Carlos Santiago Uribe

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.

Primary angiitis of the central nervous system: report of five biopsy-confirmed cases from Colombia

INTRODUCTION Primary (isolated) angiitis of the central nervous system (PACNS) is a rare cause of cerebrovascular disease (CVD), and few leptomeningeal and brain biopsy (LBB)-confirmed cases have been reported from South America. METHODS We retrospectively reviewed charts of patients with diagnosis of cerebral angiitis admitted between March 1991 and July 2001 to a single university hospital in Medellin, Colombia. Patients with definitive diagnosis of PACNS by Alrawi et al.s LBB criteria were selected. We excluded other causes of cerebral angiitis as well as cases without LBB confirmation. RESULTS We report five patients, four men and one woman, with a mean age at onset of 24.4 years, and an average disease progression of 12.4 days. Four presented with headache and motor weakness, three had seizures, and two had alterations of consciousness. Cerebral MRI was abnormal in all five cases; brain CT in four, and cerebral angiography in two. The cerebrospinal fluid (CSF) was abnormal in two patients. Leptomeningeal and brain biopsies revealed mononuclear infiltration in the wall of small blood vessels in all. Three had concurrent meningeal and cerebral involvement, two had necrotizing angiitis, and one had vascular and encephalitic lesions. All received only steroid treatment; the 1-year follow-up revealed good prognosis without relapses. CONCLUSION We report five biopsy-proven cases of PACNS from Colombia associated with neurological and neuroimaging abnormalities; these patients presented a mild inflammatory disease that was correlated with few CSF abnormalities and good response to single steroid treatment without relapses. Leptomeningeal and brain biopsy is mandatory for a definitive diagnosis.

Clinical features of multiple sclerosis in a genetically homogeneous tropical population

Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian population in Antioquia, a tropical region of Colombia, were evaluated in order to observe the clinical behavior of the disease. The frequency of clinical manifestations in 65 patients with definite MS from Antioquia was compared with those reported from temperate regions. The most common manifestations were optic neuritis and motor symptoms with absence of cerebellar symptoms. This presentation is significantly different from the frequency distribution at onset in series from temperate regions. These differences suggest that environmental factors could modify the clinical expression of MS in this population.

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).

Multiple sclerosis: association to HLA DQalpha in a tropical population.

Studies performed in subtropical populations have found significant association between the phenotype multiple sclerosis (MS) and the major histocompatibility complex (MHC). We present the results of a case-control study conducted on a tropical population (Antioquia, Colombia) in order to detect a possible association between MS and HLA DQα (HLA DQA1*) alleles. Forty chromosomes belonging to MS patients were compared to two sets of controls (40 and 910 chromosomes, respectively). The HLA DQA1*0101 and DQA1*0102 alleles were found in a significantly higher proportion among the cases than among the controls, whereas the HLA DQA1*0103 allele was found in a significantly lower proportion of the cases. These results suggest that the association of HLA DQA1*0101, DQA1*0102 and DQA1*0103 to the MS phenotype found in Caucasian subtropical populations remains in individuals with MS inhabiting the tropics. This finding could mean that the major genetic component associated to the MHC in subtropical populations is the same in the tropics.

Accuracy of the Babinski sign in the identification of pyramidal tract dysfunction

BACKGROUND The extensor plantar response described by Joseph Babinski (1896) indicates pyramidal tract dysfunction (PTD) but has significant inter-observer variability and inconsistent accuracy. The goal of this study was to determine the accuracy of the Babinski sign in subjects with verified PTD. METHODS We studied 107 adult hospitalized and outpatient subjects evaluated by neurology. The reference standard was the blinded and independent diagnosis of an expert neurologist based on anamnesis, physical examination, imaging and complementary tests. Two neurologists elicited the Babinski sign in each patient independently, blindly and in a standardized manner to measure inter-observer variability; each examination was filmed to quantify intra-observer variability. RESULTS Compared with the reference standard, the Babinski sign had low sensitivity (50.8%, 95%CI 41.5-60.1) but high specificity (99%, 95%CI 97.7-100) in identifying PTD with a positive likelihood ratio of 51.8 (95%CI 16.6-161.2) and a calculated inter-observer variability of 0.73 (95%CI 0.598-0.858). The intraevaluator reliability was 0.571 (95%CI 0.270-0.873) and 0.467 (95%, CI 0.019-0.914) respectively, for each examiner. CONCLUSION The presence of the Babinski sign obtained by a neurologist provides valid and reliable evidence of PTD; due to its low sensitivity, absence of the Babinski sign still requires additional patient evaluation if PTD is suspected.

Complex segregation analysis of non-myoclonic idiopathic generalized epilepsy in families ascertained from probands affected with idiopathic epilepsy with tonic-clonic seizures in Antioquia, Colombia

Abstract In an attempt to identify the possible role of major genes, multifactorial inheritance, and cohort effects in the susceptibility to idiopathic epilepsy with generalized tonic-clonic seizures of the awakening type (GTCS), complex segregation analysis was performed in 196 nuclear families ascertained through affected probands with idiopathic epilepsy with GTCS belonging to the Paisa community of Antioquia (Colombia). Models postulating no transmission, single major locus (dominant and recessive) only, and multifactorial component only, were rejected. Since the codominant single major locus model could not be rejected and models that assign no major locus to transmission, no polygenic component to transmission, and no transmission of the major effect were rejected, complex segregation analysis suggested that a major autosomal codominant allele together with a multifactorial component (mixed model) best explained clustering of idiopathic epilepsy with GTCS in families of the Paisa community. The deficit of transmission of heterozygotes (0.17) is compatible with the existence of epistasis acting on a major gene whose frequency was estimated to be 0.0211. Its transmission variance accounts for 81% of the susceptibility to idiopathic epilepsy with GTCS. The complementary variance (19%) is due to the polygenic component.

Validation of Thwaites Index for diagnosing tuberculous meningitis in a Colombian population

OBJECTIVE To determine the diagnostic accuracy of Thwaites Index (TI) in a Colombian population to distinguish meningeal tuberculosis (MTB) from bacterial meningitis (BM) and from non-tuberculous meningitis. Exploratory analyses were conducted to assess the TIs validity for patients with human immunodeficiency virus (HIV) and children above six-years-old. METHODS The study included 527 patients, the TI was calculated and results compared with those of a reference standard established by expert neurologists. Sensitivity, specificity, area under the curve of receiver-operator characteristics (AUC-ROC) and likelihood ratios were calculated. RESULTS The AUC-ROC to distinguish MTB from non-tuberculous meningitis was 0.72 (95% CI: 0.67-0.77) for HIV negative adults. AUC-ROC was 0.62 (95% CI: 0.50-0.74) for HIV positive adults and 0.83 (95% CI: 0.68-0.97) for children. For distinguishing MTB from BM the AUC-ROC was 0.78 (95% CI: 0.73-0.83); furthermore, the AUC-ROC was 0.57 (95% CI: 0.31-0.83) for HIV positive adults and 0.86 (95% CI: 0.73-0.99) for children. CONCLUSION The TI was sensitive but not specific when used to distinguish MTB from BM in HIV negative adults. In HIV positive adults the index had low diagnostic accuracy. Moreover, the TI showed discrimination capability for children over 6years; however, research with larger samples is required in these.