Publications by authors named "Hidde H Huidekoper"

22 Publications

  • Page 1 of 1

Managing CLN2 disease: A treatable neurodegenerative condition among other treatable early childhood epilepsies.

Expert Rev Neurother 2021 Feb 4. Epub 2021 Feb 4.

Robert Debré University Hospital , Paris, France.

Introduction: Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a rare pediatric neurodegenerative condition, which is usually fatal by mid-adolescence. Seizures are one of the most common early symptoms of CLN2 disease, but patients often experience language deficits, movement disorders, and behavioral problems. Diagnosis of CLN2 disease is challenging (particularly when differentiating between early-onset developmental, metabolic, or epileptic syndromes), and diagnostic delays often overlap with rapid disease progression. An enzyme replacement therapy (cerliponase alfa) is now available, adding CLN2 disease to the list of potentially treatable disorders requiring a prompt diagnosis.

Areas Covered: Although advances in enzymatic activity testing and genetic testing have facilitated diagnoses of CLN2 disease, our review highlights the presenting symptoms that are vital in directing clinicians to perform appropriate tests or seek expert opinion. The authors also describe common diagnostic challenges and some potential misdiagnoses that may occur during differential diagnosis.

Expert Opinion: An awareness of CLN2 disease as a potentially treatable disorder and increased understanding of the key presenting symptoms can support selection of appropriate tests and prompt diagnosis. The available enzyme replacement therapy heralds an even greater imperative for early diagnosis, and for clinicians to direct patients to appropriate diagnostic pathways.
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http://dx.doi.org/10.1080/14737175.2021.1885374DOI Listing
February 2021

Deep phenotyping classical galactosemia: clinical outcomes and biochemical markers.

Brain Commun 2020 29;2(1):fcaa006. Epub 2020 Jan 29.

Division of Metabolic Disorders, Department of Pediatrics, Emma Children's Hospital, Amsterdam, UMC, University of Amsterdam, Amsterdam, the Netherlands.

Early diagnosis and dietary treatment do not prevent long-term complications, which mostly affect the central nervous system in classical galactosemia patients. The clinical outcome of patients is highly variable, and there is an urgent need for prognostic biomarkers. The aim of this study was first to increase knowledge on the natural history of classical galactosemia by studying a cohort of patients with varying geno- and phenotypes and second to study the association between clinical outcomes and two possible prognostic biomarkers. In addition, the association between abnormalities on brain MRI and clinical outcomes was investigated. Classical galactosemia patients visiting the galactosemia expertise outpatient clinic of the Amsterdam University Medical Centre were evaluated according to the International Classical Galactosemia guideline with the addition of an examination by a neurologist, serum immunoglobulin G -glycan profiling and a brain MRI. The biomarkers of interest were galactose-1-phosphate levels and -glycan profiles, and the clinical outcomes studied were intellectual outcome and the presence or absence of movement disorders and/or primary ovarian insufficiency. Data of 56 classical galactosemia patients are reported. The intellectual outcome ranged from 45 to 103 (mean 77 ± 14) and was <85 in 62%. Movement disorders were found in 17 (47%) of the 36 tested patients. In females aged 12 years and older, primary ovarian insufficiency was diagnosed in 12 (71%) of the 17 patients. Significant differences in -glycan peaks were found between controls and patients. However, no significant differences in either -glycans or galactose-1-phosphate levels were found between patients with a poor (intellectual outcome < 85) and normal intellectual outcome (intellectual outcome ≥ 85), and with or without movement disorders or primary ovarian insufficiency. The variant patients detected by newborn screening, with previously unknown geno- and phenotypes and currently no long-term complications, demonstrated significantly lower galactose-1-phospate levels than classical patients ( < 0.0005). Qualitative analysis of the MRI's demonstrated brain abnormalities in 18 of the 21 patients, more severely in patients with a lower intellectual outcome and/or with movement disorders. This study demonstrates a large variability in clinical outcome, which varies from a below average intelligence, movement disorders and in females primary ovarian insufficiency to a normal clinical outcome. In our cohort of classical galactosemia patients, galactose-1-phosphate levels and -glycan variations were not associated with clinical outcomes, but galactose-1-phosphate levels did differentiate between classical and variant patients detected by newborn screening. The correlation between brain abnormalities and clinical outcome should be further investigated by quantitative analysis of the MR images. The variability in clinical outcome necessitates individual and standardized evaluation of all classical galactosemia patients.
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http://dx.doi.org/10.1093/braincomms/fcaa006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425409PMC
January 2020

Toward newborn screening of cerebrotendinous xanthomatosis: results of a biomarker research study using 32,000 newborn dried blood spots.

Genet Med 2020 Oct 10;22(10):1606-1612. Epub 2020 Jun 10.

Department of Chemistry, University of Washington, Seattle, WA, USA.

Purpose: Cerebrotendinous xanthomatosis (CTX) is a treatable hereditary disorder caused by the deficiency of sterol 27-hydroxylase, which is encoded by the CYP27A1 gene. Different newborn screening biomarkers for CTX have been described, including 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4), 5β-cholestane-3α,7α,12α,25-tetrol glucuronide (GlcA-tetrol), the ratio of GlcA-tetrol to tauro-chenodeoxycholic acid (t-CDCA) (GlcA-tetrol/t-CDCA), and the ratio of tauro-trihydroxycholestanoic acid (t-THCA) to GlcA-tetrol (t-THCA/GlcA-tetrol). We set out to evaluate these screening methods in a research study using over 32,000 newborn dried blood spots (DBS).

Methods: Metabolites were extracted from DBS with methanol containing internal standard, which was then quantified by ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS).

Results: The measurement of 7α12αC4 was complicated by isobaric interferences and was discontinued. A total of 32,737 newborns were screened based on the GlcA-tetrol concentration in DBS. GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios were also calculated. Newborns displaying both elevated GlcA-tetrol and GlcA-tetrol/t-CDCA ratio were considered to be screen positives. The t-THCA/GlcA-tetrol ratio was used to further distinguish CTX screen positives from Zellweger Spectrum Disorder (ZSD) screen positives. Only one newborn displayed both elevated GlcA-tetrol concentration in DBS and a typical CTX biochemical profile. This newborn was interpreted as a CTX-affected patient as CYP27A1 gene sequencing identified two known pathogenic variants.

Conclusion: The results indicate that both GlcA-tetrol and the GlcA-tetrol/t-CDCA ratio are excellent CTX biomarkers suitable for newborn screening. By characterizing the relationship of GlcA-tetrol, t-CDCA, and t-THCA as secondary markers, 100% assay specificity can be achieved.
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http://dx.doi.org/10.1038/s41436-020-0846-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529987PMC
October 2020

The 1- C galactose breath test in GALT deficient patients distinguishes NBS detected variant patients but does not predict outcome in classical phenotypes.

J Inherit Metab Dis 2020 05 22;43(3):507-517. Epub 2020 Jan 22.

Department of Pediatrics, Division of Metabolic Disorders, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Classical galactosemia (CG) patients frequently develop long-term complications despite early dietary treatment. The highly variable clinical outcome is poorly understood and a lack of prognostic biomarkers hampers individual prognostication and treatment. The aim of this study was to investigate the association between residual galactose oxidation capacity and clinical and biochemical outcomes in CG patients with varying geno- and phenotypes. The noninvasive 1- C galactose breath test was used to assess whole body galactose oxidation capacity. Participants received a 7 mg/kg oral dose of 1- C labelled galactose. The galactose oxidation capacity was determined by calculating the cumulative percentage dose of the administered galactose (CUMPCD) recovered as CO in exhaled air. Forty-one CG patients (5-47 years) and four adult controls were included. The median galactose oxidation capacity after 120 minutes (CUMPCDT120) of 34 classical patients (0.29; 0.08-7.51) was significantly lower when compared to two homozygous p.Ser135Leu patients (9.44; 8.66-10.22), one heterozygous p.Ser135Leu patient 18.59, four NBS detected variant patients (13.79; 12.73-14.87) and four controls (9.29; 8.94-10.02). There was a clear correlation between Gal-1-P levels and CUMPCDT120 (P < .0005). In the classical patients, the differences in CUMPCDT120 were small and did not distinguish between patients with poor and normal clinical outcomes. The galactose breath test distinguished classical patients from homo- and heterozygous p.Ser135Leu and NBS detected variant patients, but was not able to predict clinical outcomes in classical patients. Future studies are warranted to enable individualised prognostication and treatment, especially in NBS variants with galactose oxidation capacities in the control range.
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http://dx.doi.org/10.1002/jimd.12207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317391PMC
May 2020

Untargeted Metabolomics-Based Screening Method for Inborn Errors of Metabolism using Semi-Automatic Sample Preparation with an UHPLC- Orbitrap-MS Platform.

Metabolites 2019 Nov 26;9(12). Epub 2019 Nov 26.

Center for Lysosomal and Metabolic Diseases, Department of Clinical Genetics, Erasmus University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.

Routine diagnostic screening of inborn errors of metabolism (IEM) is currently performed by different targeted analyses of known biomarkers. This approach is time-consuming, targets a limited number of biomarkers and will not identify new biomarkers. Untargeted metabolomics generates a global metabolic phenotype and has the potential to overcome these issues. We describe a novel, single platform, untargeted metabolomics method for screening IEM, combining semi-automatic sample preparation with pentafluorophenylpropyl phase (PFPP)-based UHPLC- Orbitrap-MS. We evaluated analytical performance and diagnostic capability of the method by analysing plasma samples of 260 controls and 53 patients with 33 distinct IEM. Analytical reproducibility was excellent, with peak area variation coefficients below 20% for the majority of the metabolites. We illustrate that PFPP-based chromatography enhances identification of isomeric compounds. Ranked z-score plots of metabolites annotated in IEM samples were reviewed by two laboratory specialists experienced in biochemical genetics, resulting in the correct diagnosis in 90% of cases. Thus, our untargeted metabolomics platform is robust and differentiates metabolite patterns of different IEMs from those of controls. We envision that the current approach to diagnose IEM, using numerous tests, will eventually be replaced by untargeted metabolomics methods, which also have the potential to discover novel biomarkers and assist in interpretation of genetic data.
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http://dx.doi.org/10.3390/metabo9120289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950026PMC
November 2019

Prediction of disease severity in multiple acyl-CoA dehydrogenase deficiency: A retrospective and laboratory cohort study.

J Inherit Metab Dis 2019 09 17;42(5):878-889. Epub 2019 Jul 17.

Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Multiple acyl-CoA dehydrogenase deficiency (MADD) is an ultra-rare inborn error of mitochondrial fatty acid oxidation (FAO) and amino acid metabolism. Individual phenotypes and treatment response can vary markedly. We aimed to identify markers that predict MADD phenotypes. We performed a retrospective nationwide cohort study; then developed an MADD-disease severity scoring system (MADD-DS3) based on signs and symptoms with weighed expert opinions; and finally correlated phenotypes and MADD-DS3 scores to FAO flux (oleate and myristate oxidation rates) and acylcarnitine profiles after palmitate loading in fibroblasts. Eighteen patients, diagnosed between 1989 and 2014, were identified. The MADD-DS3 entails enumeration of eight domain scores, which are calculated by averaging the relevant symptom scores. Lifetime MADD-DS3 scores of patients in our cohort ranged from 0 to 29. FAO flux and [U- C]C2-, C5-, and [U- C]C16-acylcarnitines were identified as key variables that discriminated neonatal from later onset patients (all P < .05) and strongly correlated to MADD-DS3 scores (oleate: r = -.86; myristate: r = -.91; [U- C]C2-acylcarnitine: r = -.96; C5-acylcarnitine: r = .97; [U- C]C16-acylcarnitine: r = .98, all P < .01). Functional studies in fibroblasts were found to differentiate between neonatal and later onset MADD-patients and were correlated to MADD-DS3 scores. Our data may improve early prediction of disease severity in order to start (preventive) and follow-up treatment appropriately. This is especially relevant in view of the inclusion of MADD in population newborn screening programs.
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http://dx.doi.org/10.1002/jimd.12147DOI Listing
September 2019

Glycogen Storage Disease Type IV: A Rare Cause for Neuromuscular Disorders or Often Missed?

JIMD Rep 2019 20;45:99-104. Epub 2018 Dec 20.

Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, The Netherlands.

Advancements in genetic testing now allow early identification of previously unresolved neuromuscular phenotypes. To illustrate this, we here present diagnoses of glycogen storage disease IV (GSD IV) in two patients with hypotonia and delayed development of gross motor skills. Patient 1 was diagnosed with congenital myopathy based on a muscle biopsy at the age of 6 years. The genetic cause of his disorder (two compound heterozygous missense mutations in GBE1 (c.[760A>G] p.[Thr254Ala] and c.[1063C>T] p.[Arg355Cys])), however, was only identified at the age of 17, after panel sequencing of 314 genes associated with neuromuscular disorders. Thanks to the availability of next-generation sequencing, patient 2 was diagnosed before the age of 2 with two compound heterozygous mutations in GBE1 (c.[691+2T>C] (splice donor variant) and the same c.[760A>G] p.[Thr254Ala] mutation as patient 1). GSD IV is an autosomal recessive metabolic disorder with a broad and expanding clinical spectrum, which hampers targeted diagnostics. The current cases illustrate the value of novel genetic testing for rare genetic disorders with neuromuscular phenotypes, especially in case of clinical heterogeneity. We argue that genetic testing by gene panels or whole exome sequencing should be considered early in the diagnostic procedure of unresolved neuromuscular disorders.
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http://dx.doi.org/10.1007/8904_2018_148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336674PMC
December 2018

Long-term treatment effect in cerebrotendinous xanthomatosis depends on age at treatment start.

Neurology 2019 01 7;92(2):e83-e95. Epub 2018 Dec 7.

From the Department of Neurology (B.M.L.S.), Catharina Hospital, Eindhoven; Department of Neurology (B.M.L.S., A.V.), Canisius Wilhelmina Hospital, Nijmegen; Department of Pediatrics (H.H.H.), Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center-University Hospital, Rotterdam; Department of Neurology (B.P.C.v.d.W.), Donders Institute for Brain, Cognition and Behaviour (B.P.C.v.d.W., R.A.W.), and Department of Laboratory Medicine (L.A.J.K., R.A.W.), Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen; Department of Genetics (E.H.B.), University Medical Center Utrecht; Department of Internal Medicine (C.E.M.H.), Division of Endocrinology and Metabolism, Academic Medical Center, Amsterdam; Department of Internal Medicine (H.R.H.), Máxima Medical Center Eindhoven; Department of Internal Medicine (H.R.H.), Maastricht University Medical Center; and CAPHRI School for Public Health and Primary Care, Ageing and Long-Term Care (H.R.H.), Maastricht University, the Netherlands.

Objective: To evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX).

Methods: In this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up.

Results: Median follow-up time was 8 years (6 months-31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabilization in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively.

Conclusions: Treatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a rationale to include CTX in newborn screening programs.
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http://dx.doi.org/10.1212/WNL.0000000000006731DOI Listing
January 2019

Autism spectrum disorder: an early and frequent feature in cerebrotendinous xanthomatosis.

J Inherit Metab Dis 2018 07 11;41(4):641-646. Epub 2017 Sep 11.

Department of Neurology, Canisius Wilhelmina Hospital, PO Box 9015, 6500GS, Nijmegen, The Netherlands.

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessively inherited inborn error of metabolism (IEM) due to mutations in the CYP27A1 gene. The clinical picture ranges from being nearly asymptomatic in early childhood, up to severe disability at adult age. Infantile-onset diarrhea and juvenile-onset cataract are the earliest symptoms in childhood. In the current study, we evaluated the presence of autism spectrum disorder (ASD) in a large cohort of CTX patients.

Methods: We performed a retrospective patient file study in 77 genetically confirmed Dutch CTX patients to determine the frequency of ASD. In addition, we compared plasma cholestanol levels in CTX patients with and without a diagnosis of ASD and tried to establish a relation between CYP27A1 genotype and ASD.

Results: In our CTX cohort, 10 patients (13%; nine pediatric and one adult) with ASD were identified. At the time of diagnosis of ASD, most patients only exhibited symptoms of diarrhea and/or intellectual disability without signs of cataract or neurological symptoms. No correlation was found between the presence of ASD and the level of cholestanol or CYP27A1 genotype. The behavioral problems stabilized or improved after treatment initiation with chenodeoxycholic acid (CDCA) in all pediatric patients.

Conclusions: We conclude that ASD is an early and probably underestimated frequent feature in CTX. Metabolic screening for CTX should be performed in patients with ASD when accompanied by diarrhea, intellectual disability, juvenile cataract, and/or neurological involvement. Early recognition allows for earlier initiation of specific treatment and will improve clinical outcome. Our results add CTX to the list of treatable IEMs associated with ASD.
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http://dx.doi.org/10.1007/s10545-017-0086-7DOI Listing
July 2018

A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios.

J Lipid Res 2017 05 17;58(5):1002-1007. Epub 2017 Mar 17.

Department of Pediatrics, Center for Lysosomal and Metabolic Diseases, Erasmus Medical Center, Rotterdam, The Netherlands.

Cerebrotendinous xanthomatosis (CTX) is a treatable neurodegenerative metabolic disorder of bile acid synthesis in which symptoms can be prevented if treatment with chenodeoxycholic acid supplementation is initiated early in life, making CTX an excellent candidate for newborn screening. We developed a new dried blood spot (DBS) screening assay for this disorder on the basis of different ratios between the accumulating cholestanetetrol glucuronide (tetrol) and specific bile acids/bile acid intermediates, without the need for derivatization. A quarter-inch DBS punch was extracted with methanol, internal standards were added, and after concentration the extract was injected into the tandem mass spectrometer using a 2 min flow injection analysis for which specific transitions were measured for cholestanetetrol glucuronide, taurochenodeoxycholic acid (t-CDCA), and taurotrihydroxycholestanoic acid (t-THCA). A proof-of-principle experiment was performed using 217 Guthrie cards from healthy term/preterm newborns, CTX patients, and Zellweger patients. Using two calculated biomarkers, tetrol:t-CDCA and t-THCA:tetrol, this straightforward method achieved an excellent separation between DBSs of CTX patients and those of controls, Zellweger patients, and newborns with cholestasis. The results of this small pilot study indicate that the tetrol:t-CDCA ratio is an excellent derived biomarker for CTX that has the potential to be used in neonatal screening programs.
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http://dx.doi.org/10.1194/jlr.P075051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5408618PMC
May 2017

Extended Abstract: Deficiency of Sodium Taurocholate Cotransporting Polypeptide (SLC10A1): A New Inborn Error of Metabolism with an Attenuated Phenotype.

Dig Dis 2017 1;35(3):259-260. Epub 2017 Mar 1.

Laboratory Genetic Metabolic Disease, Academic Medical Center, Amsterdam, The Netherlands.

We present the first patient with a defect in the Na+-taurocholate cotransporting polypeptide SLC10A1 (NTCP), which plays a key role in the enterohepatic circulation of bile salts. The clinical presentation of the child was mild and the child showed no signs of liver dysfunction or pruritus despite extremely elevated plasma bile salt levels (>100-fold upper-limit of normal). A homozygous point mutation was found in the SLC10A1 gene (resulting in amino acid change R252H) and functional studies confirmed the pathogenicity of the mutation. This confirms the role of NTCP as the major transporter of conjugated bile salts into the liver as part of the enterohepatic circulation and shows that other transporters partly can take over its function, resulting in a relatively mild phenotype. This work was published previously in [Vaz et al.: Hepatology 2015;61:260-267] and supplemented with some follow-up information of the patient.
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http://dx.doi.org/10.1159/000450984DOI Listing
May 2017

Update on newborn dried bloodspot testing for cerebrotendinous xanthomatosis: An available high-throughput liquid-chromatography tandem mass spectrometry method.

Mol Genet Metab Rep 2016 Jun 12;7:11-5. Epub 2016 Mar 12.

BioAnalytical Shared Resource Facility, Department of Physiology & Pharmacology, Oregon Health & Science University (OHSU), Portland, OR, United States.

Background: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective treatment is available. We previously described a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) test with potential to screen newborn dried bloodspots (DBS) for CTX. We report here modifications to the methodology and application of the modified test to analysis of DBS from a CTX-affected and unaffected newborns.

Methods: The testing methodology utilizes keto derivatization to enable sensitive LC-ESI-MS/MS measurement of elevated 7α,12α-dihydroxy-4-cholesten-3-one (7α12αC4) in CTX newborn DBS. We report here method modifications, including use of a DBS extraction procedure used in newborn screening laboratories and a reduced analysis time of 2 min per sample.

Results: Rapid isotope-dilution LC-ESI/MS/MS quantification of the ketosterol bile acid precursor 7α12αC4 provides a test that could readily discriminate a CTX positive newborn DBS sample (with a concentration of 104.4 ng/ml) from unaffected newborn samples (with a mean concentration of 4.1 ± 3.4 ng/ml; range 0.2-15.6 ng/ml, n = 39) analyzed in a blinded manner.

Conclusions: We provide additional evidence suggesting 7α12αC4 may be a promising test marker to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefit those affected with CTX, preventing morbidity and mortality.
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http://dx.doi.org/10.1016/j.ymgmr.2016.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4908045PMC
June 2016

Quantification of naive and memory T-cell turnover during HIV-1 infection.

AIDS 2015 Oct;29(16):2071-80

aLaboratory of Translational Immunology, Department of Immunology, University Medical Center Utrecht bTheoretical Biology and Bioinformatics, Utrecht University, Utrecht cDepartment of Gastroenterology and Hepatology, Erasmus MC Rotterdam, Rotterdam, The Netherlands dDepartment of Infectious Disease Epidemiology, Imperial College, London, UK eDepartment of Internal Medicine and Infectious Diseases, University Medical Center Utrecht, Utrecht fDepartment of Internal Medicine and Gastroenterology, Kennemer Gasthuis, Haarlem gDepartment of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center hIATEC, Academic Medical Center iDepartment of Internal Medicine, Academic Medical Center jDepartment of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands. *Nienke Vrisekoop, Julia Drylewicz, Rogier Van Gent contributed equally to this study; Rob J. de Boer, Kiki Tesselaar, José A.M. Borghans also contributed equally to this study.

Background: In HIV infection, the homeostasis of CD4 and CD8 T cells is dramatically disturbed, and several studies have pointed out that T-cell turnover rates are increased. To understand how the CD4 and CD8 T-cell pools are affected, it is important to have quantitative insights into the lifespans of the cells constituting the different T-lymphocyte populations.

Methods: We used long-term in-vivo H2O labeling and mathematical modeling to estimate the average lifespans of naive and memory CD4 and CD8 T cells in untreated (n = 4) and combination antiretroviral therapy-treated (n = 3) HIV-1-infected individuals.

Results: During untreated chronic HIV-1 infection, naive CD4 and CD8 T cells lived on average 618 and 271 days, whereas memory CD4 and CD8 T cells had average lifespans of 53 and 43 days, respectively. These lifespans were at least three-fold shorter than those in healthy controls (n = 5). In patients on effective combination antiretroviral therapy with total CD4 T-cell counts in the normal range, we found that naive CD4 and CD8 T-cell lifespans had not completely normalized and were still two-fold shortened.

Conclusion: The average lifespan of both naive and memory CD4 and CD8 T cells decreased during untreated chronic HIV-1 infection. Although the turnover of the memory T-cell populations nearly normalized during effective treatment, the turnover of naive CD4 and CD8 T cells did not seem to normalize completely.
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http://dx.doi.org/10.1097/QAD.0000000000000822DOI Listing
October 2015

Hepatotoxicity due to chenodeoxycholic acid supplementation in an infant with cerebrotendinous xanthomatosis: implications for treatment.

Eur J Pediatr 2016 Jan 10;175(1):143-6. Epub 2015 Jul 10.

Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Unlabelled: We present a two-week old girl who was diagnosed with cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, after a diagnostic workup for convulsions which were shown to be caused by a parechovirus encephalitis. The diagnosis of CTX was confirmed with CYP27A1 mutation analysis. She was started on chenodeoxycholic acid (CDCA) supplementation, which inhibits cholestanol production through a feedback mechanism, at the advised dosage of 15 mg/kg/day. Within 6 weeks, she developed jaundice with hepatomegaly. CDCA supplementation was stopped after which liver size and function rapidly normalised. CDCA supplementation was then restarted and maintained at 5 mg/kg/day. Cholestanol, liver enzymes and total bilirubin were frequently monitored in the patient, who is now 2.8 years of age, and have remained within normal range. Her psychomotor development has been normal.

Conclusion: adequate metabolic control was achieved in an infant with CTX with CDCA supplementation at a dosage of 5 mg/kg/day and was well tolerated. CDCA supplementation at 15 mg/kg/day seems hepatotoxic in infants and should not be used. This is relevant in view of the possible inclusion of CTX in newborn screening programs in the near future.

What Is Known: Cerebrotendinous xanthomatosis (CTX), an inborn error of bile acid synthesis, is a progressive neurological disorder. Symptoms of CTX can be halted, and likely prevented, with chenodeoxycholic acid (CDCA) supplementation, making CTX a good candidate for newborn screening. What is New: CDCA supplementation at the advised dosage of 15 mg/kg/day in children seems hepatoxic in infants with CTX. Adequate metabolic control in an infant with CTX was achieved with CDCA supplementation at 5 mg/kg/day and well tolerated.
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http://dx.doi.org/10.1007/s00431-015-2584-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709371PMC
January 2016

High prevalence of complementary and alternative medicine use in patients with genetically proven mitochondrial disorders.

J Inherit Metab Dis 2015 May 11;38(3):477-82. Epub 2014 Oct 11.

Nijmegen Centre for Mitochondrial Disorders (NCMD) at the Amalia Children's Hospital, Radboudumc, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Despite major advances in understanding the pathophysiology of mitochondrial diseases, clinical management of these conditions remains largely supportive, and no effective treatment is available. We therefore assumed that the burden of disease combined with the lack of adequate treatment leaves open a big market for complementary and alternative medicine use. The objective of this study was to evaluate the use and perceived effectiveness of complementary and alternative medicine in children and adults with genetically proven mitochondrial disease. The reported use was surprisingly high, with 88% of children and 91% of adults having used some kind of complementary and alternative medicine in the last 2 years. Also, the mean cost of these treatments was impressive, being 489/year for children and 359/year for adult patients. Over-the-counter remedies (e.g., food supplements, homeopathy) and self-help techniques (e.g., Reiki, yoga) were the most frequently used complementary and alternative therapies in our cohort: 54% of children and 60% of adults reported the various complementary and alternative medicine therapies to be effective. Given the fact that currently no effective treatment exists, further research toward the different therapies is needed, as our study clearly demonstrates that such therapies are highly sought after by affected patients.
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http://dx.doi.org/10.1007/s10545-014-9773-9DOI Listing
May 2015

Endogenous glucose production from infancy to adulthood: a non-linear regression model.

Arch Dis Child 2014 Dec 4;99(12):1098-102. Epub 2014 Jul 4.

Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Objective: To construct a regression model for endogenous glucose production (EGP) as a function of age, and compare this with glucose supplementation using commonly used dextrose-based saline solutions at fluid maintenance rate in children.

Design: A model was constructed based on EGP data, as quantified by [6,6-(2)H2] glucose dilution after fasting overnight during normoglycaemia, in 40 healthy subjects aged 2.5-54.3 years old. The data were analysed using non-linear regression modelling with a 1-phase exponential decay curve fit. This model was compared to the amount of glucose provided with 2.5% or 5% dextrose-based saline solutions infused at fluid maintenance rate.

Results: Non-linear regression analysis of the EGP data yielded the following regression model: EGP (mg/kg/min) = 6.50 × 2.72(-0.145 × age (y))+1.93. Glucose supplementation at fluid maintenance rate with a 5% dextrose-based saline solution ranged from 46% at age 1 year to 55% at age 18 years of the glucose required to preclude the need for EGP. With a 2.5% dextrose-based solution, these percentages are 23% at age 1 year to 27% at age 18 years.

Conclusions: we present an accurate non-linear regression model for EGP as a function of age. With standard dextrose-based saline solutions infused at fluid maintenance rate, only approximately 50% or less of EGP is provided. With prolonged infusion of these solutions, the deficit between exogenous glucose supplementation and EGP may induce a catabolic state and may ultimately lead to hypoglycaemia, especially in younger children.
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http://dx.doi.org/10.1136/archdischild-2013-305718DOI Listing
December 2014

Normal rates of whole-body fat oxidation and gluconeogenesis after overnight fasting and moderate-intensity exercise in patients with medium-chain acyl-CoA dehydrogenase deficiency.

J Inherit Metab Dis 2013 Sep 14;36(5):831-40. Epub 2012 Sep 14.

Department of Pediatrics, University of Amsterdam, Amsterdam, The Netherlands.

Background: Impairments in gluconeogenesis have been implicated in the pathophysiology of fasting hypoglycemia in medium-chain acyl-CoA dehydrogenase deficiency. However, whole body glucose and fat metabolism have never been studied in vivo.

Methods: Stable isotope methodology was applied to compare fat and glucose metabolism between four adult patients with MCADD and four matched controls both at rest and during 1.5 h of moderate-intensity exercise. Additionally, intramyocellular lipid and glycogen content and intramyocellular acylcarnitines were assessed in muscle biopsies collected prior to and immediately after cessation of exercise.

Results: At rest, plasma FFA turnover was significantly higher in patients with MCADD, whereas the plasma FFA concentrations did not differ between patients and controls. Blood glucose kinetics did not differ between groups both at rest and during exercise. Palmitate and FFA turnover, total fat and carbohydrate oxidation rates, the use of muscle glycogen and muscle derived triglycerides during exercise did not differ between patients and controls. Plasma FFA oxidation rates were significantly lower in patients at the latter stages of exercise. Free carnitine levels in muscle were lower in patients, whereas no differences were detected in muscle acetylcarnitine levels.

Conclusions: Whole-body or skeletal muscle glucose and fat metabolism were not impaired in adult patients with MCADD. This implies that MCADD is not rate limiting for energy production under the conditions studied. In addition, patients with MCADD have a higher FFA turnover rate after overnight fasting, which may stimulate ectopic lipid deposition and, as such, make them more susceptible for developing insulin resistance.
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http://dx.doi.org/10.1007/s10545-012-9532-8DOI Listing
September 2013

Extended metabolic evaluation of suspected symptomatic hypoglycemia: the prolonged fast and beyond.

Metabolism 2010 Nov 1;59(11):1543-50. Epub 2010 Mar 1.

Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

The diagnostic evaluation of spontaneous hypoglycemia in adults is mainly directed at detecting an insulinoma. Its interpretation is troublesome in those patients who develop low venous plasma glucose levels with appropriate hypoinsulinemia during a prolonged supervised fast. In this study, we investigated in this group of patients whether abnormalities in intermediary metabolism (fatty acid oxidation and amino/organic acids) could be detected that might explain the hypoinsulinemic hypoglycemia. Ten patients with otherwise unexplained low venous plasma glucose levels (<3 mmol/L) during prolonged fasting were included in the study. The patients participated in an extended metabolic protocol based on stable isotope techniques after an overnight fast to explore abnormalities in endogenous glucose production and intermediary metabolism. Endogenous glucose production, glucoregulatory hormones, plasma acylcarnitines, gluconeogenic amino acids, and rates of fatty acid and carbohydrate oxidation after 16 and 22 hours of fasting were measured. Although during the prolonged fast all patients had low venous plasma glucose level, there were no hypoglycemic events during the extended metabolic protocol. No abnormalities in endogenous glucose production (compared with reference values obtained in young healthy volunteers), fatty acid oxidation, or amino acid/organic acids were found in this patient group. In a group of patients exhibiting low venous plasma glucose levels during prolonged fasting in whom insulinoma was excluded, we found no signs of metabolic disorders. Therefore, the observation of low plasma glucose values in this subgroup of patients probably does not warrant extensive metabolic evaluation.
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http://dx.doi.org/10.1016/j.metabol.2010.01.024DOI Listing
November 2010

A potential role for muscle in glucose homeostasis: in vivo kinetic studies in glycogen storage disease type 1a and fructose-1,6-bisphosphatase deficiency.

J Inherit Metab Dis 2010 Feb 2;33(1):25-31. Epub 2010 Feb 2.

Department of Pediatrics Academic Medical Center, University Hospital of Amsterdam, The Netherlands.

Background: A potential role for muscle in glucose homeostasis was recently suggested based on characterization of extrahepatic and extrarenal glucose-6-phosphatase (glucose-6-phosphatase-beta). To study the role of extrahepatic tissue in glucose homeostasis during fasting glucose kinetics were studied in two patients with a deficient hepatic and renal glycogenolysis and/or gluconeogenesis.

Design: Endogenous glucose production (EGP), glycogenolysis (GGL), and gluconeogenesis (GNG) were quantified with stable isotopes in a patient with glycogen storage disease type 1a (GSD-1a) and a patient with fructose-1,6-bisphosphatase (FBPase) deficiency. The [6,6-(2)H(2)]glucose dilution method in combination with the deuterated water method was used during individualized fasting tests.

Results: Both patients became hypoglycemic after 2.5 and 14.5 h fasting, respectively. At that time, the patient with GSD-1a had EGP 3.84 micromol/kg per min (30% of normal EGP after an overnight fast), GGL 3.09 micromol/kg per min, and GNG 0.75 micromol/kg per min. The patient with FBPase deficiency had EGP 8.53 micromol/kg per min (62% of normal EGP after an overnight fast), GGL 6.89 micromol/kg per min GGL, and GNG 1.64 micromol/kg per min.

Conclusion: EGP was severely hampered in both patients, resulting in hypoglycemia. However, despite defective hepatic and renal GNG in both disorders and defective hepatic GGL in GSD-1a, both patients were still able to produce glucose via both pathways. As all necessary enzymes of these pathways have now been functionally detected in muscle, a contribution of muscle to EGP during fasting via both GGL as well as GNG is suggested.
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http://dx.doi.org/10.1007/s10545-009-9030-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828550PMC
February 2010

Fasting adaptation in idiopathic ketotic hypoglycemia: a mismatch between glucose production and demand.

Eur J Pediatr 2008 Aug 13;167(8):859-65. Epub 2007 Oct 13.

Department of Pediatrics, Academic Medical Center, University of Amsterdam, P.O. Box 22660, NL-1100 DD, Amsterdam, The Netherlands.

In order to study the pathophysiology of hypoglycemia in idiopathic ketotic hypoglycemia (KH), glucose kinetics during fasting in patients with KH were determined. A fasting test was performed in 12 children with previously documented KH. Besides determination of glucoregulatory hormones, plasma ketones, FFA and alanine, the rates of endogenous glucose production (EGP), glucose uptake, gluconeogenesis (GNG) and glycogenolysis (GGL) were quantified using the [6,6-(2)H(2)] glucose isotope dilution method and the deuterated water method. The five youngest subjects (age 2.5-3.9 years) became hypoglycemic (glucose <3.0 mmol/l) during the test. Mean differences in glucose kinetics between overnight fasting and the end of the test in the hypoglycemic vs. the normoglycemic subjects were: EGP: -31.9% vs. -17.9% (p = 0.007), GGL: -66.2% vs. -50.8% (p = 0.465) and GNG 6.8% vs. 19.5% (p = 0.465). Plasma alanine levels were significantly lower (p = 0.028) at the end of the test in the hypoglycemic subjects. Plasma ketones and FFA levels were in the normal range for fasting duration in all subjects. We conclude that hypoglycemia in KH is caused by the inability to sustain an adequate EGP during fasting in view of the higher glucose requirement in young children. The decrease in GGL is not accompanied by a significant increase in GNG, possibly because of a limitation in the supply of alanine. Our results support the hypothesis that KH represents the lower tail of the Gaussian distribution of fasting tolerance in children.
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http://dx.doi.org/10.1007/s00431-007-0598-5DOI Listing
August 2008

Postponing urine acidification for 24 h does not change the oxalate concentration.

Clin Chim Acta 2007 Sep 16;384(1-2):184-5. Epub 2007 Jun 16.

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http://dx.doi.org/10.1016/j.cca.2007.06.007DOI Listing
September 2007

Short-term exogenous galactose supplementation does not influence rate of appearance of galactose in patients with classical galactosemia.

Mol Genet Metab 2005 Mar 11;84(3):265-72. Epub 2004 Nov 11.

Department of Paediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Introduction: Recently, evidence has been presented that adult patients with classical galactosemia have higher than expected galactose tolerance. This may be caused by a decrease of endogenous galactose production with ageing. Alternatively, suppression of endogenous galactose production by exogenous galactose might be implicated. The aim of this study was to determine if the rate of appearance of galactose is suppressed by exogenous galactose.

Materials And Methods: Two adult patients with classical galactosemia and three healthy control subjects were given a primed continuous infusion of D-[1-13C]galactose to determine the rate of appearance of galactose (GAR, expressed as micromol/kg/h) before and during additional galactose supplementation. After initial assessment of GAR (GAR1), GAR was determined during doubled (GAR2) or quadrupled (GAR4) galactose infusion.

Results: GAR1 was 2.48 and 2.44 in patients 1 and 2, and 0.46, 0.34, and 0.39 in control subjects 1, 2, and 3, respectively. GAR(2) was 2.43 and 2.13 in patients 1 and 2, and 0.57, 0.38, and 0.47 in control subjects 1, 2, and 3, respectively. In patient 1 the experiment was repeated during quadrupled galactose infusion. Here GAR1 was 3.01 and GAR4 was 3.26.

Conclusions: No significant differences between GAR before and during additional galactose infusion were found in patients and in control subjects. GAR1 was significantly higher in patients than in control subjects. We conclude that the rate of appearance of galactose is not influenced by exogenous galactose, at least under short-term conditions, in patients with classical galactosemia and in control subjects.
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http://dx.doi.org/10.1016/j.ymgme.2004.09.013DOI Listing
March 2005