Cou Cou, flying fish and a whole exome please... lessons learned from genetic testing in Barbados.

Millions of patients, with suspected complex neurogenetic disorders, living in resource limited regions around the world have no access to genetic testing despite the rapidly expanding availability and decreasing costs of genetic testing in first world nations. The barriers to increasing availability of genetic testing in resource limited nations are multifactorial but can be attributed, in large part, to a lack of awareness of the power of genetic testing to lead to a rapid, cost-effective, diagnosis that potentially will have profound clinical implications on treatment and patient outcomes. We report our experience with whole exome sequencing (WES) done for the first time in 5 patients of African descent with a suspected neurogenetic disorder living in a resource limited setting on the Eastern Caribbean island of Barbados. A diagnostic pathogenic mutation was found in 3 patients in the SCN1A, STXBP1 and SCN4A, who clinically were diagnosed with Dravet syndrome, Lennox-Gastaut syndrome, paramytonia and seizures respectively. A variant of undetermined significance was found in a patient with global developmental delays, hypotonia, with abnormal eye movements. In one patient WES was non-diagnostic. This result highlights the high yield of WES in carefully selected patients with a neurologic disease and the need for increase access to genetic testing in resource limited settings globally.

A Proposal for Classification of Retinal Degeneration in Spinocerebellar Ataxia Type 7.

The aim of this study is to propose a classification system for the spinocerebellar ataxia type 7 retinal degeneration (SCA7-RD). Twenty patients with molecularly confirmed SCA7 underwent slit lamp examination, fundus photography, and optical coherence tomography (Spectralis®). Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale (ICARS) were applied, and age, sex, age at symptom onset, and number of CAG expansions were recorded. After analyzing the ophthalmological findings in each participant, a panel of retinal disease experts created a qualitative classification system for SCA7-RD comprising four stages. We assessed the correlations of retinal degeneration severity with SARA and ICARS scores, number of CAG repeats in ATXN7 allele, and age at symptom onset. We graded retinal degeneration as stage 1 in nine participants, as stage 2 in five, and as stage 3 in six. No differences in age and visual symptoms duration were found between groups. SARA and ICARS scores correlated with the severity of SCA7-RD on the classification system (p = 0.024 and p = 0.014, respectively). After adjusting for disease duration, retinal disease stage association with SARA and ICARS scores remained significant (ANCOVA, p < 0.05). The classification system for SCA7-RD was able to characterize different disease stages representing the landmarks in the cone-rod dystrophy natural history. Neurodegeneration appears to occur in parallel in the cerebellum and in the visual pathway. We conclude that retinal degeneration in SCA7 is a potential biomarker of the neurological phenotype severity.

Frecuencia de algunas enfermedades genéticas en Neuropediatría / Frequency of some genetic diseases in Neuropediatrics

Introducción: las enfermedades neurológicas en Pediatría son diversas y obedecen a un gran número de causas: infecciosas, genéticas, metabólicas y degenerativas, entre otras. El diagnóstico genético, dentro del método clínico en Neurología, está relacionado con el diagnóstico etiológico. Existen muy pocas publicaciones que reflejen la frecuencia de las enfermedades neurogenéticas como grupo etiológico. Objetivo: describir la frecuencia de algunas enfermedades neuropediátricas en la Consulta de Neurogenética del Instituto de Neurología y Neurocirugía. Métodos: se realizó una investigación descriptiva y prospectiva en el periodo 2008-2010. Se clasificó a los pacientes por grupos etarios, y se calculó el porcentaje de frecuencia para la atrofia muscular espinal de la infancia, la distrofia muscular tipo Duchenne/Becker, las lesiones estáticas del sistema nervioso central de causa prenatal genética, y para la clasificación de los grupos según tipo de herencia. Resultados: el universo de estudio estuvo conformado por 161 pacientes, 72,6 % del sexo masculino, para una razón de la variable sexo de 2,5. Los escolares fueron mayoría (37,8 %), y la edad promedio 5 años. La distrofia muscular tipo Duchenne fue la enfermedad más frecuente (24,8 %). El 41,40 % clasificó en la herencia autosómica recesiva. Los resultados coinciden con lo reportado en la literatura. Conclusiones: las enfermedades neuromusculares hereditarias, y las lesiones estáticas del sistema nervioso central de causa prenatal genética, son las más frecuentes de solicitud de asesoramiento genético en un servicio de Neurogenética.

Introduction: diverse neurological diseases are present in pediatrics and respond to a great number of causes, that is, infectious, genetic, metabolic and degenerative, among others. Within the clinical method in neurology, the genetic diagnosis is related to the etiological diagnosis. There are very few publications that show the frequency of neurogenetic diseases as an etiologic group. Objective: to describe the frequency of some neuropediatric diseases in the Neurogenetics Service of the Institute of Neurology and Neurosurgery. Methods: a prospective and descriptive research study was conducted in the 2008-2010 period. The patients were grouped by age and the frequency rate was estimated for infantile spinal muscular atrophy, Dechenne/Becker-type muscular dystrophy, the static lesions of prenatal genetic origin in the central nervous system, and finally for the classification of the groups by the type of inheritance. Results: the universe of study was composed by 161 patients of whom 72.6 % were males, for a sex ratio of 2.5. The schoolchildren were the majority (37.8 %) and the average age was 5 years. Duchene type muscular dystrophy was the most frequent (24.8 %). Of the total number, 41.40 % was classified as recessive autosomal inheritance. The results agreed with those of the literature. Conclusions: the hereditary neuromuscular diseases and the static lesions of the central nervous system of prenatal genetic origin are the most common reasons for the request of genetic counseling in the Neurogenetics Service.

Determinismo biológico e as neurociências no caso do transtorno de déficit de atenção com hiperatividade / Biological determinism and neuroscience in the case of attention deficit disorder with hyperactivity

Nosso objetivo é refletir de que forma as neurociências podem ser fortemente reducionistas quando tentam explicar comportamentos somente com base em processos cerebrais, e usamos como exemplo o caso do transtorno de déficit de atenção com hiperatividade (TDAH). O reducionismo ao qual nos referimos, também chamado determinismo biológico ou neurogenético, na questão das neurociências, é o epistemológico, ou seja, aquele que tenta explicar um problema complexo apenas por algumas de suas partes, desconsiderando outros fatores, tais como sociais e culturais. Como o TDAH atualmente é descrito essencialmente como uma doença cerebral, aplicamos um modelo de sequência redutora defeituosa para o determinismo neurogenético proposto por Steven Rose, que inclui: objetivação, aglomeração arbitrária, quantificação improcedente, crença na normalidade estatística, localização ilegítima, causalidade fora de lugar, classificação dicotômica de causas genéticas e ambientais e a confusão de metáfora com homologia. A vida é um fenômeno complexo e está relacionada com aspectos biológicos e sociais. Dessa forma, explicações sobre ela são adequadas somente quando levam em conta esses dois aspectos. Sugerimos, dessa forma, que parte das neurociências utiliza explicações reducionistas para várias condições mentais classificadas como doenças, incluindo o TDAH.

Our goal is to reflect how the neurosciences can be strongly reductionist when trying to explain behaviors based solely on brain processes, and use as an example the case of attention deficit disorder with hyperactivity (ADHD). The reductionism to which we refer, also called biological or neurogenetic determinism, the question of neuroscience, is the epistemological, ie one that tries to explain a complex problem for only some of its parts, ignoring other factors such as social and cultural. As ADHD is currently described as essentially a disease of the brain, we applied a model for defective reductive sequence neurogenetic determinism proposed by Steven Rose, which includes: objectification, arbitrary agglomeration, quantification unfounded belief in statistical normality, location illegitimate, causality outside place, dichotomous classification of genetic and environmental causes and confusion of metaphor with homology. Life is a complex phenomenon and is related to biological and social aspects. Thus, explanations are appropriate only when it takes into account these two aspects. We suggest, therefore, that some uses of neuroscience reductionist explanations for various conditions classified as mental illnesses, including ADHD.