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ABSTRACT: Peroxisomal blood tests are generally considered to be conclusive. We observed several patients with a clinical and MRI phenotype suggestive of an infantile onset peroxisomal defect, but no convincing abnormalities in initial peroxisomal blood tests. Brain MRI showed typical abnormalities as observed in the neonatal adrenoleukodystrophy variant of infantile peroxisomal disorders. Our aim was to evaluate the accuracy of this MRI diagnosis with further peroxisomal testing.
We searched our database of unclassified leukoencephalopathies and found 6 such patients. We collected clinical data and scored available MRIs of these patients. We performed further peroxisomal studies in fibroblasts, including immunofluorescence microscopy analysis with antibodies against catalase, a peroxisomal matrix enzyme. We performed complementation analysis and analyzed the suspected genes.
We confirmed the diagnosis of Zellweger spectrum disorder in 3 patients and D-bifunctional protein deficiency in the others. The clinical findings were within the spectrum known for these diagnoses. Sequential MRIs showed that the abnormalities started in the hilus of the dentate nucleus and superior cerebellar peduncles. Subsequently, the cerebellar white matter and brainstem tracts were affected, followed by the parieto-occipital white matter, splenium of the corpus callosum, and posterior limb of the internal capsule. Eventually, all cerebral white matter became abnormal. The thalamus was typically affected as well.
If MRI reveals abnormalities suggestive of infantile onset peroxisomal defects, negative peroxisomal blood tests do not exclude the diagnosis. Further tests in fibroblasts should be performed, most importantly immunofluorescence microscopy analysis with antibodies against catalase to stain peroxisomes.
Neurology 03/2012; 78(17):1304-8. · 8.31 Impact Factor
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ABSTRACT: Isovaleric acidemia (IVA) is one of the most common organic acidemias found in South Africa. Since 1983, a significant number of IVA cases have been identified in approximately 20,000 Caucasian patients screened for metabolic defects. IVA is caused by an autosomal recessive deficiency of isovaleryl-CoA dehydrogenase (IVD) resulting in the accumulation of isovaleryl-CoA and its metabolites. In total, 10 IVA patients and three carriers were available for phenotypic and genotypic investigation in this study. All patients were found to be homozygous for a single c.367 G > A (p.G123R) mutation. The amino acid substitution of a glycine to arginine resulted in a markedly reduced steady-state level of the IVD protein, which explains the nearly complete lack of IVD enzyme activity as assessed in fibroblast homogenates. Despite the genetic homogeneity of this South African IVA group, the clinical presentation varied widely, ranging from severe mental handicap and multiple episodes of metabolic derangement to an asymptomatic state. The variation may be due to poor dietary intervention, delayed diagnosis or even epigenetic and polygenetic factors of unknown origin.
Journal of Inherited Metabolic Disease 02/2012; 35(6):1021-9. · 3.58 Impact Factor
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ABSTRACT: Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is an autosomal recessive inborn error of metabolism, most frequently associated with developmental delay and/or epilepsy. Most SCADD patients carry common SCAD-encoding gene ( ACADS) variants or these variants in combination with a rare ACADS mutation, in the Netherlands predominantly the c.1058C>T. Epilepsy in childhood often remains unexplained and patients with epilepsy related to SCADD may remain undiagnosed because studies for SCADD are often not performed. To test this hypothesis and to further estimate the extent of the Dutch SCADD population, we performed a study on blood spot samples in 131 paediatric patients with epilepsy and 909 anonymous newborns and investigated the presence of the 2 common ACADS variants and the rare c.1058C>T mutation. Overall, the 2 common ACADS variants and the rare c.1058C>T mutation were detected in either homozygous or compound heterozygous forms in 9.2% of the epilepsy and 7.5% of the reference group. A birth prevalence of SCADD with a mutation/variant genotype in the Netherlands as high as >1:1,000 was calculated. This is in contrast with the low number of patients diagnosed clinically and supports the hypothesis that SCADD is clinically irrelevant. Furthermore our study does not support an association between SCADD and epilepsy.
Neuropediatrics 02/2011; 42(1):13-7. · 0.94 Impact Factor
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Neurology 10/2010; 75(14):1300-2. · 8.31 Impact Factor
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ABSTRACT: Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder caused by mutations in the MVK gene resulting in decreased activity of the enzyme mevalonate kinase (MK). Although MK is required for biosynthesis of all isoprenoids, in MKD, in particular, the timely synthesis of geranylgeranyl pyrophosphate appears to be compromised. Because small guanosine triphosphatases (GTPases) depend on geranylgeranylation for their proper signaling function, we studied the effect of MK deficiency on geranylgeranylation and activation of the two small GTPases, RhoA and Rac1. We demonstrate that both geranylgeranylation and activation of the two GTPases are more easily disturbed in MKD cells than in control cells when the flux though the isoprenoid biosynthesis pathway is suppressed by low concentrations of simvastatin. The limited capacity of geranylgeranylation in MKD cells readily leads to markedly increased levels of nonisoprenylated and activated GTPases, which will affect proper signaling by these GTPases.
Journal of Inherited Metabolic Disease 10/2010; 33(5):625-32. · 3.58 Impact Factor
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ABSTRACT: The peroxisomal biogenesis disorders (PBDs) comprise the Zellweger spectrum disorders (i.e., Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease) and rhizomelic chondrodysplasia punctata. Peroxisomal biogenesis disorders can be caused by mutations in any of 13 currently known PEX genes, which encode peroxins involved in peroxisomal protein import and/or assembly of the organelle. We report here on a Turkish patient who presented with unusual clinical findings, that included non-immune hydrops, dermal erythropoiesis and hypoplastic toenails, as well as common dysmorphic features of Zellweger syndrome. The patient has also pulmonary hypoplasia, which has been reported in only a few patients with Zellweger syndrome. A peroxisomal biogenesis disorder was confirmed by enzyme analysis and abnormal very long-chain fatty acid (VLCFA) profiles in plasma and fibroblast and immunofluorescence microscopy studies. Subsequent molecular genetic analysis revealed a homozygous c.856C>T mutation (R268X) in the PEX3 gene, which made this patient the third to have a defect in this gene. In contrast to those of the two previously reported patients, the cells of this patient still contained peroxisomal membrane structures (ghosts), seen by immunofluorescence microscopy analysis. The case presented here and the two previously reported cases point out that a PEX3 gene defect may present with fairly heterogeneous clinical findings. This case also raises a possibility that hydrops fetalis may be associated with a PEX3 gene defect and that peroxisomal disorders can be considered in the etiology of hydrops fetalis as well as other cell organelle disorders when one is considering yet undiscovered complementation groups in peroxisomal disorders.
Journal of Inherited Metabolic Disease 12/2009; · 3.58 Impact Factor
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ABSTRACT: One important area of clinical genomics research involves the elucidation of molecular mechanisms underlying (complex) disorders which eventually may lead to new diagnostic or drug targets. To further advance this area of clinical genomics one of the main challenges is the acquisition and integration of data, information and expert knowledge for specific biomedical domains and diseases. Currently the required information is not very well organized but scattered over biological and biomedical databases, basic text books, scientific literature and experts' minds and may be highly specific, heterogeneous, complex and voluminous.
We present a new framework to construct knowledge bases with concept maps for presentation of information and the web ontology language OWL for the representation of information. We demonstrate this framework through the construction of a peroxisomal knowledge base, which focuses on four key peroxisomal pathways and several related genetic disorders. All 155 concept maps in our knowledge base are linked to at least one other concept map, which allows the visualization of one big network of related pieces of information.
The peroxisome knowledge base is available from www.bioinformaticslaboratory.nl (Support-->Web applications).
Supplementary data is available from www.bioinformaticslaboratory.nl (Research-->Output--> Publications--> KB_SuppInfo)
Bioinformatics 09/2008; 24(16):i21-7. · 5.47 Impact Factor
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ABSTRACT: To describe the clinical, genetic, and biochemical characteristics of short-chain acyl-CoA dehydrogenase deficiency (SCADD), a clinically heterogeneous metabolic disorder for which neonates are screened for in parts of the United States and Australia. To explore the genotype-phenotype relation and to discuss neonatal screening for SCADD.
Retrospective study of 31 Dutch SCADD patients and 8 SCADD relatives.
Patients and relatives were included ifbiochemical SCADD characteristics (increased C4-carnitine and/or ethylmalonic acid) were present in combination with a mutation and/or the c.511C>T or c.625G>A variant on each SCAD-encoding (ACADS) allele. The patients were subdivided into 3 genotype groups: mutation/mutation, mutation/variant and variant/variant group.
A birth prevalence for SCADD of at least 1:50,000 was calculated. Most patients presented before the age of 3 years, mainly with developmental delay, epilepsy, behavioural disturbances and/or hypoglycaemia. The ACADS genotype showed a statistically significant association with biochemical, but not with clinical characteristics. In total 7 out of 8 SCADD relatives were free of symptoms. In 5 of the 31 patients, of whom 2 had severe symptoms, a second diagnosis was made which might explain the symptoms.
SCADD was far more common than had previously been assumed and clinical symptoms in SCADD were non-specific, often transient or absent and not correlated with specific ACADS genotypes. SCADD does not meet major neonatal screening criteria and is therefore not suited for inclusion in neonatal screening programmes.
Nederlands tijdschrift voor geneeskunde 07/2008; 152(30):1678-85.
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T G J Derks,
T S Boer,
A van Assen,
T Bos,
J Ruiter, H R Waterham,
K E Niezen-Koning,
R J A Wanders,
J M M Rondeel,
J G Loeber,
L P Ten Kate,
G P A Smit,
D-J Reijngoud
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ABSTRACT: The outcome was determined of population-wide neonatal screening for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency using tandem mass spectrometry (MS/MS) in The Netherlands, between October 2003 and September 2005. Prospective population-wide neonatal screening for MCAD deficiency was performed in the northern part of The Netherlands. In newborns with blood octanoylcarnitine (C(8:0)) concentrations > or =0.3 micromol/L, clinical and laboratory follow-up was initiated, including MCAD enzymatic measurements which played a decisive role. In a 2-year period, 66 216 newborns were investigated for MCAD deficiency and follow-up was initiated in 28 newborns. True-positives (n = 14) were identified based upon MCAD enzyme activity <50%, measured with hexanoyl-CoA as substrate. The observed prevalence of MCAD deficiency was 1/6600 (95% CI: 1/4100-1/17 400). In addition to an elevated C(8:0) concentration, a C(8:0)/C(10:0) molar ratio >5.0 turned out to differentiate between false-positives and true-positives. Measurement of MCAD activity using phenylpropionyl-CoA as a substrate further discriminated between newborns with MCAD deficiency and so-called mild MCAD deficiency. To summarize, neonatal screening for MCAD deficiency in the northern part of The Netherlands resulted in the predicted number of affected newborns. Measurement of MCAD activity in leukocytes or lymphocytes using phenylpropionyl-CoA as a substrate can be regarded as the gold standard to diagnose MCAD deficiency upon initial positive screening test results.
Journal of Inherited Metabolic Disease 02/2008; 31(1):88-96. · 3.58 Impact Factor
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ECCB'08 Proceedings, Seventh European Conference on Computational Biology, 22-26 September 2008, Cagliari, Italy; 01/2008
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ABSTRACT: Primary hyperoxaluria type I (PH1) is a congenital defect in glyoxylate metabolism caused by a deficiency in the liver-specific peroxisomal enzyme known as alanine glyoxylate aminotransferase (AGT). The deficiency is due to mutations in the AGXT gene, located on chromosome 2q37.3, and results in the conversion of glyoxylate to oxalate. The crystallisation of oxalate with calcium results in symptoms varying from a solitary kidney stone to end-stage renal disease with systemic oxalosis. The diagnosis is based on increased oxalate and glycolate excretion in the urine, reduced AGT activity in liver tissue, and confirmed mutations in the AGXT gene. Over 50 disease-causing mutations have been identified in PH1, which are associated with a wide range of effects on the AGT enzyme. Homozygous Gly170Arg or Phei52Ile mutations are associated with a reduction in urinary oxalate excretion upon pyridoxine administration and long-term preservation of renal function when treatment is initiated in a timely manner. Homozygous 33insC and Gly82Arg mutations result in a much poorer prognosis. Mutational analysis of the AGXT gene in PH1 patients can be a useful tool for establishing the diagnosis and choosing an appropriate therapeutic strategy.
Nederlands tijdschrift voor geneeskunde 08/2006; 150(30):1669-72.
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ABSTRACT: Methylmalonic aciduria (MMA-uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl-coenzyme A (methylmalonyl-CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl-CoA mutase as well as the vitamin B12-responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA-uria are known in whom no defect could be identified. Here we present a 16-year-old female patient with persisting moderate MMA-uria (approximately 50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C-propionate into macromolecules suggested a defect in the propionate-to-succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism.
Human Mutation 07/2006; 27(7):640-3. · 5.69 Impact Factor
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ABSTRACT: Methylmalonic aciduria (MMA-uria) is an autosomal recessive inborn error of amino acid metabolism, involving valine, threonine, isoleucine, and methionine. This organic aciduria may present in the neonatal period with life-threatening metabolic acidosis, hyperammonemia, feeding difficulties, pancytopenia, and coma. Most affected patients have mutations in the methylmalonyl-coenzyme A (methylmalonyl-CoA) mutase gene. Mildly affected patients may present in childhood with failure to thrive and recurrent attacks of metabolic acidosis. Both a higher residual activity of methylmalonyl-CoA mutase as well as the vitamin B12–responsive defects (cblA and cblB) may form the basis of the mild disorder. A few patients with moderate MMA-uria are known in whom no defect could be identified. Here we present a 16-year-old female patient with persisting moderate MMA-uria (∼50 mmol/mol creatinine). She was born to consanguineous Caucasian parents. Her fibroblast mutase activity was normal and no effect of vitamin B12 supplementation could be established. Reduced incorporation of 14C-propionate into macromolecules suggested a defect in the propionate-to-succinate pathway. We found a homozygous nonsense mutation (c.139C>T) in the methylmalonyl-CoA epimerase gene (MCEE), resulting in an early terminating signal (p.R47X). Both parents were heterozygous for this mutation; they were found to excrete normal amounts of methylmalonic acid (MMA). This is the first report of methylmalonyl-CoA epimerase deficiency, thereby unequivocally demonstrating the biochemical role of this enzyme in human metabolism. Hum Mutat 27(7), 640–643, 2006. © 2006 Wiley-Liss, Inc.
Human Mutation 06/2006; 27(7):640 - 643. · 5.69 Impact Factor
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ABSTRACT: We present a rare case of peroxisomal acyl-CoA oxidase deficiency that was not detected by the common metabolic screening program for peroxisomal disorders. The patient presented with a typical MRI pattern showing pachygyria, perisylvian polymicrogyria, cerebral and cerebellar white matter abnormalities, and facial dysmorphia, progressive psychomotor retardation, deafness, retinopathy, peripheral neuropathy, and infantile seizures strongly indicative for a peroxisomal disorder. Yet, repetitive measurements of very long-chain fatty acids (VLCFAs) and phytanic acid in serum and plasma as well as plasmalogens in erythrocytes revealed normal values apparently excluding a peroxisomal defect (methods of measurement published by Moser and co-workers in 1980 [4 ] and 1981 [2 ]). Subsequent biochemical investigation in cultured skin fibroblasts of the patient, however, revealed elevated concentrations of VLCFAs, deficient oxidation of C26:0, but normal oxidation of both phytanic acid and pristanic acid and normal DE NOVO plasmalogen synthesis, indicative for a defect in the peroxisomal beta-oxidation system. Enzymatic studies in these fibroblasts pointed to peroxisomal acyl-CoA oxidase deficiency and subsequent molecular analyses revealed a homozygous acceptor splice site mutation IVS3-1G>A in the ACOX1 gene (MIM *609751).
Neuropediatrics 04/2006; 37(2):95-8. · 0.94 Impact Factor
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ABSTRACT: We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.
Journal of Inherited Metabolic Disease 11/2005; 28(6):1172-1174. · 3.58 Impact Factor
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ABSTRACT: The peroxisomal disorders represent a group of genetic diseases in humans in which there is an impairment in one or more peroxisomal functions. The peroxisomal disorders are usually subdivided into two subgroups including (i) the peroxisome biogenesis disorders (PBDs) and (ii) the single peroxisomal (enzyme-) protein deficiencies. The PBD group is comprised of four different disorders including Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum's disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). ZS, NALD, and IRD are clearly distinct from RCDP and are usually referred to as the Zellweger spectrum with ZS being the most severe and NALD and IRD the less severe disorders. Studies in the late 1980s had already shown that the PBD group is genetically heterogeneous with at least 12 distinct genetic groups as concluded from complementation studies. Thanks to the much improved knowledge about peroxisome biogenesis notably in yeasts and the successful extrapolation of this knowledge to humans, the genes responsible for all these complementation groups have been identified making molecular diagnosis of PBD patients feasible now. It is the purpose of this review to describe the current stage of knowledge about the clinical, biochemical, cellular, and molecular aspects of PBDs, and to provide guidelines for the post- and prenatal diagnosis of PBDs. Less progress has been made with respect to the pathophysiology and therapy of PBDs. The increasing availability of mouse models for these disorders is a major step forward in this respect.
Clinical Genetics 03/2005; 67(2):107-33. · 3.13 Impact Factor
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ABSTRACT: We present a relatively mild case of peroxisomal D-bifunctional protein deficiency with inconsistent screening results in plasma for peroxisomal disorders.
Journal of Inherited Metabolic Disease 02/2005; 28(6):1172-4. · 3.58 Impact Factor
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ABSTRACT: The 625G>A variant of the short-chain acyl-CoA dehydrogenase (SCAD) gene is considered to confer susceptibility for developing 'clinical SCAD deficiency' and appears to be common in the general population. To determine the frequency of the 625G>A variant in The Netherlands, we analysed 1036 screening cards of 5- to 8-day-old newborns and found 5.5% homozygous and 31.3% heterozygous for the 625G>A variant. An increased blood/plasma C4-carnitine concentration is considered to be one of the biochemical characteristics of SCAD deficiency. To explore the correlation of C4-carnitine levels with the 625G>A variant, we determined the C4-carnitine concentration, as well as the ratio of C4- to free carnitine, in blood spots from newborns, who were detected as homozygous, heterozygous or noncarriers for the gene variant. No significant differences were found between these groups. Our study demonstrates a high frequency of the 625G>A SCAD gene variant in the Dutch population, but no correlation to significantly increased C4-carnitine levels in blood spots taken between the 5th and 8th days of life. This latter observation might be the result of the relatively late timing of neonatal screening in our country, implying that fatty acid oxidation disorders may be missed at that stage. If the 625G>A variant is associated with clinical SCAD deficiency, the high frequency of the variant suggests a possible involvement of SCAD deficiency in the pathogenesis of common disorders, probably in relation to other genetic and/or environmental factors. However, homozygosity for the 625G>A variant might be only a biochemical phenomenon, representing a 'nondisease'.
Journal of Inherited Metabolic Disease 01/2005; 28(4):557-62. · 3.58 Impact Factor
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ABSTRACT: To define neuroimaging characteristics of peroxisome biogenesis disorders (PBD) with prolonged survival belonging to the Zellweger spectrum (ZeS).
The authors studied MR images of 25 patients surviving the first year. Neuroimages were compared to neurologic profiles, PBD-ZeS specific compound developmental scores, and two common PEX1 mutations.
Three groups are defined based on normal findings, developmental anomalies, and regressive changes. Regressive changes consisting of leukoencephalopathy were identified in patients who had either stable clinical course or progressive deterioration. Concomitant neocortical atrophy was encountered in a minority. Leukoencephalopathy with stable clinical course represents the largest subgroup (48%). The authors found the central cerebellar white matter a focus for early changes in both asymptomatic and symptomatic leukoencephalopathy. A relationship between white matter involvement in clinically stable leukoencephalopathy and degree of developmental failure could not be established. The common homozygous PEX1 G843D mutation is represented in the three main outcome groups. This result points to variable phenotypic expression of the most common PEX1 mutation.
MR findings in ZeS patients surviving the first year differ from Zellweger syndrome in predominance of regressive over developmental changes. Distribution pattern suggests identical pathomechanisms for symptomatic and asymptomatic leukoencephalopathy.
Neurology 03/2004; 62(3):439-44. · 8.31 Impact Factor
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ABSTRACT: Classical galactosaemia (Mendelian Inheritance in Man, no 230400) is an autosomal recessive disorder of galactose metabolism caused by a deficiency of the enzyme galactose-1-phosphate uridyltransferase (GALT). The GALT enzyme is responsible for the conversion of galactose-1-phosphate with UDP glucose to glucose-1-phosphate and UDP galactose. The gene encoding for GALT is located on chromosome 9p13. Patients present with hepatomegaly, liver failure, food intolerance, hypoglycaemia, muscle hypotonia, sepsis and cataract. Treatment involving the total restriction of lactose-containing foods is life-saving but many patients develop late complications such as problems of mental development, disorders of motor function, disorders of speech and hypergonadotrophic hypogonadism.
Nederlands tijdschrift voor geneeskunde 02/2004; 148(2):80-1.
