Voltage-gated potassium channel complex antibodies, particularly those directed against leucine-rich glioma inactivated 1, are associated with a common form of limbic encephalitis that presents with cognitive impairment and seizures. Faciobrachial dystonic seizures have recently been reported as immunotherapy-responsive, brief, frequent events that often predate the cognitive impairment associated with this limbic encephalitis. However, these observations were made from a retrospective study without serial cognitive assessments. Here, we undertook the first prospective study of faciobrachial dystonic seizures with serial assessments of seizure frequencies, cognition and antibodies in 10 cases identified over 20 months. We hypothesized that (i) faciobrachial dystonic seizures would show a differential response to anti-epileptic drugs and immunotherapy; and that (ii) effective treatment of faciobrachial dystonic seizures would accelerate recovery and prevent the development of cognitive impairment. The 10 cases expand both the known age at onset (28 to 92 years, median 68) and clinical features, with events of longer duration, simultaneously bilateral events, prominent automatisms, sensory aura, and post-ictal fear and speech arrest. Ictal epileptiform electroencephalographic changes were present in three cases. All 10 cases were positive for voltage-gated potassium channel-complex antibodies (346-4515 pM): nine showed specificity for leucine-rich glioma inactivated 1. Seven cases had normal clinical magnetic resonance imaging, and the cerebrospinal fluid examination was unremarkable in all seven tested. Faciobrachial dystonic seizures were controlled more effectively with immunotherapy than anti-epileptic drugs (P = 0.006). Strikingly, in the nine cases who remained anti-epileptic drug refractory for a median of 30 days (range 11-200), the addition of corticosteroids was associated with cessation of faciobrachial dystonic seizures within 1 week in three and within 2 months in six cases. Voltage-gated potassium channel-complex antibodies persisted in the four cases with relapses of faciobrachial dystonic seizures during corticosteroid withdrawal. Time to recovery of baseline function was positively correlated with time to immunotherapy (r = 0.74; P = 0.03) but not time to anti-epileptic drug administration (r = 0.55; P = 0.10). Of 10 cases, the eight cases who received anti-epileptic drugs (n = 3) or no treatment (n = 5) all developed cognitive impairment. By contrast, the two who did not develop cognitive impairment received immunotherapy to treat their faciobrachial dystonic seizures (P = 0.02). In eight cases without clinical magnetic resonance imaging evidence of hippocampal signal change, cross-sectional volumetric magnetic resonance imaging post-recovery, after accounting for age and head size, revealed cases (n = 8) had smaller brain volumes than healthy controls (n = 13) (P < 0.001). In conclusion, faciobrachial dystonic seizures can be prospectively identified as a form of epilepsy with an expanding phenot...

PLA2G6 mutations are associated with infantile neuroaxonal dystrophy and have been reported previously to cause early cerebellar signs, and the syndrome was classified as neurodegeneration with brain iron accumulation (type 2). Our cases have neither of these previously pathognomic features. Thus, mutations in PLA2G6 should additionally be considered in patients with adult-onset dystonia-parkinsonism even with absent iron on brain imaging.

Paroxysmal dyskinesias are episodic movement disorders that can be inherited or are sporadic in nature. The pathophysiology underlying these disorders remains largely unknown but may involve disrupted ion homeostasis due to defects in cell-surface channels or nutrient transporters. In this study, we describe a family with paroxysmal exertion-induced dyskinesia (PED) over 3 generations. Their PED was accompanied by epilepsy, mild developmental delay, reduced CSF glucose levels, hemolytic anemia with echinocytosis, and altered erythrocyte ion concentrations. Using a candidate gene approach, we identified a causative deletion of 4 highly conserved amino acids (Q282_S285del) in the pore region of the glucose transporter 1 (GLUT1). Functional studies in Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1.

Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson’s disease including supranu-clear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome. 3 2010 Movement Disorder Society

SummaryApproximately 10% of subjects thought clinically to have early Parkinson's disease (PD) have normal dopaminergic functional imaging (SWEDDs -Scans Without Evidence of Dopaminergic Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia. Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4) essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical features, the lack of true bradykinesia, occurrence of dystonia, and position-and task-specificity of tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to PAS, and the response of ET patients was no different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adultonset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.

In this study, we combined linkage analysis with whole-exome sequencing of two individuals to identify candidate causal variants in a moderately-sized UK kindred exhibiting autosomal-dominant inheritance of craniocervical dystonia. Subsequent screening of these candidate causal variants in a large number of familial and sporadic cases of cervical dystonia led to the identification of a total of six putatively pathogenic mutations in ANO3, a gene encoding a predicted Ca(2+)-gated chloride channel that we show to be highly expressed in the striatum. Functional studies using Ca(2+) imaging in case and control fibroblasts demonstrated clear abnormalities in endoplasmic-reticulum-dependent Ca(2+) signaling. We conclude that mutations in ANO3 are a cause of autosomal-dominant craniocervical dystonia. The locus DYT23 has been reserved as a synonym for this gene. The implication of an ion channel in the pathogenesis of dystonia provides insights into an alternative mechanism that opens fresh avenues for further research.

Clinical-pathological studies remain the gold-standard for the diagnosis of Parkinson’s disease (PD). However mounting data from genetic-PD autopsies challenge the diagnosis of PD based on Lewy body pathology. Most of the confirmed genetic risks for PD show heterogenous neuropathology, even within kindreds, which may or may not include Lewy body pathology. Here we review the literature of genetic-PD autopsies from cases with molecularly-confirmed PD or parkinsonism and summarize main findings on SNCA (n=25), Parkin (n=20, 17 bi-allelic and 3 heterozygotes), PINK1 (n=5, 1 bi-allelic and 4 heterozygotes), DJ-1 (n=1), LRRK2 (n=55), GBA (n=10 Gaucher disease patients with parkinsonism), DNAJC13, GCH1, ATP13A2, PLA2G6 (n= 8 patients, two with PD), MPAN (n=2), FBXO7, RAB39B and ATXN2 (SCA2), as well as on 22q deletion syndrome (n=3). Findings from autopsies of heterozygous mutation carriers of genes which are traditionally considered recessively-inherited are also discussed. Lewy bodies may be present in syndromes clinically distinctive from PD (e.g., MPAN-related neurodegeneration) and absent in patients with clinical PD syndrome (e.g., LRRK2-PD or Parkin-PD). Therefore, we may conclude that the presence of Lewy bodies are not specific to the diagnosis of PD and that PD can be diagnosed even in the absence of Lewy body pathology. Interventions that reduce alpha-synuclein load may be more justified in SNCA-PD or GBA-PD than in other genetic forms of PD. The number of reported genetic-PD autopsies remains small and there are limited genotype-clinical-pathological-phenotype studies. Therefore, larger series of autopsies from genetic-PD patients are required.

We present the clinical details and dopamine transporter SPECT scan results of 10 patients with arm tremor, including a rest component and reduced arm swing on the affected side, in whom the possibility of PD had been raised. All patients had signs of dystonia or components of their arm tremor that were compatible with dystonic tremor, and none had true akinesia with fatiguing or decrement, even after a mean follow-up period of 5.8 years. All patients had normal dopamine transporter SPECT scans. Clinicians should be aware that primary adult-onset dystonia can present with an asymmetric resting arm tremor, with impaired arm swing and sometimes also facial hypomimia or a jaw tremor, but without evidence of true akinesia. Given the important consequences of misdiagnosing such patients as PD, in cases with diagnostic uncertainty functional imaging should be considered. Among patients suspected of PD, dystonic tremor may be one cause of SWEDDs (Scans Without Evidence of Dopaminergic Deficit).