Sarah Teixeira Camargos

Familial Parkinsonism and Early Onset Parkinson's Disease in a Brazilian Movement Disorders Clinic: Phenotypic Characterization and Frequency of SNCA, PRKN, PINK1, and LRRK2 Mutations

The aim of the study was to evaluate the frequency and to perform phenotypic and genotypic characterization of familial Parkinsonism and early onset Parkinsons disease (EOPD) in a Brazilian movement disorder unit. We performed a standardized clinical assessment of patients followed by sequencing of PRKN, PINK1 in EOPD cases and SNCA, LRRK2 in familial Parkinsonism individuals. During the period of study (January through December, 2006), we examined 575 consecutive patients of whom 226 (39.3%) met the diagnosis of Parkinsonism and idiopathic Parkinsons disease (IPD) was diagnosed in 202 of the latter. Of the IPD cases, 45 (22.3%) had EOPD. The age at onset in the EOPD cases (n = 45) was 34.8 ± 5.4 years (mean ± standard deviation). The age at onset in the familial late‐onset PD patients (n = 8) was 52.3 ± 12.2 years. In the early onset cases, we identified five known mutations in PRKN, two single heterozygous and three compound heterozygous (P153R, T240M, 255Adel, W54R, V3I); in addition, we identified one novel mutation in PINK1 (homozygous deletion of exon 7). In the familial cases (late onset), 1 patient had a novel LRRK2 variant, Q923H, but no SNCA mutations were identified. We have demonstrated that EOPD accounts for a high frequency of IPD cases in our tertiary referral center. PRKN was the most commonly mutated gene, but we also identified a novel mutation in PINK1 and a novel variant in LRRK2.

ETIOLOGY OF PARKINSONISM IN A BRAZILIAN MOVEMENT DISORDERS CLINIC

OBJECTIVE The aim of the present study is to investigate whether there are geographic differences in the etiology of parkinsonism (PA). BACKGROUND 72% of patients with PA evaluated at movement disorders clinics in the Northern Hemisphere are diagnosed with Parkinsons disease (PD). Data regarding other regions are not available. METHODS We reviewed the charts of all patients with PA seen at the Federal University of Minas Gerais Movement Disorders Clinic from July 1993 through October 1995. PA was diagnosed by the presence of at least two of the following: rest tremor, bradykinesia, rigidity, and postural instability. The different etiologies were diagnosed based on standard clinical criteria. RESULTS During the period of the study, PA was recognized in 338 subjects. The following clinical diagnoses were made: PD (68.9%), drug-induced PA (DIP) (13.3%), vascular PA (4.7%), Progressive supranuclear palsy (PSP) (2%), multiple system atrophy (MSA) (1.8%), others (9.7%). Cinnarizine, haloperidol and flunarizine were the commonest drugs related to DIP. CONCLUSIONS Similarly to other studies, PD accounts for about 70% of PA patients. However, there are differences between our results and previous series. DIP is much more common in the present series. This may be accounted for a more liberal use of antidopaminergic drugs in our environment, especially Calcium channel blockers. The lower frequency of MSA and PSP in our study may reflect a short follow-up, since many patients initially diagnosed with PD later are found to have Parkinson-plus syndromes.

Pregnancy in patients with Sydenham’s Chorea

BACKGROUND Sydenhams Chorea is a frequent cause of chorea during pregnancy, chorea gravidarum. The aim of this article is to describe the effect of pregnancy in a consecutive series of patients with diagnosis of Sydenhams Chorea. METHODS A chart review was performed of all patients with the diagnosis of Sydenhams Chorea followed up at our institution from 07/1993 through 08/2010 and who became pregnant. RESULTS From 66 patients, 20 became pregnant. Of these 20 patients, 15 (75%) developed chorea gravidarum. Generalized chorea was found in 67% of these 15 patients, focal or multifocal chorea was identified in 20% and 13.4% developed hemichorea. In 80% of cases chorea began in the first 6 months of gestation. Three women with previous persistent chorea experienced worsening of the movement disorder during pregnancy. Remission occurred after delivery in 11 patients whereas the other four remained with non-disabling chorea during the first 12 months after delivery. Abortion occurred in two patients (13%). All patients with chorea gravidarum subsequently treated with oral contraceptives developed recurrence of chorea. CONCLUSIONS Chorea gravidarum is a frequent complication of pregnancy in patients with previous history of Sydenhams Chorea and an increased risk of miscarriage should be considered. Our findings confirm the notion that chorea gravidarum results from hormonal changes acting on previously dysfunctional basal ganglia.

Sensory tricks in focal dystonia and hemifacial spasm

Sensory tricks are sensory, often but not exclusively tactile, stimuli usually in the body part affected by the movement disorder that produce a meaningful alleviation of dystonia. The frequency and clinical features of sensory tricks in different types of dystonia are poorly studied in the literature. There is no information regarding the presence of a similar phenomenon in HFS.

A Brazilian family with Brown-Vialetto-van Laere syndrome with autosomal recessive inheritance

We report the first Brazilian family with Brown-Vialetto-van Laere syndrome. The presence of consanguineous marriages and illness affecting three sisters and one niece support an autosomal recessive transmission. The age at onset of the illness ranged from 12 to 20 years old. The time interval between hearing loss and involvement of other cranial nerves varied from 3 to 12 years. MRI demonstrated bulbar atrophy and also high intensity signal at T2 weighted and fluid attenuated inversion recovery (FLAIR) sequences.

Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT.

Background: Point mutation P222L in PKR activator PACT causes movement disorder dystonia. Results: PACT mutant P222L causes delayed and prolonged PKR and eIF2α phosphorylation in response to the ER stress. Conclusion: Altered kinetics of PKR activation in response to the ER stress enhances apoptosis in dystonia cells. Significance: This is the first study of molecular mechanisms involved in dystonia 16. PACT is a stress-modulated activator of the interferon-induced double-stranded RNA-activated protein kinase (PKR). Stress-induced phosphorylation of PACT is essential for PACTs association with PKR leading to PKR activation. PKR activation leads to phosphorylation of translation initiation factor eIF2α inhibition of protein synthesis and apoptosis. A recessively inherited form of early-onset dystonia DYT16 has been recently identified to arise due to a homozygous missense mutation P222L in PACT. To examine if the mutant P222L protein alters the stress-response pathway, we examined the ability of mutant P222L to interact with and activate PKR. Our results indicate that the substitution mutant P222L activates PKR more robustly and for longer duration albeit with slower kinetics in response to the endoplasmic reticulum stress. In addition, the affinity of PACT-PACT and PACT-PKR interactions is enhanced in dystonia patient lymphoblasts, thereby leading to intensified PKR activation and enhanced cellular death. P222L mutation also changes the affinity of PACT-TRBP interaction after cellular stress, thereby offering a mechanism for the delayed PKR activation in response to stress. Our results demonstrate the impact of a dystonia-causing substitution mutation on stress-induced cellular apoptosis.

Ziprasidone-related oculogyric crisis in an adult

INTRODUCTION Drug-induced dyskinesias are common side-effects of first-generation antipsychotics (FGAs) but are not usually related to second-generation antipsychotics (SGAs). Oculogyric crisis (OGC) is a disabling acute dystonia that affects extra-ocular muscles usually resulting in an upward deviation of the eyes, which lasts from minutes to hours. CASE REPORT We describe an adult patient, previously exposed to an FGA, who developed OGC on 80mg/day of ziprasidone. The movement disorder significantly improved after use of 1mg/day of clonazepam without the need to switch to another SGA. DISCUSSION The clinical features of the movement disorder of our patient meet the criteria for OGC. It is, sometimes, difficult to directly correlate a drug-induced dyskinesia to a SGA due to previous exposures to FGAs. The onset of OGC after exposure to ziprasidone without simultaneous use of other antipsychotic suggests a casual relationship between the former and the movement disorder. It is possible that previous use of an FGA was a risk factor for the development of OGC. CONCLUSION To the best of our knowledge, this is the first report of ziprasidone-related OGC in an adult patient. Physicians must be aware of its occurrence in order to improve care of patients treated with these agents.

DYT6 in Brazil: Genetic Assessment and Clinical Characteristics of Patients.

Background Several genes associated with dystonia have been identified. A mutation in one of these, THAP1 (DYT6), is linked to isolated dystonia. The aim of this study was to assess the prevalence of THAP1 gene mutations and the clinical characteristics of patients with these mutations in a clinical population in Brazil. Methods Seventy-four patients presenting with dystonia involving the cervical muscles and without mutations in the TOR1A (DYT1) gene or any other movement disorders were recruited at a movement disorders clinic between June 2008 and June 2009. All the patients underwent clinical examination and were screened for mutations of the THAP1 gene. Results Three patients had the novel p.Gln97Ter THAP1 nonsense mutation in heterozygosis. One of them had no family history of dystonia. Symptoms in this patient first appeared in his right arm, and the condition progressed to the generalized form. The other two patients belonged to the same family (cousins). Symptoms in the first patient started in her right arm at the age of 18 years and the condition progressed to the segmental form. The second patient, who carried the p.Arg169Gln missense mutation, developed dystonia in her left arm at the age of 6 years. The condition progressed to generalized dystonia. Discussion We conclude that THAP1 mutations are also a cause, albeit uncommon, of segmental and generalized dystonia in the Brazilian population.

The genetics of the dystonias – a review based on the new classification of the dystonias

The definition and classification of the dystonias was recently revisited. In the new 2013 classification, the dystonias are subdivided in terms of their etiology according to whether they are the result of pathological changes or structural damage, have acquired causes or are inherited. As hereditary dystonias are clinically and genetically heterogeneous, we sought to classify them according to the new recently defined criteria. We observed that although the new classification is still the subject of much debate and controversy, it is easy to use in a logical and objective manner with the inherited dystonias. With the discovery of new genes, however, it remains to be seen whether the new classification will continue to be effective.

Cervical dystonia: about familial and sporadic cases in 88 patients

Cervical dystonia (CD) affects the musculature of the neck in a focal way or associated to other parts of the body. The aim of this study was to identify clinical differences between patients with dystonia patients without family history and with family history (sporadic). Eighty-eight patients with CD were recruited in a Movement Disorders Clinic between June of 2008 and June of 2009. Only patients with no etiological diagnosis were accepted for analysis. The age of onset of symptoms was later in patients with focal and segmental dystonia than in patients with generalized dystonia (p<0.001). The severity of symptoms was higher in patients with sporadic dystonia than in familial patients (p<0.01). Generalized cases were more severe in patients with a family history (p<0.01). Sporadic patients had higher levels of pain than familial cases (p<0.05). We expect soon to present the results of genetic analyzes of these patients.