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See detailDouble genetic defect in a case of congenital hypogonadotropic hypogonadism
Potorac, Iulia ULg; Pintiaux, Axelle ULg; VALDES SOCIN, Hernan Gonzalo ULg et al

in Abstract book - 17th World Congress of Gynecological Endocrinology (2016, March)

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See detailNouvelle mutation du Fibroblast Growth Factor Receptor 1 (FGFR1)-cause d'hypogonadisme hypogonadotrope idiopathique normosmique
Potorac, Iulia ULg; Chachati, Anne-Sophie ULg; Debray, François-Guillaume ULg et al

in Abstract book- Annales d'Endocrinologie - 32ème Congrès de la Société Française d'Endocrinologie (2015, October)

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See detailHypogonadisme hypogonadotrope normosmique familial : identification d'une nouvelle mutation c.1664-2A> T du gène FGFR1
VALDES SOCIN, Hernan Gonzalo ULg; Pintiaux, Axelle ULg; LIBIOULLE, Cécile ULg et al

in Abstract book - Annales d'Endocrinologie - 32ème Congrès de la Société Française d'Endocrinologie (2015, October)

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See detailSchizencephaly associated with a severe prothrombotic syndrome caused by antithombin III deficiency
Daron, Aurore; DRESSE, Marie-Françoise ULg; Hoyoux, Claire ULg et al

in Tijdschrift van de Belgische Kinderarts = Journal du Pédiatre Belge (2015), 17(1), 109

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See detailIn-depth phenotyping of a Donnai-Barrow patient helps clarify proximal tubule dysfunction.
Dachy, Angelique; Paquot, Francois ULg; Debray, François-Guillaume ULg et al

in Pediatric nephrology (Berlin, Germany) (2015), 30(6), 1027-31

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin ... [more ▼]

BACKGROUND: The megalin/cubilin/amnionless complex is essential for albumin and low molecular weight (LMW) protein reabsorption by renal proximal tubules (PT). Mutations of the LRP2 gene encoding megalin cause autosomal recessive Donnai-Barrow/facio-oculo-acoustico-renal syndrome (DB/FOAR), which is characterized by LMW proteinuria. The pathophysiology of DB/FOAR-associated PT dysfunction remains unclear. CLINICAL CASE: A 3-year-old girl presented with growth retardation and proteinuria. Clinical examination was unremarkable, except for a still-opened anterior fontanel and myopia. Psychomotor development was delayed. At 6, she developed sensorineural hearing loss. Hypertelorism was noted when she turned 12. Blood analyses, including renal function parameters, were normal. Urine sediment was bland. Proteinuria was significant and included albumin and LMW proteins. Immunoblotting analyses detected cubilin and type 3 carbonic anhydrase (CA3) in the urine. Renal ultrasound was unremarkable. Optical examination of a renal biopsy did not disclose any tubular or glomerular abnormality. Electron microscopy revealed that PT apical endocytic apparatus was significantly less developed. Immunostaining for megalin showed a faint signal in PT cytosol contrasting with the distribution of cubilin at the apical membrane. The diagnostic procedure led to identifying two mutations of the LRP2 gene. CONCLUSIONS: The functional loss of megalin in DB/FOAR causes PT dysfunction characterized by increased urinary shedding of CA3 and cubilin. [less ▲]

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See detailMutation Update of the CLCN5 Gene Responsible for Dent Disease 1.
Mansour-Hendili, Lamisse; Blanchard, Anne; Le Pottier, Nelly et al

in Human mutation (2015), 36(8), 743-52

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable ... [more ▼]

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies. [less ▲]

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See detailCorrigendum: Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
Simons, Cas; Rash, Lachlan D.; Crawford, Joanna et al

in Nature genetics (2015), 47(3), 304

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See detailMutation of the iron-sulfur cluster assembly gene IBA57 causes fatal infantile leukodystrophy.
DEBRAY, François-Guillaume ULg; Stumpfig, Claudia; Vanlander, Arnaud V. 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 ▲]

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See detailDiagnostic pitfall in antenatal manifestations of CPT II deficiency.
BOEMER, François ULg; DEBERG, Michelle ULg; SCHOOS, Roland ULg 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 ▲]

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See detailMutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy.
Simons, Cas; Rash, Lachlan D.; Crawford, Joanna et al

in Nature genetics (2015), 47(1), 73-7

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we ... [more ▼]

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether a go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations. [less ▲]

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See detailEccentric training for elbow hypermobility
Kaux, Jean-François ULg; Delvaux, François ULg; Forthomme, Bénédicte ULg et al

in British Journal of Sports Medicine (2014, April), 48(7), 154

Background: Patients with hypermobility suffer from joints problems and chronic pain is the most frequently reported symptom. Objective: Eccentric muscle strengthening could be very important to protect ... [more ▼]

Background: Patients with hypermobility suffer from joints problems and chronic pain is the most frequently reported symptom. Objective: Eccentric muscle strengthening could be very important to protect hypermobile joints. Design: Case report. Patient: A girl (16 y.o.) affected by an Ehler-Danlos syndrome presented pain in the right elbow and the right wrist after a season of tennis. Interventions: Her training consisted of wrist prono-supination and flexion-extension muscle group reinforcement and proprioceptive training. To protect the wrist against excessive load, the eccentric strengthening exercises of prono-supinator and flexor-extensor muscles of elbow and wrist were undertaken gradually, at increasing speeds within a limited range of motion in flexion and extension, on an isokinetic device after an evaluation. She was also given an orthesis restricting the joint range of motion of the wrist. Main outcome measurements: The evaluation was made by isokinetic evaluation, visual analog scale and MOS-SF36 questionnaire before and after training. Results: The patient rapidly noted a decrease in pain and an increase in the stability of her right arm even when playing tennis. Isokinetic evaluation objectified a significant improvement in maximal torque in flexion-extension muscles of the right elbow. She was also given individualized home exercises. Conclusions: The goal of this eccentric training is to avoid hypermobility by using the muscles as a protective brake in the control of joint positioning. Muscles can be reinforced in eccentric mode with starting position at the maximum length of these muscles when unstreched. The exercises can be carried out safely on an isokinetic device, at slow speed and limited range of joint motion to avoid risk of luxation. Thus, in this case report, the eccentric exercises using an isokinetic device were effective to safely reinforce the muscles as a protective brake for joint hypermobility and prevent pain during practicing tennis. [less ▲]

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See detailNovel fibroblast growth factor receptor 1 mutation causing normosmic idiopathic hypogonadotropic hypogonadism
Chachati, AS; Potorac, I; DEBRAY, François-Guillaume ULg et al

in Abstract book - Symposium "Perspectives in Endocrinology" Congresses Highlights 2013:ECE Copenhagen, ENDO SF, SFE Paris (2014, February)

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See detailCowden Syndrome: a novel PTEN mutation description and how to recognize a not so rare hereditary cancer syndrome
Delannoy, Pauline; DEBRAY, François-Guillaume ULg; BECKERS, Albert ULg et al

in Acta Clinica Belgica (2014), 69(suppl 3), 16

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See detailReproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.
VALDES SOCIN, Hernan Gonzalo ULg; Rubio Almanza, Matilde; Tome Fernandez-Ladreda, Mariana et al

in Frontiers in endocrinology (2014), 5

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the ... [more ▼]

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology. [less ▲]

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See detailMitochondrial encephalomyopathy with cytochrome c oxidase deficiency caused by a novel mutation in the MTCO1 gene.
Debray, François-Guillaume ULg; Seneca, Sara; Gonce, Michel 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 ▲]

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See detailNeonatal progeroid variant of Marfan syndrome with congenital lipodystrophy results from mutations at the 3' end of FBN1 gene.
Jacquinet, Adeline ULg; Verloes, Alain; Callewaert, Bert et al

in European journal of medical genetics (2014), 57(5), 230-4

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of ... [more ▼]

We report a 16-year-old girl with neonatal progeroid features and congenital lipodystrophy who was considered at birth as a possible variant of Wiedemann-Rautenstrauch syndrome. The emergence of additional clinical signs (marfanoid habitus, severe myopia and dilatation of the aortic bulb) lead to consider the diagnosis of the progeroid variant of Marfan syndrome. A de novo donor splice-site mutation (c.8226+1G>A) was identified in FBN1. We show that this mutation leads to exon 64 skipping and to the production of a stable mRNA that should allow synthesis of a truncated profibrillin-1, in which the C-terminal furin cleavage site is altered. FBN1 mutations associated with a similar phenotype have only been reported in four other patients. We confirm the correlation between marfanoid phenotype with congenital lipodystrophy and neonatal progeroid features (marfanoid-progeroid-lipodystrophy syndrome) and frameshift mutations at the 3' end of FBN1. This syndrome should be considered in differential diagnosis of neonatal progeroid syndromes. [less ▲]

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See detailUse of sapropterin dihydrochloride in maternal phenylketonuria. A European experience of eight cases.
Feillet, Francois; Muntau, Ania C.; DEBRAY, François-Guillaume ULg et al

in Journal of inherited metabolic disease (2014)

Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA ... [more ▼]

Sapropterin dihydrochloride (SD) is the first drug treatment for phenylketonuria (PKU), but due to the lack of data, its use in maternal PKU must be undertaken with caution as noted in the FDA and EMEA labels. We collected data from eight pregnancies in PKU women treated with SD and we analysed the phenotypes of these patients, their tetrahydrobiopterin (BH4) responsiveness, the indications for SD treatment, the efficacy (metabolic control, phenylalanine (Phe) tolerance and offspring outcome) and the safety data. Results showed that in the seven patients known to be responsive to BH4, the use of SD during pregnancy was efficient in terms of metabolic control and Phe tolerance. The indications for giving SD included the failure of the low-Phe diet (n = 3), the fact that some of these women had never experienced the low Phe diet (n = 2), one unexpected pregnancy in a woman currently on SD and one pregnancy where the foetus was known to have PKU. The offspring of these seven pregnancies were all normal babies with normal birth measurements and outcomes. No side effect related to SD was observed in these seven cases. In the eighth case, SD was prescribed as a rescue treatment without previous knowledge of the BH4 responsiveness to a woman who was already 8 weeks pregnant without diet. The birth occurred at 33 weeks of gestational age with Potter syndrome (probably related to the absence of metabolic control during the first trimester) and the baby died in the first hours of life. In conclusion, the data presented here provides the first evidence that treatment with pharmacological doses of SD appears to be efficient and safe in women with PKU during pregnancy. Its use should, however, be restricted to those women previously identified to be clear responders to BH4. [less ▲]

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See detailClinical variability in neurohepatic syndrome due to combined mitochondrial DNA depletion and Gaucher disease
HARVENGT, Julie ULg; wanty, catherine; De Paepe, Boel et al

in Molecular Genetics and Metabolism Reports (2014)

A one year old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the ... [more ▼]

A one year old girl born to consanguineous parents presented with unexplained liver failure, leading to transplantation at 19 months. Subsequent partial splenectomy for persistent cytopenia showed the presence of foamy cells, and Gaucher disease was confirmed by homozygosity for the p.Leu483Pro mutation in the GBA gene. She was treated by enzyme replacement therapy (ERT). Clinical follow-up showed mild developmental delay, strabism, nystagmus and oculomotor apraxia. Biochemical studies revealed multiple respiratory chain deficiencies and a mosaic pattern of deficient complex IV immunostaining in liver and fibroblast. Molecular analysis identified a mtDNA depletion syndrome due to the homozygous p.Pro98Leu mutation in MPV17. A younger sister unaffected by mtDNA depletion, presented with pancytopenia and hepatosplenomegaly. ERT for Gaucher disease resulted in visceral normalization, without any neurological symptom. A third sister, affected by both conditions, had marked developmental delay, strabism and ophthalmoplegia but no liver cirrhosis. In conclusion, intrafamilal variability occurs in MPV17 related disease. The combined pathological effect of Gaucher and mitochondrial diseases can negatively impact neurological and liver functions, and influence the outcome in consanguineous families. Immunocytochemical staining of OXPHOS protein in tissues and cultured cells is a powerful tool revealing mosaic pattern of deficiency pointing to mtDNA related mitochondrial disorders. [less ▲]

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See detailSurprising causes of C5-carnitine false positive results in newborn screening.
BOEMER, François ULg; SCHOOS, Roland ULg; de HALLEUX, Virginie ULg 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 ▲]

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See detailNovel fibroblast growth factor receptor 1 mutation causing normosmic idiopathic hypogonadotropic hypogonadism
Chachati, Anne-Sophie ULg; Potorac, Iulia ULg; DEBRAY, François-Guillaume ULg et al

in 23rd meeting of the Belgian Endocrine Society - Abstract book (2013, October 19)

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