Hans R Waterham

University of Florence, Florens, Tuscany, Italy

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Publications (333)

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    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Zellweger spectrum disorders (ZSDs) are characterized by a failure in peroxisome formation, caused by autosomal recessive mutations in different PEX genes. At least some of the progressive and irreversible clinical abnormalities in patients with a ZSD, particularly liver dysfunction, are likely caused by the accumulation of toxic bile acid intermediates. We investigated whether cholic acid supplementation can suppress bile acid synthesis, reduce accumulation of toxic bile acid intermediates and improve liver function in these patients. Methods: An open label, pretest-posttest design study was conducted including 19 patients with a ZSD. Participants were followed longitudinally during a period of 2.5 years prior to the start of the intervention. Subsequently, all patients received oral cholic acid and were followed during 9 months of treatment. Bile acids, peroxisomal metabolites, liver function and liver stiffness were measured at baseline and 4, 12 and 36 weeks after start of cholic acid treatment. Results: During cholic acid treatment, bile acid synthesis decreased in the majority of patients. Reduced levels of bile acid intermediates were found in plasma and excretion of bile acid intermediates in urine was diminished. In patients with advanced liver disease (n = 4), cholic acid treatment resulted in increased levels of plasma transaminases, bilirubin and cholic acid with only a minor reduction in bile acid intermediates. Conclusions: Oral cholic acid therapy can be used in the majority of patients with a ZSD, leading to at least partial suppression of bile acid synthesis. However, caution is needed in patients with advanced liver disease due to possible hepatotoxic effects.
    Full-text Article · Jul 2016 · Journal of Inherited Metabolic Disease
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    [Show abstract] [Hide abstract] ABSTRACT: We describe the management and outcomes of pregnancy in a 27-year-old woman with infantile-onset Adult Refsum’s disease (ARD). She presented in infancy but was diagnosed with ARD at the age of 10 on basis of phytanic acidaemia and later confirmed to have the phytanoyl-CoA hydroxylase ((PHYH) c.164delT, p.L55fsX12) mutation. Despite repeated plasmapheresis sessions and strict dietary surveillance for 20 years, her phytanic acid levels persistently stayed above the ideal target level of 100 μmol/L but remained below 400 μmol/L. Initially the pregnancy was uncomplicated but in the third trimester of pregnancy the patient was admitted to the hospital with fluctuating hypertension, sinus tachycardia and breathlessness. The patient was compliant with diet during pregnancy and her phytanic levels were remained well controlled: 177 and 188 μmol/L in the first and second trimester, respectively. Peri-partum management required a coordinated team approach including a high-calorie and restricted diet to reduce the risk of acute metabolic decompensation. During the induced labour she required 10% dextrose infusions. Post-partum it took the mother a long time to recover from childbirth – her appetite was poor due to post-natal depression and her body weight decreased rapidly by 11 kg within 3 weeks after childbirth, resulting in a spike in phytanic acid to 366 μmol/L. Measures were taken to minimise the risk of acute neurological decompensation. The infant was unaffected and has made normal developmental progress in the subsequent 2 years.
    Full-text Article · Jun 2016 · Journal of Inherited Metabolic Disease
  • [Show abstract] [Hide abstract] ABSTRACT: Peroxisomes are subcellular organelles involved in various metabolic processes, including fatty acid and phospholipid homeostasis. The Zellweger Spectrum Disorders (ZSDs) represent a group of diseases caused by a defect in the biogenesis of peroxisomes. Accordingly, cells from ZSD patients are expected to have an altered composition of fatty acids and phospholipids. Using an LC/MS-based lipidomics approach, we show that the phospholipid composition is characteristically altered in cultured primary skin fibroblasts from ZSD patients when compared to healthy controls. We observed a marked overall increase of phospholipid species containing very long chain fatty acids, and a decrease of phospholipid species with shorter fatty acid species in ZSD patient fibroblasts. In addition, we detected a distinct phosphatidylcholine profile in ZSD patients with a severe and mild phenotype when compared to control cells. Based on our data, we present a set of specific phospholipid ratios for fibroblasts that clearly discriminate between mild and severe ZSD patients, and those from healthy controls. Our findings will aid in the diagnosis and prognosis of ZSD patients, including an increasing number of mild patients in whom hardly any abnormalities are observed in biochemical parameters commonly used for diagnosis.
    Article · Jun 2016 · Journal of Lipid Research
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    [Show abstract] [Hide abstract] ABSTRACT: Cofactors such as nicotinamide adenine dinucleotide (NAD), AMP, or CoA are essential for a diverse set of reactions and pathways in the cell. Specific carrier proteins are required to distribute these cofactors to different cell compartments, including peroxisomes. We previously identified a peroxisomal transport protein in Arabidopsis called PXN (peroxisomal NAD carrier). When assayed in vitro, this carrier exhibits versatile transport functions, e.g., catalyzing the import of NAD or CoA, the exchange of NAD/NADH, and the export of CoA. These observations raise the question about the physiological function of PXN in plants. Here, we used Saccharomyces cerevisiae to address this question. Firstly, we confirmed that PXN, when expressed in yeast, is active and targeted to yeast peroxisomes. Secondly, detailed uptake analyses revealed that the CoA transport function of PXN can be excluded under physiological conditions due to its low affinity for this substrate. Thirdly, we expressed PXN in diverse mutant yeast strains and investigated the suppression of the mutant phenotypes. These studies provided strong evidences that PXN was not able to function as a CoA transporter or a redox shuttle by mediating a NAD/NADH exchange, but rather catalyzed the import of NAD into peroxisomes against AMP in intact yeast cells.
    Full-text Article · May 2016 · Plant physiology
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    [Show abstract] [Hide abstract] ABSTRACT: Peroxisomal disorders are a heterogeneous group of genetic metabolic disorders, caused by a defect in peroxisome biogenesis or a deficiency of a single peroxisomal enzyme. The peroxisomal disorders include the Zellweger spectrum disorders, the rhizomelic chondrodysplasia punctata spectrum disorders, X-linked adrenoleukodystrophy, andmultiple single enzyme deficiencies. There are several core phenotypes caused by peroxisomal dysfunction that clinicians can recognize. The diagnosis is suggested by biochemical testing in blood and urine and confirmed by functional assays in cultured skin fibroblasts, followed by mutation analysis. This review describes the phenotype of the main peroxisomal disorders and possible pitfalls in (laboratory) diagnosis to aid clinicians in the recognition of this group of diseases.
    Full-text Article · Apr 2016 · Neuropediatrics
  • Peter Witters · Luc Régal · Hans R Waterham · [...] · Eva Morava
    Article · Mar 2016 · American Journal of Medical Genetics Part A
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    [Show abstract] [Hide abstract] ABSTRACT: Peroxisomes are dynamic organelles that play an essential role in a variety of metabolic pathways. Peroxisomal dysfunction can lead to various biochemical abnormalities and result in abnormal metabolite levels, such as increased very long-chain fatty acid or reduced plasmalogen levels. The metabolite abnormalities in peroxisomal disorders are used in the diagnostics of these disorders. In this paper we discuss in detail the different diagnostic tests available for peroxisomal disorders and focus specifically on the important role of biochemical and functional studies in cultured skin fibroblasts in reaching the right diagnosis. Several examples are shown to underline the power of such studies.
    Full-text Article · Mar 2016 · Journal of Inherited Metabolic Disease
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    [Show abstract] [Hide abstract] ABSTRACT: Objective Mevalonate kinase (MVK) deficiency is a rare autosomal recessive auto-inflammatory disorder characterised by recurring episodes of fever associated with multiple non-specific inflammatory symptoms and caused by mutations in the MVK gene. The phenotypic spectrum is wide and depends mostly on the nature of the mutations. Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) is a relatively mild presentation and predominantly associated with a c.1129G>A (p.V377I) mutation in the MVK gene. We report cases of two sisters homozygous for this mutation but exhibiting distinct (symptomatic vs asymptomatic) phenotypes. Methods Patient history was obtained; physical and clinical examination and laboratory tests were performed; lipopolysaccharide (LPS) response of peripheral blood mononuclear cells was quantified. Results Low MVK enzymatic activity is not necessarily associated with inflammatory symptoms. Increased inflammatory cytokine secretion in response to LPS is associated with symptomatic MVK deficiency. Conclusions Individuals who are homozygous for the common p.V377I mutation in the MVK gene may not display the characteristic inflammatory episodes diagnostic of MKD and thus may be lost for correct and timely diagnosis.
    Full-text Article · Mar 2016
  • Ronald J. A. Wanders · Hans R. Waterham · Sacha Ferdinandusse
    [Show abstract] [Hide abstract] 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.
    Article · Jan 2016 · Frontiers in Cell and Developmental Biology
  • C. Maxit · I. Denzler · D. Marchione · [...] · H. R. Waterham
    [Show abstract] [Hide abstract] ABSTRACT: Background: Peroxisome biogenesis disorders (PBDs) may have a variable clinical expression, ranging from severe, lethal to mild phenotypes with progressive evolution. PBDs are autosomal recessive disorders caused by mutations in PEX genes, which encode proteins called peroxins, involved in the assembly of the peroxisome. Patient Description: We herein report a patient who is currently 9 years old and who is compound heterozygous for two novel mutations in the PEX3 gene. Results: Mild biochemical abnormalities of the peroxisomal parameters suggested a Zellweger spectrum defect in the patient. Sequence analysis of the PEX3 gene identified two novel heterozygous, pathogenic mutations. Conclusion: Mutations in PEX3 usually result in a severe, early lethal phenotype. We report a patient compound heterozygous for two novel mutations in the PEX3 gene, who is less affected than previously reported patients with a defect in the PEX3 gene. Our findings indicate that PEX3 defects may cause a disease spectrum similar as previously observed for other PEX gene defects.
    Article · Jan 2016
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    Natalia Lüsebrink · Luciana Porto · Hans R. Waterham · [...] · Matthias Kieslich
    [Show abstract] [Hide abstract] 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.
    Full-text 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
    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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
  • [Show abstract] [Hide abstract] 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.
    Article · Oct 2015
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    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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
  • [Show abstract] [Hide abstract] 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.
    Article · Jul 2015 · Human Molecular Genetics
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    [Show abstract] [Hide abstract] 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

Publication Stats

11k Citations


  • 2007
    • University of Florence
      Florens, Tuscany, Italy
  • 2002-2007
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • Academic Medical Center
      Amsterdamo, North Holland, Netherlands
  • 2004
    • Ghent University
      Gand, Flemish, Belgium
  • 2003-2004
    • Utrecht University
      Utrecht, Utrecht, Netherlands
  • 2000
    • University of Amsterdam
      • Department of Clinical Biochemistry
      Amsterdamo, North Holland, Netherlands
  • 1999
    • Erasmus Universiteit Rotterdam
      • Department of Biochemistry
      Rotterdam, South Holland, Netherlands