Publications by authors named "Mirian C H Janssen"

79 Publications

Monitoring phenylalanine concentrations in the follow-up of phenylketonuria patients: An inventory of pre-analytical and analytical variation.

JIMD Rep 2021 Mar 22;58(1):70-79. Epub 2020 Nov 22.

Translational Metabolic Laboratory, Department of Laboratory Medicine Radboud University Medical Centre Nijmegen The Netherlands.

Background: Reliable measurement of phenylalanine (Phe) is a prerequisite for adequate follow-up of phenylketonuria (PKU) patients. However, previous studies have raised concerns on the intercomparability of plasma and dried blood spot (DBS) Phe results. In this study, we made an inventory of differences in (pre-)analytical methodology used for Phe determination across Dutch laboratories, and compared DBS and plasma results.

Methods: Through an online questionnaire, we assessed (pre-)analytical Phe measurement procedures of seven Dutch metabolic laboratories. To investigate the difference between plasma and DBS Phe, participating laboratories received simultaneously collected plasma-DBS sets from 23 PKU patients. In parallel, 40 sample sets of DBS spotted from either venous blood or capillary fingerprick were analyzed.

Results: Our data show that there is no consistency on standard operating procedures for Phe measurement. The association of DBS to plasma Phe concentration exhibits substantial inter-laboratory variation, ranging from a mean difference of -15.5% to +30.6% between plasma and DBS Phe concentrations. In addition, we found a mean difference of +5.8% in Phe concentration between capillary DBS and DBS prepared from venous blood.

Conclusions: The results of our study point to substantial (pre-)analytical variation in Phe measurements, implicating that bloodspot Phe results should be interpreted with caution, especially when no correction factor is applied. To minimize variation, we advocate pre-analytical standardization and analytical harmonization of Phe measurements, including consensus on application of a correction factor to adjust DBS Phe to plasma concentrations.
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http://dx.doi.org/10.1002/jmd2.12186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932865PMC
March 2021

Cognitive functioning and mental health in mitochondrial disease: A systematic scoping review.

Neurosci Biobehav Rev 2021 Feb 11;125:57-77. Epub 2021 Feb 11.

Radboud University Medical Center, Amalia Children's Hospital, Radboud Institute for Health Sciences, Radboud Center for Mitochondrial Medicine, Department of Medical Psychology, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB, Nijmegen, the Netherlands.

Mitochondrial diseases (MDs) are rare, heterogeneous, hereditary and progressive in nature. In addition to the serious somatic symptoms, patients with MD also experience problems regarding their cognitive functioning and mental health. We provide an overview of all published studies reporting on any aspect of cognitive functioning and/or mental health in patients with MD and their relatives. A total of 58 research articles and 45 case studies were included and critically reviewed. Cognitive impairments in multiple domains were reported. Mental disorders were frequently reported, especially depression and anxiety. Furthermore, most studies showed impairments in self-reported psychological functioning and high prevalence of mental health problems in (matrilineal) relatives. The included studies showed heterogeneity regarding patient samples, measurement instruments and reference groups, making comparisons cautious. Results highlight a high prevalence of cognitive impairments and mental disorders in patients with MD. Recommendations for further research as well as tailored patientcare with standardized follow-up are provided. Key gaps in the literature are identified, of which studies on natural history are of highest importance.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.004DOI Listing
February 2021

One mutation, three phenotypes: novel metabolic insights on MELAS, MIDD and myopathy caused by the m.3243A > G mutation.

Metabolomics 2021 01 12;17(1):10. Epub 2021 Jan 12.

Mitochondria Research Laboratory, Human Metabolomics, North-West University, Potchefstroom, South Africa.

Introduction: The m.3243A > G mitochondrial DNA mutation is one of the most common mitochondrial disease-causing mutations, with a carrier rate as high as 1:400. This point mutation affects the MT-TL1 gene, ultimately affecting the oxidative phosphorylation system and the cell's energy production. Strikingly, the m.3243A > G mutation is associated with different phenotypes, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited diabetes and deafness (MIDD) and myopathy.

Objectives: We investigated urine metabolomes of MELAS, MIDD and myopathy patients in order to identify affected metabolic pathways and possible treatment options.

Methods: A multiplatform metabolomics approach was used to comprehensively analyze the metabolome and compare metabolic profiles of different phenotypes caused by the m.3243A > G mutation. Our analytical array consisted of NMR spectroscopy, LC-MS/MS and GC-TOF-MS.

Results: The investigation revealed phenotypic specific metabolic perturbations, as well as metabolic similarities between the different phenotypes. We show that glucose metabolism is highly disturbed in the MIDD phenotype, but not in MELAS or myopathy, remodeled fatty acid oxidation is characteristic of the MELAS patients, while one-carbon metabolism is strongly modified in both MELAS and MIDD, but not in the myopathy group. Lastly we identified increased creatine in the urine of the myopathy patients, but not in MELAS or MIDD.

Conclusion: We conclude by giving novel insight on the phenotypes of the m.3243A > G mutation from a metabolomics point of view. Directives are also given for future investigations that could lead to better treatment options for patients suffering from this debilitating disease.
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http://dx.doi.org/10.1007/s11306-020-01769-wDOI Listing
January 2021

A predictive model for estimating the number of erythrocytapheresis or phlebotomy treatments for patients with naïve hereditary hemochromatosis.

J Clin Apher 2020 Dec 24. Epub 2020 Dec 24.

Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.

Background And Aims: Standard treatment for naïve hereditary hemochromatosis patients consists of phlebotomy or a personalized erythrocytapheresis. Erythrocytapheresis is more efficient, but infrequently used because of perceived costs and specialized equipment being needed. The main aim of our study was to develop a model that predicts the number of initial treatment procedures for both treatment methods. This information may help the clinician to select the optimal treatment modality for the individual patient.

Methods: We analyzed retrospective data of 125 newly diagnosed patients (C282Y homozygous), treated either with phlebotomy (n = 54) or erythrocytapheresis (n = 71) until serum ferritin (SF) reached levels ≤100 μg/L. To estimate the required number of treatment procedures multiple linear regression analysis was used for each treatment method separately.

Results: The linear regression model with the best predictive quality (R = 0.74 and 0.73 for erythrocytapheresis and phlebotomy respectively) included initial SF, initial hemoglobin (Hb) level, age, and BMI, where initial SF was independently related to the total number of treatment procedures for both treatment methods. The prediction error expressed in RMSPE and RMSDR was lower for erythrocytapheresis than for phlebotomy (3.8 and 4.1 vs 7.0 and 8.0 respectively), CONCLUSIONS: Although the prediction error of the developed model was relatively large, the model may help the clinician to choose the most optimal treatment method for an individual patient. Generally erythrocytapheresis halves the number of treatment procedures for all patients, where the largest reduction (between 55% and 64%) is reached in patients with an initial Hb level ≥ 9 mmol/L (14.5 g/dL). ClinicalTrials.gov number NCT00202436.
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http://dx.doi.org/10.1002/jca.21867DOI Listing
December 2020

Gray and white matter are both affected in classical galactosemia: An explorative study on the association between neuroimaging and clinical outcome.

Mol Genet Metab 2020 12 6;131(4):370-379. Epub 2020 Nov 6.

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

Background: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome.

Methods: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated.

Results: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM.

Conclusion: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.
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http://dx.doi.org/10.1016/j.ymgme.2020.11.001DOI Listing
December 2020

Clinical and molecular characterization of adult patients with late-onset MTHFR deficiency.

J Inherit Metab Dis 2020 Oct 22. Epub 2020 Oct 22.

APHP, La Pitié-Salpêtrière University Hospital, Department of Genetics, Paris, France.

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.
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http://dx.doi.org/10.1002/jimd.12323DOI Listing
October 2020

Response to Energy Requirements in m.3243A>G Carriers Depend on Multiple Factors.

JPEN J Parenter Enteral Nutr 2021 02 7;45(2):229. Epub 2020 Nov 7.

Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1002/jpen.2023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984434PMC
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

Correction to: Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities.

Orphanet J Rare Dis 2020 09 7;15(1):238. Epub 2020 Sep 7.

Department of Pediatrics, room H7-270, Amsterdam University Medical Centre, MC, PO BOX 22660, 1100 DD, Amsterdam, The Netherlands.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s13023-020-01447-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487470PMC
September 2020

Optimal Estimate for Energy Requirements in Adult Patients With the m.3243A>G Mutation in Mitochondrial DNA.

JPEN J Parenter Enteral Nutr 2021 01 1;45(1):158-164. Epub 2020 Aug 1.

Department of Gastroenterology and Hepatology, Radboudumc, Nijmegen, the Netherlands.

Aim: We aimed to identify the optimal method to estimate total energy expenditure (TEE) in mitochondrial disease (MD) patients.

Methods: Resting energy expenditure (REE) was measured in MD patients carrying the m3243A>G mutation using indirect calorimetry (IC) and compared with results of 21 predictive equations (PEs) for REE and with REE-IC measurements in healthy controls. Physical activity level (PAL) was measured using accelerometery (SenseWear) and compared with a fixed average PAL (1.4) as well as patients' self-estimated activity levels. TEE was calculated as REE-IC × PAL SenseWear and compared with usual care and energy recommendations for healthy adults.

Results: Thirty-eight MD patients (age: 48 ± 13 years; body mass index 24 ± 4 kg/m ; male 20%) and 25 matched controls were included. The accuracy of most PEs was between 63% and 76%. The difference in REE-IC in healthy controls (1532 ± 182 kcal) and MD patients (1430 ± 221) was borderline not significant (P = .052). Patients' estimations PAL were 18%-34% accurate at the individual level. The fixed activity factor was 53% accurate. Patients overestimated their PAL. Usual care predicted TEE accurately in only 32% of patients.

Conclusion: TEE is lower in these MD patients than the recommendations for healthy adults because of their lower physical activity. In MD patients, 6 PEs for REE provide a reliable alternative for IC, with an accuracy of 71%-76%. As PAL is highly variable and not reliably estimated by patients, measurement of PAL using accelerometery is recommended in this population.
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http://dx.doi.org/10.1002/jpen.1965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891583PMC
January 2021

Mitochondrial migraine; a prevalence, impact and treatment efficacy cohort study.

Mitochondrion 2020 07 25;53:128-132. Epub 2020 May 25.

Radboud University Medical Center Amalia Children's Hospital, Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands; Radboud University Medical Center, Department of Internal Medicine, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands. Electronic address:

Mitochondrial respiratory chain dysfunction may be predisposing for the development of migraine, reflected in high migraine prevalence in patients with mitochondrial disease. Prevalence and impact of migraine in patients with proven mitochondrial disease and the current treatment efficacy were studied using online questionnaires. Patients were selected at the Internal Medicine Department. Headache was reported by 34 (55%) out of 62 patients. Migraine-criteria were met by 85% of them. Efficacy of migraine treatment was achieved in 4 patients. Given the high prevalence of migraine and current treatment insufficiency, migraine is a major threat of quality of life patients with mitochondrial disease.
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http://dx.doi.org/10.1016/j.mito.2020.05.004DOI Listing
July 2020

Psychological functioning in children suspected for mitochondrial disease: the need for care.

Orphanet J Rare Dis 2020 03 24;15(1):76. Epub 2020 Mar 24.

Radboud Institute for Health Sciences, Department of Medical Psychology, Radboud Center for Mitochondrial Medicine, Amalia Children's Hospital, Radboud University Medical Center, Geert Grooteplein Zuid 10, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands.

Background: Mitochondrial diseases (MD) are generally serious and progressive, inherited metabolic diseases. There is a high comorbidity of anxiety and depression and limitations in daily functioning. The complexity and duration of the diagnostic process and lack of knowledge about prognosis leads to uncertainty. In this study, we investigated the psychological well-being of children who are suspected for MD and their parents.

Methods: In total 122 children suspected for MD and their parents, received questionnaires as part of standard clinical investigation.

Results: Parent proxy report revealed a lower quality of life (QoL) compared to norms and even more physical problems compared to chronically ill patients. They also reported more behavioral problems in general and more internalizing problems compared to the norms. Most frequent reported somatic complaints were tiredness and pain. Parents did not report enhanced levels of stress regarding parenting and experienced sufficient social support. At the end of the diagnostic process, 5.7% of the children received the genetically confirmed diagnosis of MD, 26% showed non-conclusive abnormalities in the muscle biopsy, 54% did not receive any diagnosis, and the remaining received other diagnoses. Strikingly, children without a diagnosis showed equally QoL and behavioral problems as children with a diagnosis, and even more internalizing problems.

Conclusions: This study highlights the psychological concerns of children with a suspicion of MD. It is important to realize that as well as children with a confirmed diagnosis, children without a diagnosis are vulnerable since explanation for their complaints is still lacking.
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http://dx.doi.org/10.1186/s13023-020-1342-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092429PMC
March 2020

Association of Body Composition, Physical Functioning, and Protein Intake in Adult Patients With Mitochondrial Diseases.

JPEN J Parenter Enteral Nutr 2021 01 19;45(1):165-174. Epub 2020 Mar 19.

Department of Gastroenterology and Hepatology-Dietetics, Radboudumc, Nijmegen, the Netherlands.

Background: Whether decreased physical functioning of patients with mitochondrial disease (MD) is related to altered body composition or low protein intake needs clarification at the background of the nutrition state.

Methods: In this 2-site cross-sectional study, MD patients were age-, body mass index (BMI)-, and gender-matched to controls. Body composition was assessed by dual-energy x-ray absorptiometry. Physical functioning was measured by handgrip strength, 6-minute walking test, 30-second sit-to-stand test (30SCT), and 6-minute mastication test. Total daily protein intake was calculated by 3-day food records. Malnutrition was assessed by Patient-Generated Subjective Global Assessment and the Global Leadership Initiative on Malnutrition (GLIM) criteria and sarcopenia by the 2018 consensus. Data were analyzed using independent samples t-tests, Fisher exact test, and Spearman and Pearson correlation coefficients.

Results: Thirty-seven MD patients (42 ± 12 years, BMI: 23 ± 4 kg/m , 59% females) and 37 matched controls were included. Handgrip strength was moderate, inversely related to fat mass index in both MD patients and controls, whereas it correlated with fat-free mass index in controls solely. Protein intake was associated with muscle strength (handgrip strength and 30SCT) in MD patients but not in controls. Twenty-seven MD patients (73%) were malnourished, and 5 (14%) were classified as sarcopenic.

Conclusions: Muscle strength is related to body composition and protein intake in MD patients. This, in combination with the high incidence of both malnutrition and sarcopenia, warrants individual nutrition assessment in MD patients.
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http://dx.doi.org/10.1002/jpen.1826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891597PMC
January 2021

Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities.

Orphanet J Rare Dis 2020 02 7;15(1):42. Epub 2020 Feb 7.

Department of Pediatrics, room H7-270, Amsterdam University Medical Centre, MC, PO BOX 22660, 1100 DD, Amsterdam, The Netherlands.

Background: Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, behavior and social functioning has not been studied systematically in CG patients.

Methods: To determine if CG patients demonstrate a specific neuropsychological and psychosocial profile, we investigated intelligence, functioning on multiple cognitive domains, behavior and social functioning with a comprehensive neuropsychological test battery and questionnaires (self- and proxy-reported).

Results: The data of 48 patients, aged 4-47 years are reported. FSIQ ranged from 45 to 103 (mean 77 ± 14). A negative correlation between age and FSIQ was demonstrated (p = 0.037) which resulted directly from the inclusion of four young 'milder' patients detected by newborn screening (NBS) with an expected better clinical outcome. Compared to normative data, patients had significantly lower but highly variable scores on all cognitive domains, especially on tests requiring mental speed. In the context of the FSIQ, 43% of the cognitive test results exceeded IQ based expectations. Overall, the patients' scores on social functioning were in the normal range but internalizing problems were frequently reported. In our cohort, an early initiation of dietary treatment due to NBS or family screening did not result in a more favorable neuropsychological outcome.

Conclusions: In this study, we demonstrated that as a cohort, CG patients have a below average intelligence and impaired cognitive functioning without a distinctive neuropsychological profile. The effect of age on neurocognitive functioning should be assessed in longitudinal studies. Social functioning was not impaired, but patients may be at risk for internalizing problems. Considering the large variability in cognitive, behavioral and social functioning and the finding that cognitive outcomes may exceed IQ based expectations, an individual evaluation and follow-up is warranted in all CG patients to ensure timely support if needed.
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http://dx.doi.org/10.1186/s13023-019-1277-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007688PMC
February 2020

The Galactose Index measured in fibroblasts of GALT deficient patients distinguishes variant patients detected by newborn screening from patients with classical phenotypes.

Mol Genet Metab 2020 03 9;129(3):171-176. Epub 2020 Jan 9.

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

Background: The high variability in clinical outcome of patients with Classical Galactosemia (CG) is poorly understood and underlines the importance of prognostic biomarkers, which are currently lacking. The aim of this study was to investigate if residual galactose metabolism capacity is associated with clinical and biochemical outcomes in CG patients with varying geno- and phenotypes.

Methods: Galactose Metabolite Profiling (GMP) was used to determine residual galactose metabolism in fibroblasts of CG patients. The association between the galactose index (GI) defined as the ratio of the measured metabolites [UC]Gal-1-P/ [C]UDP-galactose, and both intellectual and neurological outcome and galactose-1-phosphate (Gal-1-P) levels was investigated.

Results: GMP was performed in fibroblasts of 28 patients and 3 control subjects. The GI of the classical phenotype patients (n = 22) was significantly higher than the GI of four variant patients detected by newborn screening (NBS) (p = .002), two homozygous p.Ser135Leu patients (p = .022) and three controls (p = .006). In the classical phenotype patients, 13/18 (72%) had a poor intellectual outcome (IQ < 85) and 6/12 (50%) had a movement disorder. All the NBS detected variant patients (n = 4) had a normal intellectual outcome (IQ ≥ 85) and none of them has a movement disorder. In the classical phenotype patients, there was no significant difference in GI between patients with a poor and normal clinical outcome. The NBS detected variant patients had significantly lower GI levels and thus higher residual galactose metabolism than patients with classical phenotypes. There was a clear correlation between Gal-1-P levels in erythrocytes and the GI (p = .001).

Conclusions: The GI was able to distinguish CG patients with varying geno- and phenotypes and correlated with Gal-1-P. The data of the NBS detected variant patients demonstrated that a higher residual galactose metabolism may result in a more favourable clinical outcome. Further research is needed to enable individual prognostication and treatment in all CG patients.
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http://dx.doi.org/10.1016/j.ymgme.2020.01.002DOI Listing
March 2020

Does the 48-hour BH4 loading test miss responsive PKU patients?

Mol Genet Metab 2020 03 24;129(3):186-192. Epub 2019 Dec 24.

Department of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Centre Groningen, the Netherlands. Electronic address:

Background: Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism. Besides dietary treatment, some patients are responsive to and treated with tetrahydrobiopterin (BH4). Our primary objective was to examine whether the 48-hour BH4 loading test misses BH4-responsive PKU patients. Secondary, we assessed if it would be beneficial to 1) use a cut-off value of 20% Phe reduction instead of commonly used 30%, and 2) extend the loading test to 7 days.

Methods: 24 patients with a 20-30% decrease of blood Phe levels during their initial 48-hour BH4 loading test or at least one mutation associated with long-term BH4 responsiveness, were invited to participate. 22 of them underwent the 7-day BH4 loading test. During the BH4 loading test, BH4 was administered orally once daily for 7 days (20 mg/kg/day). Blood samples on filter paper were collected at 13 time points. Potential BH4 responders (≥20% decrease in blood Phe concentrations at ≥1 moment within the first 48 h or ≥30% at ≥1 moment during the entire test) underwent a treatment trial to assess true long-term responsiveness (≥30% decrease of Phe levels compared to baseline and/or ≥50% increase in natural protein tolerance in accordance with the Dutch guidelines before 2017). The duration of the treatment trial varied from 2 to 18 months.

Results: Of the 22 patients who completed the 7-day BH4 loading test, 2 were excluded, 8 had negative tests and 12 were considered to be potential BH4 responders. Of these 12 potential BH4-responsive PKU patients, 5 turned out to be false positive, 6 true-responder and 1 was withdrawn.

Conclusion: Even though the 48-hour BH4 loading test has proven its efficacy in the past, a full week may be necessary to detect all responders. So, if blood Phe concentrations during the 48-hour BH4 test shows a clear tendency, but not sufficient decrease, a full week (with only measurements each 24 h) could be offered. A threshold of ≥20% decrease within 48 h is not useful for predicting true BH4 responsiveness.
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http://dx.doi.org/10.1016/j.ymgme.2019.12.011DOI Listing
March 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

Five non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype adult patients with m.3243A>G mutation after kidney transplantation: follow-up and review of the literature.

Clin Kidney J 2019 Dec 21;12(6):840-846. Epub 2019 Apr 21.

Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center Amalia Children's Hospital, Nijmegen, The Netherlands.

Background: Renal involvement in patients with the m.3243A>G mutation may result in end-stage renal disease (ESRD) requiring renal replacement therapy. Although kidney transplantations have been performed in a small number of patients, short- and long-term follow-up data are lacking.

Methods: We describe five patients with the m.3243AG carriers described in the literature.

Results: Proteinuria with or without renal failure was the first clinical presentation of renal involvement in 13 of 18 (72%) patients. Focal segmental glomerulosclerosis (FSGS) was found in 9 of 13 (69%) biopsies. Sixteen of 18 (84%) patients developed hearing loss. All patients were diagnosed with diabetes mellitus, of whom eight (44%) developed the disease after transplantation. All patients with reported follow-up data (13/18) had stable kidney function from 6 months to 13 years of follow-up after transplantation.

Conclusions: Renal involvement in carriers of the m.3243A>G mutation most commonly leads to proteinuria and FSGS and may lead to ESRD. Proper recognition of the mitochondrial origin of the renal disease in these patients is important for adequate treatment selection and suitable supportive care. This case series and review of the available literature on long-term follow-up after kidney transplantation shows it is feasible for non-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes phenotype carriers of the m.3243A>G mutation to be considered for kidney transplantation in case of ESRD. These patients should not be excluded from transplant solely for their mitochondrial diagnosis.
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http://dx.doi.org/10.1093/ckj/sfz020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885678PMC
December 2019

Individual dietary intervention in adult patients with mitochondrial disease due to the m.3243 A>G mutation.

Nutrition 2020 01 4;69:110544. Epub 2019 Jul 4.

Radboudumc, Nijmegen, The Netherlands.

Objective: The aim of this study was to evaluate the effect of an individually tailored dietary intervention on personalized goals, body composition (BC), functioning, and quality of life (QoL) in adult patients with mitochondrial disease (MD) due to the m.3243 A>G mutation.

Methods: This explorative randomized controlled trial included 39 patients with MD. The intervention group (n = 20) received an individually tailored dietary intervention over a 6-mo period. The control group (n = 19) received standard care over a 6-mo timeframe (control period), followed by an individually tailored dietary intervention for the next 6 mo (intervention period). Nutritional assessment and QoL measurements were performed at 3-mo intervals. Personalized treatment goals of the patients with MD were evaluated at 3 and 6 mo during the dietary intervention. Achievement of the personalized goals was assessed using descriptive statistics and mixed models. Linear mixed models were used to test the effect of the dietary intervention on continuous outcomes.

Results: The personal goals of patients were significantly more frequently achieved in the intervention group than in the control group. After 3 mo of intervention, 57% of the goals were achieved. Most goals were achieved for BC, handgrip strength (HGS), and gastrointestinal complaints. Intervention increased HGS (P = 0.037), the vitality component of QoL (P = 0.026), and decreased the fatigue score (P = 0.024) after 3 mo of treatment. Effects did not seem to last after 3 mo, however.

Conclusion: An individually tailored dietary intervention is promising to achieve personalized goals of patients with MD, especially with regard to BC, HGS, and gastrointestinal complaints. The intervention also improves QoL, and decreases fatigue.
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http://dx.doi.org/10.1016/j.nut.2019.06.025DOI Listing
January 2020

Movement disorders and nonmotor neuropsychological symptoms in children and adults with classical galactosemia.

J Inherit Metab Dis 2019 05 27;42(3):451-458. Epub 2019 Feb 27.

Department of Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Although movement disorders (MDs) are known complications, the exact frequency and severity remains uncertain in patients with classical galactosemia, especially in children. We determined the frequency, classification and severity of MDs in a cohort of pediatric and adult galactosemia patients, and assessed the association with nonmotor neuropsychological symptoms and daily functioning. Patients from seven centers in the United Kingdom and the Netherlands with a confirmed galactosemia diagnosis were invited to participate. A videotaped neurological examination was performed and an expert panel scored the presence, classification and severity of MDs. Disease characteristics, nonmotor neuropsychological symptoms, and daily functioning were evaluated with structured interviews and validated questionnaires (Achenbach, Vineland, Health Assessment Questionnaire, SIP68). We recruited 37 patients; 19 adults (mean age 32.6 years) and 18 children (mean age 10.7 years). Subjective self-reports revealed motor symptoms in 19/37 (51.4%), similar to the objective (video) assessment, with MDs in 18/37 patients (48.6%). The objective severity scores were moderate to severe in one third (6/37). Dystonia was the overall major feature, with additional tremor in adults, and myoclonus in children. Behavioral or psychiatric problems were present in 47.2%, mostly internalizing problems, and associated with MDs. Daily functioning was significantly impaired in the majority of patients. Only one patient received symptomatic treatment for MDs. We show that MDs and nonmotor neuropsychological symptoms are frequent in both children and adults with classical galactosemia.
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http://dx.doi.org/10.1002/jimd.12054DOI Listing
May 2019

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

J Inherit Metab Dis 2019 03 17;42(2):333-352. Epub 2019 Feb 17.

Inherited Metabolic Diseases Clinic, Section of Clinical Genetics and Metabolism, University of Colorado Denver, Aurora, Colorado.

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.

Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.

Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
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http://dx.doi.org/10.1002/jimd.12041DOI Listing
March 2019

Intra-patient variability of heteroplasmy levels in urinary epithelial cells in carriers of the m.3243A>G mutation.

Mol Genet Genomic Med 2019 02 4;7(2):e00523. Epub 2018 Dec 4.

Department of Pediatrics, Radboudumc Amalia Childrens Hospital, Radboud Center for Mitochondrial Medicine, Nijmegen, The Netherlands.

Background: The mitochondrial DNA m.3243A>G mutation is one the most prevalent mutation causing mitochondrial disease in adult patients. Several cohort studies have used heteroplasmy levels in urinary epithelial cells (UEC) to correlate the genotype of the patients to the clinical severity. However, the interpretation of these data is hampered by a lack of knowledge on the intra-patient variability of the heteroplasmy levels. The goal of this study was to determine the day-to-day variation of the heteroplasmy levels in UEC.

Methods: Fifteen carriers of the m.3243A>G mutation collected five urine samples in a 14-day window. Heteroplasmy levels of the m.3243A>G mutation were determined in these samples. Data from the national cohort study, including Newcastle Mitochondrial Disease Adult Scale scores and clinical diagnosis, were used.

Results: In the samples of six patients, heteroplasmy levels were within a 5% margin. In the samples collected from five patients, the margin was >20%.

Conclusion: Heteroplasmy levels of UEC in carriers of the m.3243A>G mutation have a significant day-to-day variation. The interpretation of a correlation between heteroplasmy levels in urine and disease severity is therefore not reliable. Therefore, heteroplasmy levels in UEC should not be used as a prognostic biomarker in these patients.
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http://dx.doi.org/10.1002/mgg3.523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393655PMC
February 2019

Fear of disease progression in carriers of the m.3243A > G mutation.

Orphanet J Rare Dis 2018 11 13;13(1):203. Epub 2018 Nov 13.

Department of Medical Psychology, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: Being diagnosed with mitochondrial disease due to the m.3243A > G mutation is frequently preceded by a long diagnostic process. The disease itself is characterized by heterogeneous course and expression, so leaving patients with considerable uncertainty regarding their prognosis and treatment possibilities. This could easily result in fear of disease progression. This study investigated the presence of this fear and its correlates with genetic characteristics and clinical disease severity in m.3243A > G carriers.

Methods: In total 125 eligible m.3243A > G mutation carriers were invited to participate in this cross-sectional study. After informed consent, participants completed questionnaires including items on socio-demographics, fear of progression, depression, anxiety, and quality of life. Clinical disease severity was assessed by the NMDAS questionnaire. Heteroplasmy levels were assessed in leucocytes, urine epithelial cells and buccal mucosa.

Results: Seventy-six carriers participated in this study. Results showed that 18% reported high fear of progression. Fear of progression was significantly related to all domains of quality of life. Furthermore, fear of progression was moderately correlated with feelings of depression (r = .37), and anxiety (r = .44). Patients with moderate or severe clinical symptoms on the NMDAS experienced more fear of progression than patients with mild clinical symptoms. Fear of progression was weakly correlated with heteroplasmy in leucocytes (r = .27) and buccal mucosa (r = .31).

Conclusions: A substantial part of m.3243A > G mutation carriers experience high levels of fear of progression which coincide with significantly lower quality of life. Only a small relation with disease characteristics was found. The impact of receiving a diagnosis without therapeutic possibilities on fear is important to consider.
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http://dx.doi.org/10.1186/s13023-018-0951-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234600PMC
November 2018

Anthropomorphic measurements and nutritional biomarkers after 5 years of BH treatment in phenylketonuria patients.

Mol Genet Metab 2018 08 20;124(4):238-242. Epub 2018 Jun 20.

University of Groningen, University Medical Center Groningen, Division of Metabolic Diseases, PO box 30.001, 9700 RB Groningen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.ymgme.2018.06.009DOI Listing
August 2018

The KHENERGY Study: Safety and Efficacy of KH176 in Mitochondrial m.3243A>G Spectrum Disorders.

Clin Pharmacol Ther 2019 01 3;105(1):101-111. Epub 2018 Sep 3.

Khondrion BV, Nijmegen, The Netherlands.

KH176 is a potent intracellular reduction-oxidation-modulating compound developed to treat mitochondrial disease. We studied tolerability, safety, pharmacokinetics, pharmacodynamics, and efficacy of twice daily oral 100 mg KH176 for 28 days in a double-blind, randomized, placebo-controlled, two-way crossover phase IIA study in 18 adult m.3243A>G patients without cardiovascular involvement. Efficacy parameters included clinical and functional outcome measures and biomarkers. The trial was registered within ClinicalTrials.gov (NCT02909400), the European Clinical Trials Database (2016-001696-79), and ISRCTN (43372293) (The KHENERGY study). Twice daily oral 100 mg KH176 was well tolerated and appeared safe. No serious treatment-emergent adverse events were reported. No significant improvements in gait parameters or other outcome measures were obtained, except for a positive effect on alertness and mood, although a coincidence due to multiplicity cannot be ignored. The results of the study provide first data on safety and efficacy of KH176 in patients with mitochondrial disease and will be instrumental in designing future clinical trials.
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http://dx.doi.org/10.1002/cpt.1197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6704357PMC
January 2019

Intact transferrin and total plasma glycoprofiling for diagnosis and therapy monitoring in phosphoglucomutase-I deficiency.

Transl Res 2018 09 10;199:62-76. Epub 2018 May 10.

Department of Neurology and Translational Metabolic Laboratory, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Phosphoglucomutase 1 (PGM1) deficiency results in a mixed phenotype of a Glycogen Storage Disorder and a Congenital Disorder of Glycosylation (CDG). Screening for abnormal glycosylation has identified more than 40 patients, manifesting with a broad clinical and biochemical spectrum which complicates diagnosis. Together with the availability of D-galactose as dietary therapy, there is an urgent need for specific glycomarkers for early diagnosis and treatment monitoring. We performed glycomics profiling by high-resolution QTOF mass spectrometry in a series of 19 PGM1-CDG patients, covering a broad range of biochemical and clinical severity. Bioinformatics and statistical analysis were used to select glycomarkers for diagnostics and define glycan-indexes for treatment monitoring. Using 3 transferrin glycobiomarkers, all PGM1-CDG patients were diagnosed with 100% specificity and sensitivity. Total plasma glycoprofiling showed an increase in high mannose glycans and fucosylation, while global galactosylation and sialylation were severely decreased. For treatment monitoring, we defined 3 glycan-indexes, reflecting normal glycosylation, a lack of complete glycans (LOCGI) and of galactose residues (LOGI). These indexes showed improved glycosylation upon D-galactose treatment with a fast and near-normalization of the galactose index (LOGI) in 6 out of 8 patients and a slower normalization of the LOCGI in all patients. Total plasma glycoprofiling showed improvement of the global high mannose glycans, fucosylation, sialylation, and galactosylation status on D-galactose treatment. Our study indicates specific glycomarkers for diagnosis of mildly and severely affected PGM1-CDG patients, and to monitor the glycan-specific effects of D-galactose therapy.
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http://dx.doi.org/10.1016/j.trsl.2018.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041963PMC
September 2018

The impact of metabolic control and tetrahydrobiopterin treatment on health related quality of life of patients with early-treated phenylketonuria: A PKU-COBESO study.

Mol Genet Metab 2018 09 7;125(1-2):96-103. Epub 2018 Jul 7.

Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, the Netherlands.

The aim of this study was to examine Health-Related Quality of Life (HRQoL) of patients with Phenylketonuria (PKU) in three different age groups and to investigate the impact of metabolic control and tetrahydrobiopterin (BH4) treatment on HRQoL of these patients. Participants were 90 early-treated patients aged 7 to 40 years (M = 21.0, SD = 10.1) and 109 controls aged 7 to 40.8 years (M = 19.4, SD = 8.6). HRQoL was assessed with the (generic) TNO-AZL questionnaires. Overall, good HRQoL was reported for children below 12 years of age, although they were judged to be less autonomic than their healthy counterparts. Adolescents aged 12-15 years showed poorer HRQoL in the domain "cognitive functioning" compared to controls. For adults ≥16 years, poorer age-controlled HRQoL was found for the domains cognition, depressive moods, and anger, with a further trend for the domain "pain". With respect to metabolic control, only for adult PKU-patients robust associations were observed, indicating poorer functioning, most notably in the domains cognition, sleep, pain, sexuality and anger, with higher historical and concurrent Phe-levels. With respect to BH4-use, effects on HRQoL were again only observed for adult PKU-patients. After controlling for age and historical Phe-levels, small but significant differences in favor of adult BH4-users compared to non-users were observed for HRQoL-categories happiness, anger, and social functioning. Together, these results show that, particularly for adult PKU-patients, HRQoL-problems are evident and that many of these problems are related to (history of) metabolic control. Beneficial effects of BH4-use appear to be limited to those associated with relief from the practical burdens related to the strict dietary treatment regimen, i.e. general mood and sociability, whereas metabolic control is more strongly related to basic physical and cognitive functioning.
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http://dx.doi.org/10.1016/j.ymgme.2018.07.002DOI Listing
September 2018

The need for additional care in patients with classical galactosaemia.

Disabil Rehabil 2019 11 31;41(22):2663-2668. Epub 2018 May 31.

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

Classical galactosaemia is an inborn error of galactose metabolism which may lead to impairments in body functions and accordingly, need for additional care. The primary aim of this study was to establish the type and intensity of this additional care. Patients with classical galactosaemia aged ≥2 years were evaluated with the Capacity Profile, a standardised method to classify additional care needs according to type and intensity. Based on a semi-structured interview, current impairments in five domains of body functions were determined. The intensity of additional care was assessed (from 0, usual care, to 5, total dependence). Forty-four patients with classical galactosaemia, 18 males and 26 females (median age 15 years, range 2-49 years), were included. There was a wide spectrum of impairments in mental functions. Motor function impairments were present in four patients, and mild speech impairments in eight patients. Additional care for sensory functions was uncommon. All patients needed a diet, which care is scored in the physical health domain. Apart from the diet all patients need, classical galactosaemia leads to the need for additional care mainly in the domains of mental functions and speech and voice functions. Implications for rehabilitation The Capacity Profile is a useful tool to demonstrate additional care needs in classical galactosaemia. In classical galactosaemia additional care is mostly indicated by mental impairments and speech and voice functions. One-fifth of patients have impairment of speech and voice functions at time of the study, and half of all patients had received speech therapy in childhood. Over 70% of patients need additional care/help due to impairment of mental functions, ranging from coaching due to social vulnerability to full day care.
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http://dx.doi.org/10.1080/09638288.2018.1475514DOI Listing
November 2019

Quantification of gait in children with mitochondrial disease.

J Inherit Metab Dis 2018 07 12;41(4):731-740. Epub 2018 Mar 12.

Radboud Center for Mitochondrial Medicine (RCMM) at the Department of Pediatrics, Radboud University Medical Center Nijmegen, Geert Grooteplein Zuid 10, PO BOX 9101, 6500 HB, Nijmegen, The Netherlands.

Mitochondrial disorders are multisystem conditions that can potentially affect gait in many ways. The aim of this study was to select the optimal protocol to quantify the spatiotemporal parameters of gait in ambulatory children with mitochondrial disorders based on feasibility, test-retest reliability, and the difference between patients and controls. Gait at self-selected pace was quantified in ambulatory children with a genetically confirmed primary mitochondrial disease using the GAITRite electronic walkway. Three protocols were tested: pre-exercise, post-exercise (after a 3-min walking test), and recovery. In 14 ambulatory patients, we showed good to perfect reliability for velocity, cadence, step length, step time, step time variability, and step width in the recovery condition. The difference between patients and 70 individually age- and gender matched healthy controls only became apparent in the post-exercise protocol. In conclusion, measuring spatiotemporal parameters of gait using the GAITRite in ambulatory children with mitochondrial disease is feasible and reliable for most of the parameters measured. When using gait analysis in future studies in children with mitochondrial disease, we advise i) to use an exercise test prior to the gait analysis, ii) to let children practice the test before the actual data collection, and iii) not to use symmetry parameters.
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http://dx.doi.org/10.1007/s10545-018-0148-5DOI Listing
July 2018

A urinary biosignature for mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes (MELAS).

Mitochondrion 2019 03 19;45:38-45. Epub 2018 Feb 19.

Mitochondria Research Laboratory, Centre for Human Metabolomics, North-West University, Potchefstroom, South Africa. Electronic address:

We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A>G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.
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http://dx.doi.org/10.1016/j.mito.2018.02.003DOI Listing
March 2019