Publications of François-Guillaume DEBRAY
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See detailMale and female hypogonadotropic hypogonadism associated with two novel non sense heterozygous mutations of Klotho beta gene (KLB)
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; PETIGNOT, Sandrine ULiege et al

Poster (2021, September 17)

Clinical Case 1: A 15-year-old boy, with congenital deafness of the right ear, without olfaction disorders, consults for pubertal and growth retardation (1.59m, 47kg). Bone age of 14 years, GH: 6.4 ng/ml ... [more ▼]

Clinical Case 1: A 15-year-old boy, with congenital deafness of the right ear, without olfaction disorders, consults for pubertal and growth retardation (1.59m, 47kg). Bone age of 14 years, GH: 6.4 ng/ml after ITT, LHRH-stimulateable gonadotropins, testosterone-total 99ng/dl (28-1110 ng/dl). Pituitary MRI is normal. His father and sister had late puberty around the age of 16. The patient treated with GH and Sustanon, reaches 1.77m and 79 kg. At the age of 16, suffering from MS, like his father. At 18 years, the gonadic balance is re-evaluated, normal (bilateral testicular volume: 14 ml). Clinical case 2: A 30 years old woman (1.62m, 61 kg) consults for secondary amenorrhea and infertility after clomiphene stimulation. She is normal weighted. After some left hypoesthesic symptomatology, a brain neuro inflammatory pathology was suspected on MRI (several frontal hyper intense T2 lesions) without a precise diagnosis. No pituitary lesions were identified. During follow up, a normal pregnancy was obtained. She delivered a 3.3 kg girl in 2019 . Genetic analysis: A panel of 61 genes of hypogonadotropic hypogonadism found in case 1 an heterozygous variant KLB c.3092T>A, p.(Leu1031*). This new variant (likely pathogenic, class IV), causes the appearance of a premature stop codon in exon 5 of the KLB gene. In case 2, a novel mutation c.2230_2231insGGTT, p.(Ala744Glyfs*45) was confirmed, causing a frame shift and stop codon (since codon Ala744).. Discussion: We describe two novel non sense KLB mutations and for the first time, a reproductive phenotype in a female affected patient. In our series of 54 consecutive patients with congenital hypogonadotropic hypogonadism sequenced with a panel of 61 candidate genes, KLB mutations represents 3.7% . This prevalence is in line with the 4% finding of Xu. et al(EMBO Mol Med 2017). In the series of XU et al, patients with missense KLB mutations had (n= 9/13) a metabolic syndrome too, unlike our patients, carrying a nonsense mutation. In mice, the loss of the klb gene leads to delayed puberty, impaired estrogenic cycle, subfertility. The association with multiple sclerosis/brain inflammatory lesions is intriguing, so other family members will be studied. [less ▲]

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See detailComment j'explore... un trouble du spectre de l'autisme
Barrea, Christophe ULiege; JADOT, Annick ULiege; DEBRAY, François-Guillaume ULiege et al

in Revue Médicale de Liège (2021), 76(10), 761-767

Le trouble du spectre de l’autisme (TSA) est une pathologie neurodéveloppementale complexe, caractérisée par des déficits de la communication et des interactions sociales associés à un caractère restreint ... [more ▼]

Le trouble du spectre de l’autisme (TSA) est une pathologie neurodéveloppementale complexe, caractérisée par des déficits de la communication et des interactions sociales associés à un caractère restreint et répétitif des comportements, des intérêts et des activités. Etant donné le caractère très hétérogène du trouble et l’absence de biomarqueur, son approche diagnostique doit être globale, multidisciplinaire, et répondre aux critères des classifications internationales. Par ailleurs, les TSA résultent d’un modèle multifactoriel dont l’étiologie demeure inconnue dans la majorité des cas. Afin d’optimiser le rendement exploratoire et d’homogénéiser les pratiques, ce document propose un cadre pour la mise au point des TSA en pédiatrie. [less ▲]

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See detailComment j’explore… Une pathologie organique à l’origine d’un trouble pédopsychiatrique
BARREA, Christophe ULiege; DEBRAY, François-Guillaume ULiege; SIMON, Michaël ULiege et al

in Revue Médicale de Liège (2020), 75(1),

Psychiatric disorders in children may be the expression of underlying organic conditions. These are numerous and varied. The clinical presentation is often frustrating: psychiatric signs can remain ... [more ▼]

Psychiatric disorders in children may be the expression of underlying organic conditions. These are numerous and varied. The clinical presentation is often frustrating: psychiatric signs can remain isolated for years before other more specific organic signs appear. More recently, new treatments have been developed, making it possible to improve the prognosis of some of these organic diseases; screening them is therefore a daily concern for the child psychiatrist. This literature review discusses various paediatric treatable organic disorders that may have an isolated psychiatric presentation, to finally propose a decision tree algorithm based on somatic and psychiatric complaints reported. [less ▲]

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See detailGenetic and phenotypic spectrum associated with IFIH1 gain-of-function
Rice, Gillian I.; DEBRAY, François-Guillaume ULiege; HARVENGT, Julie ULiege et al

in Human Mutation (2020)

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 ... [more ▼]

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. [less ▲]

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See detailResearch activity and capability in the European reference network MetabERN
Heard, Jean-Michel; Bellettato, Cinzia; van Lingen, Corine et al

in Orphanet journal of rare diseases (2019), 14(1), 119

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 ... [more ▼]

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. RESULTS: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. CONCLUSIONS: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups. [less ▲]

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See detailBrain imaging and genetics in patients with congenital hypogonadotropic hypogonadism: a multicenter Belgian study.
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; HARVENGT, Julie ULiege et al

in Jorgensen, Jens OL (Ed.) NENEG Abstract Book Communications (2018, April 19)

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See detailLe Syndrome de Kallmann: un vieux syndrome revisité par la génétique
VALDES SOCIN, Hernan Gonzalo ULiege; LIBIOULLE, Cécile ULiege; DEBRAY, François-Guillaume ULiege et al

in Urologic (2018), 14

Le contrôle neuroendocrinien de la reproduction chez l’homme est régi par un réseau d’environ 1.500 neurones hypothalamiques sécrétant la gonadotropin-releasing hormone (GnRH). Ce réseau module l’activité ... [more ▼]

Le contrôle neuroendocrinien de la reproduction chez l’homme est régi par un réseau d’environ 1.500 neurones hypothalamiques sécrétant la gonadotropin-releasing hormone (GnRH). Ce réseau module l’activité de l’axe de reproduction au cours de la vie. L’hypogonadisme hypogonadotrope congénital isolé (HHCI) est un syndrome clinique complexe, caractérisé par une insuffisance pubertaire partielle ou complète. Il peut découler d’une insuffisance hypothalamique sécrétoire de la GnRH ou d’une insuffisance de la sécrétion et/ou des effets des gonadotrophines hypophysaires. Chez l’homme, plusieurs gènes participant au développement olfactif et à la migration des neurones à GnRH interagissent pendant la vie embryonnaire. Les stéroïdes sexuels sont, à leur tour, nécessaires pour promouvoir la neurogenèse et le développement neurocognitif. Un nombre croissant de mutations de gènes participant à ce développement ont été identifiées comme étant responsables de HHCI. Sur base de la présence ou de l’absence d’un déficit de l’olfaction, l’HH est répertorié en deux syndromes, à savoir: HH avec altérations olfactives (syndrome de Kallmann) et l’hypogonadisme hypogonadotrophique idiopathique (IHH) avec une olfaction intacte ou normosmique (hypogonadisme IHH). Le syndrome de Kallmann (KS) est une condition hétérogène qui affecte 1 homme sur 5.000, avec un rapport homme/femme de 3/1. Le KS est associé à des mutations des gènes KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, SEMA7A, NELF, WDR11, SOX10, NSMF, AXL, FEZF1, DCC/NTN1 et KLB. Ces mutations entraînent des défauts de la migration neuronale, avec, comme possibles conséquences, un déficit variable au niveau de l’axe reproducteur, des troubles de l’olfaction, une surdité neurosensorielle. Des malformations y sont parfois associées, y compris un colobome, des syncinésies controlatérales, une malformation crâniofaciale et/ou une agénésie rénale. Dans cet article de synthèse, nous revisitons le syndrome de Kallmann vis-à-vis de ses conséquences sur la reproduction et sur le développement cérébral. [less ▲]

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See detailAre heterozygous carriers for hereditary fructose intolerance predisposed to metabolic disturbances when exposed to fructose?
DEBRAY, François-Guillaume ULiege; DAMJANOVIC, Katarina; ROSSET, Robin et al

in American Journal of Clinical Nutrition (2018), 108

Background: High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin ... [more ▼]

Background: High fructose intake causes hepatic insulin resistance and increases postprandial blood glucose, lactate, triglyceride, and uric acid concentrations. Uric acid may contribute to insulin resistance and dyslipidemia in the general population. In patients with hereditary fructose intolerance, fructose consumption is associated with acute hypoglycemia, renal tubular acidosis, and hyperuricemia. Objective: We investigated whether asymptomatic carriers for hereditary fructose intolerance (HFI) would have a higher sensitivity to adverse effects of fructose than would the general population. Design: Eight subjects heterozygous for HFI (hHFI; 4 men, 4 women) and 8 control subjects received a low-fructose diet for 7 d and on the eighth day ingested a test meal, calculated to provide 25% of the basal energy requirement, containing 13C-labeled fructose (0.35 g/kg), glucose (0.35 g/kg), protein (0.21 g/kg), and lipid (0.22 g/kg). Glucose rate of appearance (GRa, calculated with [6,6-2H2]glucose), fructose, net carbohydrate, and lipid oxidation, and plasma triglyceride, uric acid, and lactate concentrations were monitored over 6 h postprandially. Results: Postprandial GRa, fructose, net carbohydrate, and lipid oxidation, and plasma lactate and triglyceride concentrations were not significantly different between the 2 groups. Postprandial plasma uric acid increased by 7.2% compared with fasting values in hHFI subjects (P < 0.01), but not in control subjects (−1.1%, ns). Conclusions: Heterozygous carriers of hereditary fructose intolerance had no significant alteration of postprandial fructose metabolism compared with control subjects. They did, however, show a postprandial increase in plasma uric acid concentration that was not observed in control subjects in responses to ingestion of a modest amount of fructose. This trial was registered at the US Clinical Trials Registry as NCT02979106. [less ▲]

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See detailReverse-Transcriptase Inhibitors in the Aicardi-Goutieres Syndrome
Rice, Gillian I.; Meyzer, Candice; Bouazza, Naim et al

in New England Journal of Medicine (2018), 379(23), 2275-7

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See detailFaiblesse progressive des membres inferieurs revelatrice d'une dystrophie musculaire des ceintures.
Saintmard, G.; Brands, G.; Debray, François-Guillaume ULiege et al

in Revue Médicale de Liège (2017), 72(7-8), 373-376

We report the case of a 26-year-old man who initiated a limb girdle muscular dystrophy (lgmd2b). It is a rare and slowly progressive autosomal recessive dysferlinopathy occurring in young adults and for ... [more ▼]

We report the case of a 26-year-old man who initiated a limb girdle muscular dystrophy (lgmd2b). It is a rare and slowly progressive autosomal recessive dysferlinopathy occurring in young adults and for which no treatment is currently known. [less ▲]

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See detailA next-generation newborn screening pilot study: NGS on dried blood spots detects causal mutations in patients with inherited metabolic diseases.
BOEMER, François ULiege; Fasquelle, Corinne ULiege; D'OTREPPE DE BOUVETTE, Stéphanie ULiege et al

in Scientific Reports (2017), 7(1), 17641

The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview ... [more ▼]

The range of applications performed on dried blood spots (DBS) widely broadened during the past decades to now include next-generation sequencing (NGS). Previous publications provided a general overview of NGS capacities on DBS-extracted DNA but did not focus on the identification of specific disorders. We thus aimed to demonstrate that NGS was reliable for detecting pathogenic mutations on genomic material extracted from DBS. Assuming the future implementation of NGS technologies into newborn screening (NBS), we conducted a pilot study on fifteen patients with inherited metabolic disorders. Blood was collected from DBS. Whole-exome sequencing was performed, and sequences were analyzed with a specific focus on genes related to NBS. Results were compared to the known pathogenic mutations previously identified by Sanger sequencing. Causal mutations were readily characterized, and multiple polymorphisms have been identified. According to variant database prediction, an unexplained homozygote pathogenic mutation, unrelated to patient's disorder, was also found in one sample. While amount and quality of DBS-extracted DNA are adequate to identify causal mutations by NGS, bioinformatics analysis revealed critical drawbacks: coverage fluctuations between regions, difficulties in identifying insertions/deletions, and inconsistent reliability of database-referenced variants. Nevertheless, results of this study lead us to consider future perspectives regarding "next-generation" NBS. [less ▲]

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See detailPOLG2 deficiency causes adult-onset syndromic sensory neuropathy, ataxia and parkinsonism.
Van Maldergem, Lionel; Besse, Arnaud; De Paepe, Boel et al

in Annals of Clinical and Translational Neurology (2017), 4(1), 4-14

OBJECTIVE: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven ... [more ▼]

OBJECTIVE: Mitochondrial dysfunction plays a key role in the pathophysiology of neurodegenerative disorders such as ataxia and Parkinson's disease. We describe an extended Belgian pedigree where seven individuals presented with adult-onset cerebellar ataxia, axonal peripheral ataxic neuropathy, and tremor, in variable combination with parkinsonism, seizures, cognitive decline, and ophthalmoplegia. We sought to identify the underlying molecular etiology and characterize the mitochondrial pathophysiology of this neurological syndrome. METHODS: Clinical, neurophysiological, and neuroradiological evaluations were conducted. Patient muscle and cultured fibroblasts underwent extensive analyses to assess mitochondrial function. Genetic studies including genome-wide sequencing were conducted. RESULTS: Hallmarks of mitochondrial dysfunction were present in patients' tissues including ultrastructural anomalies of mitochondria, mosaic cytochrome c oxidase deficiency, and multiple mtDNA deletions. We identified a splice acceptor variant in POLG2, c.970-1G>C, segregating with disease in this family and associated with a concomitant decrease in levels of POLG2 protein in patient cells. INTERPRETATION: This work extends the clinical spectrum of POLG2 deficiency to include an overwhelming, adult-onset neurological syndrome that includes cerebellar syndrome, peripheral neuropathy, tremor, and parkinsonism. We therefore suggest to include POLG2 sequencing in the evaluation of ataxia and sensory neuropathy in adults, especially when it is accompanied by tremor or parkinsonism with white matter disease. The demonstration that deletions of mtDNA resulting from autosomal-dominant POLG2 variant lead to a monogenic neurodegenerative multicomponent syndrome provides further evidence for a major role of mitochondrial dysfunction in the pathomechanism of nonsyndromic forms of the component neurodegenerative disorders. [less ▲]

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