1. |
- Timmers, Elze R, et al.
(author)
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Gut Microbiome Composition in Dystonia Patients
- 2023
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 24:3, s. 1-15
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Journal article (peer-reviewed)abstract
- Dystonia is a movement disorder in which patients have involuntary abnormal movements or postures. Non-motor symptoms, such as psychiatric symptoms, sleep problems and fatigue, are common. We hypothesise that the gut microbiome might play a role in the pathophysiology of the (non-)motor symptoms in dystonia via the gut-brain axis. This exploratory study investigates the composition of the gut microbiome in dystonia patients compared to healthy controls. Furthermore, the abundance of neuro-active metabolic pathways, which might be implicated in the (non-)motor symptoms, was investigated. We performed both metagenomic and 16S rRNA sequencing on the stool samples of three subtypes of dystonia (27 cervical dystonia, 20 dopa-responsive dystonia and 24 myoclonus-dystonia patients) and 25 controls. While microbiome alpha and beta diversity was not different between dystonia patients and controls, dystonia patients had higher abundances of Ruminococcus torques and Dorea formicigenerans, and a lower abundance of Butyrivibrio crossotus compared to controls. For those with dystonia, non-motor symptoms and the levels of neurotransmitters in plasma explained the variance in the gut microbiome composition. Several neuro-active metabolic pathways, especially tryptophan degradation, were less abundant in the dystonia patients compared to controls. This suggest that the gut-brain axis might be involved in the pathophysiology of dystonia. Further studies are necessary to confirm our preliminary findings.
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2. |
- Koens, Lisette H, et al.
(author)
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How to detect late-onset inborn errors of metabolism in patients with movement disorders - A modern diagnostic approach
- 2021
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In: Parkinsonism & Related Disorders. - : Elsevier BV. - 1873-5126 .- 1353-8020. ; 85, s. 124-132
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Research review (peer-reviewed)abstract
- We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists. Adult-onset presentations of IEMs differ from childhood-onset phenotypes, which may lead to considerable diagnostic delay. The identification of adult-onset phenotypes at the earliest stage of the disease is important, since early treatment may prevent or lessen further brain damage. Our approach is based on a systematic review of all papers that concerned movement disorders due to an IEM in patients of 16 years or older. Detailed clinical phenotyping is the diagnostic cornerstone of the approach. An underlying IEM should be suspected in particular in patients with more than one movement disorder, or in patients with additional neurological, psychiatric, or systemic manifestations. As IEMs are all genetic disorders, we recommend next-generation sequencing (NGS) as the first diagnostic approach to confirm an IEM. Biochemical tests remain the first choice in acute-onset or treatable IEMs that require rapid diagnosis, or to confirm the metabolic diagnosis after NGS results. With the use of careful and systematic clinical phenotyping combined with novel diagnostic approaches such as NGS, the diagnostic yield of late-onset IEMs will increase, in particular in patients with mild or unusual phenotypes.
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3. |
- Timmers, Elze R., et al.
(author)
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Serotonergic system in vivo with [11C]DASB PET scans in GTP-cyclohydrolase deficient dopa-responsive dystonia patients
- 2022
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In: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Journal article (peer-reviewed)abstract
- GTP-cyclohydrolase deficiency in dopa-responsive dystonia (DRD) patients impairs the biosynthesis of dopamine, but also of serotonin. The high prevalence of non-motor symptoms suggests involvement of the serotonergic pathway. Our study aimed to investigate the serotonergic system in vivo in the brain of`DRD patients and correlate this to (non-)motor symptoms. Dynamic [11C]DASB PET scans, a marker of serotonin transporter availability, were performed. Ten DRD, 14 cervical dystonia patients and 12 controls were included. Univariate- and network-analysis did not show differences in binding between DRD patients compared to controls. Sleep disturbances were correlated with binding in the dorsal raphe nucleus (all participants: rs = 0.45, p = 0.04; patients: rs = 0.64, p = 0.05) and participants with a psychiatric disorder had a lower binding in the hippocampus (all participants: p = 0.00; patients: p = 0.06). Post-hoc analysis with correction for psychiatric co-morbidity showed a significant difference in binding in the hippocampus between DRD patients and controls (p = 0.00). This suggests that psychiatric symptoms might mask the altered serotonergic metabolism in DRD patients, but definite conclusions are difficult as psychiatry is considered part of the phenotype. We hypothesize that an imbalance between different neurotransmitter systems is responsible for the non-motor symptoms, and further research investigating multiple neurotransmitters and psychiatry in DRD is necessary.
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4. |
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5. |
- van Noort, Suus A M, et al.
(author)
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Early onset ataxia with comorbid myoclonus and epilepsy : A disease spectrum with shared molecular pathways and cortico-thalamo-cerebellar network involvement
- 2023
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In: European Journal of Paediatric Neurology. - 1090-3798. ; 45, s. 47-54
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Journal article (peer-reviewed)abstract
- OBJECTIVES: Early onset ataxia (EOA) concerns a heterogeneous disease group, often presenting with other comorbid phenotypes such as myoclonus and epilepsy. Due to genetic and phenotypic heterogeneity, it can be difficult to identify the underlying gene defect from the clinical symptoms. The pathological mechanisms underlying comorbid EOA phenotypes remain largely unknown. The aim of this study is to investigate the key pathological mechanisms in EOA with myoclonus and/or epilepsy.METHODS: For 154 EOA-genes we investigated (1) the associated phenotype (2) reported anatomical neuroimaging abnormalities, and (3) functionally enriched biological pathways through in silico analysis. We assessed the validity of our in silico results by outcome comparison to a clinical EOA-cohort (80 patients, 31 genes).RESULTS: EOA associated gene mutations cause a spectrum of disorders, including myoclonic and epileptic phenotypes. Cerebellar imaging abnormalities were observed in 73-86% (cohort and in silico respectively) of EOA-genes independently of phenotypic comorbidity. EOA phenotypes with comorbid myoclonus and myoclonus/epilepsy were specifically associated with abnormalities in the cerebello-thalamo-cortical network. EOA, myoclonus and epilepsy genes shared enriched pathways involved in neurotransmission and neurodevelopment both in the in silico and clinical genes. EOA gene subgroups with myoclonus and epilepsy showed specific enrichment for lysosomal and lipid processes.CONCLUSIONS: The investigated EOA phenotypes revealed predominantly cerebellar abnormalities, with thalamo-cortical abnormalities in the mixed phenotypes, suggesting anatomical network involvement in EOA pathogenesis. The studied phenotypes exhibit a shared biomolecular pathogenesis, with some specific phenotype-dependent pathways. Mutations in EOA, epilepsy and myoclonus associated genes can all cause heterogeneous ataxia phenotypes, which supports exome sequencing with a movement disorder panel over conventional single gene panel testing in the clinical setting.
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6. |
- Koens, Lisette H, et al.
(author)
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Eye movement disorders in inborn errors of metabolism : A quantitative analysis of 37 patients
- 2022
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In: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 45:5, s. 981-995
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Journal article (peer-reviewed)abstract
- Inborn errors of metabolism are genetic disorders that need to be recognized as early as possible because treatment may be available. In late-onset forms, core symptoms are movement disorders, psychiatric symptoms, and cognitive impairment. Eye movement disorders are considered to be frequent too, although specific knowledge is lacking. We describe and analyze eye movements in patients with an inborn error of metabolism, and see whether they can serve as an additional clue in the diagnosis of particularly late-onset inborn errors of metabolism. Demographics, disease characteristics, and treatment data were collected. All patients underwent a standardized videotaped neurological examination and a video-oculography. Videos are included. We included 37 patients with 15 different inborn errors of metabolism, including 18 patients with a late-onset form. With the exception of vertical supranuclear gaze palsy in Niemann-Pick type C and external ophthalmolplegia in Kearns-Sayre syndrome, no relation was found between the type of eye movement disorder and the underlying metabolic disorder. Movement disorders were present in 29 patients (78%), psychiatric symptoms in 14 (38%), and cognitive deficits in 26 patients (70%). In 87% of the patients with late-onset disease, eye movement disorders were combined with one or more of these core symptoms. To conclude, eye movement disorders are present in different types of inborn errors of metabolism, but are often not specific to the underlying disorder. However, the combination of eye movement disorders with movement disorders, psychiatric symptoms, or cognitive deficits can serve as a diagnostic clue for an underlying late-onset inborn error of metabolism.
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7. |
- Mposhi, Archibold, et al.
(author)
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The Mitochondrial Epigenome : An Unexplored Avenue to Explain Unexplained Myopathies?
- 2022
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:4
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Journal article (peer-reviewed)abstract
- Mutations in either mitochondrial DNA (mtDNA) or nuclear genes that encode mitochondrial proteins may lead to dysfunctional mitochondria, giving rise to mitochondrial diseases. Some mitochondrial myopathies, however, present without a known underlying cause. Interestingly, methylation of mtDNA has been associated with various clinical pathologies. The present study set out to assess whether mtDNA methylation could explain impaired mitochondrial function in patients diagnosed with myopathy without known underlying genetic mutations. Enhanced mtDNA methylation was indicated by pyrosequencing for muscle biopsies of 14 myopathy patients compared to four healthy controls, at selected cytosines in the Cytochrome B (CYTB) gene, but not within the displacement loop (D-loop) region. The mtDNA methylation patterns of the four healthy muscle biopsies were highly consistent and showed intriguing tissue-specific differences at particular cytosines with control skin fibroblasts cultured in vitro. Within individual myopathy patients, the overall mtDNA methylation pattern correlated well between muscle and skin fibroblasts. Despite this correlation, a pilot analysis of four myopathy and five healthy fibroblast samples did not reveal a disease-associated difference in mtDNA methylation. We did, however, detect increased expression of solute carrier family 25A26 (SLC25A26), encoding the importer of S-adenosylmethionine, together with enhanced mtDNA copy numbers in myopathy fibroblasts compared to healthy controls. To confirm that pyrosequencing indeed reflected DNA methylation and not bisulfite accessibility, mass spectrometry was employed. Although no myopathy-related differences in total amount of methylated cytosines were detected at this stage, a significant contribution of contaminating nuclear DNA (nDNA) was revealed, and steps to improve enrichment for mtDNA are reported. In conclusion, in this explorative study we show that analyzing the mitochondrial genome beyond its sequence opens novel avenues to identify potential molecular biomarkers assisting in the diagnosis of unexplained myopathies.
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8. |
- Polet, Sjoukje S., et al.
(author)
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A detailed description of the phenotypic spectrum of North Sea Progressive Myoclonus Epilepsy in a large cohort of seventeen patients
- 2020
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In: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 72, s. 44-48
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Journal article (peer-reviewed)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 to be further elucidated.
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9. |
- Timmers, Elze R., et al.
(author)
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Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients
- 2021
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In: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 91, s. 48-54
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Journal article (peer-reviewed)abstract
- Introduction: In dystonia, dopaminergic alterations are considered to be responsible for the motor symptoms. Recent attention for the highly prevalent non-motor symptoms suggest also a role for serotonin in the pathophysiology. In this study we investigated the dopaminergic, serotonergic and noradrenergic metabolism in blood samples of dystonia patients and its relation with (non-)motor manifestations. Methods: Concentrations of metabolites of dopaminergic, serotonergic and noradrenergic pathways were measured in platelet-rich plasma in 41 myoclonus-dystonia (M-D), 25 dopa-responsive dystonia (DRD), 50 cervical dystonia (CD) patients and 55 healthy individuals. (Non-)motor symptoms were assessed using validated instruments, and correlated with concentrations of metabolites. Results: A significantly higher concentration of 3-methoxytyramine (0.03 vs. 0.02 nmol/L, p < 0.01), a metabolite of dopamine, and a reduced concentration of tryptophan (50 vs. 53 μmol/L, p = 0.03), the precursor of serotonin was found in dystonia patients compared to controls. The dopamine/levodopa ratio was higher in CD patients compared to other dystonia groups (p < 0.01). Surprisingly, relatively high concentrations of levodopa were found in the untreated DRD patients. Low concentrations of levodopa were associated with severity of dystonia (rs = −0.3, p < 0.01), depression (rs = −0.3, p < 0.01) and fatigue (rs = −0.2, p = 0.04). Conclusion: This study shows alterations in the dopaminergic and serotonergic metabolism of patients with dystonia, with dystonia subtype specific changes. Low concentrations of levodopa, but not of serotonergic metabolites, were associated with both motor and non-motor symptoms. Further insight into the dopaminergic and serotonergic systems in dystonia with a special attention to the kinetics of enzymes involved in these pathways, might lead to better treatment options.
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10. |
- Timmers, Elze R, et al.
(author)
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Methylation of the serotonin reuptake transporter gene and non-motor symptoms in dystonia patients
- 2022
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In: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 14, s. 1-10
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Journal article (peer-reviewed)abstract
- BACKGROUND: Dystonia is a rare movement disorder, in which patients suffer from involuntary twisting movements or abnormal posturing. Next to these motor symptoms, patients have a high prevalence of psychiatric comorbidity, suggesting a role for serotonin in its pathophysiology. This study investigates the percentage of DNA methylation of the gene encoding for the serotonin reuptake transporter (SLC6A4) in dystonia patients and the associations between methylation levels and presence and severity of psychiatric symptoms.METHODS: Patients with cervical dystonia (n = 49), myoclonus dystonia (n = 41) and dopa-responsive dystonia (DRD) (n = 27) and a group of healthy controls (n = 56) were included. Psychiatric comorbidity was evaluated with validated questionnaires. Methylation levels of 20 CpG sites situated 69 to 213 base pairs upstream of the start codon of SLC6A4 were investigated. Methylation in dystonia patients was compared to healthy controls, correcting for age, and correlated with psychiatric comorbidity.RESULTS: Bootstrapped quantile regression analysis showed that being a dystonia patient compared to a healthy control significantly explains the methylation level at two CpG sites (CpG 24: pseudo-R 2 = 0.05, p = 0.04, CpG 32: pseudo-R 2 = 0.14, p = 0.03). Subgroup analysis revealed that being a DRD patient significantly explained a part of the variance of methylation levels at two CpG sites (CpG 21: pseudo-R 2 = 0.03, p = 0.00, CpG 24: pseudo-R 2 = 0.06, p = 0.03). Regression analysis showed that methylation level at CpG 38 significantly explained a small proportion of the variance of severity score for anxiety (R 2 = 0.07, p = 0.04) and having a diagnosis of depression (Nagelkerke R 2: 0.11, p = 0.00). Genotype of the 5-HTTLPR polymorphism had no additional effect on these associations. CONCLUSIONS: This study showed an association between percentage of methylation at several specific sites of the promoter region of SLCA64 and (dopa-responsive) dystonia patients compared to healthy controls. Furthermore, methylation levels were associated with severity of anxiety and presence of a depressive disorder in the dystonia group. This study suggests alterations in the serotonergic metabolism in dystonia patients, and its relation with the non-motor symptoms.
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11. |
- van der Veen, Sterre, et al.
(author)
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The natural history of progressive myoclonus Ataxia
- 2024
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In: Neurobiology of Disease. - 0969-9961. ; 199
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Journal article (peer-reviewed)abstract
- Progressive myoclonus ataxia (PMA) is a rare clinical syndrome characterized by the presence of progressive myoclonus and ataxia, and can be accompanied by mild cognitive impairment and infrequent epileptic seizures. This is the first study to describe the natural history of PMA and identify clinical, electrophysiological, and genetic features explaining the variability in disease progression. A Dutch cohort of consecutive patients meeting the criteria of the refined definition of PMA was included. The current phenotype was assessed during in-person consultation by movement disorders experts, and retrospective data was collected to describe disease presentation and progression, including brain imaging and therapy efficacy. Extensive genetic and electrophysiological tests were performed. The presence of cortical hyperexcitability was determined, by either the identification of a cortical correlate of myoclonic jerks with simultaneous electromyography-electroencephalography or a giant somatosensory evoked potential. We included 34 patients with PMA with a median disease duration of 15 years and a clear progressive course in most patients (76%). A molecular etiology was identified in 82% patients: ATM, CAMTA1, DHDDS, EBF3, GOSR2, ITPR1, KCNC3, NUS1, POLR1A, PRKCG, SEMA6B, SPTBN2, TPP1, ZMYND11, and a 12p13.32 deletion. The natural history is a rather homogenous onset of ataxia in the first two years of life followed by myoclonus in the first 5 years of life. Main accompanying neurological dysfunctions included cognitive impairment (62%), epilepsy (38%), autism spectrum disorder (27%), and behavioral problems (18%). Disease progression showed large variability ranging from an epilepsy free PMA phenotype (62%) to evolution towards a progressive myoclonus epilepsy (PME) phenotype (18%): the existence of a PMA-PME spectrum. Cortical hyperexcitability could be tested in 17 patients, and was present in 11 patients and supported cortical myoclonus. Interestingly, post-hoc analysis showed that an absence of cortical hyperexcitability, suggesting non-cortical myoclonus, was associated with the PMA-end of the spectrum with no epilepsy and milder myoclonus, independent of disease duration. An association between the underlying genetic defects and progression on the PMA-PME spectrum was observed. By describing the natural history of the largest cohort of published patients with PMA so far, we see a homogeneous onset with variable disease progression, in which phenotypic evolution to PME occurs in the minority. Genetic and electrophysiological features may be of prognostic value, especially the determination of cortical hyperexcitability. Furthermore, the identification of cortical and non-cortical myoclonus in PMA helps us gain insight in the underlying pathophysiology of myoclonus.
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12. |
- Gannamani, Rahul, et al.
(author)
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Challenges in Clinicogenetic Correlations : One Phenotype – Many Genes
- 2021
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In: Movement Disorders Clinical Practice. - : Wiley. - 2330-1619. ; 8:3, s. 311-321
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Research review (peer-reviewed)abstract
- Background: In the field of movement disorders, what you see (phenotype) is seldom what you get (genotype). Whereas 1 phenotype was previously associated to 1 gene, the advent of next-generation sequencing (NGS) has facilitated an exponential increase in disease-causing genes and genotype-phenotype correlations, and the "one-phenotype-many-genes" paradigm has become prominent.Objectives: To highlight the "one-phenotype-many-genes" paradigm by discussing the main challenges, perspectives on how to address them, and future directions.Methods: We performed a scoping review of the various aspects involved in identifying the underlying molecular cause of a movement disorder phenotype.Results: The notable challenges are (1) the lack of gold standards, overlap in clinical spectrum of different movement disorders, and variability in the interpretation of classification systems; (2) selecting which patients benefit from genetic tests and the choice of genetic testing; (3) problems in the variant interpretation guidelines; (4) the filtering of variants associated with disease; and (5) the lack of standardized, complete, and up-to-date gene lists. Perspectives to address these include (1) deep phenotyping and genotype-phenotype integration, (2) adherence to phenotype-specific diagnostic algorithms, (3) implementation of current and complementary bioinformatic tools, (4) a clinical-molecular diagnosis through close collaboration between clinicians and genetic laboratories, and (5) ongoing curation of gene lists and periodic reanalysis of genetic sequencing data.Conclusions: Despite the rapidly emerging possibilities of NGS, there are still many steps to take to improve the genetic diagnostic yield. Future directions, including post-NGS phenotyping and cohort analyses enriched by genotype-phenotype integration and gene networks, ought to be pursued to accelerate identification of disease-causing genes and further improve our understanding of disease biology.
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13. |
- Huang, Miaozhen, et al.
(author)
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Cross-disease analysis of depression, ataxia and dystonia highlights a role for synaptic plasticity and the cerebellum in the pathophysiology of these comorbid diseases
- 2021
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In: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier BV. - 0925-4439. ; 1867:1
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Journal article (peer-reviewed)abstract
- Background: There is growing evidence that the neuropsychiatric and neurological disorders depression, ataxia and dystonia share common biological pathways. We therefore aimed to increase our understanding of their shared pathophysiology by investigating their shared biological pathways and molecular networks. Methods: We constructed gene sets for depression, ataxia, and dystonia using the Human Phenotype Ontology database and genome-wide association studies, and identified shared genes between the three diseases. We then assessed shared genes in terms of functional enrichment, pathway analysis, molecular connectivity, expression profiles and brain-tissue-specific gene co-expression networks. Results: The 33 genes shared by depression, ataxia and dystonia are enriched in shared biological pathways and connected through molecular complexes in protein–protein interaction networks. Biological processes common/shared to all three diseases were identified across different brain tissues, highlighting roles for synaptic transmission, synaptic plasticity and nervous system development. The average expression of shared genes was significantly higher in the cerebellum compared to other brain regions, suggesting these genes have distinct cerebellar functions. Several shared genes also showed high expression in the cerebellum during prenatal stages, pointing to a functional role during development. Conclusions: The shared pathophysiology of depression, ataxia and dystonia seems to converge onto the cerebellum that maybe particularly vulnerable to changes in synaptic transmission, regulation of synaptic plasticity and nervous system development. Consequently, in addition to regulating motor coordination and motor function, the cerebellum may likely play a role in mood processing.
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14. |
- Koens, Lisette H, et al.
(author)
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A Screening Tool to Quickly Identify Movement Disorders in Patients with Inborn Errors of Metabolism
- 2023
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 38:4, s. 646-653
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Journal article (peer-reviewed)abstract
- BACKGROUND: Movement disorders are frequent in patients with inborn errors of metabolism (IEMs) but poorly recognized, particularly by nonmovement disorder specialists. We propose an easy-to-use clinical screening tool to help recognize movement disorders.OBJECTIVE: The aim is to develop a user-friendly rapid screening tool for nonmovement disorder specialists to detect moderate and severe movement disorders in patients aged ≥4 years with IEMs.METHODS: Videos of 55 patients with different IEMs were scored by experienced movement disorder specialists (n = 12). Inter-rater agreements were determined on the presence and subtype of the movement disorder. Based on ranking and consensus, items were chosen to be incorporated into the screening tool.RESULTS: A movement disorder was rated as present in 80% of the patients, with a moderate inter-rater agreement (κ =0.420, P < 0.001) on the presence of a movement disorder. When considering only moderate and severe movement disorders, the inter-rater agreement increased to almost perfect (κ = 0.900, P < 0.001). Dystonia was most frequently scored (27.3%) as the dominant phenotype. Treatment was mainly suggested for patients with moderate or severe movement disorders. Walking, observations of the arms, and drawing a spiral were found to be the most informative tasks and were included in the screening tool.CONCLUSIONS: We designed a screening tool to recognize movement disorders in patients with IEMs. We propose that this screening tool can contribute to select patients who should be referred to a movement disorder specialist for further evaluation and, if necessary, treatment of the movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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15. |
- Kok, Gautam, et al.
(author)
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Treatment of ARS deficiencies with specific amino acids
- 2021
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In: Genetics in Medicine. - : Elsevier BV. - 1098-3600. ; 23:11, s. 2202-2207
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Journal article (peer-reviewed)abstract
- Purpose: Recessive cytosolic aminoacyl-tRNA synthetase (ARS) deficiencies are severe multiorgan diseases, with limited treatment options. By loading transfer RNAs (tRNAs) with their cognate amino acids, ARS are essential for protein translation. However, it remains unknown why ARS deficiencies lead to specific symptoms, especially early life and during infections. We set out to increase pathophysiological insight and improve therapeutic possibilities. Methods: In fibroblasts from patients with isoleucyl-RS (IARS), leucyl-RS (LARS), phenylalanyl-RS-beta-subunit (FARSB), and seryl-RS (SARS) deficiencies, we investigated aminoacylation activity, thermostability, and sensitivity to ARS-specific amino acid concentrations, and developed personalized treatments. Results: Aminoacylation activity was reduced in all patients, and further diminished at 38.5/40 °C (PLARS and PFARSB), consistent with infectious deteriorations. With lower cognate amino acid concentrations, patient fibroblast growth was severely affected. To prevent local and/or temporal deficiencies, we treated patients with corresponding amino acids (follow-up: 1/2–2 2/3rd years), and intensified treatment during infections. All patients showed beneficial treatment effects, most strikingly in growth (without tube feeding), head circumference, development, coping with infections, and oxygen dependency. Conclusion: For these four ARS deficiencies, we observed a common disease mechanism of episodic insufficient aminoacylation to meet translational demands and illustrate the power of amino acid supplementation for the expanding ARS patient group. Moreover, we provide a strategy for personalized preclinical functional evaluation.
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16. |
- Nanetti, Lorenzo, et al.
(author)
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Child-to-adult transition : a survey of current practices within the European Reference Network for Rare Neurological Diseases (ERN-RND)
- 2024
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In: Neurological Sciences. - 1590-1874. ; 45:3, s. 1007-1016
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Journal article (peer-reviewed)abstract
- Background: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. Aim: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). Methods: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. Results: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. Conclusions: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.
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17. |
- Polet, Sjoukje S., et al.
(author)
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Conventional and novel anti-seizure medications reveal a particular role for GABAA in a North Sea progressive myoclonus Epilepsy Drosophila model
- 2024
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In: Epilepsy Research. - 0920-1211. ; 203
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Journal article (peer-reviewed)abstract
- Objective: North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disorder characterized by ataxia, myoclonus and seizures with a progressive course. Although the cause of NS-PME is known, namely a homozygous mutation in the GOSR2 gene (c.430 G>T; p. Gly144Trp), sufficient treatment is lacking. Despite combinations of on average 3–5 anti-seizure medications (ASMs), debilitating myoclonus and seizures persist. Here we aimed to gain insight into the most effective anti-convulsive target in NS-PME by evaluating the individual effects of ASMs in a NS-PME Drosophila model. Method: A previously generated Drosophila model for NS-PME was used displaying progressive heat-sensitive seizures. We used this model to test 1. a first-generation ASM (sodium barbital), 2. common ASMs used in NS-PME (clonazepam, valproic acid, levetiracetam, ethosuximide) and 3. a novel third-generation ASM (ganaxolone) with similar mode of action to sodium barbital. Compounds were administered by adding them to the food in a range of concentrations. After 7 days of treatment, the percentage of heat-induced seizures was determined and compared to non-treated but affected controls. Results: As previously reported in the NS-PME Drosophila model, sodium barbital resulted in significant seizure suppression, with increasing effect at higher dosages. Of the commonly prescribed ASMs, clonazepam and ethosuximide resulted in significant seizure suppression, whereas both valproic acid and levetiracetam did not show any changes in seizures. Interestingly, ganaxolone did result in seizure suppression as well. Conclusion: Of the six drugs tested, three of the four that resulted in seizure suppression (sodium barbital, clonazepam, ganaxolone) are primary known for their direct effect on GABAA receptors. This suggests that GABAA could be a potentially important target in the treatment of NS-PME. Consequently, these findings add rationale to the exploration of the clinical effect of ganaxolone in NS-PME and other progressive myoclonus epilepsies.
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18. |
- van Verseveld, M, et al.
(author)
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Case Report: "Niemann-Pick Disease Type C in a Catatonic Patient Treated With Electroconvulsive Therapy"
- 2021
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In: Frontiers in Psychiatry. - : Frontiers Media SA. - 1664-0640. ; 12, s. 1-4
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Journal article (peer-reviewed)abstract
- We describe a case of an adolescent male with Niemann-Pick Type C (NP-C), a neurodegenerative lysosomal lipid storage disorder, who presented with recurrent catatonia which required repeated treatment with electroconvulsive therapy (ECT). During the ECT-course, seizure threshold increased substantially, leading to questions about the influence of NP-C on neuronal excitability. In this exemplary ECT-patient, NP-C was diagnosed not until after the first ECT-course when initial psychopharmacology for catatonia had failed and antipsychotics and benzodiazepines showed significant side-effects. Clinicians should be aware of NP-C in patients referred for ECT, especially in the case of treatment resistance, neurological symptoms and intolerance of psychopharmacological drugs. As was shown in our NP-C patient, ECT can be repeatedly effective for catatonic features. In the literature, effectiveness of ECT in patients with NP-C has sparsely been reported. This case demonstrates that detection of NP-C is beneficial for patients because more optimal treatment with ECT can be provided earlier without further exposure to side-effects.
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19. |
- von Scheibler, Emma N.M.M., et al.
(author)
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Parkinsonism in Genetic Neurodevelopmental Disorders : A Systematic Review
- 2023
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In: Movement Disorders Clinical Practice. - : Wiley. - 2330-1619. ; 10:1, s. 17-31
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Research review (peer-reviewed)abstract
- Background: With advances in clinical genetic testing, associations between genetic neurodevelopmental disorders and parkinsonism are increasingly recognized. In this review, we aimed to provide a comprehensive overview of reports on parkinsonism in genetic neurodevelopmental disorders and summarize findings related to genetic diagnosis, clinical features and proposed disease mechanisms. Methods: A systematic literature review was conducted in PubMed and Embase on June 15, 2021. Search terms for parkinsonism and genetic neurodevelopmental disorders, using generic terms and the Human Phenotype Ontology, were combined. Study characteristics and descriptive data were extracted from the articles using a modified version of the Cochrane Consumers and Communication Review Group's data extraction template. The protocol was registered in PROSPERO (CRD42020191035). Results: The literature search yielded 208 reports for data-extraction, describing 69 genetic disorders in 422 patients. The five most reported from most to least frequent were: 22q11.2 deletion syndrome, beta-propeller protein-associated neurodegeneration, Down syndrome, cerebrotendinous xanthomatosis, and Rett syndrome. Notable findings were an almost equal male to female ratio, an early median age of motor onset (26 years old) and rigidity being more common than rest tremor. Results of dopaminergic imaging and response to antiparkinsonian medication often supported the neurodegenerative nature of parkinsonism. Moreover, neuropathology results showed neuronal loss in the majority of cases. Proposed disease mechanisms included aberrant mitochondrial function and disruptions in neurotransmitter metabolism, endosomal trafficking, and the autophagic-lysosomal and ubiquitin-proteasome system. Conclusion: Parkinsonism has been reported in many GNDs. Findings from this study may provide clues for further research and improve management of patients with GNDs and/or parkinsonism.
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20. |
- Castela Forte, José, et al.
(author)
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Development and Validation of Decision Rules Models to Stratify Coronary Artery Disease, Diabetes, and Hypertension Risk in Preventive Care : Cohort Study of Returning UK Biobank Participants
- 2021
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In: Journal of Personalized Medicine. - : MDPI AG. - 2075-4426. ; 11:12
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Journal article (peer-reviewed)abstract
- Many predictive models exist that predict risk of common cardiometabolic conditions. However, a vast majority of these models do not include genetic risk scores and do not distinguish between clinical risk requiring medical or pharmacological interventions and pre-clinical risk, where lifestyle interventions could be first-choice therapy. In this study, we developed, validated, and compared the performance of three decision rule algorithms including biomarkers, physical measurements, and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension against commonly used clinical risk scores in 60,782 UK Biobank participants. The rules models were tested for an association with incident CAD, T2D, and hypertension, and hazard ratios (with 95% confidence interval) were calculated from survival models. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), and Net Reclassification Index (NRI). The higher risk group in the decision rules model had a 40-, 40.9-, and 21.6-fold increased risk of CAD, T2D, and hypertension, respectively (p < 0.001 for all). Risk increased significantly between the three strata for all three conditions (p < 0.05). Based on genetic risk alone, we identified not only a high-risk group, but also a group at elevated risk for all health conditions. These decision rule models comprising blood biomarkers, physical measurements, and polygenic risk scores moderately improve commonly used clinical risk scores at identifying individuals likely to benefit from lifestyle intervention for three of the most common lifestyle-related chronic health conditions. Their utility as part of digital data or digital therapeutics platforms to support the implementation of lifestyle interventions in preventive and primary care should be further validated.
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21. |
- De Koning, Tom J., et al.
(author)
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Amino Acid Synthesis Deficiencies
- 2022. - 2
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In: Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases, Second Edition. - Cham : Springer International Publishing. - 9783030721848 - 9783030721831 ; , s. 453-467
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Book chapter (peer-reviewed)abstract
- In recent years the list of disorders affecting amino acid synthesis has grown rapidly. Not only the number of defects has increased, but also the associated clinical phenotypes have expanded spectacular, the latter mainly due to the advances of next-generation sequencing diagnostics. An important reason for the contribution of NGS in the diagnosis of amino acid synthesis disorders is the fact that the biochemical diagnosis of some of these synthesis disorders can be quite challenging, synthesis defects may present with low values of amino acids, or their concentrations can even be completely normal. Defects in the synthesis pathways of serine metabolism, glutamine, glutamate, proline, and asparagine have been reported, and all pose specific challenges to a biochemical diagnosis. An exception to this are the disorders of pyrroline-5-carboxylate (P5C) synthesis where ornithine or proline is strongly elevated and easily detected by plasma amino acid analysis. Finally, Snyder-Robinson, a defect in the synthesis of the polyamine spermine, is discussed here as well, and molecular testing is advised for this disorder as well. Although the amino acid synthesis defects in this chapter are not all in related metabolic pathways, they do share some clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early-onset seizures, and mental retardation to a variable degree. The brain abnormalities can be accompanied by skin disorders such as cutis laxa in proline defects, collodion-like skin and ichthyosis in serine deficiency, necrolytic erythema in glutamine deficiency, and difficult to classify skin abnormalities in glutaminase hyperactivity. In adults with serine or proline disorders, several forms of polyneuropathy with or without intellectual disability appear to be the major presenting symptom. An exception to this is ornithine aminotransferase deficiency which primarily affects the choroid and retina and Snyder-Robinson syndrome in which mental retardation is accompanied by seizures, dysmorphic features, and severe osteoporosis.
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22. |
- Hentrich, Lea, et al.
(author)
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Novel Genetic and Phenotypic Expansion in GOSR2-Related Progressive Myoclonus Epilepsy
- 2023
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In: Genes. - 2073-4425. ; 14:10
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Journal article (peer-reviewed)abstract
- Biallelic variants in the Golgi SNAP receptor complex member 2 gene ( GOSR2) have been reported in progressive myoclonus epilepsy with neurodegeneration. Typical clinical features include ataxia and areflexia during early childhood, followed by seizures, scoliosis, dysarthria, and myoclonus. Here, we report two novel patients from unrelated families with a GOSR2-related disorder and novel genetic and clinical findings. The first patient, a male compound heterozygous for the GOSR2 splice site variant c.336+1G>A and the novel c.364G>A,p.Glu122Lys missense variant showed global developmental delay and seizures at the age of 2 years, followed by myoclonus at the age of 8 years with partial response to clonazepam. The second patient, a female homozygous for the GOSR2 founder variant p.Gly144Trp, showed only mild fine motor developmental delay and generalized tonic-clonic seizures triggered by infections during adolescence, with seizure remission on levetiracetam. The associated movement disorder progressed atypically slowly during adolescence compared to its usual speed, from initial intention tremor and myoclonus to ataxia, hyporeflexia, dysmetria, and dystonia. These findings expand the genotype-phenotype spectrum of GOSR2-related disorders and suggest that GOSR2 should be included in the consideration of monogenetic causes of dystonia, global developmental delay, and seizures.
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23. |
- Janzing, Anna M, et al.
(author)
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Clinical Characteristics Suggestive of a Genetic Cause in Cerebral Palsy : A Systematic Review
- 2024
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In: Pediatric Neurology. - 0887-8994. ; 153, s. 144-151
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Research review (peer-reviewed)abstract
- BACKGROUND: Cerebral palsy (CP) is a clinical diagnosis and was long categorized as an acquired disorder, but more and more genetic etiologies are being identified. This review aims to identify the clinical characteristics that are associated with genetic CP to aid clinicians in selecting candidates for genetic testing.METHODS: The PubMed database was systematically searched to identify genes associated with CP. The clinical characteristics accompanying these genetic forms of CP were compared with published data of large CP populations resulting in the identification of potential indicators of genetic CP.RESULLTS: Of 1930 articles retrieved, 134 were included. In these, 55 CP genes (described in two or more cases, n = 272) and 79 candidate genes (described in only one case) were reported. The most frequently CP-associated genes were PLP1 (21 cases), ARG1 (17 cases), and CTNNB1 (13 cases). Dyskinesia and the absence of spasticity were identified as strong potential indicators of genetic CP. Presence of intellectual disability, no preterm birth, and no unilateral distribution of symptoms were classified as moderate genetic indicators.CONCLUSIONS: Genetic causes of CP are increasingly identified. The clinical characteristics associated with genetic CP can aid clinicians regarding to which individual with CP to offer genetic testing. The identified potential genetic indicators need to be validated in large CP cohorts but can provide the first step toward a diagnostic algorithm for genetic CP.
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24. |
- Mainka, Tina, et al.
(author)
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The neurological and neuropsychiatric spectrum of adults with late-treated phenylketonuria
- 2021
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In: Parkinsonism and Related Disorders. - : Elsevier BV. - 1353-8020. ; 89, s. 167-175
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Journal article (peer-reviewed)abstract
- Introduction: Phenylketonuria (PKU) is a rare, treatable inborn error of metabolism with frequent neurological and neuropsychiatric complications, especially in undiagnosed or insufficiently treated individuals. Given the wide range of clinical presentations and the importance of treatment implications, we here delineate the neurological and neuropsychiatric symptom spectrum in a large cohort of previously unreported adults with late-treated PKU. Methods: We consecutively evaluated late-treated PKU cases and pooled clinical and paraclinical data, including video-material, from three centers with expertise in complex movement disorders, inborn errors of metabolism and pediatrics. Results: 26 individuals were included (10 females, median age 52 years). Developmental delay and intellectual disability were omnipresent with severe impairment of expressive communication noted in 50% of cases. Movement disorders were prevalent (77%), including tremor (38%, mostly postural), stereotypies (38%), and tics (19%). One case had neurodegenerative levodopa-responsive parkinsonism. Mild ataxia was noted in 54% of cases and 31% had a history of seizures. Neuropsychiatric characteristics included obsessive-compulsive (35%) and self-injurious behaviors (31%), anxiety (27%), depression (19%) and features compatible with those observed in individuals with autism spectrum disorder (19%). Neuroimaging revealed mild white matter changes. Adherence to dietary treatment was inconsistent in the majority of cases, particularly throughout adolescence. Conclusion: A history of movement disorders, particularly tremor, stereotypies and tics, in the presence of developmental delay, intellectual disability and neuropsychiatric features, such as obsessive-compulsive and self-injurious behaviors in adults should prompt the diagnostic consideration of PKU. Initiation and adherence to (dietary) treatment can ameliorate the severity of these symptoms.
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25. |
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