A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects.

BACKGROUND: The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. METHODS: We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer's disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. RESULTS: We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. CONCLUSIONS: Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

Frequency of Aspirin Resistance in Ischemic Stroke Patients and Healthy Controls from Colombia.

OBJECTIVE: To evaluate the aspirin resistance prevalence in patients with previous ischemic cerebrovascular disease undergoing aspirin therapy for secondary prevention. MATERIALS AND METHODS: Three hundred fifty patients presenting ischemic strokes and 100 healthy controls under aspirin treatment were evaluated using the optic platelet aggregation test. RESULTS: Aspirin resistance was found in 7.4% of the patients with ischemic stroke and 4% of controls. Aspirin resistance was associated with stroke recurrence in univariate analysis (p = 0.004). Aspirin resistance was not associated with smoking, diabetes, or hypercholesterolemia. CONCLUSION: Aspirin resistance is present in Colombian patients with ischemic stroke as well as in healthy controls.

Impaired Muscle Mitochondrial Biogenesis and Myogenesis in Spinal Muscular Atrophy.

IMPORTANCE: The important depletion of mitochondrial DNA (mtDNA) and the general depression of mitochondrial respiratory chain complex levels (including complex II) have been confirmed, implying an increasing paucity of mitochondria in the muscle from patients with types I, II, and III spinal muscular atrophy (SMA-I, -II, and -III, respectively). OBJECTIVE: To investigate mitochondrial dysfunction in a large series of muscle biopsy samples from patients with SMA. DESIGN, SETTING, AND PARTICIPANTS: We studied quadriceps muscle samples from 24 patients with genetically documented SMA and paraspinal muscle samples from 3 patients with SMA-II undergoing surgery for scoliosis correction. Postmortem muscle samples were obtained from 1 additional patient. Age-matched controls consisted of muscle biopsy specimens from healthy children aged 1 to 3 years who had undergone analysis for suspected myopathy. Analyses were performed at the Neuromuscular Unit, Istituto di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico-Milano, from April 2011 through January 2015. EXPOSURES: We used histochemical, biochemical, and molecular techniques to examine the muscle samples. MAIN OUTCOMES AND MEASURES: Respiratory chain activity and mitochondrial content. RESULTS: Results of histochemical analysis revealed that cytochrome-c oxidase (COX) deficiency was more evident in muscle samples from patients with SMA-I and SMA-II. Residual activities for complexes I, II, and IV in muscles from patients with SMA-I were 41%, 27%, and 30%, respectively, compared with control samples (P < .005). Muscle mtDNA content and cytrate synthase activity were also reduced in all 3 SMA types (P < .05). We linked these alterations to downregulation of peroxisome proliferator-activated receptor coactivator 1α, the transcriptional activators nuclear respiratory factor 1 and nuclear respiratory factor 2, mitochondrial transcription factor A, and their downstream targets, implying depression of the entire mitochondrial biogenesis. Results of Western blot analysis confirmed the reduced levels of the respiratory chain subunits that included mitochondrially encoded COX1 (47.5%; P = .004), COX2 (32.4%; P < .001), COX4 (26.6%; P < .001), and succinate dehydrogenase complex subunit A (65.8%; P = .03) as well as the structural outer membrane mitochondrial porin (33.1%; P < .001). Conversely, the levels of expression of 3 myogenic regulatory factors-muscle-specific myogenic factor 5, myoblast determination 1, and myogenin-were higher in muscles from patients with SMA compared with muscles from age-matched controls (P < .05). CONCLUSIONS AND RELEVANCE: Our results strongly support the conclusion that an altered regulation of myogenesis and a downregulated mitochondrial biogenesis contribute to pathologic change in the muscle of patients with SMA. Therapeutic strategies should aim at counteracting these changes.

Caracterización clínica y de conglomerados de clases latentes de la migraña familiar en el aislado genético de Antioquia / Clinical and latent class cluster characteristics of familiar migraine in the antioquian genetic isolate

INTRODUCCIÓN: la migraña es una entidad de alta prevalencia cuya etiología parece tener un gran componente genético. OBJETIVOS: determinar las características clínicas y la de conglomerados de clases latentes (CCL) en las familias colombianas de la región de Antioquia con un caso índice con cefalea crónica. MATERIAL Y MÉTODOS: se estudiaron 550 individuos (374 mujeres y 176 hombres) de 121 familias colombianas de la región de Antioquia. A todos se les hizo una pregunta de rastreo para seleccionar a los miembros con posible migraña. A los sospechosos se les hizo una entrevista con los criterios de la International Headache Society (IHS) y un examen neurológico para establecer el diagnóstico y su clasificación en migraña con aura (MCA) y migraña sin aura (MSA). Los criterios de la IHS fueron usados para hacer un análisis de CCL, calculando índices de máxima verosimilitud y controlando el cumplimiento del supuesto de la independencia local. RESULTADOS: el 61,6 % de los miembros de las familias tuvieron migraña. El 40 % tuvo MSA y el 21,6 % MCA. La intensidad fue de moderada a severa en 96,4 % de los casos. Aproximadamente el 70 % presentaron síntomas de náuseas, vómitos, sonofobia, fotofobia e incremento con el ejercicio. Se derivaron 4 CCL: uno con MSA+MCA, con alta probabilidad de ser mujeres y con crisis de inicio temprano; otro grupo de personas sanas de ambos sexos; un tercero con MSA de aparición a edad intermedia, con crisis moderadas a severas de larga duración y predominante de mujeres; y un cuarto grupo de mujeres con MSA de aparición temprana y crisis de corta duración. CONCLUSIONES: las características clínicas de los pacientes con migraña de estas familias son similares a lo informado en otros estudios. La distribución de los CCL hace pensar en una probable transmisión de una predisposición genética que, en interacción con factores ambientales, determinaría la edad de inicio de las crisis y si esas son de tipo MSA o MSA+MCA.

INTRODUCTION: migraine is a disorder with high prevalence and with probable genetic etiology. OBJECTIVE: to determine the clinical and latent class cluster (LCC) characteristics of Antioquian families with one probands with chronic headache. MATERIALS AND METHODS: 550 individuals (374 females and 176 males) were studied. All participants were asked with one screening question in order to select suspicious of migraine. An interview with the International Headache Society (IHS) criteria and a neurological examination were administered to all probably migraine affected patients. Migraine diagnosis and classification into migraine with aura (MA) and migraine without aura (M0) was done. The IHS were used to develop a LCC analysis, calculating maximum likelihood index and controlling the local independence assumption. RESULTS: 61,6 per cent of the family members were affected with migraine, 40 per cent had M0 and 21,6 per cent had MA. Intensity was estimated between moderate to severe by 96,4 per cent of the cases. Approximately 70 per cent had nausea, vomiting, sonophobia, photophobia and worsening with exercise. 4 LCC were derived: one with M0 + MA, with high probability to be females, and early onset crisis; other group was constituted by healthy people of both genders; the third cluster had M0 of intermediate age onset, with moderate to severe attack, with long duration and predominantly females; finally a 4th cluster of females with M0 of early onset and short duration. CONCLUSIONS: clinical characteristics of migraine patients in these Antioquian families were similar to those informed by others studies. The distribution of LCC suggests a genetic transmission of vulnerability, which interacting with several environmental factors, would determine the age of onset and the types of attacks as M0, or M0+MA.