Mutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy.
DEBRAY, François-Guillaume ; ; et al
in Journal of inherited metabolic disease (2015)
Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive ... [more ▼]
Leukodystrophies are a heterogeneous group of severe genetic neurodegenerative disorders. A multiple mitochondrial dysfunctions syndrome was found in an infant presenting with a progressive leukoencephalopathy. Homozygosity mapping, whole exome sequencing, and functional studies were used to define the underlying molecular defect. Respiratory chain studies in skeletal muscle isolated from the proband revealed a combined deficiency of complexes I and II. In addition, western blotting indicated lack of protein lipoylation. The combination of these findings was suggestive for a defect in the iron-sulfur (Fe/S) protein assembly pathway. SNP array identified loss of heterozygosity in large chromosomal regions, covering the NFU1 and BOLA3, and the IBA57 and ABCB10 candidate genes, in 2p15-p11.2 and 1q31.1-q42.13, respectively. A homozygous c.436C > T (p.Arg146Trp) variant was detected in IBA57 using whole exome sequencing. Complementation studies in a HeLa cell line depleted for IBA57 showed that the mutant protein with the semi-conservative amino acid exchange was unable to restore the biochemical phenotype indicating a loss-of-function mutation of IBA57. In conclusion, defects in the Fe/S protein assembly gene IBA57 can cause autosomal recessive neurodegeneration associated with progressive leukodystrophy and fatal outcome at young age. In the affected patient, the biochemical phenotype was characterized by a defect in the respiratory chain complexes I and II and a decrease in mitochondrial protein lipoylation, both resulting from impaired assembly of Fe/S clusters. [less ▲]Detailed reference viewed: 7 (4 ULg)
Diagnostic pitfall in antenatal manifestations of CPT II deficiency.
BOEMER, François ; DEBERG, Michelle ; SCHOOS, Roland et al
in Clinical genetics (2015)
Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of ... [more ▼]
Carnitine palmitoyltransferase II (CPT2) deficiency is a rare inborn error of mitochondrial fatty acid metabolism associated with various phenotypes. Whereas most patients present with postnatal signs of energetic failure affecting muscle and liver, a small subset of patients presents antenatal malformations including brain dysgenesis and neuronal migration defects. Here, we report recurrence of severe cerebral dysgenesis with Dandy-Walker malformation in three successive pregnancies and review previously reported antenatal cases. Interestingly, we also report that acylcarnitines profile, tested retrospectively on the amniotic fluid of last pregnancy, was not sensitive enough to allow reliable prenatal diagnosis of CPT2 deficiency. Finally, because fetuses affected by severe cerebral malformations are frequently aborted, CPT2 deficiency may be underestimated and fatty acid oxidation disorders should be considered when faced with a fetus with Dandy-Walker anomaly or another brain dysgenesis. [less ▲]Detailed reference viewed: 16 (5 ULg)
Les nouveaux outils de diagnostic et de pronostic de la myopathie atypique
Habyarimana, Jean ; BOEMER, François ; Amory, Hélène et al
in Proceeding de la 41ème Journée de la Recherche équine (2015)
In equines, ingestion of hypoglycin A, a toxin produced in the seeds (samaras) of sycamore maple (Acer pseudoplatanus) tree alters the energetic metabolism of muscle cells and results in atypical myopathy ... [more ▼]
In equines, ingestion of hypoglycin A, a toxin produced in the seeds (samaras) of sycamore maple (Acer pseudoplatanus) tree alters the energetic metabolism of muscle cells and results in atypical myopathy (AM). This alterations leads to a characteristic biochemical profile of acylcarnitines (AC) that enables to confirm the diagnosis of AM. This study aims at validating a methodology for the dosage of hypoglycin A in vegetal extracts but also in blood. In addition, the biochemical profile in AC has been determined in AM cases (5 survivors and 13 deceased) and in 5 horses suffering from exercise-induced myopathy. The AC profiles of these horses have been compared to the one of healthy horses (n = 35). This study showed that hypoglycin A was present in seeds and spring seedlings of sycamore and also in blood of AM cases horses. In addition, the establishment of AC profile contributes to the diagnostic and helps to assess the prognosis of AM cases. [less ▲]Detailed reference viewed: 76 (25 ULg)
Cystic Fibrosis screening by simultaneous ELISA for IRT1 and PAP proteins. A pilot study.
Scientific conference (2014, December 11)Detailed reference viewed: 11 (1 ULg)
6-Years Experience of NBS for Hemoglobin Disorders using TMS
Conference (2014, October)Detailed reference viewed: 12 (0 ULg)
Falsos positivos de C5-carnitina elevada en cribado neonatal: A que son debidos?
; ; et al
in Medicina Clinica (2014)Detailed reference viewed: 20 (2 ULg)
Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.
RAMAEKERS, Vincent ; ; et al
in Molecular genetics and metabolism (2014), 113(4), 307-14
BACKGROUND: Auto-antibodies against folate receptor alpha (FRalpha) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia ... [more ▼]
BACKGROUND: Auto-antibodies against folate receptor alpha (FRalpha) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide. METHODS: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated. RESULTS: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (chi(2)=21.6; p<0.0001). FRalpha antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean+/-SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement. CONCLUSION: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRalpha antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process. [less ▲]Detailed reference viewed: 36 (3 ULg)
Mitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene.
Debray, François-Guillaume ; ; et al
in Mitochondrion (2014)
Cytochrome c oxidase (COX) deficiency is one of the most common respiratory chain deficiencies. A woman was presented at the age of 18y with acute loss of consciousness, non-convulsive status epilepticus ... [more ▼]
Cytochrome c oxidase (COX) deficiency is one of the most common respiratory chain deficiencies. A woman was presented at the age of 18y with acute loss of consciousness, non-convulsive status epilepticus, slow neurological deterioration, transient cortical blindness, exercise intolerance, muscle weakness, hearing loss, cataract and cognitive decline. Muscle biopsy revealed ragged-red fibers, COX negative fibers and a significant decreased activity of complex IV in a homogenate. Using next generation massive parallel sequencing of the mtDNA, a novel heteroplasmic mutation was identified in MTCO1, m.7402delC, causing frameshift and a premature termination codon. Single fiber PCR showed co-segregation of high mutant load in COX negative fibers. Mutation in mitochondrially encoded complex IV subunits should be considered in mitochondrial encephalomyopathies and COX negative fibers after the common mtDNA mutations have been excluded. [less ▲]Detailed reference viewed: 24 (1 ULg)
Surprising causes of C5-carnitine false positive results in newborn screening.
BOEMER, François ; SCHOOS, Roland ; de HALLEUX, Virginie et al
in Molecular genetics and metabolism (2014), 111(1), 52-4
During an 18-month period, we noticed an alarming increase of newborn screening false positivity rate in identifying isovaleric acidemia. In 50 of 50 newborns presenting elevated C5-carnitine, we ... [more ▼]
During an 18-month period, we noticed an alarming increase of newborn screening false positivity rate in identifying isovaleric acidemia. In 50 of 50 newborns presenting elevated C5-carnitine, we confirmed the presence of pivaloylcarnitine. Exogenous pivalate administration had been previously identified as the causal agent of this concern. No pivalic-ester prodrug is commercially available in Belgium, but pivalic derivates are also used in the cosmetic industry as emollient under the term "neopentanoate". We have identified neopentanoate-esters in a nipple-fissure unguent that was provided to young mothers. Ceasing distribution of this product hugely reduced the C5-carnitine false positivity rate. [less ▲]Detailed reference viewed: 60 (19 ULg)
BLOOD GROUPS, HEMOGLOBIN PHENOTYPES AND CLINICAL DISORDERS OF CONSANGUINEOUS YANSI POPULATION
Munlemvo Mavanga, Nana ; BOEMER, François ; SEIDEL, Laurence et al
in World Journal of Hematology (2013), 2(4), 109-114
AIM To study frequency of blood groups, prevalence of sickle-cell anemia trait and glucose-6-phosphate dehydrogenase deficiency, among consanguineous Yansi tribe. METHODS A total of 525 blood samples were ... [more ▼]
AIM To study frequency of blood groups, prevalence of sickle-cell anemia trait and glucose-6-phosphate dehydrogenase deficiency, among consanguineous Yansi tribe. METHODS A total of 525 blood samples were collected, of which 256 among the Yansi population, and 269 for the unrelated control group in the Bandundu province of Democratic Republic of Congo. Blood group antigens were determined in the following systems: ABO, Rh, Kell, Duffy, Kidd and MNS. Blood grouping and extended phenotype tests were performed according to standard immunohematological procedures. Spot tests and tandem mass spectrometry were used respectively for the assessment of glucose-6-phosphate dehydrogenase deficiency and sickle-cell anemia trait. RESULTS The frequency of ABO phenotypes conformed to the following order O>A>B>AB with notably 62.5, 23.8, 12.1 and 1.6% for the Yansi, and 54.6, 27.5, 14.1 and 3.7% for the unrelated control group, respectively (P=0.19). As for the Rh phenotypes, the most frequent were ccD.ee, ccD.Ee, CcD.ee, corresponding to 71.5, 12.1 and 12.1% for the Yansi, and 70.6, 15.6 and 8.2%, for the unrelated control group (P=0.27). The frequency of MN and Ss phenotypes were statistically different between groups (P=0.0021 and P=0.0006). G6PD deficiency was observed in 11.3% of subjects in the Yansi group, and in 12.4% of controls (P = 0.74). The sickle-cell anemia trait was present in 22.4% of Yansi subjects and 17.8% in the control group (P=0.24). Miscarriages and deaths in young age were more common among Yansi people. CONCLUSION This study shows a significant difference in MNS blood group distribution between the Yansi tribe and a control population. The distribution of other blood groups and the prevalence of hemoglobinopathies did not differ in the Yansi tribe. [less ▲]Detailed reference viewed: 93 (17 ULg)
Evaluation of Physiological Amino Acids Profiling by Tandem Mass Spectrometry
; ; BOEMER, François
in Journal of Inherited Metabolic Disease Reports (2013)Detailed reference viewed: 18 (4 ULg)
HETEROGENOUS CLINICAL AND LABORATORY PRESENTATIONS IN MAD DEFICIENCY
BOEMER, François ; SCHOOS, Roland ; et al
Poster (2013, September)Detailed reference viewed: 16 (6 ULg)
Identification of methylenecyclopropyl acetic acid in serum of European horses with atypical myopathy
Votion, Dominique ; ; et al
in Equine Veterinary Journal (2013)Detailed reference viewed: 170 (34 ULg)
Enhanced interpretation of newborn screening results without analyte cutoff values
; ; et al
in Genetics in Medicine (2012), 14(7), 648-655
Purpose: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. Methods: A database of 767,464 ... [more ▼]
Purpose: To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries. Methods: A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors. Results: Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events. Conclusion: Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%. © 2012 American College of Medical Genetics and Genomics. [less ▲]Detailed reference viewed: 45 (10 ULg)
Hepatocyte transplantation using the domino concept in a child with Tetrabiopterin non-responsive phenylketonuria.
; DEBRAY, François-Guillaume ; et al
in Cell Transplantation (2012), 21(12), 2765-70
Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and ... [more ▼]
Phenylketonuria is a metabolic disease caused by phenylalanine hydroxylase deficiency. Treatment is based on a strict natural protein-restricted diet that is associated with the risk of malnutrition and severe psychosocial burden. Oral administration of tetrahydrobiopterin can increase residual enzyme activity, but most patients with severe clinical phenotypes are non-responders. We performed liver cell transplantation in 6 years-old boy with severe tetrahydrobiopterin non-responsive phenylketonuria, who failed to comply with diet prescriptions. The transplanted hepatocytes were obtained in part from an explanted glycogen storage type 1b liver. Following two infusions, blood phenylalanine levels returned within the therapeutic target while the phenylalanine half-life assessed by loading tests decreased from 43 h to 19 h. However, three months later, blood phenylalanine concentrations increased and the phenylalanine intake had to be reduced. Cell based therapy is a promising therapeutic option in phenylketonuria and the domino concept may solve the issue of cell sources for hepatocyte transplantation. [less ▲]Detailed reference viewed: 35 (12 ULg)
Neonatal thyroid-stimulating hormone concentrations in Belgium: a useful indicator for detecting mild iodine deficiency?
; ; et al
in PLoS ONE (2012)Detailed reference viewed: 12 (6 ULg)
Clinical validation of cutoff target ranges in newborn screening of metabolic disorders by tandem mass spectrometry: a worldwide collaborative project.
; ; et al
in Genetics in Medicine : Official Journal of the American College of Medical Genetics (2011), 13(3), 230-54Detailed reference viewed: 24 (4 ULg)
3-years experience review of neonatal screening for hemoglobin disorders using tandem mass spectrometry.
BOEMER, François ; Cornet, Yves ; LIBIOULLE, Cécile et al
in Clinica Chimica Acta (2011), 412(15-16), 1476-9
BACKGROUND: Neonatal screening programs for sickle cell disease are common in North America and in some European countries. Isoelectric Focusing or High Performance Liquid Chromatography is the main ... [more ▼]
BACKGROUND: Neonatal screening programs for sickle cell disease are common in North America and in some European countries. Isoelectric Focusing or High Performance Liquid Chromatography is the main technique used for hemoglobin variant detection. METHODS: Since tandem mass spectrometry is being used for screening of inherited metabolic disorders and allows protein identification, we had developed an application to identify the most relevant hemoglobin mutations with this technology. RESULTS: This approach had been previously validated and has been routinely applied in our laboratory for the last three years. We report here our experience with this new method in the field, applied to our East-Belgian population. CONCLUSIONS: To conclude, mass spectrometry provides an efficient alternative approach for laboratories performing neonatal screening of hemoglobin disorders. [less ▲]Detailed reference viewed: 60 (12 ULg)
Newborn Screening for Sickle Cell Disease using Tandem Mass Spectrometry
Conference (2009, April)Detailed reference viewed: 17 (5 ULg)
Dépistage Néonatal de la Drépanocytose: Nouvelles Méthodologies
Doctoral thesis (2009)Detailed reference viewed: 7 (1 ULg)