Publications by authors named "Charlotte M A Lubout"

8 Publications

  • Page 1 of 1

Bone mineral density is within normal range in most adult phenylketonuria patients.

J Inherit Metab Dis 2020 03 6;43(2):251-258. Epub 2020 Feb 6.

Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC - Location AMC, Amsterdam, The Netherlands.

Low bone mineral density (BMD) as a risk factor for fractures has been a long-standing concern in phenylketonuria (PKU). It is hypothesised that the disease itself or the dietary treatment might lead to a low BMD. Previous studies show conflicting results of BMD in PKU due to differences in age, techniques to assess BMD and criteria used. To assess the prevalence of low BMD and define possible risk factors in a large number of adult, early treated PKU (ETPKU) patients. European centres were invited for a survey, collecting retrospective data including results of dual-energy X-ray absorptiometry (DXA) scans of adult ETPKU patients. BMD of 183 adult ETPKU patients aged 18-46 (median age 28, all females premenopausal) years was lower than in the general population at most skeletal sites but the frequency of low BMD (Z-score <-2) was at maximum 5.5%. No risk factors for low BMD in PKU patients could be identified. Low BMD occurs only in a small subset of PKU patients. DXA scans should be considered for well controlled patients from age 35-40 years and up and on indication in those PKU patients considered to be at increased risk for fractures.
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http://dx.doi.org/10.1002/jimd.12177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078943PMC
March 2020

The first European guidelines on phenylketonuria: Usefulness and implications for BH responsiveness testing.

J Inherit Metab Dis 2020 03 20;43(2):244-250. Epub 2019 Nov 20.

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

Objective: This study aimed to investigate and improve the usefulness of the 48-hour BH loading test and to assess genotype for BH responsiveness prediction, using the new definition of BH responsiveness from the European guidelines, as well as an amended definition.

Method: Applying the definition of the European guidelines (≥100% increase in natural protein tolerance) and an amended definition (≥100% increase in natural protein tolerance or tolerating a safe natural protein intake) to a previous dataset, we first assessed the positive predictive value (PPV) of the 48-hour BH loading test using a cutoff value of 30%. Then, we tried to improve this PPV by using different cutoff values and separate time points. Last, using the BIOPKU database, we compared predicted BH responsiveness (according to genotype) and genotypic phenotype values (GPVs) in BH -responsive and BH -unresponsive patients.

Results: The PPV of the 48-hour loading test was 50.0% using the definition of the European guidelines, and 69.4% when applying the amended definition of BH responsiveness. Higher cutoff values led to a higher PPV, but resulted in an increase in false-negative tests. Parameters for genotype overlapped between BH -responsive and BH -unresponsive patients, although BH responsiveness was not observed in patients with a GPV below 2.4.

Conclusion: The 48-hour BH loading test is not as useful as previously considered and cannot be improved easily, whereas genotype seems mainly helpful in excluding BH responsiveness. Overall, the definition of BH responsiveness and BH responsiveness testing require further attention.
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http://dx.doi.org/10.1002/jimd.12173DOI Listing
March 2020

Biomarkers of Micronutrients in Regular Follow-Up for Tyrosinemia Type 1 and Phenylketonuria Patients.

Nutrients 2019 Aug 27;11(9). Epub 2019 Aug 27.

Division of Metabolic Diseases, Groningen, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.

Phenylketonuria (PKU) is treated with dietary restrictions and sometimes tetrahydrobiopterin (BH4). PKU patients are at risk for developing micronutrient deficiencies, such as vitamin B12 and folic acid, likely due to their diet. Tyrosinemia type 1 (TT1) is similar to PKU in both pathogenesis and treatment. TT1 patients follow a similar diet, but nutritional deficiencies have not been investigated yet. In this retrospective study, biomarkers of micronutrients in TT1 and PKU patients were investigated and outcomes were correlated to dietary intake and anthropometric measurements from regular follow-up measurements from patients attending the outpatient clinic. Data was analyzed using Kruskal-Wallis, Fisher's exact and Spearman correlation tests. Furthermore, descriptive data were used. Overall, similar results for TT1 and PKU patients (with and without BH4) were observed. In all groups high vitamin B12 concentrations were seen rather than B12 deficiencies. Furthermore, all groups showed biochemical evidence of vitamin D deficiency. This study shows that micronutrients in TT1 and PKU patients are similar and often within the normal ranges and that vitamin D concentrations could be optimized.
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http://dx.doi.org/10.3390/nu11092011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769775PMC
August 2019

Successful Treatment of Hereditary Folate Malabsorption With Intramuscular Folinic Acid.

Pediatr Neurol 2020 01 22;102:62-66. Epub 2019 Jun 22.

Department of Pediatric Metabolic Diseases, Emma Children's Hospital, Amsterdam Gastro-Enterology & Metabolism Research Institute, Amsterdam University Medical Centres, Amsterdam, The Netherlands; Department of Clinical Genetics, Amsterdam University Medical Centres, Amsterdam, The Netherlands. Electronic address:

Background: Hereditary folate malabsorption is a multisystem disease owing to biallelic variants in the gene encoding the proton-coupled folate transporter. Hereditary folate malabsorption is treated with folinic acid, aimed to restore blood and cerebrospinal fluid folate levels. Little is known as to whether oral or intramuscular supplementation of folinic acid is most effective.

Methods: Here we describe a one-year-old boy with hereditary folate malabsorption presenting with the typical features including failure to thrive, aphthous stomatitis, macrocytic anemia along with severe developmental impairment and epilepsy, as well as a magnetic resonance imaging of the brain showing bilateral occipital, cortical calcifications characteristic of hereditary folate malabsorption. We compared the effect of treatment with oral folinic acid versus intramuscular folinic acid supplementation by measuring plasma and cerebrospinal fluid folate levels.

Results: Compared with oral administration, intramuscular treatment resulted in higher folate levels in blood and, most importantly, normalization of folate levels in cerebrospinal fluid. Clinically, nearly all systemic and neurological symptoms resolved.

Conclusion: Normal cerebrospinal fluid folate levels can be achieved in individuals with hereditary folate malabsorption with intramuscular (but not with oral) administration of folinic acid.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.06.009DOI Listing
January 2020

Safety issues associated with dietary management in patients with hepatic glycogen storage disease.

Mol Genet Metab 2018 09 18;125(1-2):79-85. Epub 2018 Jul 18.

Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Introduction: Hepatic glycogen storage diseases (GSDs) are a group of inherited disorders of carbohydrate metabolism for which dietary management is the cornerstone. Safety and acute complications associated with dietary management have been poorly documented. We hypothesized that safety issues and complications associated with dietary management are prevalent amongst patients with these ultra-rare disorders.

Methods: A questionnaire was developed consisting of 40 questions and was distributed via eight GSD patient organizations from multiple countries. Respondents were (caregivers of) patients with self-reported hepatic GSD.

Results: 249 GSD patients from 26 countries responded with a median age of 14.8 years (range: 0.5-66.1). Although management was considered safe by 71% of patients, 51% reported at least one acute complication associated with dietary management, with a total number of 425 reported complications. Most frequently reported causes were: not waking up by an alarm clock (n = 70), forgetting a meal (n = 57) and infections (n = 43). Most frequently reported complications were: hypoglycemia (n = 112), hospital admissions (n = 79) and drowsiness (n = 74). Most complications occurred before the age of 12 years (82%; 637/774 total number of reported events) and during night time (63%; 340/536). Only 61% (152/249) of the GSD patients reported using a written emergency protocol.

Conclusions: Safety issues and complications associated with dietary management are prevalently reported by (caregivers of) 249 GSD patients. A discrepancy has been observed between the patient's perspective on safety of dietary management and occurrence of complications as a result of dietary management.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.004DOI Listing
September 2018

A preliminary study of telemedicine for patients with hepatic glycogen storage disease and their healthcare providers: from bedside to home site monitoring.

J Inherit Metab Dis 2018 11 29;41(6):929-936. Epub 2018 Mar 29.

Section of Metabolic Diseases, Beatrix Children's Hospital University Medical Center Groningen, University of Groningen, PO Box 30 001, 9700 RB, Groningen, The Netherlands.

Background: The purpose of this project was to develop a telemedicine platform that supports home site monitoring and integrates biochemical, physiological, and dietary parameters for individual patients with hepatic glycogen storage disease (GSD).

Methods And Results: The GSD communication platform (GCP) was designed with input from software developers, GSD patients, researchers, and healthcare providers. In phase 1, prototyping and software design of the GCP has occurred. The GCP was composed of a GSD App for patients and a GSD clinical dashboard for healthcare providers. In phase 2, the GCP was tested by retrospective patient data entry. The following software functionalities were included (a) dietary registration and prescription module, (b) emergency protocol module, and (c) data import functions for continuous glucose monitor devices and activity wearables. In phase 3, the GSD App was implemented in a pilot study of eight patients with GSD Ia (n = 3), GSD IIIa (n = 1), and GSD IX (n = 4). Usability was measured by the system usability scale (SUS). The mean SUS score was 64/100 [range: 38-93].

Conclusions: This report describes the design, development, and validation process of a telemedicine platform for patients with hepatic GSD. The GCP can facilitate home site monitoring and data exchange between patients with hepatic GSD and healthcare providers under varying circumstances. In the future, the GCP may support cross-border healthcare, second opinion processes and clinical trials, and could possibly also be adapted for other diseases for which a medical diet is the cornerstone.
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http://dx.doi.org/10.1007/s10545-018-0167-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326981PMC
November 2018

Molybdenum cofactor deficiency type A: Prenatal monitoring using MRI.

Eur J Paediatr Neurol 2018 May 28;22(3):536-540. Epub 2017 Nov 28.

Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, PO Box 30.001, 9700 RB Groningen, the Netherlands. Electronic address:

Molybdenum cofactor deficiency type A (MoCD-A) is an inborn error of metabolism presenting early after birth with severe seizures. Recently, experimental substitution treatment with cyclic pyranopterin monophosphate (cPMP) has become available. Because prenatal data is scarce, we report data of prenatal Magnetic Resonance Imaging (MRI) in two cases with MoCD-A demonstrating signs of possible early brain injury. Prenatal MRI can be used for monitoring in MoCD-A to guide decision-making in timing of delivery.
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http://dx.doi.org/10.1016/j.ejpn.2017.11.006DOI Listing
May 2018

Cervical high-intensity intramedullary lesions without spinal cord compression in achondroplasia.

J Neurosurg Spine 2007 Apr;6(4):304-8

Department of Neurosurgery, Leiden University Medical Center, Leiden, The Netherlands.

Object: In the authors' experience, the appearance of a cervical high-intensity intramedullary (CHII) lesion on magnetic resonance (MR) images in the absence of local spinal cord compression is frequently observed in patients with achondroplasia, although it has been mentioned only sporadically in the literature. Hence, the authors conducted a retrospective study in a consecutive single-center series of patients with achondroplasia to determine the prevalence and imaging features of this entity. They also reviewed the literature.

Methods: Cervical MR imaging studies obtained to establish diagnoses in 25 adult patients with achondroplasia and assessed at the Leiden University Medical Center after neurogenic claudication developed were evaluated for the presence of a CHII lesion. Imaging features of the lesion were described, and a literature search was performed. The CHII lesion was demonstrated in 16 of 25 adult patients with achondroplasia (64%) in the absence of local spinal cord compression. All lesions were located at the C-2 level and appeared to be confined to the gray matter. The CHII lesion was associated with local spinal cord thinning, most likely representing focal atrophy. In their literature search the authors found no description of the CHII lesion in adults, although its presence has been mentioned as a peculiarity in the pediatric achondroplastic population.

Conclusions: In this large series of adults with achondroplasia and symptomatic neurogenic claudication, a CHII lesion was frequently depicted on imaging studies, but it remains a fully explored imaging phenomenon. Its cause and clinical relevance require investigation, as does its prevalence in the general achondroplastic population.
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http://dx.doi.org/10.3171/spi.2007.6.4.3DOI Listing
April 2007