Omar Buriticá

A novel Cys212Tyr founder mutation in parkin and allelic heterogeneity of juvenile Parkinsonism in a population from North West Colombia

We report the molecular characterization of three multiplex families and a sporadic case of juvenile Parkinsonism identified in the province of Antioquia (Colombia). Linkage and haplotype analysis using markers in 6q25.2-27 indicated that Parkinsonism in the pedigrees is linked to the parkin gene (maximum LOD-score of 3.85) but that they carry two different mutant haplotypes. Sequence analysis revealed a novel G to A transition in exon 6 at position 736 (G736A) of parkin. This change results in a non-conservative cysteine for tyrosine substitution. All affected individuals from two families were homozygous for this mutation, which was not detected in 100 normal controls. Patients from the family carrying the second haplotype and the sporadic case were homozygous for a GT insertion in exon 3. This mutation has been previously identified in French families with juvenile Parkinsonism. The concomitant presence of founder effects and allelic heterogeneity in Antioquia might relate to the founding admixture at the origin of this population.

Syntax, action verbs, action semantics, and object semantics in Parkinson's disease: Dissociability, progression, and executive influences

Several studies have recently shown that basal ganglia (BG) deterioration leads to distinctive impairments in the domains of syntax, action verbs, and action semantics. In particular, such disruptions have been repeatedly observed in Parkinsons disease (PD) patients. However, it remains unclear whether these deficits are language-specific and whether they are equally dissociable from other reported disturbances -viz., processing of object semantics. To address these issues, we administered linguistic, semantic, and executive function (EFs) tasks to two groups of non-demented PD patients, with and without mild cognitive impairment (PD-MCI and PD-nMCI, respectively). We compared these two groups with each other and with matched samples of healthy controls. Our results showed that PD patients exhibited linguistic and semantic deficits even in the absence of MCI. However, not all domains were equally related to EFs and MCI across samples. Whereas EFs predicted disturbances of syntax and object semantics in both PD-nMCI and PD-MCI, they had no impact on action-verb and action-semantic impairments in either group. Critically, patients showed disruptions of action-verb production and action semantics in the absence of MCI and without any executive influence, suggesting a sui generis deficit present since early stages of the disease. These findings indicate that varied language domains are differentially related to the BG, contradicting popular approaches to neurolinguistics.

Autosomal recessive juvenile parkinsonism Cys212Tyr mutation in parkin renders lymphocytes susceptible to dopamine- and iron-mediated apoptosis

Mutations in parkin are implicated in the pathogenesis of autosomal recessive juvenile parkinsonism (AR‐JP) disease. We show that homozygote Cys212Tyr parkin mutation in AR‐JP patients renders lymphocytes sensitive to dopamine, iron and hydrogen peroxide stimuli. Indeed, dopamine‐induced apoptosis by four alternative mechanisms converging on caspase‐3 activation and apoptotic morphology: (1) NF‐κB‐dependent pathway; mitochondrial dysfunction either by (2) H2O2 or (3) hydroxyl exposure and (4) increase of unfolded–protein stress. We also demonstrate that 17β‐estradiol and testosterone prevent homozygote lymphocytes from oxidative stressors‐evoked apoptosis. These results may contribute to understanding the relationship between genetic and environmental factors and iron in AR‐JP.

Prevalence of Parkinson's disease and parkinsonism in a Colombian population using the capture-recapture method.

Our objective was to estimate the prevalence of Parkinsons disease (PD) and Parkinsonism (Ps) in Antioquia (Colombia), using the Capture-Recapture method. The two biggest institutions for attending neurological patients in Antioquia were selected as sources for the use of the Capture-Recapture method. Prevalences of PD (PPD) and Ps (PPs) were estimated according to the following expression: PPD (or PPs) = n/Nl105. The number of cases (n) of PD (or Ps), n = a + b + c + d, where a = cases identified from the two sources, b = cases identified only in the first source, c = cases identified only in the second source, and d = nondetected cases from any source = bc/a. The projected Antioquian population for the year 2000 was used as denominator. Information obtained between January 1, 1996, and December 31, 2000, was reviewed in order to identify the clinical records of all patients that fulfilled the Ps or PD criteria. General prevalence of PD in Antioquia was 30.7/100.000 (C195% = 29.2-32.2), and that of Ps was 42.1/100.000 (CI95% = 40.3-43.8). Prevalence of PD in people older than 50 years was 176.4/100.000 (CI95% = 166.6-186.3) and that of Ps was of 339.6/100.000 (C195% = 326.0-353.2). Ps and PD prevalences in Antioquia were lower than the figures reported by the National Neuroepidemiologic Study (470/100.000) and similar to the estimated prevalence of these diseases in Caucasian populations (80 to 270/100.000). These findings evidence the great variability of PD prevalence in different regions; therefore, a nationwide study is necessary to determine the prevalence of PD and Ps in Colombia

A genetic cluster of early onset Parkinson's disease in a Colombian population†

We previously identified in two families with early onset Parkinsons Disease (PD) from the isolated population of Antioquia (Colombia), a parkin Cys212Tyr substitution caused by a G736A mutation. This mutation was subsequently observed in a Spanish family, suggesting that it could have been taken to Antioquia by Spanish immigrants. Here we screened for the G736A mutation in additional Antioquian early onset PD cases and used haplotype analysis to investigate the relationship between Spanish and Antioquian G736A chromosomes. We confirmed the occurrence of an extensive founder effect in Antioquia. Thirteen individuals (10 homozygotes) from seven nuclear families were identified with the G736A mutation. Genealogical investigations demonstrated the existence of shared ancestors between six of these families four to five generations ago and no evidence of Spanish ancestry during this period. A second parkin mutation (a duplication of exon 3), was detected in the three G736A heterozygote carriers. Haplotype data exclude a recent common ancestry between the Spanish and Antioquian patients studied here and is consistent with the introduction of the G736A mutation in Antioquia during early colonial times (about 16 generations ago).

Alteraciones cognitivas en Parkinson Juvenil causado por la mutación C212Y en el gen Parkin.

In Antioquia, Colombia, four families have been reported with juvenile Parkinson´s disease and carrying the C212Y mutation in the Parkin gene. Many cognitive alterations associated with idiopathic, late-onset Parkinson´s disease have been described; however, little attention has been paid to the description of neuropsychological profiles in families carrying mutations in genes associated with juvenile Parkinson´s disease. For this study we selected a group of ten homozygous carriers of Parkin mutation C212Y with the clinical and a group of molecular diagnosis of Parkinson´s disease, and ten healthy relatives as controls. The neuropsychological evaluation revealed statistically significant differences between the two groups (p < 0.05) in Minimental State Examination and in tests evaluating working memory and attention in which prolonged execution times and marked slowing down of information processing were observed. We suggest that the observed alterations could be considered as neuropsychological features of patients with the C212Y mutation in the Parkin gene, the phenotypic expression of which seems to be associated in this population with slow evolution, mild cognitive impairment and functional involvement.