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Eyes on MEGDEL: distinctive basal ganglia involvement in dystonia deafness syndrome

Wortmann SB, van Hasselt PM, Barić I, Burlina A, Darin N, Hörster F, et al.

Neuropediatrics, 2015 Apr;46(2):98-103.
PMID: 25642805 DOI: 10.1055/s-0034-1399755

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.

Matched MeSH terms: Dystonic Disorders/complications; Dystonic Disorders/genetics; Dystonic Disorders/pathology*
Anesthetic considerations in scoliosis patient with dopa-responsive dystonia or Segawa's syndrome

Hasan MS, Leong KW, Chan CY, Kwan MK

J Orthop Surg (Hong Kong), 2017 01;25(1):2309499016684743.
PMID: 28166704 DOI: 10.1177/2309499016684743

Segawa's syndrome or dopa-responsive dystonia is a rare hereditary disorder characterized by progressive dystonia of childhood onset, diurnal fluctuation of symptoms and complete or near complete alleviation of symptoms with administration of low-dose oral levodopa. From our literature search in PubMed, we found only three related publications: two on anesthesia for cesarean section and one on anesthesia for electroconvulsive therapy. We report our experience in providing anesthesia for corrective scoliosis surgery in two biological sisters with Segawa's syndrome. A review of the literature is also included.

Matched MeSH terms: Dystonic Disorders/surgery*
DYT1 mutations amongst adult primary dystonia patients in Singapore with review of literature comparing East and West

Jamora RD, Tan EK, Liu CP, Kathirvel P, Burgunder JM, Tan LC

J Neurol Sci, 2006 Aug 15;247(1):35-7.
PMID: 16631205

Dystonia is a heterogenous group of movement disorders whose clinical spectrum is very wide. At least 13 different genes and gene loci have been reported. While a 3-bp deletion in the DYT1 gene is the most frequent cause of early limb-onset, generalized dystonia, it has also been found in non-generalized forms of sporadic dystonia. An 18-bp deletion in the DYT1 gene has also been reported.

Matched MeSH terms: Dystonic Disorders/genetics*
Fulltext Metoclopramide-Induced Acute Dystonic Reactions May Be Associated With the CYP2D6 Poor Metabolizer Status and Pregnancy-Related Hormonal Changes

Chua EW, Harger SP, Kennedy MA

Front Pharmacol, 2019;10:931.
PMID: 31507424 DOI: 10.3389/fphar.2019.00931

We report two cases of metoclopramide-induced acute dystonia in pregnant women and consider the role of genetic variation in the pathogenesis of the adverse effect. By whole-gene sequencing, we found that both women were CYP2D6 poor metabolizers. We theorize that CYP2D6 governs the risk of metoclopramide-related acute dystonia through its role in the synthesis of serotonin, which inhibits the dopamine tone. The effect of CYP2D6 poor metabolism is exaggerated by rises in the estrogen levels during pregnancy, as the hormone augments dopamine sensitivity. Together, the two factors may create a hyper-dopaminergic state that is easily upset by metoclopramide, resulting in acute dystonia.

Matched MeSH terms: Dystonic Disorders
Fulltext TAF1 Transcripts and Neurofilament Light Chain as Biomarkers for X-linked Dystonia-Parkinsonism

Al Ali J, Vaine CA, Shah S, Campion L, Hakoum A, Supnet ML, et al.

Mov Disord, 2021 01;36(1):206-215.
PMID: 32975318 DOI: 10.1002/mds.28305

BACKGROUND: X-linked dystonia-parkinsonism is a rare neurological disease endemic to the Philippines. Dystonic symptoms appear in males at the mean age of 40 years and progress to parkinsonism with degenerative pathology in the striatum. A retrotransposon inserted in intron 32 of the TAF1 gene leads to alternative splicing in the region and a reduction of the full-length mRNA transcript.
OBJECTIVES: The objective of this study was to discover cell-based and biofluid-based biomarkers for X-linked dystonia-parkinsonism.
METHODS: RNA from patient-derived neural progenitor cells and their secreted extracellular vesicles were used to screen for dysregulation of TAF1 expression. Droplet-digital polymerase chain reaction was used to quantify the expression of TAF1 mRNA fragments 5' and 3' to the retrotransposon insertion and the disease-specific splice variant TAF1-32i in whole-blood RNA. Plasma levels of neurofilament light chain were measured using single-molecule array.
RESULTS: In neural progenitor cells and their extracellular vesicles, we confirmed that the TAF1-3'/5' ratio was lower in patient samples, whereas TAF1-32i expression is higher relative to controls. In whole-blood RNA, both TAF1-3'/5' ratio and TAF1-32i expression can differentiate patient (n = 44) from control samples (n = 18) with high accuracy. Neurofilament light chain plasma levels were significantly elevated in patients (n = 43) compared with both carriers (n = 16) and controls (n = 21), with area under the curve of 0.79.
CONCLUSIONS: TAF1 dysregulation in blood serves as a disease-specific biomarker that could be used as a readout for monitoring therapies targeting TAF1 splicing. Neurofilament light chain could be used in monitoring neurodegeneration and disease progression in patients. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Matched MeSH terms: Dystonic Disorders
Fulltext Deep Brain Stimulation (DBS) for Movement Disorders: An Experience in Hospital Universiti Sains Malaysia (HUSM) Involving 12 Patients

Hooi LL, Fitzrol DN, Rajapathy SK, Chin TY, Halim SA, Kandasamy R, et al.

Malays J Med Sci, 2017 Mar;24(2):87-93.
PMID: 28894408 MyJurnal DOI: 10.21315/mjms2017.24.2.11

Deep brain stimulation (DBS) was first introduced in 1987 to the developed world. As a developing country Malaysia begun its movement disorder program by doing ablation therapy using the Radionics system. Hospital Universiti Sains Malaysia a rural based teaching hospital had to take into consideration both health economics and outcomes in the area that it was providing neurosurgical care for when it initiated its Deep Brain Stimulation program. Most of the patients were from the low to medium social economic groups and could not afford payment for a DBS implant. We concentrated our DBS services to Parkinson's disease, Tourette's Syndrome and dystonia patients who had exhausted medical therapy. The case series of these patients and their follow-up are presented in this brief communication.

Matched MeSH terms: Dystonic Disorders
Neuropharmacological potentials of β-carboline alkaloids for neuropsychiatric disorders

Ayipo YO, Mordi MN, Mustapha M, Damodaran T

Eur J Pharmacol, 2021 Feb 15;893:173837.
PMID: 33359647 DOI: 10.1016/j.ejphar.2020.173837

Neuropsychiatric disorders are diseases of the central nervous system (CNS) which are characterised by complex pathomechanisms that including homeostatic failure, malfunction, atrophy, pathology remodelling and reactivity anomaly of the neuronal system where treatment options remain challenging. β-Carboline (βC) alkaloids are scaffolds of structurally diverse tricyclic pyrido[3,4-b]indole alkaloid with vast occurrence in nature. Their unique structural features which favour interactions with enzymes and protein receptor targets account for their potent neuropharmacological properties. However, our current understanding of their biological mechanisms for these beneficial effects, especially for neuropsychiatric disorders is sparse. Therefore, we present a comprehensive review of the scientific progress in the last two decades on the prospective pharmacology and physiology of the βC alkaloids in the treatment of some neuropsychiatric conditions such as depression, anxiety, Alzheimer's disease, Parkinson's disease, brain tumour, essential tremor, epilepsy and seizure, licking behaviour, dystonia, agnosia, spasm, positive ingestive response as demonstrated in non-clinical models. The current evidence supports that βC alkaloids offer potential therapeutic agents against most of these disorders and amenable for further drug design.

Matched MeSH terms: Dystonic Disorders