Henry Keijzer

Maastricht University Medical Centre

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Marcel G. Smits

Ziekenhuis Gelderse Vallei

Leopold Curfs

Maastricht University Medical Centre

Wiebe Braam

Maastricht University

Robert Didden

Radboud University Nijmegen

Ingeborg M. van Geijlswijk

Utrecht University

Silvia C. Endenburg

Ziekenhuis Gelderse Vallei

Karen Spruyt

Université Paris Cité

Miriam Koopmann

Ziekenhuis Gelderse Vallei

Friederike Ehrhart

Maastricht University

Harry Struijker Boudier

Centre de Recherche en Sciences et Technologies de l'Information et de la Communication

Cooperative Institutions

Rijnstate Hospital

Ziekenhuis Gelderse Vallei

Maastricht University

Radboud University Nijmegen

Maastricht University Medical Centre

Rotterdam University of Applied Sciences

Erasmus University Rotterdam

University Medical Center

Radboud University Medical Center

Utrecht University

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Melatonin treatment in circadian rhythm sleep-wake disorders

Henry Keijzer

This dissertation evaluates and describes techniques to promote personalised medicine in circadian rhythm sleep disorders. The most important technique described is salivary melatonin analysis to calculate the Dim Light Melatonin Onset (DLMO = the time of melatonin secretion). The DLMO is used for diagnosis and fine tuning of therapy. Although this dissertation shows that DLMO measurement is accurate, it also shows that a sleep diary and polysomnography do not accurately predict the DLMO. Melatonin is a very effective treatment for circadian rhythm sleep disorders, provided that the DLMO is taken into account when administering melatonin. Melatonin is available as an over-the-counter medicine. However, this is less useful because it is usually taken without the necessary knowledge.

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10.26481/dis.20171019hk

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CYP1A2 polymorphisms in slow melatonin metabolisers: a possible relationship with autism spectrum disorder?

Journal of Intellectual Disability Research (2012)

Wiebe Braam Henry Keijzer Harry Struijker Boudier Robert Didden Marcel G. Smits

Abstract Background In some of our patients with intellectual disabilities (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment. In these patients melatonin levels at noon were extremely high (>50 pg/ml). We hypothesise that the disappearing effectiveness is associated with slow metabolisation of melatonin because of a single nucleotide polymorphism (SNP) of CYP1A2. Method In this pilot study we analysed DNA extracted from saliva samples of 15 consecutive patients with disappearing effectiveness of melatonin. Saliva was collected at noon and 4 pm for measuring melatonin levels. Results In all patients' salivary melatonin levels at noon were >50 or melatonin half time was >5 h. A SNP was found in eight of 15 patients. The allele *1C was found in two patients and in six patients the *1F allele was found. Conclusions Of 15 patients with disappearing effectiveness of melatonin, seven were diagnosed with autism spectrum disorder, and in four of them a SNP was found. The other eight patients were known with a genetic syndrome. In six of them behaviour was considered to be autistic‐type and in three of them a SNP was found. This finding may give a new direction for research into the genetic background of autism.

SNP

10.1111/j.1365-2788.2012.01595.x

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Loss of response to melatonin treatment is associated with slow melatonin metabolism

Journal of Intellectual Disability Research (2010)

Wiebe Braam Ingeborg M. van Geijlswijk Henry Keijzer Marcel G. Smits Robert Didden

In some of our patients with intellectual disability (ID) and sleep problems, the initial good response to melatonin disappeared within a few weeks after starting treatment, while the good response returned only after considerable dose reduction. The cause for this loss of response to melatonin is yet unknown. We hypothesise that this loss of response is associated with slow melatonin metabolism.In this study, we determined melatonin clearance in two female (aged 61 and 6 years) and one male (aged 3 years) patients who had chronic insomnia, late melatonin onset and mild ID, and whose sleep quality worsened a few weeks after initial good response to melatonin treatment, suggesting melatonin tolerance. After a 3-week washout period, patients received melatonin 1.0, 0.5 or 0.1 mg, respectively. Salivary melatonin level was measured just before melatonin administration, and 2 and 4 h thereafter. After this melatonin clearance test, melatonin treatment was resumed with a considerably lower dose.In all patients melatonin concentrations remained >50 pg/mL at 2 and 4 h after melatonin administration. After resuming melatonin treatment sleep problems disappeared. The same procedure was followed in three patients who did not show loss of response to melatonin after 6 months of treatment. In all patients in the control group melatonin concentrations decreased between 2 and 4 h after melatonin administration with a mean of 83%.We hypothesise that loss of response to melatonin treatment can be caused by slow metabolisation of exogenous melatonin. As melatonin is metabolised in the liver almost exclusively by cytochrome P450 enzyme CYP1A2, this slow melatonin metabolism is probably due to decreased activity/inducibility of CYP1A2. In patients with loss of response to melatonin, a melatonin clearance test should be considered and a considerably dose reduction is advised.

10.1111/j.1365-2788.2010.01283.x

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Evaluation of salivary melatonin measurements for Dim Light Melatonin Onset calculations in patients with possible sleep–wake rhythm disorders

Clinica Chimica Acta (2011)

Henry Keijzer Marcel G. Smits Twan Peeters Caspar W.N. Looman Silvia C. Endenburg

Sleep

10.1016/j.cca.2011.05.014

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Prospective risk analysis adjusted to the reality of clinical and fertility laboratory processes

Diagnosis (2015)

Pim M.W. Janssens Anja Scholten Harm De Waard Natascha Tiemens Monique Van Uum

Prospective risk analysis (PRA) is a valuable instrument in quality assurance. The practical application of PRA in clinical laboratories according to the method we have described elsewhere leaves room for a number of adaptations to make it more applicable to and consistent with actual laboratory processes.We distinguished between more and less critical tests and products in the laboratory processes and scored the consequences of failures at different steps in line with the previously described failure type and effect analysis (FMEA) method. PRA was carried out for two typical laboratory processes: standard clinical laboratory testing and the cryopreservation of semen.Tests in standard clinical laboratory in processes were labeled critical, semi-critical or non-critical. Consequence scoring (C) and assessed risk (R) were significantly higher for processes containing tests considered to be critical (C=6.6±1.5, R=19.3±13.5) as compared to processes containing tests considered semi- or non-critical (C=3.0±1.4, R=8.2±5.3 and C=3.2±1.8, R=8.6±5.9, respectively). There were no differences in the C and R scores for processes with tests considered semi- or non-critical. In the semen cryopreservation process, a distinction between the processes involving private semen and generally accessible semen was made. The C scores for these were significantly different (C=5.9±2.2 and 5.0±2.0, respectively), the R scores did not differ.Introduction of a test criticality classification for the purpose of consequence scoring led to an improved PRA methodology, better reflecting the reality of clinical laboratory practice. We found that two levels of criticality, critical and less critical, were sufficient to achieve this improvement.

10.1515/dx-2015-0027

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Automated genomic DNA extraction from saliva using the QIAxtractor

Clinical Chemistry and Laboratory Medicine (CCLM) (2010)

Henry Keijzer Silvia C. Endenburg Marcel G. Smits Miriam Koopmann

Venipuncture is an invasive procedure to obtain whole blood in order to obtain high quality and sufficient amounts of genomic DNA. Obtaining DNA from non-invasive sources is preferred by patients, medical doctors and researchers. Saliva collected with cotton swabs (Salivette) is increasingly being used to study chemical compounds, and it can also be a source of DNA. However, extracting DNA from Salivettes is very laborious and time consuming. Therefore, we developed a protocol for automated genomic DNA extraction from saliva collected in Salivette using the QIAxtractor.Saliva (0.1-2.0 mL) was collected by chewing on a Salivette for 1-2 min. A total of 70 samples, collected from healthy volunteers, were extracted with the QIAxtractor robot and a Qiagen DX reagent pack. Quantity and quality was assessed using UV spectrometry and real-time polymerase chain reaction (PCR) (substitution at position -729 in the CYP1A2 gene).The average DNA concentration from the saliva samples was 6.0 microg/mL (95% CI 5.4-6.6 microg/mL). In 100% of the saliva samples, PCR products were detected with an average cycle threshold of 23.1 (95% CI 22.6-23.6).DNA can be extracted in sufficient amounts from Salivette with a fully automated system with a short turnaround time. Real-time PCR can be performed with these samples.

genomic DNA

Venipuncture

Buccal swab

10.1515/cclm.2010.139

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Can dim light melatonin onset be predicted by the timing of sleep in patients with possible circadian sleep-wake rhythm disorders?

Biological Rhythm Research (2017)

Henry Keijzer Karen Spruyt Marcel G. Smits Antoon de Geest Leopold Curfs

Dim Light Melatonin Onset (DLMO) is a reliable marker of the endogenous circadian rhythm. To determine if sleep timing can predict DLMO, we investigated the relationship between sleep timing and DLMO in patients in various circadian sleep-wake rhythm disorders (CSWRDs), ages and genders. We found that correlations were only moderate between DLMO and sleep-onset in the complete data-set, but they increased in patients with delayed sleep-wake phase disorder (DSWPD), DSWPD patients with a regular sleep pattern and patients with advanced sleep-wake phase disorder (ASWPD); the levels of correlation were r = 0.542, 0.657, 0.728 and 0.814, respectively. In DSWPD patients with a regular sleep pattern, mid-sleep strongly correlated (r = 0.839) with DLMO. Correlation in other CSRWDs was not significant. DLMO, sleep-onset and age were most discriminated factors between the various CSRWDs. Estimation of DLMO is only possible in patients with ASWPD and in DSWPD patients with a regular sleep pattern.

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Free-running sleep

10.1080/09291016.2017.1287817

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Metabolisatie problemen bij melatoninegebruik

Wiebe Braam Henry Keijzer Marcel G. Smits A. Maas Ingeborg M. van Geijlswijk

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Why Dim Light Melatonin Onset (DLMO) should be measured before starting melatonin treatment

Marcel G. Smits Henry Keijzer H.C.M. Didden Wiebe Braam Leopold Curfs

a Gelderse Vallei Hospital, Ede, The Netherlands b Governor Kremers Center, University Maastricht, the Netherlands c ‘s Heeren Loo Zuid-Veluwe, Wekerom, The Netherlands d Behavioural Science Institute, Radboud University Nijmegen, Nijmegen,The Netherlands e Trajectum, Zutphen,The Netherlands f GROW School for Oncology and Developmental Biology, University Maastricht, Maastricht,The Netherlands g Institute for Management Research, Radboud University Nijmegen, Nijmegen,The Netherlands h Department of Clinical Genetics, Academic Hospital Maastricht/University Maastricht, Maastricht,The Netherlands

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Personalized sleep medicine applied to melatonin treatment for circadian rhythm sleep disorders: current status and future

Sleep Medicine (2013)

Marcel G. Smits Henry Keijzer Wiebe Braam Jacques Vervoort Leopold Curfs

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Sleep medicine

10.1016/j.sleep.2013.11.661

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