Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica / Friedreich's ataxia, review and literature update with a systematic search for cases in Latin America

La Ataxia de Friedreich (AF) es una enfermedad neurodegenerativa autosómica recesiva con compromiso multisistémico. En esta revisión, se actualizan aspectos epidemiológicos, fisiopatológicos y clínico-terapéuticos y se conduce una búsqueda sistemática de casos de AF reportados en Latinoamérica. La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países. Causada por la expansión anormal de repeticiones GAA en el gen FXN, la etiopatogenia está asociada a una reducción en los niveles de la proteína frataxina (que altera el metabolismo energético) y el acúmulo de hierro mitocondrial. El fenotipo clásico de AF suele comenzar antes de los 25 años, aunque hay otros de inicio tardío y retención de reflejos. La sintomatología se caracteriza por ataxia progresiva, alteración sensitiva, arreflexia, disartria, y alteraciones oculomotoras, además de compromiso cardiaco, endocrino y musculoesquelético. El diagnóstico requiere evaluación neurológica detallada, estudios neurofisiológicos, neuroimágenes y pruebas bioquímicas pero el enfoque determinante es el estudio genético que demuestre variantes genéticas bialélicas en el gen FXN. El manejo es multidisciplinario, orientado a aminorar los síntomas, prevenir complicaciones y brindar asesoramiento genético apropiado. Recientemente se ha aprobado el primer tratamiento farmacológico para AF con varios más en fases de experimentación.

SUMMARY Friedreich Ataxia (FA) is an autosomal recessive neurodegenerative disease with multisystemic involvement. This update of epidemiological, pathophysiological, and clinico-therapeutic aspects of FA, includes a systematic review of cases in Latin America. The estimated FA prevalence in Caucasian populations is between 2 to 5 cases per 100 000. In Latin America, 1481 cases have been published in 35 articles from six different countries. Caused by an abnormally repeated expansion of GAA trinucleotide inside the FXN gene, FA's etiopathogenesis is associated with reduced levels of the frataxin protein, which disturb the energy metabolism and result in mitochondrial iron accumulation. The classic phenotype usually shows symptoms before the age of 25, although there are others with a later onset. The main symptoms of AF are progressive ataxia, sensory disturbances, areflexia, dysarthria, and oculomotor alterations, in addition to cardiac, endocrine, and musculoskeletal compromise. Diagnostic workup requires a detailed neurological examination, neuroconduction studies, neuroimaging, and biochemical tests. The definitive diagnosis is provided by genetic testing showing biallelic variants within the FXN gene. The management is multidisciplinary, aimed at reducing symptoms, preventing complications, and providing an appropriate genetic counseling. Recently, the first pharmacological treatment for AF has been approved, with several others in clinical assessment trials.

Recent recommendations from ATA guidelines to define the upper reference range for serum TSH in the first trimester match reference ranges for pregnant women in Rio de Janeiro

ABSTRACT Objectives: American Thyroid Association (ATA)'s new guidelines recommend use of population-based trimester-specific reference range (RR) for thyrotropin (TSH) in pregnancy. The aim of this study was to determine first trimester TSH RR for a population of pregnant women in Rio de Janeiro State. Subjects and methods: Two hundred and seventy pregnant women without thyroid illness, defined by National Academy of Clinical Biochemistry, and normal iodine status were included in this sectional study. This reference group (RG) had normal median urinary iodine concentration (UIC = 219 μg/L) and negative anti-thyroperoxidase antibodies (TPOAb). Twin pregnancy, trophoblastic disease and use of drugs or supplements that influence thyroid function were excluded. In a second step, we defined a more selective reference group (SRG, n = 170) by excluding patients with thyroiditis pattern on thyroid ultrasound and positive anti-thyroglobulin antibodies. This group also had normal median UIC. At a final step, a more selective reference group (MSRG, n = 130) was defined by excluding any pregnant women with UIC < 150 μg/L. Results: In the RG, median, 2.5th and 97.5th percentiles of TSH were 1.3, 0.1, and 4.4 mIU/L, respectively. The mean age was 270 ± 5.0 and the mean body mass index was 25.6 ± 5.2 kg/m2. In the SRG and MSRG, 2.5th and 975th percentiles were 0.06 and 4.0 (SRG) and 0.1 and 3.6 mIU/L (MSRG), respectively. Conclusions: In the population studied,TSH upper limit in the first trimester of pregnancy was above 2.5 mIU/L. The value of 3.6 mIU/L, found when iodine deficiency and thyroiditis (defined by antibodies and ultrasound characteristics) were excluded, matches recent ATA guidelines.

Sobre escravos e genes: “origens” e “processos” nos estudos da genética sobre a população brasileira / On slaves and genes: “origins” and “processes” in genetic studies of the Brazilian population

Neste artigo examino como geneticistas contemporâneos que pesquisam a história e a configuração da população brasileira interagem com outras disciplinas. Para tanto, tomei como estudo de caso artigos publicados por geneticistas que investigam a presença de variantes da hemoglobina S no Brasil, os quais pretendem claramente contribuir para a análise de questões como escravidão ou identidade étnica no país. Contrastando esses estudos com trabalhos contemporâneos da história e das ciências sociais, problematizo a centralidade explanatória da “origem” nos estudos genéticos analisados, bem como a falta de interação com questões epistemológicas de outras áreas do saber.

In this article I examine how contemporary geneticists investigating the history and configuration of the Brazilian population engage with other academic disciplines. To do so I use as a case study some articles published by geneticists researching the presence of hemoglobin S variants in Brazil, in which there is a clear pretension to contribute to the analysis of issues such as slavery or Brazil’s ethnic identity. By contrasting these studies with contemporary works from history and the social science, the explanatory centrality of “origin” in the genetic studies analyzed is problematized, as is the lack of interaction with the epistemological characteristics of other areas of knowledge.

Avances en el tratamiento de las ataxias crónicas / [Therapeutic developments in chronic ataxias].

Autosomal recessive cerebellar ataxias belong to a broader group of disorders known as inherited ataxias. In most cases onset occurs before the age of 20. These neurological disorders are characterized by degeneration or abnormal development of the cerebellum and spinal cord. Currently, specific treatment is only available for some of the chronic ataxias, more specifically those related to a known metabolic defect, such as abetalipoproteinemia, ataxia with vitamin E deficiency, and cerebrotendinous xanthomatosis. Treatment based on a diet with reduced intake of fat, supplementation of oral vitamins E and A, and the administration of chenodeoxycholic acid could modify the course of the disease. Although for most of autosomal recessive ataxias there is no definitive treatment, iron chelators and antioxidants have been proposed to reduce the mitochondrial iron overload in Friederich’s ataxia patients. Corticosteroids have been used to reduce ataxia symptoms in ataxia telangiectasia. Coenzyme Q10 deficiency associated with ataxia may be responsive to Co Q10 or ubidecarenone supplementations. Early treatment of these disorders may be associated with a better drug response.

Monoallelic thyroid peroxidase gene mutation in a patient with congenital hypothyroidism with total iodide organification defect / Mutação monoalélica no gene da tireoperoxidase em paciente com hipotireoidismo congênito com defeito total de incorporação de iodeto

The aim of this study was to identify the genetic defect of a patient with dyshormonogenetic congenital hypothyroidisms (CH) with total iodide organification defect (TIOD). A male child diagnosed with CH during neonatal screening. Laboratory tests confirmed the permanent and severe CH with TIOD (99 percent perchlorate release). The coding sequence of TPO, DUOX2, and DUOXA2 genes and 2957 base pairs (bp) of the TPO promoter were sequenced. Molecular analysis of patient's DNA identified the heterozygous duplication GGCC (c.1186_1187insGGCC) in exon 8 of the TPO gene. No additional mutation was detected either in the TPO gene, TPO promoter, DUOX2 or DUOXA2 genes. We have described a patient with a clear TIOD causing severe goitrous CH due to a monoallelic TPO mutation. A plausible explanation for the association between an autosomal recessive disorder with a single TPO-mutated allele is the presence of monoallelic TPO expression.

O objetivo deste estudo foi identificar defeitos genéticos em paciente com hipotireoidismo congênito (HC) por disormonogênese e defeito total de incorporação de iodeto (DIIT). Neonato do sexo masculino com HC diagnosticado pelo rastreamento neonatal. Exames clínicos e radiológicos confirmaram que o paciente apresentava HC severo e permanente com DIIT (teste de perclorato: 99 por cento). A região codificadora dos genes TPO, DUOX2, DUOXA2 e 2957 pares de bases (pb) do promotor de TPO foram sequenciados. No paciente foi identificada a duplicação em heterozigose GGCC no éxon 8 do gene TPO (c.1186_1187insGGCC). Nenhuma outra mutação foi localizada nos genes TPO, incluindo o promotor, DUOX2 ou DUOXA2. Descrevemos paciente com grave defeito de organificação de iodeto, provocando HC severo com bócio, em consequência de uma única mutação monoalélica no gene TPO. A expressão monoalélica no tecido tireoideano explicaria a associação de uma doen­ça autossômica recessiva com uma única mutação monoalélica.

Iron homeostasis in the lung

Iron is essential for many aspects of cellular function. However, it also can generate oxygen-based free radicals that result in injury to biological molecules. For this reason, iron acquisition and distribution are tightly regulated. Constant exposure to the atmosphere results in significant exposure of the lungs to catalytically active iron. The lungs have a mechanism for detoxification to prevent associated generation of oxidative stress. Those same proteins that participate in iron uptake in the gut are also employed in the lung to transport iron intracellularly and sequester it in an inactive form within ferritin. The release of metal is expedited (as transferrin and ferritin) from lung tissue to the respiratory lining fluid for clearance by the mucocilliary pathway or to the reticuloendothelial system for long-term storage. This pathway is likely to be the major method for the control of oxidative stress presented to the respiratory tract.

Prevalence of thyroid autoimmunity in patients with pemphigus vulgaris

El pénfigo vulgar (PV)es una enfermedad ampollar clásica de etiología autoinmune que se caracteriza por la presenciade lesiones intraepiteliales. Para establecer la prevalencia de anormalidades tiroideas en el PV, realizamos unestudio prospectivo en 15 pacientes consecutivos que consultaron a la División Dermatología debido a PV y enun grupo de 15 voluntarios sanos (Grupo Control). La función tiroidea se evaluó a través de la medición de T3,T4 y TSH y la presencia de bocio se determinó por medio de la palpación tiroidea. La autoinmunidad se investigóusando un ensayo IRMA para la medición de anticuerpos antitiroperoxidasa (ATPO). En cada grupo había9 mujeres y 6 hombres que fueron apareados por edad y sexo, con edades comprendidas entre 25 y 65 años(promedio 48.2 años) en el grupo PV, y entre 25 y 69 años (promedio 45.4 años) en el grupo control. Se encontróque 7 pacientes (46.6%) del grupo PV y uno (6.6%) del grupo control presentaron alteraciones tiroideas,(p<0.015). La presencia de ATPO positivos se observó en 6 pacientes con PV y en un voluntario del grupocontrol. Un paciente con PV presentó un bocio difuso asociado a un hipotiroidismo subclínico con ATPO negativos.De los 7 casos con ATPO positivos, solo un paciente del grupo PV presentó una tiroiditis de Hashimotomanifiesta. Todos los demás casos solo tuvieron ATPO positivos sin evidencias clínicas de tiroiditis crónica. ElPV se asocia frecuentemente con ATPO positivos, aunque la mayoría de los pacientes no presentan enfermedadestiroideas que se expresen clínicamente..

Estudo longitudinal do eixo hipófise-tireóide durante a gravidez / Longitudinal study of pituitary-thyroid axis in pregnancy

A tireóide sofre importantes modificações durante a gravidez. Visando mostrar as modificações no eixo hipófise-tireóide ao longo deste período, estudamos a função tireoidiana de 587 mulheres, com dosagens de TSH, T4 livre, anti-TPO, betahCG no 1°. trimestre e TSH, T4 livre e anti-TPO no 2°. e 3°. trimestres. Observamos aumento progressivo do TSH no 2°. (média: 2,14mU/L) e 3°. (média: 2,76mU/L) trimestres, em relação ao 1°. (média: 1,39mU/L). No grupo com TSH abaixo do valor de referência (0,4mU/L) no 1°. trimestre, a média de bhCG foi de 129.200UI/L, enquanto no grupo que apresentou níveis normais de TSH, a média foi de 34.200UI/L. Observamos, também, uma ligeira diminuição do T4 livre no 2°. e 3°. trimestres em relação ao 1°. (médias: 1°: 1,15; 2°: 0,99; 3°: 0,94ng/dl). A presença de anti-TPO positivo ocorreu em 13,9 por cento das mulheres. Não foram observadas alterações significativas nos valores médios de TSH e T4 livres naquelas com ou sem auto-imunidade. Entretanto, proporções significativamente maiores de gestantes apresentaram valores hormonais fora da faixa da normalidade em todos os trimestres da gestação. Concluímos que a função tireoidiana é afetada pela gravidez, com tendência ao declínio durante seu progresso, sendo este fenômeno mais marcante no grupo de gestantes anti-TPO positivas.