João Santos Pereira

A study of LRRK2 mutations and Parkinson's disease in Brazil

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are known as a common cause of Parkinsons disease (PD) among patients from different geographic origins. In this study, we evaluated the prevalence of LRRK2 mutations in exons 31 and 41 in a cohort of 154 consecutive, unrelated Brazilian patients with familial or sporadic PD, including early and late onset patients. The LRRK2 p.G2019S mutation was present in heterozygous state in three index cases (approximately 2%), and in three additional relatives. No carriers of this mutation were found among 250 control chromosomes. Clinically, all mutation-positive patients presented a typical PD phenotype and a good response to levodopa. Mutation segregation analysis in a large sibling showed incomplete penetrance of the p.G2019S. Our findings suggest that the LRRK2 p.G2019S mutation has a substantial contribution to PD susceptibility among Brazilian population and add new clues to current research of this disease.

Análise da função respiratória na doença de Parkinson

We studied 40 parkinsonian patients (P), mean age 50-80 years, with Hoehn and Yahr stages I-III and 40 no parkinsonian patients (NP), with similar characteristics. The results of the thoracic amplitude was 1,8±0,8cm of P that showed a reduction to 4,3±1,0 cm of NP (p=0,00001), the vital capacity and forced vital capacity, 66,8±20,3% and 69,6±22,2% of P was decreased that 82,3±15,7% and 82,7±16,6% of NP (p=0,00001 and p=0,0023). There was not difference among the maximal inspiratory and expiratory mouth pressures, 33,5±12,7 cmH2O and 36,3±17,8 cmH2O of P and 37,0±12,2 cmH2O and 43,1±16,6 cmH2O of NP (p=0,1753 and p=0,0398), the forced expiratory volume in 1 second, 71,3±25,6% of P and 80,6±23,6% of NP (p=0,0899), and the forced expiratory volume in 1 second/ forced vital capacity, 104,5±19,9% of P and 97,4±22,8% of NP (p=0,1234). The parkinsonian patients present restrictive pulmonary dysfunction, low chest wall compliance and the respiratory muscle strenght do not decreased.

Effects of using the Nintendo Wii Fit Plus Platform in the sensorimotor training of gait disorders in Parkinson’s disease

The use of the Nintendo Wii has been considered a good alternative in the motor rehabilitation of individuals with Parkinson’s disease (PD), requiring simultaneous interaction to develop strategies for physical, visual, auditory, cognitive, psychological and social activities in the performing of virtual activities, resulting in improvement in functional performance and gait. The aim of this study was to analyze the effect of virtual sensorimotor activity on gait disorders in people with PD. Fifteen subjects with a clinical diagnosis of PD were submitted to the Unified Parkinson’s Disease Rating Scale (UPDRS III), Schwab and England Activities of Daily Living Scale (SE), Functional Independence Measure (FIM), and biomechanical gait analysis using digital images taken with a video camera before and after the treatment program. The activities with the Nintendo Wii virtual platform were standardized into three categories: aerobics, balance and Wii plus exercises. Participants carried out separate virtual exercises for 40 min, twice a week, for a total of 14 sessions. The program improved sensorimotor performance in PD gait, with an increase in stride length and gait speed, in addition to a reduction in motor impairment, especially in items of rigidity and flexibility of the lower limbs evaluated by UPDRS III, and greater functional independence, as evidenced in the SE and FIM scales. Improvements in items related to locomotion and stair climbing were also observed. The training was effective in motor recovery in chronic neurodegenerative diseases, showing improvement in motor performance and functional independence in individuals with PD.

Co-occurrence of Sporadic Parkinsonism and Late-Onset Alzheimer's Disease in a Brazilian Male with the LRRK2 p.G2019S Mutation

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent the most common known genetic cause of inherited and idiopathic Parkinsons disease (PD) in different populations. The predicted multifunctionality of LRRK2 product and the pleomorphic pathology associated with LRRK2 mutations place this gene as a potential candidate for other neurodegenerative disorders, mainly Alzheimers disease (AD). We report a Brazilian male expressing both late-onset AD and slowly progressive parkinsonism signs, and who presented the most frequent LRRK2 mutation (p.G2019S). Although the co-occurrence of PD and AD would be expected occasionally, the shared mechanisms between the two complex disorders are still unclear and are discussed herein. In light of recent findings about the wide role of LRRK2 under normal and pathological conditions, it is tempting to speculate that LRRK2 mutations might play an upstream influence on the etiology of not just PD but also several alpha-synuclein and tau pathologies, including AD.

Parkinson's disease dementia: Diagnostic criteria and risk factor review.

Cognitive impairment in Parkinson’s disease (PD) greatly affects the morbidity and mortality rates of the disease and can be present as mild executive dysfunction even in the early stages. In advanced PD, the prevalence of dementia (PDD) reaches more than 80%. The Movement Disorders Society (MDS) has proposed diagnostic criteria for PDD and Mild Cognitive Impairment (MCI) in PD, raising the sensibility and specificity of those diagnoses compared with DSM IV, for example. Cognition impairment is an important issue to determine in PD because of therapeutic, epidemiologic, and prognostic factors. These guidelines should be applied to a diagnosis of PD-MCI and PDD as soon as possible in order to provide a correct diagnosis. Another important topic to discuss regarding cognition in PD is which patient would be more likely to develop PDD. There are some risk factors for cognitive impairment in PD with cumulative risk. Important risk factors related to PDD are age, time of diagnosis, rigid-akinetic phenotype, severe impairment, impairment of semantic fluency, genetic factors, low education level, and postural instability. Recognizing them is also important for early diagnosis. We discuss the diagnostic criteria of PD cognitive impairment and some aspects of risk factors related to it in this review.

Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease

In the last decade, several genes have been linked to Parkinsons disease (PD), including GIGYF2, ATP13A2 and GBA. To explore whether mutations in these genes contribute to development of PD in the Brazilian population, we screened 110 patients with early-onset PD. No clearly pathogenic mutations were identified in ATP13A2 and GIGYF2. In contrast, we identified a significantly higher frequency of known pathogenic mutations in GBA gene among the PD cases (6/110=5.4%) when compared to the control group (0/155) (P=0.0047). Our results strongly support an association between GBA gene mutations and an increased risk of PD. Mutations in GIGYF2 and ATP13A2 do not seem to represent a risk factor to the development of PD in the Brazilian population. Considering the scarcity of studies on GIGYF2, ATP13A2 and GBA mutation frequency in Latin American countries, we present significant data about the contribution of these genes to PD susceptibility.

Exon dosage variations in Brazilian patients with Parkinson's disease: Analysis of SNCA, PARKIN, PINK1 and DJ-1 genes

Parkinson’s disease is one of the most common neurodegenerative disorders associated with aging, reaching ∼ 2% of individuals over 65 years. Knowledge achieved in the last decade about the genetic basis of Parkinson’s disease clearly shows that genetic factors play an important role in the etiology of this disorder. Exon dosage variations account for a high proportion of Parkinson’s disease mutations, mainly for PARKIN gene. In the present study, we screened genomic rearrangements in SNCA, PARKIN, PINK1 and DJ-1 genes in 102 Brazilian Parkinson’s disease patients with early onset (age of onset ≤ 50 years), using the multiplex ligation-dependent probe amplification method. Family history was reported by 24 patients, while 78 were sporadic cases. Screening of exon dosage revealed PARKIN and PINK1 copy number variations, but no dosage alteration was found in SNCA and DJ-1 genes. Most of the carriers harbor heterozygous deletions or duplications in the PARKIN gene and only one patient was found to have a deletion in PINK1 exon 1. Data about dosage changes are scarce in the Brazilian population, which stresses the importance of including exon dosage analysis in Parkinson’s disease genetic studies.

Hemichorea-Hemiballismus as the First Sign of Type 1b Diabetes During Adolescence and Its Recurrence in the Setting of Infection

Chorea may be secondary to hyperosmolar nonketotic hyperglycemia, but such situation has rarely been described in adolescents, particularly as the initial and single manifestation of type 1 diabetes. We describe a case of a previously healthy 14-year-old girl with sudden onset of choreic movements on her left upper and lower limbs. Brain computed tomography (CT) and magnetic resonance imaging (MRI) revealed an area of hyperdensity/hyperintensity affecting the right striatum. Blood glucose was 349 mg/dL. Despite adequate glucose control, the involuntary movements persisted and haloperidol, later substituted with valproate, was prescribed, with satisfactory but not complete resolution of the chorea. In 2 other occasions, when the patient had an infection and subsequent hyperglycemia, the chorea relapsed. Although not common, hyperglycemia must be considered in the differential diagnosis of acute hemichorea-hemiballismus in children and adolescents, particularly because it is a potentially reversible cause.

A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats

Tardive dyskinesia (TD), a serious complications of neuroleptic chronic use, has no effective therapy yet. We performed an experiment to study the action on TD, of the calcium channel blockers (CCB) drugs, verapamil and flunarizine. We obtained the TD model in rats, administering haloperidol for a 21-day period. After this, the stereotyped movement induced by apomorphine was rated. The CCB drugs were administered in acute (in the 28th day) and chronic (for 8 days, after the 25th day) experiments. Acutely, verapamil increased the stereotyped behaviour, and promoted a reduction of it in the chronic experiment. The results suggest that CCB drugs should be tested in clinical trials of TD.

Association of LRRK2 and GBA mutations in a Brazilian family with Parkinson's disease

Parkinsons disease (PD) is a neurodegenerative condition secondary to the loss of dopaminergic neurons in the substantia nigra. Its pathogenesis is not completely understood, but advances in genetics in the past 15 years have provided new insights of possible metabolic pathways involved [1]. Several causative genes and susceptibility factors have been identified and among the most common are variants in LRRK2 and GBA genes. Mutations in LRRK2, located at 12q12, represent the most common cause of autosomal dominant PD. Pimentel et al. has previously demonstrated that G2019S mutation has a substantial contribution to PD susceptibility in the Brazilian population [2]. Mutations in GBA gene, located at 1q22, are known important risk factors for the development of PD. Carriers of one mutated allele of GBA have a 5-fold increase risk to develop PD, compared with non-carriers. A previous study has shown a frequency of about 3% of GBA mutations among PD Brazilian patients [3]. We herein describe a patient with a familial history of PD whose genetic analysis revealed heterozygosis for both GBA L444P and LRRK2 G2019Smutations. Other family members, all asymptomatic, were screened and 5 out of 7 also had mutations of both genes (the others did not have any of the mutations). A 47-year-old afro-descendant woman developed progressive rigidity on her upper and lower right limbs in 2005. She was diagnosed with PD two years later. She is currently on levodopa/carbidopa 250/25 mg 1⁄2 a tablet 5 times a day, clonazepam and amytriptiline. MMSE is 26 and she has fluent speech. Neuropsychological tests revealed reduced inhibitory control and slight damages to alternate attention, working memory and speed of information process. Planning, organization verbal fluency, thinking and abstraction were within normal values. She has reduced arm swing while walking, no tremor or postural instability and significant rigidity, worse on the right. On Beck depression inventory she scores 5. She scored 46 on UPDRS part III when she was off levodopa for 24 h and 26 one hour after taking levodopa. Brain MRI was unremarkable. Her parents were cousins in second-degree. They had 16 children, of which 6 are deceased for various reasons. The patient has