Denise Hack Nicaretta

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.

Depression in Parkinson's disease: diagnosis and treatment

The prevalence of non-motor symptoms in Parkinsons disease (PD) is high. Depression varies from 20 to 50% of the PD patients, and is associated with increasing disability. The key characteristics of depression are anhedonia and low mood. The recommended scales for screening purposes are: HAM-D, BDI, HADS, MADRS and GDS. As for measurement of severity: HAM-D, MADRS, BDI and SDS. In cases with mild depression, non-pharmacological intervention is the treatment of choice. In moderate depression, antidepressants are required. The choice of an antidepressant should be based mainly on the comorbidities and unique features of the patient. Evidence for antidepressant effectiveness is seen mostly with amitriptyline and nortriptyline, but one should be cautious in elderly patients. Other antidepressants that can be prescribed are: citalopram, escitalopram, sertraline, bupropion, trazodone, venlafaxine, mirtazapine and duloxetin. The dopaminergic agonist pramipexole is a treatment option.

Paroxysmal dystonia and neuromyelitis optica

Paroxysmal dyskinesias (PD) are thought to be rare movement disorders. The overwhelming majority of reported cases are primary. Secondary PD has seen reported to occur in some conditions, mainly in multiple sclerosis and head trauma. The anatomic origin of the lesion is also rarely seen at the spinal cord. Our objective was to describe four patients with paroxysmal dystonia secondary to spinal lesions during the recovering phase of a neuromyelitis optica (NMO) bout. In the reviewed literature, we do not find any report of PD related to NMO.

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.

Genetic analysis of LRRK2 functional domains in Brazilian patients with Parkinson's disease

Background and purpose:  Mutations in the leucine‐rich repeat kinase 2 gene (LRRK2) have been associated with Parkinson’s disease (PD), and the majority of the pathogenic variants are located in the ROC and MAPKKK domains.

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.

Holmes tremor in an HIV positive patient worsened by immune recovery inflammatory syndrome (IRIS).

IRIS is characterized by a paradoxical deterioration of clinical status after initiation of Anti-Retroviral Therapy (ART), despite improved immune function. It is caused by inflammatory response against the infectious antigen [1]. IRIS typically occurs in patients with a low initial CD4 (usually <50) and a rapid decline in viral load [2]. It is seen within a broad spectrum of HIV-related opportunistic infectious diseases and autoimmune disorders in patients who had been given Highly Active Anti-Retroviral Therapy (HAART) [3]. Our objective is to describe an HIV positive patient with Holmes ́ tremor worsened by IRIS, with marked recovery after therapy with steroids.

Parkinsonism and AIDS: a clinical comparative study before and after HAART.

In 2002, after analyzing 28 HIV-positive patients with movement disorders we emphasized the decreasing not only of Parkinsonism but also of other involuntary movements in HIV patients in the last few years. The objective of this study is to compare the clinical results between HIV-positive patients with Parkinsonism before and after HAART. In 14 years (1986-1999) 2,460 HIV-positive patients were seen in our Hospital 14 (0.6%) of which presented with Parkinsonism. Eight years after (2000-2007) 970 HIV positive patients were seen and only two (0.2%) had Parkinsonism. We conclude that after the introduction of HAART there was an evident decrease in AIDS-related Parkinsonism.

Genetic Analysis of PARK2 and PINK1 Genes in Brazilian Patients with Early-Onset Parkinson's Disease

Parkinsons disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinsons disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5–10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinsons disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinsons disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide.

Tremor: adaptação de uma escala clínica

The Fahn, Tolosa e Maríns clinical rating scale for tremor was adapted to our country for evaluation of tremor. This scale was applied to 123 patients with this movement disorder, selected from the Ambulatory of General Medicine at Hospital Universitário Pedro Ernesto da Universidade do Estado do Rio de Janeiro. These patients had been chosen no matter the etiology of their condition or their age. Although some variants may had influenced the scores of this particular scale, they did not seem to change its standardization and applicability.