| 1. |
- Timmers, Elze R., et al.
(författare)
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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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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Koens, Lisette H, et al.
(författare)
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Eye movement disorders in inborn errors of metabolism : A quantitative analysis of 37 patients
- 2022
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Ingår i: Journal of Inherited Metabolic Disease. - : Wiley. - 0141-8955 .- 1573-2665. ; 45:5, s. 981-995
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Tidskriftsartikel (refereegranskat)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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| 3. |
- Mposhi, Archibold, et al.
(författare)
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The Mitochondrial Epigenome : An Unexplored Avenue to Explain Unexplained Myopathies?
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:4
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Tidskriftsartikel (refereegranskat)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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| 4. |
- Timmers, Elze R, et al.
(författare)
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Methylation of the serotonin reuptake transporter gene and non-motor symptoms in dystonia patients
- 2022
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Ingår i: Clinical Epigenetics. - : Springer Science and Business Media LLC. - 1868-7075 .- 1868-7083. ; 14, s. 1-10
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Tidskriftsartikel (refereegranskat)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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| 5. |
- De Koning, Tom J., et al.
(författare)
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Amino Acid Synthesis Deficiencies
- 2022. - 2
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Ingår i: 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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Bokkapitel (refereegranskat)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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