6) variant in a female with ataxia and the m.11778G>A (MT-ND4) variant in a male with a complex mosaic disorder and a severe ophthalmological phenotype, uncovering undiagnosed Leber's hereditary optic neuropathy (LHON). Seven secondary findings were also found, predisposing to deafness or LHON, in 7 out of 928 individuals (0.75%). This study demonstrates the usefulness of including a targeted strategy in ES pipeline to detect mtDNA variants, improving results in diagnosis and research, without resampling patients and performing targeted mtDNA strategies.
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http://dx.doi.org/10.1002/humu.23885DOI Listing
December 2019

Hearing impairment as an early sign of alpha-mannosidosis in children with a mild phenotype: Report of seven new cases.

Am J Med Genet A 2019 09 26;179(9):1756-1763. Epub 2019 Jun 26.

Centre de Génétique et Centre de Référence Maladies Rares 'Anomalies du Développement' de l'Interrégion Est, Hôpital d'Enfants, CHU, Dijon, France.

Alpha-mannosidosis (AM) is a very rare (prevalence: 1/500000 births) autosomal recessive lysosomal storage disorder. It is characterized by multi-systemic involvement associated with progressive intellectual disability, hearing loss, skeletal anomalies, and coarse facial features. The spectrum is wide, from very severe and lethal to a milder phenotype that usually progresses slowly. AM is caused by a deficiency of lysosomal alpha-mannosidase. A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. Enzyme replacement therapy (LAMZEDE ) was approved for use in Europe in August 2018. Here, we describe seven individuals from four families, diagnosed at 3-23 years of age, and who were referred to a clinical geneticist for etiologic exploration of syndromic hearing loss, associated with moderate learning disabilities. Exome sequencing had been used to establish the molecular diagnosis in five cases, including a two-sibling pair. In the remaining two patients, the diagnosis was obtained with screening of urinary oligosaccharides excretion and the association of deafness and hypotonia. These observations emphasize that the clinical diagnosis of AM can be challenging, and that it is likely an underdiagnosed rare cause of syndromic hearing loss. Exome sequencing can contribute significantly to the early diagnosis of these nonspecific mild phenotypes, with advantages for treatment and management.
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http://dx.doi.org/10.1002/ajmg.a.61273DOI Listing
September 2019

Efficacy of low dose nitisinone in the management of alkaptonuria.

Mol Genet Metab 2019 07 19;127(3):184-190. Epub 2019 Jun 19.

Pediatric Unit, Reference center for Inborn Errors of Metabolism of Nancy, University Children's Hospital, CHU Brabois, Vandoeuvre les Nancy, France; INSERM UMRS 1256 NGERE, Nutrition, Genetics, and Environmental Risk Exposure, National Center of Inborn Errors of Metabolism, Faculty of Medicine of Nancy, University of Lorraine and University Regional Hospital Center of Nancy, Vandoeuvre-les-Nancy F-54000, France. Electronic address:

Aim: To study the efficacy of low dosage of nitisinone in alkaptonuria.

Background: Alkaptonuria (AKU) is a rare genetic disease which induces deposition of homogentisic acid (HGA) in connective inducing premature arthritis, lithiasis, cardiac valve disease, fractures, muscle and tendon ruptures and osteopenia. Recent studies showed that nitisinone decreases HGA and is a beneficial therapy in AKU. This treatment induces an increase in tyrosine levels which can induces adverse effects as keratopathy.

Methods: We described the evolution HGA excretion and tyrosine evolution in 3 AKU patients treated by very low dosage of nitisinone with regards to their daily protein intakes. We also described the first pregnancy in an AKU patient treated by nitisinone.

Results: We found mild clinical signs of alkaptonuria on vertebra MRI in two young adults and homogentisate deposition in teeth of a 5 years old girl. Very low dose of nitisinone (10% of present recommended dose: 0.2 mg/day) allowed to decrease homogentisic acid by >90% without increasing tyrosine levels above 500 μmol/ in these three patients.

Interpretations: The analysis of the follow-up data shows that, in our three patients, a low-dosage of nitisinone is sufficient to decrease urinary HGA without increasing plasma tyrosine levels above the threshold of 500 μmol/L.
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http://dx.doi.org/10.1016/j.ymgme.2019.06.006DOI Listing
July 2019

Exome sequencing of cases with neural tube defects identifies candidate genes involved in one-carbon/vitamin B12 metabolisms and Sonic Hedgehog pathway.

Hum Genet 2019 Jul 28;138(7):703-713. Epub 2019 May 28.

INSERM U1256, NGERE-Nutrition, Genetics, and Environmental Risk Exposure, Faculty of Medicine of Nancy, University of Lorraine, 54000, Nancy, Vandoeuvre-lès-Nancy, France.

Neural tube defects (NTD) result from complex mechanisms between genes, nutrition and environment. The identification of genetic predictors by genome exome sequencing and their influence on genome methylation need further consideration. Gene variants related to 1-CM metabolism (1-CM) could influence the methylation of genes involved in neural tube embryogenesis through impaired synthesis of S-adenosyl methionine. We performed exome sequencing of 6116 genes referenced in OMIM and NTD risk and genome-wide methylation in 23 NTD cases. We replicated the most significant associations in 81 other cases. The analysis of exome sequencing identified one gene of 1-CM, LRP2, and one gene of Sonic Hedgehog (SHH), GLI3, in the 23 NTD cases. The analysis restricted to genes of 1-CM and neural tube embryogenesis identified five gene predictors of 1-CM (LRP2, rs137983840; MMAA, rs148142853; TCN2, rs35838082; FPGS, rs41306702; BHMT, rs763726268) and two of SHH (GLI3, rs35364414; MKS1, rs151023718). We replicated the association of TCN2, BHMT and GLI3 with NTD risk in the 81 cases. We found a significant hemimethylation of CFAP46 that may influence SHH activation in one case, who carried risk alleles in BHMT, LRP2, MMAA and GLI3. In conclusion, we identified new candidate genes and rare variants that highlight an interacting influence of genes involved in SHH and 1-CM in the puzzle of genetic components of NTD risk.
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http://dx.doi.org/10.1007/s00439-019-02015-7DOI Listing
July 2019

International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria.

Mol Genet Metab 2019 05 26;127(1):1-11. Epub 2019 Apr 26.

Genetic Metabolic Disorders Service, University of Sydney, Children's Hospital Westmead Clinical School, Sydney, NSW, Australia. Electronic address:

Phenylketonuria (PKU) is an inherited metabolic disease caused by phenylalanine hydroxylase (PAH) deficiency. As the resulting high blood phenylalanine (Phe) concentration can have detrimental effects on brain development and function, international guidelines recommend lifelong control of blood Phe concentration with dietary and/or medical therapy. Sapropterin dihydrochloride is a synthetic preparation of tetrahydrobiopterin (6R-BH4), the naturally occurring cofactor of PAH. It acts as a pharmacological chaperone, reducing blood Phe concentration and increasing dietary Phe tolerance in BH4-responsive patients with PAH deficiency. Protocols to establish responsiveness to sapropterin dihydrochloride vary widely. Two meetings were held with an international panel of clinical experts in PKU management to develop recommendations for sapropterin dihydrochloride response testing. At the first meeting, regional differences and similarities in testing practices were discussed based on guidelines, a literature review, outcomes of a global physician survey, and case reports. Statements developed based on the discussions were sent to all participants for consensus (>70% of participants) evaluation using a 7-level rating system, and further discussed during the second meeting. The experts recommend sapropterin dihydrochloride response testing in patients with untreated blood Phe concentrations of 360-2000 μmol/L, except in those with two null mutations. For neonates, a 24-h sapropterin dihydrochloride loading test is recommended; responsiveness is defined as a decrease in blood Phe ≥30%. For older infants, children, adolescents, and adults, a test duration of ≥48 h or a 4-week trial is recommended. The main endpoint for a 48-h to 7-day trial is a decrease in blood Phe, while improved Phe tolerance is the endpoint to be assessed during a longer trial. Longer trials may not be feasible in some locations due to lack of reimbursement for hospitalization, while a 4-week trial may not be possible due to limited access to sapropterin dihydrochloride or public health regulation. A 48-h response test should be considered in pregnant patients who cannot achieve blood Phe ≤360 μmol/L with a Phe-restricted diet. Durability of response and clinical benefits of sapropterin dihydrochloride should be assessed over the long term. Harmonization of protocols is expected to improve identification of responders and comparability of test results worldwide.
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http://dx.doi.org/10.1016/j.ymgme.2019.04.004DOI Listing
May 2019

Neuropsychological Profile of Children with Early and Continuously Treated Phenylketonuria: Systematic Review and Future Approaches.

J Int Neuropsychol Soc 2019 07 29;25(6):624-643. Epub 2019 Apr 29.

Laboratory of Psychology, UBL, EA4638,University of Angers,49000 Angers,France.

Objective: To provide a comprehensive systematic review of the literature by examining studies published on all cognitive aspects of children with early and continuously treated phenylketonuria (ECT-PKU) included in the databases Medline, PsycINFO, and PsycARTICLE.

Method: In addition to a classical approach, we summarized methodology and results of each study in order to discuss current theoretical and methodological issues. We also examined recent advances in biochemical markers and treatments of PKU, with implications for future research on metabolic control and its role as a determinant of neuropsychological outcome.

Results: Consistent with previous reviews, the hypothesis of a specific and central executive impairment in children with ECT-PKU was suggested. However, findings are inconclusive regarding the nature of executive impairments as well as their specificity, impact on everyday life, persistence over time, and etiology.

Conclusion: Given the current state of the science, we suggest future directions for research that utilizes a developmental and integrative approach to examine the effects of recent advances in biochemical markers and treatment of PKU. (JINS, 2019, 25, 624-643).
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http://dx.doi.org/10.1017/S1355617719000146DOI Listing
July 2019

Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects.

Am J Clin Nutr 2019 03;109(3):674-683

Inserm UMRS 954, Nutrition-Genetics-Environmental Risk Exposure, Inserm and University of Lorraine, Nancy, France.

Background: The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms.

Objectives: This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk.

Methods: We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings).

Results: The tissue concentration of vitamin B-12 (P = 0.003), but not folate, and the activity (P = 0.001), transcriptional level (P = 0.016), and protein expression (P = 0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk.

Conclusions: The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.
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http://dx.doi.org/10.1093/ajcn/nqy340DOI Listing
March 2019

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

Genet Med 2019 09 6;21(9):2025-2035. Epub 2019 Feb 6.

CHU de Nantes, Service de Génétique Médicale, Nantes, France.

Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.

Methods: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.

Results: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.

Conclusion: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
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http://dx.doi.org/10.1038/s41436-019-0445-xDOI Listing
September 2019

Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome.

Calcif Tissue Int 2019 04 15;104(4):355-363. Epub 2018 Dec 15.

Centre de référence des erreurs innées du métabolisme, Hôpital d'Enfants, CHRU Nancy, Nancy, France.

Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.
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http://dx.doi.org/10.1007/s00223-018-0505-2DOI Listing
April 2019