A Case Report of Siblings with Dystonia: A Potential Link Between DYT11 Mutation and Platelet Dysfunction.

Myoclonus-dystonia syndrome (MDS) is an autosomal dominant disorder due to a mutated epsilon-sarcoglycan gene (SGCE) at the dystonia 11 (DYT11) locus on chromosome 7q21-31. ε-sarcoglycan has been identified in vascular smooth muscle and has been suggested to stabilize the capillary system. This report describes two siblings with MDS treated with bilateral globus pallidus interna deep brain stimulation. One patient had a history of bleeding following dental procedures, menorrhagia, and DBS placement complicated by intraoperative bleeding during cannula insertion. The other sibling endorsed frequent epistaxis. Subsequent procedures were typically treated perioperatively with platelet or tranexamic acid transfusion. Hematologic workup showed chronic borderline thrombocytopenia but did not elucidate a cause-specific platelet dysfunction or underlying coagulopathy. The bleeding history and thrombocytopenia observed suggest a potential link between MDS and platelet dysfunction. Mutated ε-sarcoglycan may destabilize the capillary system, thus impairing vasoconstriction and leading to suboptimal platelet aggregation.

Dopaminergic and serotonergic alterations in plasma in three groups of dystonia patients.

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.

High prevalence of neutralizing antibodies after long-term botulinum neurotoxin therapy.

OBJECTIVE: To investigate the prevalence of neutralizing antibodies (NAbs) against botulinum neurotoxin type A (BoNT/A) during long-term BoNT/A treatment in different neurologic indications. METHODS: In this monocentric, observational cross-sectional study, 596 outpatients treated with BoNT/A for different indications were tested for BoNT/A binding antibodies by ELISA. Positive samples were investigated for NAbs with the mouse hemidiaphragm test. The prevalence of NAbs was analyzed for different indications: facial hemispasm, blepharospasm, cervical dystonia, other dystonia, and spasticity. Besides the rate of NAb-positive patients overall and per patient subgroup, a Kaplan-Meier analysis of the probability of remaining NAb negative with duration of treatment is provided, and a stepwise binary logistic regression analysis is performed to identify factors significantly contributing to the induction of NAbs. RESULTS: Overall, 83 of 596 patients (13.9%) had measurable NAbs. The probability of developing NAbs increased with the single and cumulative dose of treatment and was influenced by the BoNT/A formulation, while all other factors analyzed, including disease entity and treatment duration, had no additional influence. CONCLUSIONS: We present the largest study to date of the prevalence of BoNT/A NAbs in a large unbiased cohort of patients including the relevant neurologic indications. Repeated injections of BoNT/A inevitably bear the risk of developing NAbs. However, in addition to avoiding booster injections and providing short intervals between injections, reducing the individual injected doses may diminish the risk of NAb induction independently of the indication for which BoNT/A is used.

A randomized, controlled, double-blind, crossover trial of zonisamide in myoclonus-dystonia.

OBJECTIVE: To evaluate the efficacy and safety of zonisamide in patients with myoclonus-dystonia. METHODS: We conducted a randomized, double-blind, placebo-controlled crossover trial of zonisamide (300 mg/d) in 24 patients with myoclonus-dystonia. Each treatment period consisted of a 6-week titration phase followed by a 3-week fixed-dose phase. The periods were separated by a 5-week washout period. The co-primary outcomes were action myoclonus severity (section 4 of the Unified Myoclonus Rating Scale [UMRS 4]) and myoclonus-related functional disability (UMRS 5). Secondary outcomes included dystonia severity, assessed with the movement and disability subscales of the Burke-Fahn-Marsden-Dystonia Rating Scale (BFM), the Clinical Global Impression-Improvement scale (CGI), and safety measures. Wilcoxon signed-rank tests for paired data were used to analyze treatment effects. RESULTS: Twenty-three patients (11 men, 12 women) were analyzed in the intention-to-treat analysis. Zonisamide significantly improved both action myoclonus (median improvement [95% confidence limits] -5 [-9.25 to -1.44], p = 0.003) and myoclonus-related functional disability (median improvement [95% confidence limits] -2 [-2.58 to -2.46], p = 0.007) compared to placebo. Zonisamide also significantly improved dystonia (BFM movement) compared to placebo (median improvement [95% confidence limits] -3 [-8.46 to 0.03], p = 0.009). No difference was found between zonisamide and placebo with respect to the CGI (median improvement [95% confidence limits] -1 [-1.31 to 0.09], p = 0.1). Zonisamide was well-tolerated. CONCLUSIONS: Zonisamide is well-tolerated and effective on the motor symptoms of myoclonus-dystonia. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that zonisamide improves myoclonus and related disability in patients with myoclonus-dystonia.

[Faciobrachial dystonic seizures. Semiologic diagnosis in limbic encephalitis]. / Crisis distónicas faciobraquiales. Diagnóstico semiológico en la encefalitis límbica.

Limbic encephalitis (LE) associated with positive potassium channel complex antibodies often manifests with faciobrachial dystonic seizures (FBDS). We retrospectively analyze two cases, admitted to our video-EEG unit between 2006 and 2014. Both patients were males, aged 66 and 76 years respectively, presenting with brief, but very frequent uni/bilateral dystonic brachial movements, hand posturing and ipsilateral facial grimacing. Severe hyponatremia was found in both patients who went on to develop cognitive impairment. Immunosuppressive therapy improved both seizures and cognitive dysfunction. Serology testing confirmed anti VGKC antibody presence. FBDS are often the first manifestation of LE associated to positive anti VGKC antibodies, and are refractory to treatment with antiepileptic drugs. Early diagnosis and treatment of FBDS with immunosuppressive therapy is important, not only because of seizure suppression, but also because it may help limit the extent of the cognitive damage.

Safety aspects of incobotulinumtoxinA high-dose therapy.

Botulinum toxin (BT) used for dystonia and spasticity is dosed according to the number of target muscles and the severity of their muscle hyperactivities. With this no other drug is used in a broader dose range than BT. The upper end of this range, however, still needs to be explored. We wanted to do this by a prospective non-interventional study comparing a randomly selected group of dystonia and spasticity patients receiving incobotulinumtoxinA (Xeomin(®)) high-dose therapy (HD group, n = 100, single dose ≥400 MU) to a control group receiving incobotulinumtoxinA regular-dose therapy (RD group, n = 30, single dose ≤200 MU). At the measurement point all patients were evaluated for systemic BT toxicity, i.e. systemic motor impairment or systemic autonomic dysfunction. HD group patients (56.1 ± 13.8 years, 46 dystonia, 54 spasticity) were treated with Xeomin(®) 570.1 ± 158.9 (min 400, max 1,200) MU during 10.2 ± 7.0 (min 4, max 37) injection series. In dystonia patients the number of target muscles was 46 and the dose per target muscle 56.4 ± 19.1 MU, in spasticity patients 35 and 114.9 ± 67.1 MU. HD and RD group patients reported 58 occurrences of items on the systemic toxicity questionnaire. Generalised weakness, being bedridden, feeling of residual urine and constipation were caused by the underlying tetra- or paraparesis, blurred vision by presbyopia. Dysphagia and dryness of eye were local BT adverse effects. Neurologic examination, serum chemistry and full blood count did not indicate any systemic adverse effects. Elevated serum levels for creatine kinase/MB, creatine kinase and lactate dehydrogenase were most likely iatrogenic artefacts. None of the patients developed antibody-induced therapy failure. Xeomin(®) can be used safely in doses ≥400 MU and up to 1,200 MU without detectable systemic toxicity. This allows expanding the use of BT therapy to patients with more widespread and more severe muscle hyperactivity conditions. Further studies-carefully designed and rigorously monitored-are necessary to explore the threshold dose for clinically detectable systemic toxicity.

Pitfalls in phenylalanine loading test in the diagnosis of dopa-responsive dystonia.

Phenylalanine (Phe) loading test is a useful tool in the differential diagnosis of dopa-responsive dystonia due to autosomal dominant or recessive GTP cyclohydrolase I (GTPCH) deficiency or autosomal recessive sepiapterin reductase (SR) deficiency. In these patients hepatic phenylalanine hydroxylase system is compromised due to subnormal tetrahydrobiopterin (BH(4)) levels and hydroxylation of phenylalanine (Phe) to tyrosine (Tyr) is reduced with elevated Phe/Tyr ratio 1-2 h after oral Phe administration (100 mg/kg bw) administration. In healthy persons there is only a modest increase in Tyr production and blood Phe normalizes after 4 h. We report on a challenge with Phe (100 mg/kg bw) in a patient with dopa-responsive dystonia while on therapy with BH(4) and l-dopa. During Phe challenge Phe concentration remained below the normal range while a transient mild hypertyrosinemia was observed, leading to an extremely low Phe/Tyr ratio. A repeated test, after BH(4) withdrawal, reversed the findings and resulted normal. These data suggest activation of hepatic phenylalanine hydroxylase by BH(4). Thus, the Phe loading test should not be performed during substitution with BH(4).

Impaired behavioural pain responses in hph-1 mice with inherited deficiency in GTP cyclohydrolase 1 in models of inflammatory pain.

BACKGROUND: GTP cyclohydrolase 1 (GTP-CH1), the rate-limiting enzyme in the synthesis of tetrahydrobiopterin (BH4), encoded by the GCH1 gene, has been implicated in the development and maintenance of inflammatory pain in rats. In humans, homozygous carriers of a "pain-protective" (PP) haplotype of the GCH1 gene have been identified exhibiting lower pain sensitivity, but only following pain sensitisation. Ex vivo, the PP GCH1 haplotype is associated with decreased induction of GCH1 after stimulation, whereas the baseline BH4 production is not affected. Contrary, loss of function mutations in the GCH1 gene results in decreased basal GCH1 expression, and is associated with DOPA-responsive dystonia (DRD). So far it is unknown if such mutations affect acute and inflammatory pain. RESULTS: In the current study, we examined the involvement of the GCH1 gene in pain models using the hyperphenylalaninemia 1 (hph-1) mouse, a genetic model for DRD, with only 10% basal GTP-CH1 activity compared to wild type mice. The study included assays for determination of acute nociception as well as models for pain after sensitisation. Pain behavioural analysis of the hph-1 mice showed reduced pain-like responses following intraplantar injection of CFA, formalin and capsaicin; whereas decreased basal level of GTP-CH1 activity had no influence in naïve hph-1 mice on acute mechanical and heat pain thresholds. Moreover, the hph-1 mice showed no signs of motor impairment or dystonia-like symptoms. CONCLUSIONS: In this study, we demonstrate novel evidence that genetic mutations in the GCH1 gene modulate pain-like hypersensitivity. Together, the present data suggest that BH4 is not important for basal heat and mechanical pain, but they support the hypothesis that BH4 plays a role in inflammation-induced hypersensitivity. Our studies suggest that the BH4 pathway could be a therapeutic target for the treatment of inflammatory pain conditions. Moreover, the hph-1 mice provide a valid model to study the consequence of congenital deficiency of GCH1 in painful conditions.

Phenylalanine loading in pediatric patients with dopa-responsive dystonia: revised test protocol and pediatric cutoff values.

OBJECTIVES: The objectives of this study were to determine the value of phenylalanine (Phe) loading for diagnosing dopa-responsive dystonia (DRD) in children. METHODS: We investigated orally administered Phe loading tests (100 mg/kg) in seven patients with confirmed DRD and 17 pediatric patients with clinically suspected but excluded DRD. Results of Phe, tyrosine (Tyr), and biopterin from plasma and dried blood spot (DBS) analyses were correlated, and pediatric cutoff values established. RESULTS: The peak Phe concentration following a Phe load in the pediatric DRD population is lower than reported in adults. By using adult cutoff values and either Phe/Try ratios or biopterin concentrations only, false positive and false negative results are frequent. Only the combined analysis of the Phe/Tyr ratio and biopterin concentration is reliable in children. In children with DRD, dried blood Phe/Tyr ratio exceeded 4.6 (plasma Phe/Tyr ratio >5.4) after 2 h and biopterin concentration in dried blood remained below 16.2 nmol/L (plasma biopterin <14 nmol/L) 1 h after Phe challenge. CONCLUSIONS: Phe loading is a useful tool for diagnosing DRD in children. Test duration can be reduced to only 2 h, and specific pediatric cutoff values need to be applied. Simultaneous measurements of the Phe/Tyr ratio and biopterin in plasma or DBS are essential in pediatric patients.

White matter abnormalities and dystonic motor disorder associated with mutations in the SLC16A2 gene.

AIM: Mutations in the SLC16A2 gene have been implicated in Allan-Herndon-Dudley syndrome (AHDS), an X-linked learning disability* syndrome associated with thyroid function test (TFT) abnormalities. Delayed myelination is a non-specific finding in individuals with learning disability whose genetic basis is often uncertain. The aim of this study was to describe neuroimaging findings and neurological features in males with SLC16A2 gene mutations. METHOD: We reviewed brain magnetic resonance imaging (MRI) findings and neurological features in a cohort of five males aged between 1 year 6 months and 6 years (median 4y) from four families harbouring SLC16A2 gene mutations. RESULTS: The participants presented aged between 4 and 9 months with initial hypotonia and subsequent spastic paraparesis with dystonic posturing and superimposed paroxysmal dyskinesias. Dystonic cerebral palsy was the most common initial clinical diagnosis, and AHDS was suspected only retrospectively, considering the characteristically abnormal thyroid function tests, with high serum tri-iodothyronine (T(3)), as the most consistent finding. Brain MRI showed absent or markedly delayed myelination in all five participants, prompting the suspicion of Pelizaeus-Merzbacher disease in one patient. INTERPRETATION: Our findings indicate a consistent association between defective neuronal T(3) uptake and delayed myelination. SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. Although dysmorphic features suggestive of AHDS are not always present, T(3) measurement is a reliable screening test.

Homocysteine and serum markers of immune activation in primary dystonia.

The cause of primary dystonia remains unknown. Several reports point to immune system disturbances in primary dystonia and a recent study demonstrated hyperhomocysteinemia in cervical dystonia. Homocysteine (HCY) is an amino acid and elevated HCY concentrations were shown to be associated with immune system activation and increased neopterin serum concentrations. We examined HCY serum concentrations together with serum markers of immune activation in patients with different types of primary dystonia. Eighty-three patients with different types of primary dystonia were included and investigated at least 3 months following botulinum toxin treatment. Thirty-six healthy volunteers with similar age and sex distribution served as controls. Total serum HCY, kynurenine, and tryptophan concentrations were determined by high-performance liquid chromatography; neopterin, folate, and vitamin B12 concentrations were measured by immunoassays. Routine blood analysis, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and white blood count (WBC), was performed. Patients with primary dystonia had significantly higher HCY concentrations compared to controls. Among the dystonia subtypes, no significant difference of HCY serum concentrations was observed. CRP and ESR were within the normal range in >90% of the patients and all had normal WBC. Neopterin, kynurenine, and tryptophan serum concentrations were similar in patients and controls and not correlated with HCY serum concentrations. The results provide evidence against enhanced cellular immune activation in patients with primary dystonia. However, hyperhomocysteinemia was present in all dystonia subtypes and unrelated to immune activation in this study. HCY is a neuronal excitotoxic amino acid and hyperhomocysteinemia is considered an independent vascular risk factor. Further studies are required to define the background of hyperhomocysteinemia in primary dystonia.

Status Dystonicus: study of five cases.

Status Dystonicus (SD) is characterized by generalized muscle contractions in dystonic patients. We report 5 cases of SD, two of which in patients with dystonic cerebral palsy, one in a patient with primary segmental dystonia, one in a patient with Hallervorden-Spatz syndrome and one in a patient with Wilson's disease (WD). Three patients were admitted to an intensive care unit and treated with propofol and midazolam, and two were submitted to neurosurgical procedures (bilateral pallidotomy and bilateral pallidal deep brain stimulation). Triggering factors were identified in three patients as follows: infection, stress-induced and zinc therapy for WD. On follow-up, two patients presented with significant improvement of dystonia, whereas the other three cases the clinical picture ultimately returned to baseline pre-SD condition.

Status dystonicus: study of five cases

O "Status Dystonicus" (SD) é uma situação clínica caracterizada por contratura muscular generalizada em pacientes com distonias. Relatamos cinco casos de SD, que ocorreram em dois pacientes com distonia associada à paralisia cerebral, um paciente com distonia segmentar primária, um com síndrome de Hallervorden-Spatz e um com doença de Wilson (DW). Três pacientes foram submetidos a tratamento em terapia intensiva com uso de propofol e midazolam e dois pacientes foram submetidos ao tratamento neurocirúrgico (um paciente com palidotomia bilateral e outro com estimulador cerebral profundo palidal bilateral). Em três casos foram identificados fatores desencadeantes: infecção, estresse acentuado e o uso de zinco no tratamento da DW. Em dois pacientes ocorreu melhora importante do quadro distônico, e outros três retornaram à situação clínica pré-SD.

Adult-onset generalized dystonia due to a mutation in the neuroferritinopathy gene.

Neuroferritinopathy is a recently recognized autosomal dominant disorder that results in abnormal aggregates of iron and ferritin in the brain due to a mutation in the ferritin light chain gene on chromosome 19q13.3. We present the clinical details of a patient with adult-onset generalized dystonia associated with this mutation. Neuroferritinopathy appears to be a rare disorder; hence, there is a need to report new cases to further our understanding of the clinical phenotype, diagnostic challenges, the course of the condition and imaging characteristics.

Reduction of Menkes mRNA and copper in leukocytes of patients with primary adult-onset dystonia.

Studies on postmortem tissue of patients with primary adult-onset dystonia revealed a significant increase in copper levels and a reduction of copper transporting Menkes protein of the lentiform nuclei. Here we demonstrate that patients with idiopathic adult-onset cervical dystonia (n = 14) have reduced Menkes mRNA copies and lower copper levels in leukocytes compared to controls (n = 17; U test, p < 0.05). Changes were less distinct in patients with blepharospasm. Therefore, disturbances of copper metabolism in focal dystonia may not be restricted to the basal ganglia.

Molecular mechanisms of hereditary progressive dystonia with marked diurnal fluctuation, Segawa's disease.

The causative gene for hereditary progressive dystonia with marked diurnal fluctuation/dopa-responsive dystonia (HPD/DRD) was discovered in 1994 to be guanosine triphosphate (GTP) cyclohydrolase I, an enzyme involved in tetrahydrobiopterin biosynthesis. To the present, more than 50 mutations have been found in this gene in HPD/DRD patients. Although it is clear that HPD/DRD is caused by partial deficiency of tetrahydrobiopterin in the brain, several important issues regarding the molecular etiology of HPD/DRD remain to be addressed. We review herein the recent progress in the molecular genetics of HPD/DRD and clarify the points to be answered.