Pharmacogenetics: ethnicity, treatment and health in Latin American populations.

The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) studies Latin American populations to benefit from the implementation of personalized medicine. Since 2006, it has studied ethnicity to apply pharmacogenetics knowledge in autochthonous populations of Latin America, considering ancestral medicine. The meeting 'Pharmacogenetics: ethnicity, Treatment and Health in Latin American Populations' was held in Mexico City, Mexico, and presented the relevance of RIBEF collaboration with Latin American researchers and the governments of Mexico, Spain and the Autonomous Community of Extremadura. The results of 17 years of uninterrupted work by RIBEF, the Declaration of Mérida/T'Hó and the call for the Dr José María Cantú Award for studies focused on the pharmacogenetics of native populations in Latin America were presented.

Challenges and Opportunities for Clinical Pharmacogenetic Research Studies in Resource-limited Settings: Conclusions From the Council for International Organizations of Medical Sciences-Ibero-American Network of Pharmacogenetics and Pharmacogenomics Meeting.

PURPOSE: The symposium Health and Medicines in Indigenous Populations of America was organized by the Council for International Organizations of Medical Sciences (CIOMS) Working Group on Clinical Research in Resource-Limited Settings (RLSs) and the Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF). It was aimed to share and evaluate investigators' experiences on challenges and opportunities on clinical research and pharmacogenetics. METHODS: A total of 33 members from 22 countries participated in 2 sessions: RIBEF studies on population pharmacogenetics about the relationship between ancestry with relevant drug-related genetic polymorphisms and the relationship between genotype and phenotype in Native Americans (session 1) and case examples of clinical studies in RLSs from Asia (cancer), America (diabetes and women health), and Africa (malaria) in which the participants were asked to answer in free text their experiences on challenges and opportunities to solve the problems (session 2). Later, a discourse analysis grouping common themes by affinity was conducted. FINDINGS: The main result of session 1 was that the pharmacogenetics-related ancestry of the population should be considered when designing clinical studies in RLSs. In session 2, 21 challenges and 20 opportunities were identified. The social aspects represent the largest proportion of the challenges (43%) and opportunities (55%), and some of them seem to be common. IMPLICATIONS: The main discussion points were gathered in the Declaration of Mérida/T'Hó and announced on the Parliament of Extremadura during the CIOMS-RIBEF meeting in 4 of the major Latin American autochthonous languages (Náhualth, Mayan, Miskito, and Kichwa). The declaration highlighted the following: (1) the relevance of population pharmacogenetics, (2) the sociocultural contexts (interaction with traditional medicine), and (3) the education needs of research teams for clinical research in vulnerable and autochthonous populations.

Genomic Ancestry, CYP2D6, CYP2C9, and CYP2C19 Among Latin Americans.

We present the distribution of CYP2D6, CYP2C9, and CYP2C19 variants and predicted phenotypes in 33 native and admixed populations from Ibero-America (n > 6,000) in the context of genetic ancestry (n = 3,387). Continental ancestries are the major determinants of frequencies of the increased-activity allele CYP2C19*17 and CYP2C19 gUMs (negatively associated with Native American ancestry), decreased-activity alleles CYP2D6*41 and CYP2C9*2 (positively associated with European ancestry), and decreased-activity alleles CYP2D6*17 and CYP2D6*29 (positively associated with African ancestry). For the rare alleles, CYP2C9*2 and CYPC19*17, European admixture accounts for their presence in Native American populations, but rare alleles CYP2D6*5 (null-activity), CYP2D6-multiplication alleles (increased activity), and CYP2C9*3 (decreased-activity) were present in the pre-Columbian Americas. The study of a broad spectrum of Native American populations from different ethno-linguistic groups show how autochthonous diversity shaped the distribution of pharmaco-alleles and give insights on the prevalence of clinically relevant phenotypes associated with drugs, such as paroxetine, tamoxifen, warfarin, and clopidogrel.

Clinical features and possible founder mutation of the 8bp duplication mutation in the SLC4A11 gene causing corneal dystrophy and perceptive deafness in three South American families.

BACKGROUND: Corneal Dystrophy and Perceptive Deafness (CDPD) or Harboyan syndrome is an autosomal recessive rare disorder, characterized by congenital corneal opacities and progressive sensorineural hearing loss, which usually begins after the second decades of life. This study reports the ophthalmic, audiological and genetic features, in five CDPD affected patients from three Chilean families. MATERIALS AND METHODS: Five individuals affected with CDPD from three unrelated Chilean families were clinically and genetically examined. To evaluate a putative founder mutation 7 SNPs were analyzed in the three families, an Argentinian patient (carrier of the same mutation previously reported) and 87 Chilean controls. RESULTS: The ophthalmic symptoms in the five patients were bilateral and symmetric, starting before one year of age, and visual acuity varied from 0.1 to 0.3. In all cases, hearing loss began over 8 years old. The sequence of the 19 exons of SLC4A11 gene of all the affected patients exhibited homozygous eight nucleotide sequence duplication (c.2233_2240dup TATGACAC, p.(Ile748Metfs*5)) at the end of exon 16. All the affected patients of the three families were homozygous for a haplotype composed of five SNPs and covering 4,1 Mb. The same haplotype was present in one allele of the heterozygous Argentinean patient and has a frequency of 2.76% in Chilean population. CONCLUSIONS: The five CDPD patients were homozygous for the same mutation in the SLC4A11 gene. Haplotype analysis of all the affected, including the case reported from Argentina was in accordance with a founder mutation.

Interethnic Variability in CYP2D6, CYP2C9, and CYP2C19 Genes and Predicted Drug Metabolism Phenotypes Among 6060 Ibero- and Native Americans: RIBEF-CEIBA Consortium Report on Population Pharmacogenomics.

Pharmacogenetic variation in Latin Americans is understudied, which sets a barrier for the goal of global precision medicine. The RIBEF-CEIBA Network Consortium was established to characterize interindividual and between population variations in CYP2D6, CYP2C9, and CYP2C19 drug metabolizing enzyme genotypes, which were subsequently utilized to catalog their "predicted drug metabolism phenotypes" across Native American and Ibero American populations. Importantly, we report in this study, a total of 6060 healthy individuals from Ibero-America who were classified according to their self-reported ancestry: 1395 Native Americans, 2571 Admixed Latin Americans, 96 Afro-Latin Americans, 287 white Latin Americans (from Cuba), 1537 Iberians, and 174 Argentinean Ashkenazi Jews. Moreover, Native Americans were grouped into North-, Central-, and South Amerindians (from Mexico, Costa Rica, and Peru, respectively). All subjects were studied for the most common and functional CYP2D6, CYP2C9, and CYP2C19 allelic variants, and grouped as genotype-predicted poor or ultrarapid metabolizer phenotypes (gPMs and gUMs, respectively). Native Americans showed differences from each ethnic group in at least two alleles of CYP2D6, CYP2C9, and CYP2C19. Native Americans had higher frequencies of wild-type alleles for all genes, and lower frequency of CYP2D6*41, CYP2C9*2, and CYP2C19*17 (p < 0.05). Native Americans also showed less CYP2C19 gUMs than the rest of the population sample. In addition, differences within Native Americans (mostly North vs. South) were also found. The interethnic differences described supports the need for population-specific personalized and precision medicine programs for Native Americans. To the best of our knowledge, this is the largest study carried out in Native Americans and other Ibero-American populations analyzing CYP2D6, CYP2C9, and CYP2C19 genetic polymorphisms. Population pharmacogenomics is a nascent field of global health and warrants further research and education.

Valoración ética de las nuevas opciones reproductivas en las enfermedades mitocondriales / Ethical value of new reproductive choices in mitochondrial diseases / Valoração ética das novas opções reprodutivas nas enfermidades mitocondriais

Las enfermedades mitocondriales son un grupo de desórdenes clínicamente heterogéneo con manifestaciones clínicas muy variables y alta tasa de morbi-mortalidad. Tienen complejas implicancias en la reproducción, ya que los riesgos de repetición en la familia son variables, 25% en las formas autosómicas recesivas, alrededor de 4% en los casos de mutaciones mitocondriales de novo, y un riesgo incierto pero elevado si la madre es portadora de las mutaciones mitocondriales. Por ello, se proponen distintas técnicas de diagnóstico preimplantacional, prenatal o de reproducción asistida a fin de evitar el nacimiento de niños con esta patología. En el presente trabajo se describen y analizan las implicancias científicas y éticas de las nuevas técnicas de reproducción asistida que se proponen a las familias con alto riesgo.

Mitochondrial diseases are a clinically heterogeneous group of disorders with variable clinical features and high morbidity and mortality. As there are different hereditary patterns, complex implications in reproduction are expected; the recurrence risk may be about 25% in autosomal recessive inheritance, 4% in de novo mitochondrial mutations, and an uncertain, but high risk, when the mother is carrier of mitochondrial mutations. Thus, different preimplantation and prenatal diagnosis or assisted reproductive techniques are proposed to avoid the birth of children with these diseases. In this paper scientific and ethical implications of new assisted reproductive techniques offer to high risk families are describe and analyzed.

As enfermidades mitocondriais são um grupo de desordens clinicamente heterogêneos com manifestações clínicas muito variáveis e alta taxa de morbi-mortalidade. Têm complexas implicações na reprodução, já que os riscos de repetição na família são variáveis, 25% nas formas autossômicas recessivas, ao redor de 4% nos casos de mutações mitocondriais de novo, e um risco incerto porém elevado se a mãe é portadora das mutações mitocondriais. Por isso, se propõem distintas técnicas de diagnóstico pré-implantacional, pré-natal ou de reprodução assistida a fim de evitar o nascimento de crianças com esta patologia. No presente trabalho se descrevem e analisam as implicações científicas e éticas das novas técnicas de reprodução assistida que se propõem às famílias com alto risco.

Pharmacogenetics and ethnicity: relevance for clinical implementation, clinical trials, pharmacovigilance and drug regulation in Latin America.

Congress of Pharmacogenetics and Personalized Medicine. Ethnicity, clinical implementation and regulatory environment (MESTIFAR 2016 Quito) Quito, Ecuador, 19-21 May 2016. The Ibero-American Network of Pharmacogenetics and Pharmacogenomics (RIBEF) was created in 2006 with the main aim of promoting personalized medicine and collaborative pharmacogenetics research in Spanish- and Portuguese-speaking countries in America and the Iberian Peninsula. The final goal of this initiative was the inclusion of Latin American populations that may benefit from the implementation of personalized medicine in drug therapy. Several initiatives have been promoted including the MESTIFAR project, which aimed to analyze the ethnicity, genotype and/or metabolic phenotype in Ibero-American populations. To date, 6060 healthy volunteers have been analyzed; among them, 2571 were admixed, 1824 were Caucasians, 1395 were Native Americans, 174 were Jews and 96 were Afro-descendants. Due to the large genetic variability within Latin Americans, ethnicity may be a relevant factor for the clinical implementation of personalized medicine. Moreover, the present status of clinical implementation and the future perspectives of pharmacogenetics, pharmacovigilance and clinical trials for drug regulation in Latin America compared with the EMA-Pharmacogenomics Working Party and the US FDA initiatives were analyzed.

Derechos de los pacientes con enfermedades que se asocien con discapacidad: marco legal actual / Rights of persons with conditions associated with disability: current legal framework

Este estudio de revisión tiene como objetivo promover la diseminación de la legislación vigente en nuestro país que protege los derechos de los pacientes con enfermedades que pueden producir discapacidad. Se analizan los artículos de las leyes que resguardan los derechos de estas familias para que sean más accesibles a los profesionales de la salud que las asisten. Argentina posee una amplia legislación dedicada a protegerlos, pero no es claramente reconocida por el ciudadano en general. La propuesta es difundir esta información en el ambiente médico para que los profesionales de la salud puedan ayudar al paciente a reconocer sus derechos a través del empoderamiento.

The objective of this review study is to promote the dissemination of the legislation in force in Argentina for the protection of the rights of persons with conditions that might cause disability. Articles of bills and laws that protect the rights of these families are reviewed, so that health care providers assisting them have better access to them. Argentina has a wide range of laws and regulations dedicated to protecting them, but they are generally not clearly recognized by citizens. The aim is to disseminate this information in the medical setting so that health care providers can help patients recognize their rights through empowerment.

Rights of persons with conditions associated with disability: current legal framework. / Derechos de los pacientes con enfermedades que se asocien con discapacidad: marco legal actual.

The objective of this review study is to promote the dissemination of the legislation in force in Argentina for the protection of the rights of persons with conditions that might cause disability. Articles of bills and laws that protect the rights of these families are reviewed, so that health care providers assisting them have better access to them. Argentina has a wide range of laws and regulations dedicated to protecting them, but they are generally not clearly recognized by citizens. The aim is to disseminate this information in the medical setting so that health care providers can help patients recognize their rights through empowerment.

Este estudio de revisión tiene como objetivo promover la diseminación de la legislación vigente en nuestro país que protege los derechos de los pacientes con enfermedades que pueden producir discapacidad. Se analizan los artículos de las leyes que resguardan los derechos de estas familias para que sean más accesibles a los profesionales de la salud que las asisten. Argentina posee una amplia legislación dedicada a protegerlos, pero no es claramente reconocida por el ciudadano en general. La propuesta es difundir esta información en el ambiente médico para que los profesionales de la salud puedan ayudar al paciente a reconocer sus derechos a través del empoderamiento.

Population pharmacogenetics of Ibero-Latinoamerican populations (MESTIFAR 2014).

MESTIFAR 2014 28-30 November 2014, Panama City, Panama The CEIBA consortium was created within the Ibero-American network of Pharmacogenetics (RIBEF) to study population pharmacogenetics. The current status of these initiatives and results of the MESTIFAR project were analyzed in Panama, 28-30 November 2014. The MESTIFAR project focused on studying CYPs genetic polymorphisms in populations of different ethnic origin. So far, more than 6000 healthy volunteers have been evaluated, making this one of the largest population pharmacogenomic studies worldwide. Three symposia were organized, 'Pharmacogenetics of indigenous and mestizos populations and its clinical implications', 'Methodological innovation in pharmacogenetics and its application in health', and 'General discussion and concluding remarks', about mechanisms and proposals for training, diffusion of pharmacogenetics for Spanish- and Portuguese-speaking health professionals, and 'bench to bedside' pilot projects.

Valoración ética del diagnóstico de enfermedades fundantes de discapacidad en la vida prenatal / Valoração ética do diagnóstico de enfermidades causadoras de descapacidade na vida pré-natal / Ethical evaluation of the diagnosis of diseases causing disability in prenatal life

La finalidad del diagnóstico prenatal genera un dilema controversial. Algunos autores sostienen que favorece el mejor desarrollo y adaptación del niño por nacer y sus familias, porque, al definir el estatuto moral del feto como inherente, debe recibir las mismas consideraciones morales que el niño ya nacido. Otros consideran que son medidas preventivas que disminuyen la prevalencia de enfermedades genéticas, al evitar el nacimiento de niños con estas patologías. Así, el niño por nacer no es considerado como persona y la discapacidad se interpreta como un daño para el niño y su familia, y debe ser evitada. Hay tensión al determinar si el diagnóstico prenatal es una práctica médica al servicio del hombre, con el objetivo de limitar el daño y sufrimiento humano, o bien una práctica eugenésica liberal. Tres conceptos se involucran en este conflicto: el de persona, el de discapacidad y el de prevención de enfermedades. El objetivo del artículo es reflexionar acerca de la interpretación de estos conceptos en diferentes visiones bioéticas, para alcanzar una mejor compresión de los mismos y aplicar los avances tecnológicos respetando la condición humana.

The goal of prenatal diagnosis causes a controversial dilemma. Some authors sustain that it favors better development and adaptation of the child to be born and family, since, by defining the moral statute of the fetus as inherent, he/she must receive the same moral considerations that the child already born. Others consider that avoiding the birth of children with these pathologies is a preventive measure to diminish the prevalence of genetic diseases. Thus, the child to be born is not considered a person and the disability is interpreted as damage for the child and his/her family, which must be avoided. There is tension to determine whether prenatal diagnosis is a medical practice to the service of human beings with the goal to limit damage and human suffering, or rather an eugenic liberal practice. Three concepts are involved in this conflict: the person, disability and prevention of diseases. The goal of this article is to reflect about the interpretation of these concepts in different bioethical views, in order to reach a better understanding of them and applying technological advances while respecting human condition.

A finalidade do diagnóstico pré-natal gera um dilema controvertido. Alguns autores sustentam que favorece o melhor desenvolvimento e a adaptação da criança por nascer e suas famílias, porque, ao definir o estatuto moral do feto como inerente, deve receber as mesmas considerações morais que a criança nascida. Outros consideram que são medidas preventivas que diminuem a prevalência de enfermidades genéticas, ao evitar o nascimento de crianças com estas patologias. Assim, a criança por nascer não é considerada como pessoa e a descapacidade se interpreta como um dano para a criança e sua família, e deve ser evitada. Há tensão ao determinar se o diagnóstico pré-natal é uma prática médica a serviço do homem, com o objetivo de limitar o dano e sofrimento humano, ou uma prática eugênica liberal. Três conceitos são envolvidos neste conflito: o de pessoa, o de descapacidade e o de prevenção de enfermidades. O objetivo do artigo é refletir acerca da interpretação destes conceitos em diferentes visões bioéticas, para alcançar uma melhor compreensão deles e aplicar os avanços tecnológicos respeitando a condição humana.

La aplicación del principio de subsidiariedad en el empoderamiento de los pacientes para el cuidado de la salud: el caso de las enfermedades raras en Argentina / The application of the subsidiary principle for patients’ empowerment for health care: the case of rare diseases in Argentina / A aplicação do princípio de subsidiariedade no empoderamento dos pacientes para o cuidado da saúde: o caso das enfermidades raras na Argentina

El principio de subsidiariedad, ampliamente definido en filosofía política y social, se refiere no solo a la relación de las comunidades entre sí, sino también a las relaciones del individuo con cualquier tipo de comunidad social. La subsidiariedad, por medio de la participación, promueve la dignidad de la persona, como ser individual y social, y reconoce como primario al bien de la persona individual. Según este principio, los individuos o comunidades predominantes adoptan una actitud de ayuda -apoyo, promoción y respeto- respecto de las menores. Adaptado, puede ser utilizado como un parámetro para comprender el concepto de empoderamiento de los pacientes para el cuidado de la salud. Para que este proceso pueda establecerse se requiere, por un lado, una relación médico-paciente, centrada en el paciente y su familia, en la que reciban las herramientas necesarias para la toma de decisiones en salud y, por otro, se creen entidades sociales intermedias en las que los pacientes y sus familias puedan desarrollar estrategias que permitan mejorar el cuidado de salud. El objetivo de este trabajo es profundizar en este principio y ofrecer un marco bioético que facilite la comprensión y desarrollo del concepto de empoderamiento en salud.

The subsidiary principle, broadly defined in political and social philosophy, refers not only to the relations between communities, but also to relations of the individual with any type of social community. The subsidiary principle promotes the dignity of persons as social and individual beings by participating and it recognizes as primary the well being of the individual person. According to this principle, individuals or main communities adopt an attitude of help -support, promotion and respect- with respect to minor ones. Adapted, it can be used as parameter to understand the concept of patients’ empowerment for health care. In order to establish this process it is required, on one hand, a physician-patient relationship center in the patient and his/her family, in which they will receive the necessary tools for health care decisions and, on the other hand, the creation of intermediate social entities in which patients and their families may develop strategies for health care enhancement. The goal of this study is to reflect on this principle and to offer a bioethical framework to facilitate understanding and development of the concept of empowerment for health care.

O princípio de subsidiariedade, amplamente definido em filosofia política e social, se refere não somente na relação das comunidades entre si, senão também nas relações do indivíduo com qualquer tipo de comunidade social. A subsidiariedade, por meio da participação, promove a dignidade da pessoa como ser individual e social, e reconhece como primário ao bem da pessoa individual. Segundo este princípio, os indivíduos ou comunidades predominantes adotam uma atitude de ajuda -apoio, promoção e respeito- referente às minorias. Adaptado, pode ser utilizado como um parâmetro para compreender o conceito de empoderamento dos pacientes para o cuidado da saúde. Para que este processo possa ser estabelecido se requer, por um lado, uma relação médico-paciente centrada no paciente e na sua família, na qual recebem as ferramentas necessárias para a tomada de decisões em saúde e, por outro, se criam entidades sociais intermediárias nas quais os pacientes e suas famílias podem desenvolver estratégias que permitam melhorar o cuidado à saúde. O objetivo deste trabalho é aprofundar-se neste princípio e oferecer um marco bioético que facilite a compreensão e o desenvolvimento do conceito de empoderamento em saúde.

Borate transporter SLC4A11 mutations cause both Harboyan syndrome and non-syndromic corneal endothelial dystrophy.

Harboyan syndrome, or corneal dystrophy and perceptive deafness (CDPD), consists of congenital corneal endothelial dystrophy and progressive perceptive deafness, and is transmitted as an autosomal recessive trait. CDPD and autosomal recessive, non-syndromic congenital hereditary endothelial corneal dystrophy (CHED2) both map at overlapping loci at 20p13, and mutations of SLC4A11 were reported recently in CHED2. A genotype study on six families with CDPD and on one family with either CHED or CDPD, from various ethnic backgrounds (in the seventh family, hearing loss could not be assessed because of the proband's young age), is reported here. Novel SLC4A11 mutations were found in all patients. Why some mutations cause hearing loss in addition to corneal dystrophy is presently unclear. These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness.

El salto de la doble hélice. Consecuencias del Proyecto Genoma Humano en la medicina del siglo XXI (Segunda parte) / The leap of the double helix. Consequences of the Human Genome Project in medicine of the 21st century (Part II

El Proyecto Genoma Humano, iniciado en octubre de 1990, ha permitido desentrañar, 12 años después, la secuencia nucleotídica del ADN humano. Este hecho ha producido un avance singular en la medicina moderna, posibilitando a través de la detección de las variaciones nucleotídicas en la secuencia del ADN, el desarrollo de estudios genéticos, la determinación de pronósticos y guías terapéuticas con fármacos, y el desarrollo de nuevas drogas gracias al avance de la farmacogenómica. Todo esto permitiría, en un futuro cercano, la predicción de respuestas a maniobras terapéuticas en los procedimientos de anestesia, cuidados críticos y tratamiento del dolor. Este desarrollo introduce también problemas éticos, específicamente en los campos de la terapia génica y la clonación.

[Cadasil: a case with molecular diagnosis]. / CADASIL: un caso con diagnóstico molecular.

CADASIL disease (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) was described in 1991 by Tourmier-Lasserve. Two years later the same authors described its association with chromosome 19; nonetheless, the mutations in gene Notch3 were not described until 1996. Clinical findings depend on the age at onset. The early form of the illness is found in young patients, generally less than 30 years old, and the main clinical manifestation is a migraine headache with subcortical lesions in the white matter, while in the later form ischemic events and behavioral symptoms are predominant. Anatomo-pathological findings in CADASIL include the presence of osmophilic granular deposits in vessel walls, skin, muscles and cerebral arteries. We present a patient with CADASIL and cavernous angioma. We studied a 40-year-old woman who underwent surgery for a left temporal-parietal cavernous angioma, with aphasia as the only symptom, two years before admission. Her family history showed that her father had suffered from vascular dementia. She was admitted to our hospital with right-side hemiparesis and dysarthria. A CT scan showed the presence of ischemic vascular lesions and former surgery sequelae. The duplex scan of the neck vessels and a transesophageal echocardiogram ruled out an embolic source. Laboratory tests including VDRL, HIV, prothrombotic profile and rheumatologic screening tests were normal. An MRI in T2W and FLAIR showed the presence of multiple subcortical cerebral lesions and hyperintensity in the white matter (leukoencephalopaty). We found a left acute putaminal-capsular infarct in the diffusion-MRI. The MRA was normal. Analysis of the cerebrospinal fluid was unremarkable. A molecular DNA test was performed, and a nucleotide substitution in position 583 in exon 4 of gene Notch3 was detected. This mutation was found only in CADASIL patients. The association with cavernous angioma has not been previously reported, and we believe that it was unrelated to CADASIL, either clinically or genetically. To our knowledge, this is the first case of CADASIL diagnosed by molecular DNA test in our country.

Prenatal diagnosis of L1 cell adhesion molecule mutations. Capabilities and limitations.

OBJECTIVE: Discuss the capability for and limitations of prenatal detection of L1 cell adhesion molecule (L1CAM) mutations. METHODS: Haplotype analysis by PCR and PAGE. Mutation detection by SSCP, followed by dideoxy sequencing. Confirmation of sequencing results with PCR and NcoI digestion. RESULTS: A 1-bp deletion was found in exon 2 of L1CAM in all affected males and obligate carriers in the pedigree. Prenatal detection is now possible for subsequent pregnancies. CONCLUSION: In a large gene with widespread mutations such as L1CAM, a mutation must be detected in another family member before direct prenatal mutation testing can be done within the required timeframe. If the proper family members are available, haplotyping offers a fast but indirect test with several limitations.

Cadasil: um caso com diagnostico molecular / Cadasil: a case with molecular diagnosis

CADASIL include the presence of osmophilic granulateriopathy with Subcortical Infarcts and Leukoencephalopathy) was described in 1991 by Tourmier-Lasserve. Two years later the same authors described its association with chromosome 19; nonetheless, the mutations in gene Notch3 were not described until 1996. Clinical findings depend on the age at onset. The early form of the illness is found in young patients, generally less than 30 years old, and the main clinical manifestation is a migraine headache with subcortical lesions in the white matter, while in the later form ischemic events and behavioral symptoms are predominant. Anatomo-pathological findings in CADASIL include the presence of osmophilic granular deposits in vessel walls, skin, muscles and cerebral arteries. We present a patient with CADASIL and cavernous angioma. We studied a 40-year-old woman who underwent surgery for a left temporal-parietal cavernous angioma, with aphasia as the only symptom, two years before admission. Her family history showed that her father had suffered from vascular dementia. She was admitted to our hospital with right-side hemiparesis and dysarthria. A CT scan showed the presence of ischemic vascular lesions and former surgery sequelae. The duplex scan of the neck vessels and a transesophageal echocardiogram ruled out an embolic source. Laboratory tests including VDRL, HIV, prothrombotic profile and rheumatologic screening tests were normal. An MRI in T2W and FLAIR showed the presence of multiple subcortical cerebral lesions and hyperintensity in the white matter (leukoencephalopaty). We found a left acute putaminal-capsular infarct in the diffusion-MRI. The MRA was normal. Analysis of the cerebrospinal fluid was unremarkable. A molecular DNA test was performed, and a nucleotide substitution in position 583 in exon 4 of gene Notch3 was detected. This mutation was found only in CADASIL patients. The association with cavernous angioma has not been previously reported, and we believe that it was unrelated to CADASIL, either clinically or genetically. To our knowledge, this is the first case of CADASIL diagnosed by molecular DNA test in our country.