161 results on '"Willemsen, M.A."'
Search Results
2. Effects of Sodium Lactate Infusion in Two Girls with Glucose Transporter 1 Deficiency Syndrome.
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Gemert, L.A. van, Alfen, N. van, Gaal, L. van, Wortmann, S.B., Willemsen, M.A., Gemert, L.A. van, Alfen, N. van, Gaal, L. van, Wortmann, S.B., and Willemsen, M.A.
- Abstract
Contains fulltext : 300003.pdf (Publisher’s version ) (Open Access), BACKGROUND: Glucose is an important fuel for the brain. In glucose transporter 1 deficiency syndrome (GLUT1DS), the transport of glucose across the blood-brain barrier is limited. Most individuals with GLUT1DS present with developmental problems, epilepsy, and (paroxysmal) movement disorders, and respond favorably to the ketogenic diet. Similar to ketones, lactate is an alternative energy source for the brain. The aim of this study is to investigate whether intravenous infusion of sodium lactate in children with GLUT1DS has beneficial effects on their epilepsy. METHODS: We performed a proof of principle study with two subjects with GLUT1DS who were not on a ketogenic diet and suffered from absence epilepsy. After overnight fasting, sodium lactate (600 mmol/L) was infused during 120 minutes, under video electroencephalographic (EEG) recording and monitoring of serum lactate, glucose, electrolytes, and pH. Furthermore, the EEGs were compared with pre-/postprandial EEGs of both subjects, obtained shortly before the study. RESULTS: Fasting EEGs of both subjects showed frequent bilateral, frontocentral polyspike and wave complexes. In one subject, no more epileptic discharges were seen postprandially and after the start of lactate infusion. The EEG of the other subject did not change, neither postprandially nor after lactate infusion. Serum pH, lactate, and sodium changed temporarily during the study. CONCLUSION: This study suggests that sodium lactate infusion is possible in individuals with GLUT1DS, and may have potential therapeutic effects. Cellular abnormalities, beyond neuronal energy failure, may contribute to the underlying disease mechanisms of GLUT1DS, explaining why not all individuals respond to the supplementation of alternative energy sources., 01 december 2023
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- 2023
3. Teaching NeuroImage: Bilateral Nucleus Tractus Solitarius Lesions in Neurogenic Respiratory Failure
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Sankaran, Bindu Parayil, Wortmann, S.B., Willemsen, M.A., Balasubramaniam, S., Sankaran, Bindu Parayil, Wortmann, S.B., Willemsen, M.A., and Balasubramaniam, S.
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Item does not contain fulltext
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- 2022
4. Head circumference in glucose transporter 1 deficiency syndrome: Normal for individuals, abnormal as a group
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Gemert, Loes A. Van, Leen, W.G., Draaisma, J.M.T., Roeleveld, N., Willemsen, M.A., Gemert, Loes A. Van, Leen, W.G., Draaisma, J.M.T., Roeleveld, N., and Willemsen, M.A.
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Item does not contain fulltext
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- 2022
5. Retinal Capillary Abnormalities in Sjögren-Larsson Syndrome Maculopathy
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Staps, P., Breuk, A. de, Cruysberg, J.R.M., Willemsen, M.A., Theelen, T., Staps, P., Breuk, A. de, Cruysberg, J.R.M., Willemsen, M.A., and Theelen, T.
- Abstract
Contains fulltext : 251558.pdf (Publisher’s version ) (Open Access), Sjögren-Larsson syndrome (SLS) is a neurometabolic disease with a peculiar crystalline maculopathy. It is yet unclear if vascular abnormalities play a role in SLS maculopathy pathogenesis. We used optical coherence tomography angiography (OCT-A) to search for vessel abnormalities in SLS maculopathy. We performed a cross-sectional study in 4 patients (2 males, 2 females, aged 12-36 years) with various stages of SLS maculopathy. Besides OCT-A imaging, a complete ophthalmological examination and additional retinal imaging by transversal and en face spectral domain (SD) OCT were performed. OCT-A images were qualitatively assessed for vascular abnormalities, and imaging was compared to eight eyes of four healthy controls. On OCT-A, all eyes of patients with SLS showed a reduced capillary density around the fovea, and an enlarged foveal avascular zone (FAZ; SLS patients [n = 6 eyes] mean 0.70 mm(2) [SD 0.18]; healthy controls [n = 8 eyes] mean 0.34 mm(2) [SD 0.07], p = 0.004). In 2 patients, telangiectatic vessels were seen in the deep capillary layer. In conclusion, OCT angiography showed capillary paucity and morphological vessel abnormalities in these 4 patients with SLS.
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- 2022
6. Lactate infusion as therapeutical intervention: a scoping review
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Gemert, Loes A. Van, Galan, B.E. de, Wevers, R.A., Heine, R. ter, Willemsen, M.A., Gemert, Loes A. Van, Galan, B.E. de, Wevers, R.A., Heine, R. ter, and Willemsen, M.A.
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Contains fulltext : 251188.pdf (Publisher’s version ) (Open Access), Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer's disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury. CONCLUSION: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children. WHAT IS KNOWN: • Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain. • Lactate infusion is not incorporated in standard care for any patient population. WHAT IS NEW: • Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols. • Literature shows that lactate infusion may have beneficial effects in
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- 2022
7. Lactate infusion as therapeutical intervention: a scoping review
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Gemert, L.A. van, Galan, B.E. de, Wevers, R.A., Heine, R. ter, Willemsen, M.A., Gemert, L.A. van, Galan, B.E. de, Wevers, R.A., Heine, R. ter, and Willemsen, M.A.
- Abstract
Contains fulltext : 251188.pdf (Publisher’s version ) (Open Access), Traditionally, clinicians consider lactate as a waste product of anaerobic glycolysis. Interestingly, research has shown that lactate may serve as an alternative fuel for the brain to protect it against harm. The increasing scientific awareness of the potential beneficial side of lactate, however, is entering the clinic rather slowly. Following this, and realizing that the application of potential novel therapeutic strategies in pediatric populations often lags behind the development in adults, this review summarizes the key data on therapeutic use of intravenous infusion of sodium lactate in humans. PubMed and clinicaltrial.gov were searched up until November 2021 focusing on interventional studies in humans. Thirty-four articles were included in this review, with protocols of lactate infusion in adults with diabetes mellitus, traumatic brain injury, Alzheimer's disease, and cardiac disease. One study on lactate infusion in children was also included. Results of our literature search show that sodium lactate can be safely administrated, without major side effects. Additionally, the present literature clearly shows the potential benefits of therapeutic lactate infusion under certain pathological circumstances, including rather common clinical conditions like traumatic brain injury. CONCLUSION: This review shows that lactate is a save, alternative energy source for the adult brain warranting studies on the potential therapeutic effects of sodium lactate infusion in children. WHAT IS KNOWN: • Lactate is generally considered a waste product of anaerobic glycolysis. However, lactate also is an alternative fuel for different organs, including the brain. • Lactate infusion is not incorporated in standard care for any patient population. WHAT IS NEW: • Thirty-four studies investigated the therapeutic use of intravenous sodium lactate in different patient populations, all with different study protocols. • Literature shows that lactate infusion may have beneficial effects in
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- 2022
8. Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia
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Schon, Katherine, Os, N.J.H. van, Oscroft, Nicholas, Baxendale, Helen, Scoffings, Daniel, Ray, Julian, Warrenburg, B.P.C. van de, Weemaes, C.M.R., Willemsen, M.A., Taylor, A.M., and Hensiek, Anke E.
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All institutes and research themes of the Radboud University Medical Center ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] - Abstract
Contains fulltext : 201142.pdf (Publisher’s version ) (Open Access)
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- 2019
9. Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency
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Wassenberg, T., Deinum, J., Ittersum, F.J. van, Kamsteeg, E.J., Pennings, M., Verbeek, M.M., Wevers, R.A., Albada, M.E. van, Kema, I.P., Versmissen, J., Meiracker, T. van den, Lenders, J.W.M., Monnens, L.A., Willemsen, M.A., Wassenberg, T., Deinum, J., Ittersum, F.J. van, Kamsteeg, E.J., Pennings, M., Verbeek, M.M., Wevers, R.A., Albada, M.E. van, Kema, I.P., Versmissen, J., Meiracker, T. van den, Lenders, J.W.M., Monnens, L.A., and Willemsen, M.A.
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Item does not contain fulltext, Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.
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- 2021
10. Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity
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Tristán-Noguero, A., Borràs, E., Molero-Luis, M., Wassenberg, T., Peters, T.M.A., Verbeek, M.M., Willemsen, M.A., Opladen, T., Jeltsch, K., Pons, R., Thony, B., Horvath, G., Yapici, Z., Friedman, J., Hyland, K., Agosta, G.E., López-Laso, E., Artuch, R., Sabidó, E., García-Cazorla, À., Tristán-Noguero, A., Borràs, E., Molero-Luis, M., Wassenberg, T., Peters, T.M.A., Verbeek, M.M., Willemsen, M.A., Opladen, T., Jeltsch, K., Pons, R., Thony, B., Horvath, G., Yapici, Z., Friedman, J., Hyland, K., Agosta, G.E., López-Laso, E., Artuch, R., Sabidó, E., and García-Cazorla, À.
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Item does not contain fulltext
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- 2021
11. De Novo variants in EEF2 cause a neurodevelopmental disorder with benign external hydrocephalus
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Nabais Sá, M.J., Olson, A.N., Yoon, G., Nimmo, G.A.M., Gomez, C.M., Willemsen, M.A., Millan, F., Schneider, A., Pfundt, R.P., Brouwer, A.P.M. de, Dinman, J.D., Vries, B.B.A. de, Nabais Sá, M.J., Olson, A.N., Yoon, G., Nimmo, G.A.M., Gomez, C.M., Willemsen, M.A., Millan, F., Schneider, A., Pfundt, R.P., Brouwer, A.P.M. de, Dinman, J.D., and Vries, B.B.A. de
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Contains fulltext : 231523.pdf (Publisher’s version ) (Closed access), Eukaryotic translation elongation factor 2 (eEF2) is a key regulatory factor in gene expression that catalyzes the elongation stage of translation. A functionally impaired eEF2, due to a heterozygous missense variant in the EEF2 gene, was previously reported in one family with spinocerebellar ataxia-26 (SCA26), an autosomal dominant adult-onset pure cerebellar ataxia. Clinical exome sequencing identified de novo EEF2 variants in three unrelated children presenting with a neurodevelopmental disorder (NDD). Individuals shared a mild phenotype comprising motor delay and relative macrocephaly associated with ventriculomegaly. Populational data and bioinformatic analysis underscored the pathogenicity of all de novo missense variants. The eEF2 yeast model strains demonstrated that patient-derived variants affect cellular growth, sensitivity to translation inhibitors and translational fidelity. Consequently, we propose that pathogenic variants in the EEF2 gene, so far exclusively associated with late-onset SCA26, can cause a broader spectrum of neurologic disorders, including childhood-onset NDDs and benign external hydrocephalus.
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- 2021
12. NANS-CDG: Delineation of the Genetic, Biochemical, and Clinical Spectrum
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Hollander, Bibiche den, Rasing, Anne, Post, M.A., Klein, W.M., Oud, M.M., Brands, Marion M., Boer, L. de, Engelke, U.F.H., Essen, P. van, Haaxma, C.A., Kluijtmans, L.A.J., Peters, G.T.M., Coene, K.L.M., Willemsen, M.A., Lefeber, D.J., Karnebeek, C.D. van, Hollander, Bibiche den, Rasing, Anne, Post, M.A., Klein, W.M., Oud, M.M., Brands, Marion M., Boer, L. de, Engelke, U.F.H., Essen, P. van, Haaxma, C.A., Kluijtmans, L.A.J., Peters, G.T.M., Coene, K.L.M., Willemsen, M.A., Lefeber, D.J., and Karnebeek, C.D. van
- Abstract
Contains fulltext : 235034.pdf (Publisher’s version ) (Open Access)
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- 2021
13. Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene
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Beusichem, A.E. Van, Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M.A., Kamsteeg, E.J., Stumpel, C., Vermeulen, R.J., Beusichem, A.E. Van, Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M.A., Kamsteeg, E.J., Stumpel, C., and Vermeulen, R.J.
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Item does not contain fulltext, Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10-18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found.In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes.We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted.
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- 2020
14. Glut1 Deficiency Syndrome (Glut1DS): State of the art in 2020 and recommendations of the international Glut1DS study group
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Klepper, J., Akman, C.I., Armeno, Marisa, Auvin, S., Cervenka, Mackenzie, Cross, Helen J., Willemsen, M.A., Zuberi, S.M., Vivo, D.C. De, Klepper, J., Akman, C.I., Armeno, Marisa, Auvin, S., Cervenka, Mackenzie, Cross, Helen J., Willemsen, M.A., Zuberi, S.M., and Vivo, D.C. De
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Contains fulltext : 233745.pdf (Publisher’s version ) (Open Access)
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- 2020
15. De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy
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Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, Trimouille, A., Lasseaux, E., Naudion, S., Lacombe, D., Piton, A., Vincent-Delorme, C., Zweier, C., Reis, A., Trollmann, R., Ruiz, A., Gabau, E., Vetro, A., Guerrini, R., Bakhtiari, S., Kruer, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, Koolen, D.A., Nabais Sá, M.J., Venselaar, H., Wiel, L.J.M. van de, Trimouille, A., Lasseaux, E., Naudion, S., Lacombe, D., Piton, A., Vincent-Delorme, C., Zweier, C., Reis, A., Trollmann, R., Ruiz, A., Gabau, E., Vetro, A., Guerrini, R., Bakhtiari, S., Kruer, M.C., Amor, D.J., Cooper, M.S., Bijlsma, E.K., Barakat, T.S., Dooren, M.F. van, Slegtenhorst, M. van, Pfundt, R.P., Gilissen, C.F., Willemsen, M.A., Vries, B.B.A. de, Brouwer, A.P.M. de, and Koolen, D.A.
- Abstract
Contains fulltext : 218155.pdf (Publisher’s version ) (Closed access), PURPOSE: To delineate the genotype-phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. METHODS: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. RESULTS: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. CONCLUSIONS: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.
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- 2020
16. Variable Selection in Untargeted Metabolomics and the Danger of Sparsity
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Tinnevelt, G.H., Engelke, U.F.H., Wevers, R.A., Veenhuis, S.J.G., Willemsen, M.A., Coene, K.L.M., Kulkarni, P., Jansen, J.J., Tinnevelt, G.H., Engelke, U.F.H., Wevers, R.A., Veenhuis, S.J.G., Willemsen, M.A., Coene, K.L.M., Kulkarni, P., and Jansen, J.J.
- Abstract
Contains fulltext : 226684.pdf (publisher's version ) (Open Access)
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- 2020
17. Oculoectodermal Syndrome - Encephalocraniocutaneous Lipomatosis Associated With NRAS Mutation
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Richters, R.J.H., Seyger, M.M.B., Meeuwis, K.A.P., Rinne, T.K., Eijkelenboom, A., Willemsen, M.A., Richters, R.J.H., Seyger, M.M.B., Meeuwis, K.A.P., Rinne, T.K., Eijkelenboom, A., and Willemsen, M.A.
- Abstract
Contains fulltext : 220456.pdf (publisher's version ) (Open Access)
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- 2020
18. The Phenotypic Spectrum of PNKP-Associated Disease and the Absence of Immunodeficiency and Cancer Predisposition in a Dutch Cohort
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Garrelfs, M.R., Takada, Sanami, Kamsteeg, E.J., Pegge, Sjoert, Mancini, Grazia, Engelen, Marc, Warrenburg, B.P.C. van de, Rennings, A.J., Gaalen, J. van, Weemaes, C.M., Burg, Mirjam van der, Willemsen, M.A., Garrelfs, M.R., Takada, Sanami, Kamsteeg, E.J., Pegge, Sjoert, Mancini, Grazia, Engelen, Marc, Warrenburg, B.P.C. van de, Rennings, A.J., Gaalen, J. van, Weemaes, C.M., Burg, Mirjam van der, and Willemsen, M.A.
- Abstract
Contains fulltext : 228578.pdf (Publisher’s version ) (Open Access)
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- 2020
19. Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy
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Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), Reversade, B. (Bruno), Hengel, H. (Holger), Bosso-Lefèvre, C. (Célia), Grady, G. (George), Szenker-Ravi, E. (Emmanuelle), Li, H. (Hankun), Pierce, S. (Sarah), Lebigot, É. (Élise), Tan, T.-T. (Thong-Teck), Eio, M.Y. (Michelle Y.), Narayanan, G. (Gunaseelan), Utami, K.H. (Kagistia Hana), Yau, M. (Monica), Handal, N. (Nader), Deigendesch, W. (Werner), Keimer, R. (Reinhard), Marzouqa, H.M. (Hiyam M.), Gunay-Aygun, M. (Meral), Muriello, M.J. (Michael J.), Verhelst, H. (H.), Weckhuysen, S. (Sarah), Mahida, S. (Sonal), Naidu, S. (Sakkubai), Thomas, T.G. (Terrence G.), Lim, J.Y. (Jiin Ying), Tan, E.S. (Ee Shien), Haye, D. (Damien), Willemsen, M.A. (Michél), Oegema, R. (Renske), Mitchell, W.G. (Wendy G.), Pierson, T.M. (Tyler Mark), Andrews, M.V. (Marisa V.), Willing, M.C. (Marcia C.), Rodan, L.H. (Lance H.), Barakat, T.S. (Tahsin Stefan), Slegtenhorst, M.A. (Marjon) van, Gavrilova, R.H. (Ralitza H.), Martinelli, D. (Diego), Gilboa, T. (Tal), Tamim, A.M. (Abdullah M.), Hashem, M.O. (Mais O.), AlSayed, M.D. (Moeenaldeen D.), Abdulrahim, M.M. (Maha M.), Al-Owain, M. (Mohammed), Awaji, A. (Ali), Mahmoud, A.A.H. (Adel A. H.), Faqeih, E.A. (Eissa A.), Asmari, A.A. (Ali Al), Algain, S.M. (Sulwan M.), Jad, L.A. (Lamyaa A.), Aldhalaan, H.M. (Hesham M.), Helbig, I. (Ingo), Koolen, D.A. (David), Rieß, A. (Angelika), Kraegeloh-Mann, I. (Ingeborg), Bauer, P. (Peter), Gulsuner, S. (Suleyman), Stamberger, H. (Hannah), Ng, A.Y.J. (Alvin Yu Jin), Tang, S. (Sha), Tohari, S. (Sumanty), Keren, B. (Boris), Schultz-Rogers, L.E. (Laura E.), Klee, E.W. (Eric W.), Barresi, S. (Sabina), Tartaglia, M. (Marco), Mor-Shaked, H. (Hagar), Maddirevula, S. (Sateesh), Begtrup, A. (Amber), Telegrafi, A. (Aida), Pfundt, R. (Rolph), Schüle, R. (Rebecca), Ciruna, B. (Brian), Bonnard, C. (Carine), Pouladi, M.A. (Mahmoud A.), Stewart, J.C. (James C.), Claridge-Chang, A. (Adam), Lefeber, D.J. (Dirk J.), Alkuraya, F.S. (Fowzan S), Mathuru, A.S. (Ajay S.), Venkatesh, B. (Byrappa), Barycki, J.J. (Joseph J.), Simpson, M.A. (Melanie A.), Jamuar, S.S. (Saumya S.), Schöls, L. (Ludger), and Reversade, B. (Bruno)
- Abstract
Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids. Consistent with being loss-of-function alleles, we show using patients’ primary fibroblasts and biochemical assays, that these mutations either impair UGDH stability, oligomerization, or enzymatic activity. In vitro, patient-derived cerebral organoids are smaller with a reduced number of proliferating neuronal progenitors while mutant ugdh zebrafish do not phenocopy the human disease. Our study defines UGDH as a key player for the production of extracellular matrix components that are essential for human brain development. Based on the incidence of variants observed, UGDH mutations are likely to be a frequent cause of recessive epileptic encephalopathy.
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- 2020
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20. A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients
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Polet, S.S. (Sjoukje S.), Anderson, D.G. (David G.), Koens, L.H. (Lisette H.), van Egmond, M.E. (Martje E.), Drost, G. (Gea), Brusse, E. (Esther), Willemsen, M.A. (Michél), Sival, D.A. (Deborah), Brouwer, O.F. (Oebele), Kremer, H.P. (Hubertus PH.), de Vries, J.J. (Jeroen J.), Tijssen, M.A. (Marina), Koning, T.J. (Tom) de, Polet, S.S. (Sjoukje S.), Anderson, D.G. (David G.), Koens, L.H. (Lisette H.), van Egmond, M.E. (Martje E.), Drost, G. (Gea), Brusse, E. (Esther), Willemsen, M.A. (Michél), Sival, D.A. (Deborah), Brouwer, O.F. (Oebele), Kremer, H.P. (Hubertus PH.), de Vries, J.J. (Jeroen J.), Tijssen, M.A. (Marina), and Koning, T.J. (Tom) de
- Abstract
Introduction: In 2011, a homozygous mutation in GOSR2 (c.430G > T; p. Gly144Trp) was reported as a novel cause of Progressive Myoclonus Epilepsy (PME) with early-onset ataxia. Interestingly, the ancestors of patients originate from countries bound to the North Sea, hence the condition was termed North Sea PME (NSPME). Until now, only 20 patients have been reported in literature. Here, we provide a detailed description of clinical and neurophysiological data of seventeen patients. Methods: We collected clinical and neurophysiological data from the medical records of seventeen NSPME patients (5–46 years). In addition, we conducted an interview focused on factors influencing myoclonus severity. Results: The core clinical features of NSPME are early-onset ataxia, myoclonus and seizures, with additionally areflexia and scoliosis. Factors such as fever, illness, heat, emotions, stress, noise and light (flashes) all exacerbated myoclonic jerks. Epilepsy severity ranged from the absence of or incidental clinical seizures to frequent daily seizures and status epilepticus. Some patients made use of a wheelchair during their first decade, whereas others still walked independently during their third decade. Neurophysiological features suggesting neuromuscular involvement in NSPME were variable, with findings ranging from indicative of sensory neuronopathy and anterior horn cell involvement to an isolated absent H-reflex. Conclusion: Although the sequence of symptoms is rather homogeneous, the severity of symptoms and rate of progression varied considerably among individual patients. Common triggers for myoclonus can be identified and myoclonus is difficult to treat; to what extent neuromuscular involvement contributes to the phenotype remains t
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- 2020
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21. Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene
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Van Beusichem, A.E., additional, Nicolai, J., additional, Verhoeven, J., additional, Speth, L., additional, Coenen, M., additional, Willemsen, M.A., additional, Kamsteeg, E.J., additional, Stumpel, C., additional, and Vermeulen, R.J., additional
- Published
- 2019
- Full Text
- View/download PDF
22. Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG
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van Tol, W. Michelakakis, H. Georgiadou, E. van den Bergh, P. Moraitou, M. Papadimas, G.K. Papadopoulos, C. Huijben, K. Alsady, M. Willemsen, M.A. Lefeber, D.J.
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carbohydrates (lipids) ,congenital, hereditary, and neonatal diseases and abnormalities ,lipids (amino acids, peptides, and proteins) - Abstract
The congenital disorders of glycosylation (CDG) are inborn errors of metabolism with a great genetic heterogeneity. Most CDG are caused by defects in the N-glycan biosynthesis, leading to multisystem phenotypes. However, the occurrence of tissue-restricted clinical symptoms in the various defects in dolichol-phosphate-mannose (DPM) synthesis remains unexplained. To deepen our understanding of the tissue-specific characteristics of defects in the DPM synthesis pathway, we investigated N-glycosylation and O-mannosylation in skeletal muscle of three DPM3-CDG patients presenting with muscle dystrophy and hypo-N-glycosylation of serum transferrin in only two of them. In the three patients, O-mannosylation of alpha-dystroglycan (αDG) was strongly reduced and western blot analysis of beta-dystroglycan (βDG) N-glycosylation revealed a consistent lack of one N-glycan in skeletal muscle. Recently, defective N-glycosylation of βDG has been reported in patients with mutations in guanosine-diphosphate-mannose pyrophosphorylase B (GMPPB). Thus, we suggest that aberrant O-glycosylation of αDG and N-glycosylation of βDG in skeletal muscle is indicative of a defect in the DPM synthesis pathway. Further studies should address to what extent hypo-N-glycosylation of βDG or other skeletal muscle proteins contribute to the phenotype of patients with defects in DPM synthesis. Our findings contribute to our understanding of the tissue-restricted phenotype of DPM3-CDG and other defects in the DPM synthesis pathway. © 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM
- Published
- 2019
23. Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy
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Tol, W. van, Scherpenzeel, M. van, Alsady, M., Riemersma, M., Hermans, E., Kragt, E., Tasca, G., Kamsteeg, E.J., Pennings, M., Beusekom, E. van, Vermeulen, J.R., Bokhoven, H. van, Voermans, N.C., Willemsen, M.A., Ashikov, A.M., Lefeber, D.J., Tol, W. van, Scherpenzeel, M. van, Alsady, M., Riemersma, M., Hermans, E., Kragt, E., Tasca, G., Kamsteeg, E.J., Pennings, M., Beusekom, E. van, Vermeulen, J.R., Bokhoven, H. van, Voermans, N.C., Willemsen, M.A., Ashikov, A.M., and Lefeber, D.J.
- Abstract
Contains fulltext : 208790.pdf (publisher's version ) (Closed access), BACKGROUND: Many muscular dystrophies currently remain untreatable. Recently, dietary ribitol has been suggested as a treatment for cytidine diphosphate (CDP)-l-ribitol pyrophosphorylase A (CRPPA, ISPD), fukutin (FKTN), and fukutin-related protein (FKRP) myopathy, by raising CDP-ribitol concentrations. Thus, to facilitate fast diagnosis, treatment development, and treatment monitoring, sensitive detection of CDP-ribitol is required. METHODS: An LC-MS method was optimized for CDP-ribitol in human and mice cells and tissues. RESULTS: CDP-ribitol, the product of CRPPA, was detected in all major human and mouse tissues. Moreover, CDP-ribitol concentrations were reduced in fibroblasts and skeletal muscle biopsies from patients with CRPPA myopathy, showing that CDP-ribitol could serve as a diagnostic marker to identify patients with CRPPA with severe Walker-Warburg syndrome and mild limb-girdle muscular dystrophy (LGMD) phenotypes. A screen for potentially therapeutic monosaccharides revealed that ribose, in addition to ribitol, restored CDP-ribitol concentrations and the associated O-glycosylation defect of alpha-dystroglycan. As the effect occurred in a mutation-dependent manner, we established a CDP-ribitol blood test to facilitate diagnosis and predict individualized treatment response. Ex vivo incubation of blood cells with ribose or ribitol restored CDP-ribitol concentrations in a patient with CRPPA LGMD. CONCLUSIONS: Sensitive detection of CDP-ribitol with LC-MS allows fast diagnosis of patients with severe and mild CRPPA myopathy. Ribose offers a readily testable dietary therapy for CRPPA myopathy, with possible applicability for patients with FKRP and FKTN myopathy. Evaluation of CDP-ribitol in blood is a promising tool for the evaluation and monitoring of dietary therapies for CRPPA myopathy in a patient-specific manner.
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- 2019
24. De novo SPAST mutations may cause a complex SPG4 phenotype
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Schieving, J.H., Bot, S.T. de, Pol, L.A. van de, Wolf, N.I., Brilstra, E.H., Frints, S.G., Gaalen, J. van, Misra-Isrie, M., Pennings, M., Verschuuren-Bemelmans, C.C., Kamsteeg, E.J., Warrenburg, B.P.C. van de, Willemsen, M.A., Schieving, J.H., Bot, S.T. de, Pol, L.A. van de, Wolf, N.I., Brilstra, E.H., Frints, S.G., Gaalen, J. van, Misra-Isrie, M., Pennings, M., Verschuuren-Bemelmans, C.C., Kamsteeg, E.J., Warrenburg, B.P.C. van de, and Willemsen, M.A.
- Abstract
Contains fulltext : 208476.pdf (publisher's version ) (Open Access)
- Published
- 2019
25. The Ketogenic Diet and Its Effect on Bone Mineral Density: A Retrospective Observational Cohort Study
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Draaisma, J.M.T., Hampsink, Brieke M., Janssen, M.J.R., Houdt, Nicole B.M. van, Linders, E.T.A.M., Willemsen, M.A., Draaisma, J.M.T., Hampsink, Brieke M., Janssen, M.J.R., Houdt, Nicole B.M. van, Linders, E.T.A.M., and Willemsen, M.A.
- Abstract
Contains fulltext : 213638.pdf (publisher's version ) (Closed access)
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- 2019
26. Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG
- Author
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Tol, W. van, Michelakakis, H., Georgiadou, Elissavet, Bergh, Peter van den, Moraitou, Marina, Papadimas, George K., Alsady, M., Willemsen, M.A., Lefeber, D.J., Tol, W. van, Michelakakis, H., Georgiadou, Elissavet, Bergh, Peter van den, Moraitou, Marina, Papadimas, George K., Alsady, M., Willemsen, M.A., and Lefeber, D.J.
- Abstract
Contains fulltext : 208143.pdf (publisher's version ) (Open Access)
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- 2019
27. Serum inflammatory mediators correlate with disease activity in electrical status epilepticus in sleep (ESES) syndrome
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Munckhof, B. van den, Vries, E.E. de, Braun, K.P., Boss, H.M., Willemsen, M.A., Royen-Kerkhof, A. Van, Jager, W. de, and Jansen, F.E.
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Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] - Abstract
Item does not contain fulltext We aimed to study serum cytokine levels in 11 electrical status epilepticus in sleep (ESES) patients and 20 healthy control children. Patients showed significantly higher levels of interleukin (IL)-1alpha, IL-6, IL-10, chemokine (C-C motif) ligand (CCL)2 and chemokine (C-X-C motif) ligand (CXCL)8/IL-8 than controls, while macrophage migration inhibitory factor (MIF) and CCL3 were significantly lower. Follow-up analyses in five patients revealed a significant decrease of IL-6 levels after immunomodulating treatment. IL-6 changes were accompanied by clear improvement of electroencephalography (EEG) patterns and neuropsychological evaluation. We hypothesize that IL-6 correlates with disease activity and immunomodulating treatment efficacy.
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- 2016
28. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study
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de Mol, C.L. (C. L.), Wong, Y.Y.M. (Yu Yi), Pelt - Gravesteijn, E.D. (Daniëlle) van, Ketelslegers, I.A. (Immy), Bakker, D.P. (Dewi), Boon, M. (Martin), Braun, K.P.J. (Kees P.), Dijk, K.G.J. (K. G J) van, Eikelenboom, M.J. (Merijn Judith), Engelen, M. (Marc), Geleijns, K. (Karin), Haaxma, C.A. (Charlotte A.), Niermeijer, J.M.F. (J. M.F.), Niks, E.H. (Erik), Peeters, E.A. (Els), Peeters-Scholte, C.M.P.C.D. (Cacha), Poll-The, B.T., Portier, R.P. (R. P.), De Rijk-Van Andel, J. (Johanneke), Samijn, J.P. (Johnny), Schippers, H.M., Snoeck, M.M.J. (M. M J), Stroink, H. (Hans), Vermeulen, R.J. (Jeroen), Verrips, A. (Aad), Visscher, F. (F.), Vles, J.S.H. (Johannes), Willemsen, M.A. (Michél), Catsman-Berrevoets, C.E. (Coriene), Hintzen, R.Q. (Rogier), Neuteboom, R.F. (Rinze), de Mol, C.L. (C. L.), Wong, Y.Y.M. (Yu Yi), Pelt - Gravesteijn, E.D. (Daniëlle) van, Ketelslegers, I.A. (Immy), Bakker, D.P. (Dewi), Boon, M. (Martin), Braun, K.P.J. (Kees P.), Dijk, K.G.J. (K. G J) van, Eikelenboom, M.J. (Merijn Judith), Engelen, M. (Marc), Geleijns, K. (Karin), Haaxma, C.A. (Charlotte A.), Niermeijer, J.M.F. (J. M.F.), Niks, E.H. (Erik), Peeters, E.A. (Els), Peeters-Scholte, C.M.P.C.D. (Cacha), Poll-The, B.T., Portier, R.P. (R. P.), De Rijk-Van Andel, J. (Johanneke), Samijn, J.P. (Johnny), Schippers, H.M., Snoeck, M.M.J. (M. M J), Stroink, H. (Hans), Vermeulen, R.J. (Jeroen), Verrips, A. (Aad), Visscher, F. (F.), Vles, J.S.H. (Johannes), Willemsen, M.A. (Michél), Catsman-Berrevoets, C.E. (Coriene), Hintzen, R.Q. (Rogier), and Neuteboom, R.F. (Rinze)
- Abstract
Introduction: Acquired demyelinating syndromes (ADS) are immune-mediated demyelinating disorders of the central nervous system in children. A nationwide, multicentre and prospective cohort study was initiated in the Netherlands in 2006, with a reported ADS incidence of 0.66/100,000 per year and MS incidence of 0.15/100,000 per year in the period between 2007 and 2010. In this study, we provide an update on the incidence and the long-term follow-up of ADS in the Netherlands. Methods: Children < 18 years with a first attack of demyelination were included consecutively from January 2006 to December 2016. Diagnoses were based on the International Paediatric MS study group consensus criteria. Outcome data were collected by neurological and neuropsychological assessments, and telephone call assessments. Results: Between 2011 and 2016, 55/165 of the ADS patients were diagnosed with MS (33%). This resulted in an increased ADS and MS incidence of 0.80/100,000 per year and 0.26/100,000 per year, respectively. Since 2006 a total of 243 ADS patients have been included. During follow-up (median 55 months, IQR 28–84), 137 patients were diagnosed with monophasic disease (56%), 89 with MS (37%) and 17 with multiphasic disease other than MS (7%). At least one form of residual deficit including cognitive impairment was observed in 69% of all ADS patients, even in monophasic ADS. An Expanded Disability Status Scale score of ≥ 5.5 was reached in 3/89 MS patients (3%). Conclusion: The reported incidence of ADS in Dutch children has increased since 2010. Residual deficits are common in this group, even in monophasic patients. Therefore, long-term follow-up in ADS patients is warranted.
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- 2018
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29. A Post Hoc Study on Gene Panel Analysis for the Diagnosis of Dystonia
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Egmond, M.E. van, Lugtenberg, C.H.A., Brouwer, O.F., Contarino, M.F., Fung, V.S.C., Heiner-Fokkema, M.R., Hilten, J.J. van, Hout, A.H. van der, Peall, K.J., Sinke, R.J., Roze, E., Verschuuren-Bemelmans, C.C., Willemsen, M.A., Wolf, N.I., Tijssen, M.A., and Koning, T.J. de
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gene panel analysis ,diagnostic yield ,cost ,next-generation sequencing ,dystonia ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] - Abstract
Contains fulltext : 174078.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genetic disorders causing dystonia show great heterogeneity. Recent studies have suggested that next-generation sequencing techniques such as gene panel analysis can be effective in diagnosing heterogeneous conditions. The objective of this study was to investigate whether dystonia patients with a suspected genetic cause could benefit from the use of gene panel analysis. METHODS: In this post hoc study, we describe gene panel analysis results of 61 dystonia patients (mean age, 31 years; 72% young onset) in our tertiary referral center. The panel covered 94 dystonia-associated genes. As comparison with a historic cohort was not possible because of the rapidly growing list of dystonia genes, we compared the diagnostic workup with and without gene panel analysis in the same patients. The workup without gene panel analysis (control group) included theoretical diagnostic strategies formulated by independent experts in the field, based on detailed case descriptions. The primary outcome measure was diagnostic yield; secondary measures were cost and duration of diagnostic workup. RESULTS: Workup with gene panel analysis led to a confirmed molecular diagnosis in 14.8%, versus 7.4% in the control group (P = 0.096). In the control group, on average 3 genes/case were requested. The mean costs were lower in the gene panel analysis group (euro1822/case) than in the controls (euro2660/case). The duration of the workup was considerably shorter with gene panel analysis (28 vs 102 days). CONCLUSIONS: Gene panel analysis facilitates molecular diagnosis in complex cases of dystonia, with a good diagnostic yield (14.8%), a quicker diagnostic workup, and lower costs, representing a major improvement for patients and their families. (c) 2016 International Parkinson and Movement Disorder Society.
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- 2017
30. Mobility Characteristics of Children with Spastic Paraplegia Due to a Mutation in the KIF1A Gene.
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Van Beusichem, A.E., Nicolai, J., Verhoeven, J., Speth, L., Coenen, M., Willemsen, M.A., Kamsteeg, E.J., Stumpel, C., and Vermeulen, R.J.
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FAMILIAL spastic paraplegia ,GENETIC mutation ,PARAPLEGIA ,MUSCLE weakness ,GAIT disorders ,COGNITION disorders - Abstract
Several de novo variants in the KIF1A gene have been reported to cause a complicated form of hereditary spastic paraplegia. Additional symptoms include cognitive impairment and varying degrees of peripheral neuropathy, epilepsy, decreased visual acuity, and ataxia. We describe four patients (ages 10–18 years), focusing on their mobility and gait characteristics. Two patients were not able to walk without assistance and showed a severe abnormal gait pattern, crouch gait. At examination, severe contractures were found. In addition to describing the different phenotypes with specific attention to gait in our cases, we reviewed known KIF1A mutations and summarized their associated phenotypes. We conclude that mobility and cognition are severely affected in children with spastic paraplegia due to de novo KIF1A mutations. Deterioration in mobility is most likely due to progressive spasticity, muscle weakness, and the secondary development of severe contractures, possibly combined with an additional progressive polyneuropathy. Close follow-up and treatment of these patients are warranted. [ABSTRACT FROM AUTHOR]
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- 2020
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31. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency
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Wassenberg, T., Molero-Luis, M., Jeltsch, K., Hoffmann, G.F., Assmann, B., Blau, N., Garcia-Cazorla, A., Artuch, R., Pons, R., Pearson, T.S., Leuzzi, V., Mastrangelo, M., Pearl, P.L., Lee, W.T., Kurian, M.A., Heales, S., Flint, L., Verbeek, M.M., Willemsen, M.A., Opladen, T., Wassenberg, T., Molero-Luis, M., Jeltsch, K., Hoffmann, G.F., Assmann, B., Blau, N., Garcia-Cazorla, A., Artuch, R., Pons, R., Pearson, T.S., Leuzzi, V., Mastrangelo, M., Pearl, P.L., Lee, W.T., Kurian, M.A., Heales, S., Flint, L., Verbeek, M.M., Willemsen, M.A., and Opladen, T.
- Abstract
Contains fulltext : 170061.pdf (publisher's version ) (Open Access)
- Published
- 2017
32. Congenital eyelid ptosis, decreased glomerular filtration, and orthostatic hypotension: Answers.
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Wassenberg, T., Willemsen, M.A., Dijkman, H.B., Deinum, J., Monnens, L.A., Wassenberg, T., Willemsen, M.A., Dijkman, H.B., Deinum, J., and Monnens, L.A.
- Abstract
01 juli 2017, Contains fulltext : 174487.pdf (Publisher’s version ) (Open Access)
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- 2017
33. Congenital eyelid ptosis, decreased glomerular filtration, and orthostatic hypotension: Questions.
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Wassenberg, T., Willemsen, M.A., Dijkman, H.B., Deinum, J., Monnens, L.A., Wassenberg, T., Willemsen, M.A., Dijkman, H.B., Deinum, J., and Monnens, L.A.
- Abstract
01 juli 2017, Contains fulltext : 174488.pdf (Publisher’s version ) (Open Access)
- Published
- 2017
34. Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia
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Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., Kurian, M.A., Meyer, E., Carss, K.J., Rankin, J., Nichols, J.M., Grozeva, D., Joseph, A.P., Mencacci, N.E., Papandreou, A., Ng, J., Barral, S., Ngoh, A., Ben-Pazi, H., Willemsen, M.A., Arkadir, D., Barnicoat, A., Bergman, H., Bhate, S., Boys, A., Darin, N., Foulds, N., Gutowski, N., Hills, A., Houlden, H., Hurst, J.A., Israel, Z., Kaminska, M., Limousin, P., Lumsden, D., McKee, S., Misra, S., Mohammed, S.S., Nakou, V., Nicolai, J., Nilsson, M., Pall, H., Peall, K.J., Peters, G.B., Prabhakar, P., Reuter, M.S., Rump, P., Segel, R., Sinnema, M., Smith, M., Turnpenny, P., White, S.M., Wieczorek, D., Wiethoff, S., Wilson, B.T., Winter, G., Wragg, C., Pope, S., Heales, S.J., Morrogh, D., Pittman, A., Carr, L.J., Perez-Duenas, B., Lin, J.P., Reis, A., Gahl, W.A., Toro, C., Bhatia, K.P., Wood, N.W., Kamsteeg, E.J., Chong, W.K., Gissen, P., Topf, M., Dale, R.C., Chubb, J.R., Raymond, F.L., and Kurian, M.A.
- Abstract
Item does not contain fulltext, Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.
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- 2017
35. Ataxia-telangiectasia: Immunodeficiency and survival
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Os, N.J.H. van, Jansen, A.F.M., Deuren, M. van, Haraldsson, A., Driel, N.T.M. van, Etzioni, A., Flier, M. van der, Haaxma, C.A., Morio, T., Rawat, A., Schoenaker, M.H.D., Soresina, A., Taylor, A.M., Warrenburg, B.P.C. van de, Weemaes, C.M.R., Roeleveld, N., Willemsen, M.A., Os, N.J.H. van, Jansen, A.F.M., Deuren, M. van, Haraldsson, A., Driel, N.T.M. van, Etzioni, A., Flier, M. van der, Haaxma, C.A., Morio, T., Rawat, A., Schoenaker, M.H.D., Soresina, A., Taylor, A.M., Warrenburg, B.P.C. van de, Weemaes, C.M.R., Roeleveld, N., and Willemsen, M.A.
- Abstract
Contains fulltext : 174098.pdf (publisher's version ) (Open Access), Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy). Patients with the hyper IgM phenotype with hypogammaglobulinemia (AT-HIGM) and patients with an IgG2 deficiency showed decreased survival compared to patients with normal IgG (HR 9.2, 95%CI 3.2-26.5) and patients with normal IgG2 levels (HR 7.8, 95%CI 1.7-36.2), respectively. If high risk treatment trials will become available for AT, those patients with factors indicating the poorest prognosis might be considered for inclusion first.
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- 2017
36. Health risks for ataxia-telangiectasia mutated heterozygotes: a systematic review, meta-analysis and evidence-based guideline
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Os, N.J.H. van, Roeleveld, N., Weemaes, C.M., Jongmans, M.C., Janssens, G.O., Taylor, A.M., Hoogerbrugge, N., and Willemsen, M.A.
- Subjects
Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10] ,Metabolic Disorders Radboud Institute for Health Sciences [Radboudumc 6] ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Item does not contain fulltext Ataxia-telangiectasia (AT) is an autosomal recessive neurodegenerative disorder with immunodeficiency and an increased risk of developing cancer, caused by mutations in the ataxia-telangiectasia mutated (ATM) gene. Logically, blood relatives may also carry a pathogenic ATM mutation. Female carriers of such a mutation have an increased risk of breast cancer. Other health risks for carriers are suspected but have never been studied systematically. Consequently, evidence-based guidelines for carriers are not available yet. We systematically analyzed all literature and found that ATM mutation carriers have a reduced life expectancy because of mortality from cancer and ischemic heart diseases (RR 1.7, 95% CI 1.2-2.4) and an increased risk of developing cancer (RR 1.5, 95% CI 0.9-2.4), in particular breast cancer (RRwomen 3.0, 95% CI 2.1-4.5), and cancers of the digestive tract. Associations between ATM heterozygosity and other health risks have been suggested, but clear evidence is lacking. Based on these results, we propose that all female carriers of 40-50 years of age and female ATM c.7271T>G mutation carriers from 25 years of age onwards be offered intensified surveillance programs for breast cancer. Furthermore, all carriers should be made aware of lifestyle factors that contribute to the development of cardiovascular diseases and diabetes.
- Published
- 2016
37. Long-term outcome in pyridoxine-dependent epilepsy
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Bok, L.A., Halbertsma, F.J., Houterman, S., Wevers, R.A., Vreeswijk, C.M.J.M., Jakobs, C., Struys, E., van der Hoeven, J.H., Sival, D.A., Willemsen, M.A., Clinical chemistry, NCA - Childhood White Matter Diseases, and Developmental Psychology
- Subjects
Genomic disorders and inherited multi-system disorders [IGMD 3] ,DCN MP - Plasticity and memory ,Glycostation disorders [IGMD 4] ,Glycostation disorders [DCN PAC - Perception action and control IGMD 4] ,DCN NN - Brain networks and neuronal communication - Abstract
Item does not contain fulltext Aim The long-term outcome of the Dutch pyridoxine-dependent epilepsy cohort and correlations between patient characteristics and follow-up data were retrospectively studied. Method Fourteen patients recruited from a national reference laboratory were included (four males, 10 females, from 11 families; median age at assessment 6y; range 2y 6mo-16y). The following data were retrieved: sex; age at seizure onset; age at the start of pyridoxine therapy; level of urinary alpha-aminoadipic semialdehyde; antiquitin mutations; developmental milestones; evaluation of neurocognitive functioning and school career; magnetic resonance imaging (MRI) and electroencephalography (EEG) assessments. Results Pyridoxine was started antenatally in two children, in the first week of life in five, in the first month of life in three, or after the first month of life (range 2.5-8mo) in four. No child was physically disabled; however, only five walked at 2 years of age. Mental development was delayed in most: median IQ or developmental index was 72 (SD 19). Pyridoxine monotherapy controlled seizures in 10 of 14 children, whereas four needed additional antiepileptic drugs. Seizure persistence, antiepileptic drugs (other than pyridoxine), EEG background, and epileptiform activity were not associated with outcome. On neonatal MRI, structural and white matter abnormalities occurred in five of eight children; on follow-up, the number of abnormal MRIs was increased. Delayed initiation of pyridoxine medication and corpus callosum abnormalities were significantly associated with unfavourable neurodevelopmental outcome, but normal follow-up imaging did not predict a good outcome. Interpretation Outcome of patients with pyridoxine-dependent epilepsy remains poor. Individual outcome cannot be predicted by the evaluated characteristics. We suggest that collaborated research in structured settings could help to improve treatment strategies and outcome for pyridoxine-dependent epilepsy. 01 september 2012
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- 2012
38. Understanding the Psychosocial Effects of WES Test Results on Parents of Children with Rare Diseases
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Krabbenborg, L., Vissers, L.E.L.M., Schieving, J.H., Kleefstra, T., Kamsteeg, E.J., Veltman, J.A., Willemsen, M.A., Burg, S. van der, Krabbenborg, L., Vissers, L.E.L.M., Schieving, J.H., Kleefstra, T., Kamsteeg, E.J., Veltman, J.A., Willemsen, M.A., and Burg, S. van der
- Abstract
Contains fulltext : 161440.pdf (publisher's version ) (Open Access)
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- 2016
39. Evaluating a counselling strategy for diagnostic WES in paediatric neurology: an exploration of parents' information and communication needs
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Krabbenborg, L., Schieving, J.H., Kleefstra, T., Vissers, L.E., Willemsen, M.A., Veltman, J.A., Burg, S. van der, Krabbenborg, L., Schieving, J.H., Kleefstra, T., Vissers, L.E., Willemsen, M.A., Veltman, J.A., and Burg, S. van der
- Abstract
Item does not contain fulltext, As whole exome sequencing (WES) is just starting to be used as a diagnostic tool in paediatric neurology for children with a neurological disorder, and patient experiences and preferences with regard to counselling are relatively underexplored. This article explores experiences and preferences of parents with pre-test and post-test counselling in a trial that uses WES for diagnostics. Second, it maps information and communication needs which exceed the counselling protocol, in order to acquire insight into how it can be improved. Data were gathered through in-depth interviews with parents of 15 children who were included in the trial. Information and communication needs of parents differed from the protocol with respect to (i) the type and amount of information provided about WES research, (ii) incidental findings, (iii) communication about progress of the study, and (iv) the communication of the results. Furthermore, parents preferred to have more of a communicative exchange with health care providers about their daily struggles and concerns related to their life with a diseased child and wanted to know how a diagnosis could offer help. There are different ways to meet parental needs, but we suggest that assigning a case manager might be a helpful option that deserves further exploration.
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- 2016
40. Lactate and its many faces
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Taher, M., Leen, W.G., Wevers, R.A., Willemsen, M.A., Taher, M., Leen, W.G., Wevers, R.A., and Willemsen, M.A.
- Abstract
Item does not contain fulltext
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- 2016
41. A novel SLC2A1 mutation linking hemiplegic migraine with alternating hemiplegia of childhood
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Weller, C.M., Leen, W.G., Neville, B.G., Duncan, J.S., Vries, B. de, Geilenkirchen, M.A., Haan, J., Kamsteeg, E.J., Ferrari, M.D., Maagdenberg, A.M. van den, Willemsen, M.A., Scheffer, H., Terwindt, G.M., Weller, C.M., Leen, W.G., Neville, B.G., Duncan, J.S., Vries, B. de, Geilenkirchen, M.A., Haan, J., Kamsteeg, E.J., Ferrari, M.D., Maagdenberg, A.M. van den, Willemsen, M.A., Scheffer, H., and Terwindt, G.M.
- Abstract
Item does not contain fulltext, BACKGROUND: Hemiplegic migraine (HM) and alternating hemiplegia of childhood (AHC) are rare episodic neurological brain disorders with partial clinical and genetic overlap. Recently, ATP1A3 mutations were shown to account for the majority of AHC patients. In addition, a mutation in the SLC2A1 gene was reported in a patient with atypical AHC. We therefore investigated whether mutations in these genes may also be involved in HM. Furthermore, we studied the role of SLC2A1 mutations in a small set of AHC patients without ATP1A3 mutations. METHODS: We screened 42 HM patients (21 familial and 21 sporadic patients) for ATP1A3 and SLC2A1 mutations. In addition, four typical AHC patients and one atypical patient with overlapping symptoms of both disorders were screened for SLC2A1 mutations. RESULTS: A pathogenic de novo SLC2A1 mutation (p.Gly18Arg) was found in the atypical patient with overlapping symptoms of AHC and hemiplegic migraine. No mutations were found in the HM and the other AHC patients. CONCLUSION: Screening for a mutation in the SLC2A1 gene should be considered in patients with a complex phenotype with overlapping symptoms of hemiplegic migraine and AHC.
- Published
- 2015
42. Eyes on MEGDEL: Distinctive Basal Ganglia Involvement in Dystonia Deafness Syndrome
- Author
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Wortmann, S.B., Hasselt, P.M. van, Baric, I., Burlina, A., Darin, N., Horster, F., Coker, M., Ucar, S. Kalkan, Krumina, Z., Naess, K., Ngu, L.H., Pronicka, E., Riordan, G., Santer, R., Wassmer, E., Zschocke, J., Schiff, M., Meirleir, L. de, Alowain, M.A., Smeitink, J.A.M., Morava, E., Kozicz, L.T., Wevers, R.A., Wolf, N.I., Willemsen, M.A., Wortmann, S.B., Hasselt, P.M. van, Baric, I., Burlina, A., Darin, N., Horster, F., Coker, M., Ucar, S. Kalkan, Krumina, Z., Naess, K., Ngu, L.H., Pronicka, E., Riordan, G., Santer, R., Wassmer, E., Zschocke, J., Schiff, M., Meirleir, L. de, Alowain, M.A., Smeitink, J.A.M., Morava, E., Kozicz, L.T., Wevers, R.A., Wolf, N.I., and Willemsen, M.A.
- Abstract
Contains fulltext : 155252.pdf (publisher's version ) (Closed access), Pediatric movement disorders are still a diagnostic challenge, as many patients remain without a (genetic) diagnosis. Magnetic resonance imaging (MRI) pattern recognition can lead to the diagnosis. MEGDEL syndrome (3-MethylGlutaconic aciduria, Deafness, Encephalopathy, Leigh-like syndrome MIM #614739) is a clinically and biochemically highly distinctive dystonia deafness syndrome accompanied by 3-methylglutaconic aciduria, severe developmental delay, and progressive spasticity. Mutations are found in SERAC1, encoding a phosphatidylglycerol remodeling enzyme essential for both mitochondrial function and intracellular cholesterol trafficking. Based on the homogenous phenotype, we hypothesized an accordingly characteristic MRI pattern. A total of 43 complete MRI studies of 30 patients were systematically reevaluated. All patients presented a distinctive brain MRI pattern with five characteristic disease stages affecting the basal ganglia, especially the putamen. In stage 1, T2 signal changes of the pallidum are present. In stage 2, swelling of the putamen and caudate nucleus is seen. The dorsal putamen contains an "eye" that shows no signal alteration and (thus) seems to be spared during this stage of the disease. It later increases, reflecting progressive putaminal involvement. This "eye" was found in all patients with MEGDEL syndrome during a specific age range, and has not been reported in other disorders, making it pathognomonic for MEDGEL and allowing diagnosis based on MRI findings.
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- 2015
43. Cerebral lipid accumulation in Chanarin-Dorfman Syndrome
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Huigen, C.D.G., Graaf, M. van der, Morava, E., Dassel, A.C., Steensel, M.A.M. van, Seyger, M.M.B., Wevers, R.A., Willemsen, M.A., Huigen, C.D.G., Graaf, M. van der, Morava, E., Dassel, A.C., Steensel, M.A.M. van, Seyger, M.M.B., Wevers, R.A., and Willemsen, M.A.
- Abstract
Contains fulltext : 154736.pdf (publisher's version ) (Closed access), Chanarin-Dorfman Syndrome (CDS) is caused by a defect in the CGI-58/ABHD5 gene resulting in a deficiency of CGI-58 and in intracellular accumulation of triacylglycerol in skin and liver. Patients are mainly characterized by congenital ichthyosis, but the clinical phenotype is very heterogeneous. Distinct brain involvement has never been described. We present a clinical description of two patients with congenital ichthyosis. On suspicion of Sjogren-Larsson syndrome (SLS) single-voxel 1H-MR spectroscopy of the brain was performed and biochemical testing of fatty aldehyde dehydrogenase (FALDH) to establish this diagnosis gave normal results. Vacuolisation in a peripheral blood smear has led to the CDS suspicion. In both patients the diagnosis CDS was confirmed by ABHD5 mutation analysis. Interestingly, a clear lipid accumulation in the cerebral white matter, cortex and basal ganglia was demonstrated in both CDS-patients. These results demonstrate, for the first time, cerebral involvement in CDS and give new insights in the complex phenotype. Since the clinical implications of this abnormal cerebral lipid accumulation are still unknown, further studies are warranted.
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- 2015
44. De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy
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Lee, J.R., Srour, M., Kim, D., Hamdan, F.F., Lim, S.H., Brunel-Guitton, C., Decarie, J.C., Rossignol, E., Mitchell, G.A., Schreiber, A., Moran, R., Haren, K. van, Richardson, R., Nicolai, J., Oberndorff, K.M., Wagner, J.D., Boycott, K.M., Rahikkala, E., Junna, N., Tyynismaa, H., Cuppen, I., Verbeek, N.E., Stumpel, C.T., Willemsen, M.A., Munnik, S.A. de, Rouleau, G.A., Kim, E., Kamsteeg, E.J., Kleefstra, T., Michaud, J.L., Lee, J.R., Srour, M., Kim, D., Hamdan, F.F., Lim, S.H., Brunel-Guitton, C., Decarie, J.C., Rossignol, E., Mitchell, G.A., Schreiber, A., Moran, R., Haren, K. van, Richardson, R., Nicolai, J., Oberndorff, K.M., Wagner, J.D., Boycott, K.M., Rahikkala, E., Junna, N., Tyynismaa, H., Cuppen, I., Verbeek, N.E., Stumpel, C.T., Willemsen, M.A., Munnik, S.A. de, Rouleau, G.A., Kim, E., Kamsteeg, E.J., Kleefstra, T., and Michaud, J.L.
- Abstract
Item does not contain fulltext, KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
- Published
- 2015
45. Evaluating a counselling strategy for diagnostic WES in paediatric neurology: an exploration of parents' information and communication needs
- Author
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Krabbenborg, L., primary, Schieving, J., additional, Kleefstra, T., additional, Vissers, L.E.L.M., additional, Willemsen, M.A., additional, Veltman, J.A., additional, and van der Burg, S., additional
- Published
- 2015
- Full Text
- View/download PDF
46. Low vision due to cerebral visual impairment: differentiating between acquired and genetic causes
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Bosch, D.G.M., Boonstra, F.N., Willemsen, M.A., Cremers, F.P.M., Vries, L.B.A. de, Bosch, D.G.M., Boonstra, F.N., Willemsen, M.A., Cremers, F.P.M., and Vries, L.B.A. de
- Abstract
Contains fulltext : 135955.pdf (publisher's version ) (Open Access), BACKGROUND: To gain more insight into genetic causes of cerebral visual impairment (CVI) in children and to compare ophthalmological findings between genetic and acquired forms of CVI. METHODS: The clinical data of 309 individuals (mainly children) with CVI, and a visual acuity =0.3 were analyzed for etiology and ocular variables. A differentiation was made between acquired and genetic causes. However, in persons with West syndrome or hydrocephalus, it might be impossible to unravel whether CVI is caused by the seizure disorder or increased intracranial pressure or by the underlying disorder (that in itself can be acquired or genetic). In two subgroups, individuals with 'purely' acquired CVI and with 'purely' genetic CVI, the ocular variables (such as strabismus, pale optic disc and visual field defects) were compared. RESULTS: It was possible to identify a putative cause for CVI in 60% (184/309) of the cohort. In the remaining 40% the etiology could not be determined. A 'purely' acquired cause was identified in 80 of the patients (26%). West syndrome and/or hydrocephalus was identified in 21 patients (7%), and in 17 patients (6%) both an acquired cause and West and/or hydrocephalus was present. In 66 patients (21%) a genetic diagnosis was obtained, of which 38 (12%) had other possible risk factor (acquired, preterm birth, West syndrome or hydrocephalus), making differentiation between acquired and genetic not possible. In the remaining 28 patients (9%) a 'purely' genetic cause was identified.CVI was identified for the first time in several genetic syndromes, such as ATR-X, Mowat-Wilson, and Pitt Hopkins syndrome. In the subgroup with 'purely' acquired causes (N = 80) strabismus (88% versus 64%), pale optic discs (65% versus 27%) and visual field defects (72% versus 30%) could be observed more frequent than in the subgroup with 'purely' genetic disorders (N = 28). CONCLUSIONS: We conclude that CVI can be part of a genetic syndrome and that abnormal ocular findings
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- 2014
47. Multimodal imaging of the macula in hereditary and acquired lack of macular pigment
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Theelen, T., Berendschot, T.T., Klevering, B.J., Fuijkschot, J., Hoyng, C.B., Willemsen, M.A., Theelen, T., Berendschot, T.T., Klevering, B.J., Fuijkschot, J., Hoyng, C.B., and Willemsen, M.A.
- Abstract
Item does not contain fulltext, Purpose: Macular pigment (MP) deficit has been described in macular teleangiectasia type 2 (MTA; acquired MP loss) and in Sjogren-Larsson syndrome (SLS; hereditary MP deficiency). Central blue light-induced fundus autofluorescence (FAF) and blue light fundus reflectance (BLR) are thought to reflect MP distribution. This study was performed to describe the macular morphology in SLS and MTA by multimodal imaging to further investigate the causes of FAF and BLR changes in these disorders. Methods: This was a single-centre, cross-sectional, retrospective, observational study on SLS and MTA patients treated at our institution. In a multimodal retinal imaging dataset, patterns of BLR and FAF changes were compared with the optical coherence tomography (OCT) and clinical appearance of the patients' retinas. Results: Multimodal image sets of seven eyes of four patients with SLS and of 25 eyes of 15 patients with MTA were included in this study. In MTA, areas of focal FAF increase were mainly associated with retinal pseudocysts and photoreceptor loss and were co-located with regions of increased BLR. In SLS, areas of focally decreased FAF correlated with the typical intraretinal glistening dots. Frequently, a spot of focally increased FAF was visible at the fovea of SLS patients, often independent of the presence of pseudocysts or photoreceptor loss on OCT. Conclusion: In MTA and SLS different patterns of FAF alterations could be observed. The areas of increased BLR, which are thought to correlate with MP loss, appeared to have only restricted correlation with FAF appearance.
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- 2014
48. Experimental treatment of NRAS-mutated neurocutaneous melanocytosis with MEK162, a MEK-inhibitor
- Author
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Kusters-vandevelde, H.V., Willemsen, A.E.C.A.B., Groenen, P.J.T.A., Kusters, B., Lammens, M.M., Wesseling, P., Djafarihamedani, M., Rijntjes, J., Delye, H.H., Willemsen, M.A., Herpen, C.M.L. van, Blokx, W.A.M., Kusters-vandevelde, H.V., Willemsen, A.E.C.A.B., Groenen, P.J.T.A., Kusters, B., Lammens, M.M., Wesseling, P., Djafarihamedani, M., Rijntjes, J., Delye, H.H., Willemsen, M.A., Herpen, C.M.L. van, and Blokx, W.A.M.
- Abstract
Contains fulltext : 137997.pdf (publisher's version ) (Open Access), Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by the association of large and/or multiple congenital melanocytic nevi (CMN) of the skin with melanocytic lesions of the leptomeninges, including melanocytosis. Leptomeningeal melanocytosis carries a poor prognosis once neurological symptoms develop. Despite surgery, which is often not radical, few other treatment options exist. Recently, it was demonstrated that early embryonic, post-zygotic somatic mutations in the NRAS gene are implicated in the pathogenesis of NCM.In this report, we present a 13-year-old boy with NCM and progressive symptomatic leptomeningeal melanocytosis. A somatic NRASQ61K mutation was present in both CMN as well as the melanocytosis. Despite repeated surgery, the patient showed clinical progression. Therefore, treatment with MEK162, a MEK inhibitor, was started on compassionate use base. The patient died only five days later, i.e. too early to expect a clinical effect of MEK162 therapy. We therefore studied the effect of MEK162 at the protein level in the leptomeningeal tumor by immunohistochemical and Western Blot analyses using Ki67 and pERK antibodies. We observed lower MIB-1 expression and lower pERK expression in the post-treatment samples compared to pre-treatment, suggesting a potential effect of MEK inhibiting therapy. Further studies are needed to determine whether MEK inhibitors can effectively target NRAS-mutated symptomatic NCM, a rare but potentially fatal disease.
- Published
- 2014
49. GLUT1 deficiency syndrome into adulthood: a follow-up study
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Leen, W.G., Taher, M., Verbeek, M.M., Kamsteeg, E.J., Warrenburg, B.P.C. van de, Willemsen, M.A., Leen, W.G., Taher, M., Verbeek, M.M., Kamsteeg, E.J., Warrenburg, B.P.C. van de, and Willemsen, M.A.
- Abstract
Item does not contain fulltext, GLUT1 deficiency syndrome (GLUT1DS) is a treatable neurometabolic disorder in which glucose transport into the brain is disturbed. Besides the classic phenotype of intellectual disability, epilepsy, and movement disorders, other phenotypes are increasingly recognized. These include, for example, idiopathic generalized epilepsy and paroxysmal exercise-induced dyskinesia. Since the disorder has only been recognized for two decades and is mostly diagnosed in children, little is known about the disease course. Our purpose was to investigate the disease course of GLUT1DS patients with the classic, complex phenotype from infancy into adulthood. We performed a systematic literature review as well as a cohort study, including GLUT1DS patients aged 18 years and older. The literature search yielded a total of 91 adult GLUT1DS patients, of which 33 patients (one-third) had a complex phenotype. The cohort study included seven GLUT1DS patients with a complex phenotype who were prospectively followed up in our clinic from childhood into adulthood. Our results show that epilepsy is a prominent feature during childhood in classic GLUT1DS patients. During adolescence, however, epilepsy diminishes or even disappears, but new paroxysmal movement disorders, especially paroxysmal exercise-induced dyskinesia, either appear or worsen if already present in childhood. Intellectual disability was not systematically assessed, but cognitive functions appeared to be stabile throughout life. Like children, adolescents may benefit from a ketogenic diet or variants thereof.
- Published
- 2014
50. Alpha-fetoprotein, a fascinating protein and biomarker in neurology
- Author
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Schieving, J.H., Vries, M. de, Vugt, J.M.G. van, Weemaes, C.M.R., Deuren, M. van, Nicolai, J., Wevers, R.A., Willemsen, M.A., Schieving, J.H., Vries, M. de, Vugt, J.M.G. van, Weemaes, C.M.R., Deuren, M. van, Nicolai, J., Wevers, R.A., and Willemsen, M.A.
- Abstract
Contains fulltext : 137474.pdf (publisher's version ) (Closed access), Alpha-fetoprotein (AFP) is present in fetal serum in concentrations up to 5,000,000 mug/l. After birth, AFP gene expression is turned down with a subsequent fall of the serum concentrations of this albumin-like protein to 'adult values' of circa 0.5-15 mug/l from the age of 2 years onwards. Irrespective of its assumed important functions, individuals with AFP deficiency appear fully healthy. The other way around, the presence of AFP in the circulation after the first years of life doesn't seem to harm, since individuals with 'hereditary persistence of AFP' are also without clinical abnormalities. During pregnancy, AFP (in maternal serum) has long been recognized as a marker for congenital anomalies of the fetus. Equally well known is AFP as biomarker for hepatocellular carcinoma and some other malignancies. There are at least four neurodegenerative disorders, all inherited as autosomal recessive traits and characterized by the presence of cerebellar ataxia, abnormal ocular movements, and neuropathy, for which an elevated concentration of serum AFP is an important diagnostic biomarker. The availability of a reliable biomarker is not only important during screening or diagnostic processes, but is also relevant for objective follow-up during (future) therapeutic interventions.
- Published
- 2014
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