Cognition in children and young adults with myoclonus dystonia - A case control study

INTRODUCTION: In adult patients with myoclonus dystonia (MD), cognitive deficits regarding information processing speed and executive functioning have been demonstrated, but it is unclear whether cognition is also affected in young MD patients. The present study investigates cognition in young MD patients and the role of an SGCE mutation. METHODS: In this case control study 20 young MD patients (9 children (5.75-12.58 years) and 11 adolescents/young adults (13.5-25.42 years)) were included and compared to an age-, IQ- and gender-matched healthy control group (n = 40). Within the patient group, we compared patients with (n = 12) and without (n = 8) an SGCE mutation (SGCE+/-). All participants completed neuropsychological tests for memory, attention/processing speed, executive functioning, social cognition and language. RESULTS: Overall, patients performed in the (low) average range, comparable to healthy controls. Only on a semantic fluency test, patients scored significantly lower. SGCE + patients had lower emotion recognition scores (a social cognition test) compared to SGCE-patients. CONCLUSION: We could not demonstrate cognitive deficits as found in adult MD patients in our younger group. Patients performed on the same level as healthy controls, with only a small difference in semantic fluency. We did not find executive deficits that were manifest in adult SGCE + patients, but we did find an association of an SGCE mutation and lower scores on a social cognition test. Similar to executive functioning, social cognition is a prefrontally regulated function, but had not been tested in adult MD. Hence, social cognition may precede executive problems in adulthood, suggesting growing into deficit

Diagnostic approach to paediatric movement disorders:a clinical practice guide

Paediatric movement disorders (PMDs) comprise a large group of disorders (tics, myoclonus, tremor, dystonia, chorea, Parkinsonism, ataxia), often with mixed phenotypes. Determination of the underlying aetiology can be difficult given the broad differential diagnosis and the complexity of the genotype-phenotype relationships. This can make the diagnostic process time-consuming and difficult. In this overview, we present a diagnostic approach for PMDs, with emphasis on genetic causes. This approach can serve as a framework to lead the clinician through the diagnostic process in eight consecutive steps, including recognition of the different movement disorders, identification of a clinical syndrome, consideration of acquired causes, genetic testing including next-generation sequencing, post-sequencing phenotyping, and interpretation of test results. The aim of this approach is to increase the recognition and diagnostic yield in PMDs.</p

The prognosis of functional limb weakness, a 14-year case-control study

Reliable data on the prognosis of functional motor disorder are scarce, as existing studies of the prognosis of functional motor disorder are nearly all retrospective, small and uncontrolled. In this study we used a prospectively recruited, controlled cohort design to assess misdiagnosis, mortality and symptomatic and health outcome in patients with functional limb weakness compared to neurological disease and healthy control subjects. We also carried out an exploratory analysis for baseline factors predicting outcome. One hundred and seven patients with functional limb weakness, 46 neurological and 38 healthy control subjects from our previously studied prospective cohort were traced for follow-up after an average of 14 years. Misdiagnosis was determined in a consensus meeting using information from records, patients and their GPs. Numbers and causes of death were collected via death certificates. Outcome of limb weakness, physical and psychiatric symptoms, disability/quality of life and illness perception were recorded with self-rated questionnaires. Outcome measures were compared within and between groups. Seventy-six patients (71%) with functional limb weakness, 31 (67%) neurological and 23 (61%) healthy controls were included in follow-up. Misdiagnosis was found in one patient in the functional limb weakness group (1%) and in one neurological control (2%). Eleven patients with functional limb weakness, eight neurological control subjects and one healthy control subject had died. Weakness had completely remitted in 20% of patients in the functional limb weakness group and in 18% of the neurological controls (P = 0.785) and improved in a larger proportion of functional limb weakness patients (P = 0.011). Outcomes were comparable between patient groups, and worse than the healthy control group. No baseline factors were independent predictors of outcome, although somatization disorder, general health, pain and total symptoms at baseline were univariably correlated to outcome. This study is the largest and longest follow-up study of functional limb weakness. Misdiagnosis in functional limb weakness is rare after long-term follow-up. The disorder is associated with a higher mortality rate than expected, and symptoms are persistent and disabling. It appears difficult to predict outcome based on common baseline variables. These data should help inform clinicians to provide a more realistic outlook of the outcome and emphasize the importance of active and targeted therapy

The Effect of Escitalopram on Central Serotonergic and Dopaminergic Systems in Patients with Cervical Dystonia, and Its Relationship with Clinical Treatment Effects:A Double-Blind Placebo-Controlled Trial

Purpose:The pathophysiology of cervical dystonia (CD) is thought to be related to changes in dopamine and serotonin levels in the brain. We performed a double-blind trial with escitalopram (selective serotonin reuptake inhibitor; SSRI) in patients with CD. Here, we report on changes in dopamine D(2/3)receptor (D2/3R), dopamine transporter (DAT) and serotonin transporter (SERT) binding potential (BPND) after a six-week treatment course with escitalopram or placebo.Methods:CD patients had [123I]FP-CIT SPECT (I-123 fluoropropyl carbomethoxy-3 beta-(4-iodophenyltropane) single-photon emission computed tomography) scans, to quantify extrastriatal SERT and striatal DAT, and [123I]IBZM SPECT (I-123 iodobenzamide SPECT) scans to quantify striatal D2/3R BPND before and after six weeks of treatment with either escitalopram or placebo. Treatment effect was evaluated with the Clinical Global Impression scale for dystonia, jerks and psychiatric symptoms, both by physicians and patients.Results:In both patients treated with escitalopram and placebo there were no significant differences after treatment in SERT, DAT or D2/3R BPND. Comparing scans after treatment with escitalopram (n = 8) to placebo (n = 8) showed a trend (p= 0.13) towards lower extrastriatal SERT BPND in the SSRI group (median SERT occupancy of 64.6%). After treatment with escitalopram, patients who reported a positive effect on dystonia or psychiatric symptoms had significantly higher SERT occupancy compared to patients who did not experience an effect.Conclusion:Higher extrastriatal SERT occupancy after treatment with escitalopram is associated with a trend towards a positive subjective effect on dystonia and psychiatric symptoms in CD patients

Myoclonus-dystonia : distinctive motor and non-motor phenotype from other dystonia syndromes

Background: myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with MD. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M.D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways

Potassium secretion by the descending limb or pars recta of the juxtamedullary nephron in vivo

Potassium secretion by the descending limb or pars recta of the juxtamedullary nephron in vivo. Potassium reabsorption by the juxtamedullary nephron up to the hairpin turn was studied by the micropuncture technique in the exposed renal papilla of rats. In 18 nondiuretic rats, the fraction of filtered potassium remaining at the end of the desdending limb averaged 113 ± 9%, indicating either that potassium is not reabsorbed by the juxtamedullary proximal tubule and descending limb or that potassium is reabsorbed and secreted in those segments. Furosemide, a drug which inhibits NaCl reabsorption in the ascending limb downstream from the descending limb, significantly decreased the potassium remaining at the end of the descending limb from 106 ± 12 to 72 ± 11% in seven rats. Benzolamide, a drug which inhibits reabsorption of NaHCO3 and water in the proximal tubule upstream from the descending limb, significantly increased the potassium remaining from 103 ± 13 to 177 ± 32% in eight rats. These findings support the hypothesis that in the rat, potassium is normally reabsorbed by the proximal convoluted tubule and secreted in the pars recta or descending limb of the juxtamedullary nephron

WDR45, one gene associated with multiple neurodevelopmental disorders

The WDR45 gene is localized on the X-chromosome and variants in this gene are linked to six different neurodegenerative disorders, i.e., ss-propeller protein associated neurodegeneration, Rett-like syndrome, intellectual disability, and epileptic encephalopathies including developmental and epileptic encephalopathy, early-onset epileptic encephalopathy and West syndrome and potentially also specific malignancies. WDR45/WIPI4 is a WD-repeat beta-propeller protein that belongs to the WIPI (WD repeat domain, phosphoinositide interacting) family. The precise cellular function of WDR45 is still largely unknown, but deletions or conventional variants in WDR45 can lead to macroautophagy/autophagy defects, malfunctioning mitochondria, endoplasmic reticulum stress and unbalanced iron homeostasis, suggesting that this protein functions in one or more pathways regulating directly or indirectly those processes. As a result, the underlying cause of the WDR45-associated disorders remains unknown. In this review, we summarize the current knowledge about the cellular and physiological functions of WDR45 and highlight how genetic variants in its encoding gene may contribute to the pathophysiology of the associated diseases. In particular, we connect clinical manifestations of the disorders with their potential cellular origin of malfunctioning and critically discuss whether it is possible that one of the most prominent shared features, i.e., brain iron accumulation, is the primary cause for those disorders

Axial jerks: a clinical spectrum ranging from propriospinal to psychogenic myoclonus

Propriospinal myoclonus (PSM) is a rare disorder with repetitive flexor, arrhythmic jerks of the trunk, hips and knees. Its generation is presumed to relay in the spinal cord. We report a case series of 35 consecutive patients with jerks of the trunk referred as possible PSM to a tertiary referral center for movement disorders. We review classical PSM features as well as psychogenic and tic characteristics. In our case series, secondary PSM was diagnosed in one patient only. 34 patients showed features suggestive of a psychogenic origin of axial jerks. Diagnosis of psychogenic axial jerks was based on clinical clues without additional investigations (n = 8), inconsistent findings at polymyography (n = 15), regular eye blinking preceding jerks (n = 2), or the presence of a Bereitschaftspotential (BP) (n = 9). In addition, several tic characteristics were noted. Almost all patients referred with possible PSM in our tertiary referral clinic had characteristics suggesting a psychogenic origin even in the presence of a classic polymyography pattern or in the absence of a BP. Clinical overlap with adult-onset tics seems to exist

Developmental neurobiology of cerebellar and Basal Ganglia connections

BACKGROUND: The high prevalence of mixed phenotypes of Early Onset Ataxia (EOA) with comorbid dystonia has shifted the pathogenetic concept from the cerebellum towards the interconnected cerebellar motor network. This paper on EOA with comorbid dystonia (EOA-dystonia) explores the conceptual relationship between the motor phenotype and the cortico-basal-ganglia-ponto-cerebellar network. METHODS: In EOA-dystonia, we reviewed anatomic-, genetic- and biochemical-studies on the comorbidity between ataxia and dystonia. RESULTS: In a clinical EOA cohort, the prevalence of dystonia was over 60%. Both human and animal studies converge on the underlying role for the cortico-basal-ganglia-ponto-cerebellar network. Genetic -clinical and -in silico network studies reveal underlying biological pathways for energy production and neural signal transduction. CONCLUSIONS: EOA-dystonia phenotypes are attributable to the cortico-basal-ganglia-ponto-cerebellar network, instead of to the cerebellum, alone. The underlying anatomic and pathogenetic pathways have clinical implications for our understanding of the heterogeneous phenotype, neuro-metabolic and genetic testing and potentially also for new treatment strategies, including neuro-modulation