Hans R Waterham

Academisch Medisch Centrum Universiteit van Amsterdam, Amsterdamo, North Holland, Netherlands

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Publications (294)1244.27 Total impact

  • Ronald J. A. Wanders · Hans R. Waterham · Sacha Ferdinandusse
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    ABSTRACT: Peroxisomes are unique subcellular organelles which play an indispensable role in several key metabolic pathways which include: (1.) etherphospholipid biosynthesis; (2.) fatty acid beta-oxidation; (3.) bile acid synthesis; (4.) docosahexaenoic acid (DHA) synthesis; (5.) fatty acid alpha-oxidation; (6.) glyoxylate metabolism; (7.) amino acid degradation, and (8.) ROS/RNS metabolism. The importance of peroxisomes for human health and development is exemplified by the existence of a large number of inborn errors of peroxisome metabolism in which one of these functions is impaired. Although the clinical signs and symptoms of affected patients differ depending upon the enzyme which is deficient and the extent of the deficiency, the disorders involved are usually (very) severe diseases with neurological dysfunction and early death in many of them. With respect to the role of peroxisomes in metabolism it is clear that peroxisomes are dependent on the functional interplay with other subcellular organelles to sustain their role in metabolism. Indeed, whereas mitochondria can oxidize fatty acids all the way to CO2 and H2O, peroxisomes are only able to chain-shorten fatty acids and the end products of peroxisomal beta-oxidation need to be shuttled to mitochondria for full oxidation to CO2 and H2O. Furthermore, NADH is generated during beta-oxidation in peroxisomes and beta-oxidation can only continue if peroxisomes are equipped with a mechanism to re-oxidize NADH back to NAD+, which is now known to be mediated by specific NAD(H)-redox shuttles. In this paper we describe the current state of knowledge about the functional interplay between peroxisomes and other subcellular compartments notably the mitochondria and endoplasmic reticulum for each of the metabolic pathways in which peroxisomes are involved.
    No preview · Article · Jan 2016 · Frontiers in Cell and Developmental Biology
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    ABSTRACT: Analysis of the plasma levels of very long chain fatty acids (VLCFA) is a primary screening method for peroxisomal disorders and usually identifies severe peroxisomal biogenesis defects reliably. We report a patient presenting with typical facial stigmata, a treatment resistant seizure disorder and polymicrogyria, whose plasma VLCFA levels were within normal limits until the age of 18 months. Only thereafter an elevation was found. Subsequent enzymatic and molecular genetic analysis revealed compound heterozygous mutations in the PEX6 gene. In conclusion, normal VLCFA levels do not necessarily exclude global peroxisomal biogenesis defects and the analysis should be repeated subsequently. Persisting clinical suspicion justifies further enzymatic and molecular evaluation.
    No preview · Article · Dec 2015 · European journal of paediatric neurology: EJPN: official journal of the European Paediatric Neurology Society
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    Hans R. Waterham · Sacha Ferdinandusse · Ronald J.A. Wanders
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    ABSTRACT: Peroxisomes are dynamic organelles that play an essential role in a variety of cellular catabolic and anabolic metabolic pathways, including fatty acid alpha- and beta-oxidation, and plasmalogen and bile acid synthesis. Defects in genes encoding peroxisomal proteins can result in a large variety of peroxisomal disorders affecting either specific metabolic pathways, i.e. the single peroxisomal enzyme deficiencies, or causing a generalized defect in function and assembly of peroxisomes, i.e. peroxisome biogenesis disorders. In this review we discuss the clinical, biochemical and genetic aspects of all human peroxisomal disorders currently known. This article is part of a Special Issue entitled: Peroxisomes edited by Ralf Erdmann.
    Full-text · Article · Nov 2015 · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
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    ABSTRACT: Objective: To improve the efficacy of newborn screening (NBS) for very long chain acyl-CoA dehydrogenase deficiency (VLCADD). Patients and methods: Data on all dried blood spots collected by the Dutch NBS from October 2007 to 2010 (742.728) were included. Based solely on the C14:1 levels (cutoff ≥0.8 μmol/L), six newborns with VLCADD had been identified through NBS during this period. The ratio of C14:1 over C2 was calculated. DNA of all blood spots with a C14:1/C2 ratio of ≥0.020 was isolated and sequenced. Children homozygous or compound heterozygous for mutations in the ACADVL gene were traced back and invited for detailed clinical, biochemical, and genetic evaluation. Results: Retrospective analysis based on the C14:1/C2 ratio with a cutoff of ≥0.020 identified an additional five children with known ACADVL mutations and low enzymatic activity. All were still asymptomatic at the time of diagnosis (age 2-5 years). Increasing the cutoff to ≥0.023 resulted in a sensitivity of 93% and a positive predictive value of 37%. The sensitivity of the previously used screening approach (C14:1 ≥0.8) was 50%. Conclusion: This study shows that the ratio C14:1/C2 is a more sensitive marker than C14:1 for identifying VLCADD patients in NBS. However, as these patients were all asymptomatic at the time of diagnosis, this suggests that a more sensitive screening approach may also identify individuals who may never develop clinical disease. Long-term follow-up studies are needed to establish the risk of these VLCADD-deficient individuals for developing clinical signs and symptoms.
    Full-text · Article · Oct 2015
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    ABSTRACT: Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare and severe neurometabolic disease. We present two siblings with BVVLS with a novel homozygous mutation in SLC52A3 (formerly C20orf54) gene. The first sibling was admitted with respiratory insufficiency and required mechanical ventilation. After administration of a high dose of riboflavin, all his clinical symptoms were resolved, which also strongly suggested the diagnosis of BVVLS. The second sibling was also found to have the same genetic mutation as her brother. Although she was symptom-free, riboflavin was initiated empirically. On follow-up, she developed no neurologic or metabolic problems with entirely normal growth and development. BVVLS should be considered in the differential diagnosis of unexplained neurologic symptoms such as polyneuropathy and respiratory insufficiency, as BVVLS and multiple acyl-CoA dehydrogenation defect have broadly overlapping symptoms. Furthermore, our cases once again suggest that with proper diagnosis and early high-dose riboflavin treatment, complete reversal of neurologic deficits in BVVLS is possible.
    No preview · Article · Oct 2015
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    ABSTRACT: Peroxisomes are arguably the most biochemically versatile of all eukaryotic organelles. Their metabolic functions vary between different organisms, between different tissue types of the same organism and even between different developmental stages or in response to changed environmental conditions. New functions for peroxisomes are still being discovered and their importance is underscored by the severe phenotypes that can arise as a result of peroxisome dysfunction. The beta-oxidation pathway is central to peroxisomal metabolism, but the substrates processed are very diverse, reflecting the diversity of peroxisomes across species. Substrates for beta-oxidation enter peroxisomes via ATP-binding cassette (ABC) transporters of subfamily D; (ABCD) and are activated by specific acyl CoA synthetases for further metabolism. Humans have three peroxisomal ABCD family members, which are half transporters that homodimerize and have distinct but partially overlapping substrate specificity; Saccharomyces cerevisiae has two half transporters that heterodimerize and plants have a single peroxisomal ABC transporter that is a fused heterodimer and which appears to be the single entry point into peroxisomes for a very wide variety of beta-oxidation substrates. Our studies suggest that the Arabidopsis peroxisomal ABC transporter AtABCD1 accepts acyl CoA substrates, cleaves them before or during transport followed by reactivation by peroxisomal synthetases. We propose that this is a general mechanism to provide specificity to this class of transporters and by which amphipathic compounds are moved across peroxisome membranes.
    Full-text · Article · Oct 2015 · Biochemical Society Transactions
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    ABSTRACT: Objective: In patients suffering from mevalonate kinase deficiency (MKD), the reduced enzyme activity leads to an accumulation of mevalonic acid which is excreted in the urine. This study aims to evaluate the diagnostic value of urinary mevalonic acid measurement in patients with a clinical suspicion of mevalonate kinase deficiency. Methods: In this single-center, retrospective analysis, all patients in whom both measurement of mevalonic acid and genetic testing had been performed in the preceding 17 years have been included. The presence of two pathogenic MVK mutations or demonstration of decreased enzyme activity was considered to be the gold standard for the diagnosis of MKD. Results: Sixty-one patients were included in this study. Thirteen of them harbored two MVK mutations; twelve of them showed elevated levels of mevalonic acid. Forty-eight patients did not harbor any MVK mutations, yet five of them excreted increased amounts of mevalonic acid. This corresponds to a sensitivity of 92%, a specificity of 90%, a positive predictive value of 71%, and a negative predictive value of 98%. The positive likelihood ratio is 10 and the negative likelihood ratio is 0.09. Conclusion: MKD seems very unlikely in patients with a normal mevalonic acid excretion, but it cannot be excluded completely. Further, a positive urinary mevalonic acid excretion still requires MVK analysis to confirm the diagnosis of MKD. Therefore, detection of urinary mevalonic acid should not be mandatory before genetic testing. However, as long as genetic testing is not widely available and affordable, measurement of urinary mevalonic acid is a fair way to select patients for MVK gene analysis or enzyme assay.
    Full-text · Article · Sep 2015
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    ABSTRACT: Heimler syndrome (HS) is a rare recessive disorder characterized by sensorineural hearing loss (SNHL), amelogenesis imperfecta, nail abnormalities, and occasional or late-onset retinal pigmentation. We ascertained eight families affected by HS and, by using a whole-exome sequencing approach, identified biallelic mutations in PEX1 or PEX6 in six of them. Loss-of-function mutations in both genes are known causes of a spectrum of autosomal-recessive peroxisome-biogenesis disorders (PBDs), including Zellweger syndrome. PBDs are characterized by leukodystrophy, hypotonia, SNHL, retinopathy, and skeletal, craniofacial, and liver abnormalities. We demonstrate that each HS-affected family has at least one hypomorphic allele that results in extremely mild peroxisomal dysfunction. Although individuals with HS share some subtle clinical features found in PBDs, the diagnosis was not suggested by routine blood and skin fibroblast analyses used to detect PBDs. In conclusion, our findings define HS as a mild PBD, expanding the pleiotropy of mutations in PEX1 and PEX6.
    Full-text · Article · Sep 2015 · The American Journal of Human Genetics
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    ABSTRACT: We describe the natural history of patients with a Zellweger spectrum disorder (ZSD) surviving into adulthood. Retrospective cohort study in patients with a genetically confirmed ZSD. All patients (n = 19; aged 16-35 years) had a follow-up period of 1-24.4 years (mean 16 years). Seven patients had a progressive disease course, while 12 remained clinically stable during follow-up. Disease progression usually manifests in adolescence as a gait disorder, caused by central and/or peripheral nervous system involvement. Nine were capable of living a partly independent life with supported employment. Systematic MRI review revealed T2 hyperintense white matter abnormalities in the hilus of the dentate nucleus and/or peridentate region in nine out of 16 patients. Biochemical analyses in blood showed abnormal peroxisomal biomarkers in all patients in infancy and childhood, whereas in adolescence/adulthood we observed normalization of some metabolites. The patients described here represent a distinct subgroup within the ZSDs who survive into adulthood. Most remain stable over many years. Disease progression may occur and is mainly due to cerebral and cerebellar white matter abnormalities, and peripheral neuropathy.
    Full-text · Article · Aug 2015 · Journal of Inherited Metabolic Disease
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    ABSTRACT: Import of peroxisomal matrix proteins, crucial for peroxisome biogenesis, is mediated by the cytosolic receptors PEX5 and PEX7 that recognize proteins carrying peroxisomal targeting signals 1 or 2 (PTS1 or PTS2), respectively. Mutations in PEX5 or twelve other PEX genes cause peroxisome biogenesis disorders, collectively named the Zellweger spectrum disorders (ZSD), whereas mutations in PEX7 cause rhizomelic chondrodysplasia punctata type 1 (RCDP1). Three additional RCDP types, RCDP2-3-4, are caused respectively by mutations in GNPAT, AGPS and FAR1, encoding enzymes involved in plasmalogen biosynthesis. Here we report a fifth type of RCDP (RCDP5) caused by a novel mutation in PEX5. In four patients with RCDP from two independent families, we identified a homozygous frame shift mutation c.722dupA (p.Val242Glyfs(∗)33) in PEX5 (GenBank: NM_001131023.1). PEX5 encodes two isoforms, PEX5L and PEX5S, and we show that the c.722dupA mutation, located in the PEX5L specific exon 9, results in loss of PEX5L only. Both PEX5 isoforms recognize PTS1-tagged proteins, but PEX5L is also a co-receptor for PTS2-tagged proteins. Previous patients with PEX5 mutations had ZSD, mainly due to deficient import of PTS1-tagged proteins. Similarly to mutations in PEX7, loss of PEX5L results in deficient import of PTS2-tagged proteins only, thus causing RCDP instead of ZSD. We demonstrate that PEX5L expression restores the import of PTS2-tagged proteins in patient fibroblasts. Due to the biochemical overlap between RCDP1 and RCDP5, sequencing of PEX7 and exon 9 in PEX5 should be performed in patients with a selective defect in the import of PTS2-tagged proteins. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    No preview · Article · Jul 2015 · Human Molecular Genetics
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    ABSTRACT: Short-chain enoyl-CoA hydratase (SCEH, encoded by ECHS1) catalyzes hydration of 2-trans-enoyl-CoAs to 3(S)-hydroxy-acyl-CoAs. SCEH has a broad substrate specificity and is believed to play an important role in mitochondrial fatty acid oxidation and in the metabolism of branched-chain amino acids. Recently, the first patients with SCEH deficiency have been reported revealing only a defect in valine catabolism. We investigated the role of SCEH in fatty acid and branched-chain amino acid metabolism in four newly identified patients. In addition, because of the Leigh-like presentation, we studied enzymes involved in bioenergetics. Metabolite, enzymatic, protein and genetic analyses were performed in four patients, including two siblings. Palmitate loading studies in fibroblasts were performed to study mitochondrial β-oxidation. In addition, enoyl-CoA hydratase activity was measured with crotonyl-CoA, methacrylyl-CoA, tiglyl-CoA and 3-methylcrotonyl-CoA both in fibroblasts and liver to further study the role of SCEH in different metabolic pathways. Analyses of pyruvate dehydrogenase and respiratory chain complexes were performed in multiple tissues of two patients. All patients were either homozygous or compound heterozygous for mutations in the ECHS1 gene, had markedly reduced SCEH enzymatic activity and protein level in fibroblasts. All patients presented with lactic acidosis. The first two patients presented with vacuolating leukoencephalopathy and basal ganglia abnormalities. The third patient showed a slow neurodegenerative condition with global brain atrophy and the fourth patient showed Leigh-like lesions with a single episode of metabolic acidosis. Clinical picture and metabolite analysis were not consistent with a mitochondrial fatty acid oxidation disorder, which was supported by the normal palmitate loading test in fibroblasts. Patient fibroblasts displayed deficient hydratase activity with different substrates tested. Pyruvate dehydrogenase activity was markedly reduced in particular in muscle from the most severely affected patients, which was caused by reduced expression of E2 protein, whereas E2 mRNA was increased. Despite its activity towards substrates from different metabolic pathways, SCEH appears to be only crucial in valine metabolism, but not in isoleucine metabolism, and only of limited importance for mitochondrial fatty acid oxidation. In severely affected patients SCEH deficiency can cause a secondary pyruvate dehydrogenase deficiency contributing to the clinical presentation.
    Full-text · Article · Jun 2015 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations, one of which was reported before, were observed in the majority of cases. The clinical presentation of this group of patients was inhomogeneous. Our results confirm that alpha-aminoadipic and alpha-ketoadipic aciduria is caused by mutations in DHTKD1, and further establish that DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex.
    No preview · Article · Apr 2015 · Journal of Inherited Metabolic Disease
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    ABSTRACT: Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an inherited disorder of mitochondrial long-chain fatty acid β-oxidation (LC-FAO) and is included in many newborn screening (NBS) programs worldwide. Patients may present with hypoketotic hypoglycemia, cardiomyopathy, and/or myopathy, but clinical severity varies widely and the clinical outcome is unpredictable. We investigated predictive markers that may determine clinical severity. We developed a clinical severity score (CSS), which was determined for 13 Dutch patients with VLCADD, all of whom were diagnosed before the introduction of VLCADD in NBS to prevent bias from early diagnosis. In cultured skin fibroblasts from these patients, we measured LC-FAO flux (the rate of oleate oxidation), VLCAD activity, and acylcarnitine profiles following palmitate loading. The strongest correlation (r = 0.93; P < 0.0001) was observed between LC-FAO flux and the CSS. VLCAD activity measurement and the C14/C16-to-acylcarnitine ratio correlated much less. A median LC-FAO flux of 6% of control values (range 5.6-6.8%) was associated with cardiomyopathy (P < 0.01), and 32.4% (range 5.6-50.5%) was associated with myopathy (P < 0.05). Our results demonstrate a very strong correlation between LC-FAO flux in fibroblasts and the clinical severity of VLCADD. LC-FAO flux measurements may thus predict whether patients are likely to develop symptoms.Genet Med advance online publication 02 April 2015Genetics in Medicine (2015); doi:10.1038/gim.2015.22.
    No preview · Article · Apr 2015 · Genetics in medicine: official journal of the American College of Medical Genetics
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    ABSTRACT: In neonates, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is often characterized by cardiomyopathy, hepatic encephalopathy, or severe hypoketotic hypoglycemia, or a combination thereof. The purpose of this study was to further elucidate a familial VLCAD deficiency in three patients, two of whom died in the neonatal period. We report on a family with VLCAD deficiency. Acyl-carnitine profiles were obtained from dried blood spot and/or from oxidation of 13C-palmitate by cultured skin fibroblasts. In the index patient, VLCAD deficiency was ascertained by enzyme activity measurement in fibroblasts and by molecular analysis of ACADVL. At 30 hr of life, the proband was diagnosed with hypoglycemia (1.77 mmol/L), rhabdomyolysis (CK: 12966 IU/L) and hyperlactacidemia (10.6 mmol/L). Acylcarnitine profile performed at 31 hr of life was consistent with VLCAD deficiency and confirmed by cultured skin fibroblast enzyme activity measurement. Molecular analysis of ACADVL revealed a homozygous splice-site mutation (1077 + 2T>C). The acyl-carnitine profile obtained from the sibling's original newborn screening cards demonstrated a similar, but less pronounced abnormal profile. In the proband, the initial metabolic crisis was controlled with 10% dextrose solution and oral riboflavin followed by specific diet (Basic-F and medium chain triglyceride (MCT). This clinical report demonstrates a familial history of repeated neonatal deaths explained by VLCAD deficiency, and the clinical evolution of the latest affected, surviving sibling. It shows that very early metabolic screening is an effective approach to avoid sudden unexpected death. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Jan 2015 · American Journal of Medical Genetics Part A
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    ABSTRACT: Unlabelled: The enterohepatic circulation of bile salts is an important physiological route to recycle bile salts and ensure intestinal absorption of dietary lipids. The Na(+)-taurocholate cotransporting polypeptide SLC10A1 (NTCP) plays a key role in this process as the major transporter of conjugated bile salts from the plasma compartment into the hepatocyte. Here we present the first patient with NTCP deficiency, who was clinically characterized by mild hypotonia, growth retardation, and delayed motor milestones. Total bile salts in plasma were extremely elevated (up to 1,500 μM, ref. <16.3) but there were no clinical signs of cholestatic jaundice, pruritis, or liver dysfunction. Bile salt synthesis and intestinal bile salt signaling were not affected, as evidenced by normal plasma 7α-hydroxy-4-cholesten-3-one (C4) and FGF19 levels. Importantly, the presence of secondary bile salts in the circulation suggested residual enterohepatic cycling of bile salts. Sequencing of the SLC10A1 gene revealed a single homozygous nonsynonymous point mutation in the coding sequence of the gene, resulting in an arginine to histidine substitution at position 252. Functional studies showed that this mutation resulted in a markedly reduced uptake activity of taurocholic acid. Immunofluorescence studies and surface biotinylation experiments demonstrated that the mutant protein is virtually absent from the plasma membrane. Conclusion: We describe the identification of NTCP deficiency as a new inborn error of metabolism with a relatively mild clinical phenotype. The identification of NTCP deficiency confirms that this transporter is the main import system for conjugated bile salts into the liver but also indicates that auxiliary transporters are able to sustain the enterohepatic cycle in its absence.
    No preview · Article · Jan 2015 · Hepatology
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    ABSTRACT: The European Journal of Human Genetics is the official Journal of the European Society of Human Genetics, publishing high-quality, original research papers, short reports, News and Commentary articles and reviews in the rapidly expanding field of human genetics and genomics.
    No preview · Article · Nov 2014 · European journal of human genetics: EJHG
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    ABSTRACT: Multiple acyl coenzyme A dehydrogenase deficiency (MADD) is a severe inborn error of metabolism. Experiences with sodium-d,l-3-hydroxybutyrate (3-HB) treatment are limited although positive; however, the general view on outcome of severely affected patients with MADD is relatively pessimistic. Here we present an infant with MADD in whom the previously reported dose of 3-HB did not prevent the acute, severe, metabolic decompensation or progressive cardiomyopathy in the subsequent months. Only after a physiologic dose of 2600 mg/kg of 3-HB per day were ketone bodies detected in blood associated with improvement of the clinical course, N-terminal prohormone of brain natriuretic peptide and echocardiographic parameters. Long-term studies are warranted on 3-HB treatment in patients with MADD.
    No preview · Article · Sep 2014 · Pediatrics
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    ABSTRACT: ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far the precise function of ABCD3 is not known. Here we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease, and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758 bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age, but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24-bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27-bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.
    Full-text · Article · Aug 2014 · Human Molecular Genetics
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    ABSTRACT: Two siblings with fatal Leigh disease had increased excretion of S-(2-carboxypropyl)cysteine and several other metabolites that are features of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency, a rare defect in the valine catabolic pathway associated with Leigh-like disease. However, this diagnosis was excluded by HIBCH sequencing and normal enzyme activity. In contrast to HIBCH deficiency, the excretion of 3-hydroxyisobutyryl-carnitine was normal in the children, suggesting deficiency of short-chain enoyl-CoA hydratase (ECHS1 gene). This mitochondrial enzyme is active in several metabolic pathways involving fatty acids and amino acids, including valine, and is immediately upstream of HIBCH in the valine pathway. Both children were compound heterozygous for a c.473C > A (p.A158D) missense mutation and a c.414+3G>C splicing mutation in ECHS1. ECHS1 activity was markedly decreased in cultured fibroblasts from both siblings, ECHS1 protein was undetectable by immunoblot analysis and transfection of patient cells with wild-type ECHS1 rescued ECHS1 activity. The highly reactive metabolites methacrylyl-CoA and acryloyl-CoA accumulate in deficiencies of both ECHS1 and HIBCH and are probably responsible for the brain pathology in both disorders. Deficiency of ECHS1 or HIBCH should be considered in children with Leigh disease. Urine metabolite testing can detect and distinguish between these two disorders.
    Full-text · Article · Aug 2014 · Brain
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    ABSTRACT: Protein prenylation is a post-translational modification whereby non-sterol isoprenoid lipid chains are added, thereby modifying the molecular partners with which proteins interact. The autoinflammatory disease mevalonate kinase deficiency (MKD) is characterized by a severe reduction in protein prenylation. A major class of proteins affected are small GTPases, including Rac1 and RhoA. It had not been understood how protein prenylation of small GTPases relates to GTP hydrolysis activity and downstream signaling. We here investigated the contribution of RhoA prenylation to the biochemical pathways that underlie MKD-associated IL-1β hyper secretion, using human cell cultures, Rac1 and RhoA protein variants and pharmacological inhibitors. We found that when unprenylated, the GTP-bound levels of RhoA decrease, causing a reduction in GTPase activity and increased Protein Kinase B (PKB) phosphorylation. Cells expressing unprenylated RhoA produce increased levels of interleukin 1β mRNA. Of other phenotypic cellular changes seen in MKD, increased mitochondrial potential and mitochondrial elongation, only mitochondrial elongation was observed. Finally, we show that pharmacological inactivation of RhoA boosts Rac1 activity, a small GTPase whose activity was earlier implied in MKD pathogenesis. Together our data show that RhoA plays a pivotal role in MKD pathogenesis, through Rac1/PKB signaling towards interleukin 1β production, and elucidate the effects of protein prenylation in monocytes.
    Preview · Article · Aug 2014 · Journal of Biological Chemistry

Publication Stats

10k Citations
1,244.27 Total Impact Points


  • 2001-2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Academic Medical Center
      • • Department of Clinical Chemistry
      • • Department of Biochemistry
      Amsterdamo, North Holland, Netherlands
  • 1998-2015
    • University of Amsterdam
      • • Department of Paediatrics
      • • Faculty of Medicine AMC
      • • Department of Chemistry
      • • Department of Clinical Biochemistry
      Amsterdamo, North Holland, Netherlands
  • 1990-2006
    • University of Groningen
      • • Department of Pediatrics
      • • Groningen Biomolecular Sciences and Biotechnology Institute (GBB)
      • • Department of Microbial Ecology
      Groningen, Groningen, Netherlands
  • 2004
    • Academic Medical Center (AMC)
      Amsterdamo, North Holland, Netherlands
    • Ghent University
      Gand, Flemish, Belgium
  • 2003
    • Maastricht University
      Maestricht, Limburg, Netherlands
  • 2002
    • University of Leuven
      • Laboratory for Medicinal Chemistry
      Louvain, Flemish, Belgium
  • 2000-2002
    • University Medical Center Utrecht
      • Wilhelmina Children´s Hospital
      Utrecht, Provincie Utrecht, Netherlands
    • Radboud University Nijmegen
      • Department of Organismal Animal Physiology
      Nymegen, Gelderland, Netherlands
  • 1999
    • Erasmus Universiteit Rotterdam
      • Department of Biochemistry
      Rotterdam, South Holland, Netherlands
  • 1997-1998
    • Oregon Institute of Technology
      Wilsonville, Oregon, United States