Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. ... more Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate wa...
Tim Van Damme,1,25 Thatjana Gardeitchik,2,3,25 Miski Mohamed,2,25 Sergio Guerrero-Castillo,4,5,26... more Tim Van Damme,1,25 Thatjana Gardeitchik,2,3,25 Miski Mohamed,2,25 Sergio Guerrero-Castillo,4,5,26 Peter Freisinger,6,26 Brecht Guillemyn,1,26 Ariana Kariminejad,7,26 Daisy Dalloyaux,2,5 Sanne van Kraaij,2,5 Dirk J. Lefeber,5,8 Delfien Syx,1 Wouter Steyaert,1 Riet De Rycke,9,10 Alexander Hoischen,3 Erik-Jan Kamsteeg,3 Sunnie Y. Wong,11 Monique van Scherpenzeel,5,8 Payman Jamali,12 Ulrich Brandt,4,5 Leo Nijtmans,4,5 G. Christoph Korenke,13 Brian H.Y. Chung,14 Christopher C.Y. Mak,14 Ingrid Hausser,15 Uwe Kornak,16,17 Björn Fischer-Zirnsak,16,17 Tim M. Strom,18 Thomas Meitinger,18 Yasemin Alanay,19 Gulen E. Utine,20 Peter K.C. Leung,14 Siavash Ghaderi-Sohi,7 Paul Coucke,1 Sofie Symoens,1 Anne De Paepe,1 Christian Thiel,21 Tobias B. Haack,18,22,23 Fransiska Malfait,1,27 Eva Morava,11,24,27 Bert Callewaert,1,27,* and Ron A. Wevers5,27,*
Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generali... more Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4‐kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4‐phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of P...
Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exac... more Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to HO, formaldehyde, and HS, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads...
3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome ... more 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals neve...
Journal of inherited metabolic disease, Sep 10, 2016
Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital dis... more Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The olde...
Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to... more Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafnes...
Background: Genetic diseases that affect the biosynthesis of protein O-glycans are a rapidly grow... more Background: Genetic diseases that affect the biosynthesis of protein O-glycans are a rapidly growing group of disorders. Because this group of disorders does not have a collective name, it is difficult to get an overview of O-glycosylation in relation to human health and disease. Many patients with an unsolved defect in N-glycosylation are found to have an abnormal O-glycosylation as well. It is becoming increasingly evident that the primary defect of these disorders is not necessarily localized in one of the glycan-specific transferases, but can likewise be found in the biosynthesis of nucleotide sugars, their transport to the endoplasmic reticulum (ER)/Golgi, and in Golgi trafficking. Already, disorders in O-glycan biosynthesis form a substantial group of genetic diseases. In view of the number of genes involved in O-glycosylation processes and the increasing scientific interest in congenital disorders of glycosylation, it is expected that the number of identified diseases in this...
Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. ... more Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate wa...
Tim Van Damme,1,25 Thatjana Gardeitchik,2,3,25 Miski Mohamed,2,25 Sergio Guerrero-Castillo,4,5,26... more Tim Van Damme,1,25 Thatjana Gardeitchik,2,3,25 Miski Mohamed,2,25 Sergio Guerrero-Castillo,4,5,26 Peter Freisinger,6,26 Brecht Guillemyn,1,26 Ariana Kariminejad,7,26 Daisy Dalloyaux,2,5 Sanne van Kraaij,2,5 Dirk J. Lefeber,5,8 Delfien Syx,1 Wouter Steyaert,1 Riet De Rycke,9,10 Alexander Hoischen,3 Erik-Jan Kamsteeg,3 Sunnie Y. Wong,11 Monique van Scherpenzeel,5,8 Payman Jamali,12 Ulrich Brandt,4,5 Leo Nijtmans,4,5 G. Christoph Korenke,13 Brian H.Y. Chung,14 Christopher C.Y. Mak,14 Ingrid Hausser,15 Uwe Kornak,16,17 Björn Fischer-Zirnsak,16,17 Tim M. Strom,18 Thomas Meitinger,18 Yasemin Alanay,19 Gulen E. Utine,20 Peter K.C. Leung,14 Siavash Ghaderi-Sohi,7 Paul Coucke,1 Sofie Symoens,1 Anne De Paepe,1 Christian Thiel,21 Tobias B. Haack,18,22,23 Fransiska Malfait,1,27 Eva Morava,11,24,27 Bert Callewaert,1,27,* and Ron A. Wevers5,27,*
Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generali... more Inherited cutis laxa, or inelastic, sagging skin is a genetic condition of premature and generalised connective tissue ageing, affecting various elastic components of the extracellular matrix. Several cutis laxa syndromes are inborn errors of metabolism and lead to severe neurological symptoms. In a patient with cutis laxa, a choreoathetoid movement disorder, dysmorphic features and intellectual disability we performed exome sequencing to elucidate the underlying genetic defect. We identified the amino acid substitution R275W in phosphatidylinositol 4‐kinase type IIα, caused by a homozygous missense mutation in the PI4K2A gene. We used lipidomics, complexome profiling and functional studies to measure phosphatidylinositol 4‐phosphate synthesis in the patient and evaluated PI4K2A deficient mice to define a novel metabolic disorder. The R275W residue, located on the surface of the protein, is involved in forming electrostatic interactions with the membrane. The catalytic activity of P...
Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exac... more Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to HO, formaldehyde, and HS, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads...
3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome ... more 3-Methylglutaconic aciduria, dystonia-deafness, hepatopathy, encephalopathy, Leigh-like syndrome (MEGDHEL) syndrome is caused by biallelic variants in SERAC1. This multicenter study addressed the course of disease for each organ system. Metabolic, neuroradiological, and genetic findings are reported. Sixty-seven individuals (39 previously unreported) from 59 families were included (age range = 5 days-33.4 years, median age = 9 years). A total of 41 different SERAC1 variants were identified, including 20 that have not been reported before. With the exception of 2 families with a milder phenotype, all affected individuals showed a strikingly homogeneous phenotype and time course. Severe, reversible neonatal liver dysfunction and hypoglycemia were seen in >40% of all cases. Starting at a median age of 6 months, muscular hypotonia (91%) was seen, followed by progressive spasticity (82%, median onset = 15 months) and dystonia (82%, 18 months). The majority of affected individuals neve...
Journal of inherited metabolic disease, Sep 10, 2016
Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital dis... more Alpha-1,3-glucosyltransferase congenital disorder of glycosylation (ALG6-CDG) is a congenital disorder of glycosylation. The original patients were described with hypotonia, developmental disability, epilepsy, and increased bleeding tendency. Based on Euroglycan database registration, we approached referring clinicians and collected comprehensive data on 41 patients. We found hypotonia and developmental delay in all ALG6-CDG patients and epilepsy, ataxia, proximal muscle weakness, and, in the majority of cases, failure to thrive. Nine patients developed intractable seizures. Coagulation anomalies were present in <50 % of cases, without spontaneous bleedings. Facial dysmorphism was rare, but seven patients showed missing phalanges and brachydactyly. Cyclic behavioral change, with autistic features and depressive episodes, was one of the most significant complaints. Eleven children died before the age of 4 years due to protein losing enteropathy (PLE), sepsis, or seizures. The olde...
Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to... more Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafnes...
Background: Genetic diseases that affect the biosynthesis of protein O-glycans are a rapidly grow... more Background: Genetic diseases that affect the biosynthesis of protein O-glycans are a rapidly growing group of disorders. Because this group of disorders does not have a collective name, it is difficult to get an overview of O-glycosylation in relation to human health and disease. Many patients with an unsolved defect in N-glycosylation are found to have an abnormal O-glycosylation as well. It is becoming increasingly evident that the primary defect of these disorders is not necessarily localized in one of the glycan-specific transferases, but can likewise be found in the biosynthesis of nucleotide sugars, their transport to the endoplasmic reticulum (ER)/Golgi, and in Golgi trafficking. Already, disorders in O-glycan biosynthesis form a substantial group of genetic diseases. In view of the number of genes involved in O-glycosylation processes and the increasing scientific interest in congenital disorders of glycosylation, it is expected that the number of identified diseases in this...
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