A novel complex neurological phenotype due to a homozygous mutation in FDX2.

Defects in iron-sulphur [Fe-S] cluster biogenesis are increasingly recognized as causing neurological disease. Mutations in a number of genes that encode proteins involved in mitochondrial [Fe-S] protein assembly lead to complex neurological phenotypes. One class of proteins essential in the early cluster assembly are ferredoxins. FDX2 is ubiquitously expressed and is essential in the de novo formation of [2Fe-2S] clusters in humans. We describe and genetically define a novel complex neurological syndrome identified in two Brazilian families, with a novel homozygous mutation in FDX2. Patients were clinically evaluated, underwent MRI, nerve conduction studies, EMG and muscle biopsy. To define the genetic aetiology, a combination of homozygosity mapping and whole exome sequencing was performed. We identified six patients from two apparently unrelated families with autosomal recessive inheritance of a complex neurological phenotype involving optic atrophy and nystagmus developing by age 3, followed by myopathy and recurrent episodes of cramps, myalgia and muscle weakness in the first or second decade of life. Sensory-motor axonal neuropathy led to progressive distal weakness. MRI disclosed a reversible or partially reversible leukoencephalopathy. Muscle biopsy demonstrated an unusual pattern of regional succinate dehydrogenase and cytochrome c oxidase deficiency with iron accumulation. The phenotype was mapped in both families to the same homozygous missense mutation in FDX2 (c.431C > T, p.P144L). The deleterious effect of the mutation was validated by real-time reverse transcription polymerase chain reaction and western blot analysis, which demonstrated normal expression of FDX2 mRNA but severely reduced expression of FDX2 protein in muscle tissue. This study describes a novel complex neurological phenotype with unusual MRI and muscle biopsy features, conclusively mapped to a mutation in FDX2, which encodes a ubiquitously expressed mitochondrial ferredoxin essential for early [Fe-S] cluster biogenesis.

[Adherence to interdisciplinary Pulmonary Rehabilitation Program]. / Adherencia a un programa interdisciplinario de rehabilitación respiratoria.

Participation in a Pulmonary Rehabilitation Program (PRP) improves dyspnea, functional capacity and quality of life in patients with chronic respiratory disease. A retrospective study was carried out to identify variables related to compliance in an out patient PRP at an Argentine center and to evaluate the results in compliant patients. The PRP included an "acquisition" stage consisting of 16 weeks of supervised training twice weekly and lectures on treatment benefits, inhalation devices used, smoking cessation, symptoms recognition and flair up management, among others. Patients were reassessed after this stage. Patients completing the acquisition stage were considered PRP compliant. Of 388 patients evaluated for admission 102 (26.3%) complied with PRP. Multiple logistic regression analysis (Forward Stepwise; p < 0.10 to be eligible for entry into the model) was used to identify factors related to "program compliance". The final model was as follows: having health insurance coverage (OR = 3.99; CI90% = 2.24-7.12), commute time under 60 minutes (OR = 2.07; CI90% = 1.37-3.11) and financial capacity (OR = 2.11; CI90% = 1.03-4.31). All patients complied with the PRP showed significant improvement in the six-minute walking test and quality of life. The results warn about low compliance and their relationship with socioeconomic variables.

Subacute Partially Reversible Leukoencephalopathy Expands the Aicardi-Goutières Syndrome Phenotype.

OBJECTIVE: To report a series of atypical presentations of Aicardi-Goutières syndrome. METHODS: Clinical, neuroimaging, and genetic data. RESULTS: We report a series of six unrelated patients (five males) with a subacute loss of developmental milestones, pyramidal signs, and regression of communication abilities, with onset at ages ranging from 7 to 20 months, reaching a nadir after 4 to 24 weeks. A remarkable improvement of lost abilities occurred in the follow-up, and they remained with residual spasticity and dysarthria but preserved cognitive function. Immunization or febrile illness occurred before disease onset in all patients. CSF was normal in two patients, and in four, borderline or mild lymphocytosis was present. A brain CT scan disclosed a subtle basal ganglia calcification in one of six patients. Brain MRI showed asymmetric signal abnormalities of white matter with centrum semi-ovale involvement in five patients and a diffuse white matter abnormality with contrast enhancement in one. Four patients were diagnosed and treated for acute demyelinating encephalomyelitis (ADEM). Brain imaging was markedly improved with one year or more of follow-up (average of 7 years), but patients remained with residual spasticity and dysarthria without cognitive impairment. Demyelination relapse occurred in a single patient four years after the first event. Whole-exome sequencing (WES) was performed in all patients: four of them disclosed biallelic pathogenic variants in RNASEH2B (three homozygous p.Ala177Thr and one compound heterozygous p.Ala177Thr/p.Gln58*) and in two of them the same homozygous deleterious variants in RNASEH2A (p.Ala249Val). CONCLUSIONS: This report expands the phenotype of AGS to include subacute developmental regression with partial clinical and neuroimaging improvement. Those clinical features might be misdiagnosed as ADEM.

[Optic neuritis in juvenile idiopathic arthritis patient]. / Neurite óptica em paciente com artrite idiopática juvenil.

Optic neuritis (ON) was rarely reported in juvenile idiopathic arthritis (JIA) patients, particularly in those under anti-tumor necrosis factor alpha blockage. However, to our knowledge, the prevalence of ON in JIA population has not been studied. Therefore, 5,793 patients were followed up at our University Hospital and 630 (11%) had JIA. One patient (0.15%) had ON and was reported herein. A 6-year-old male was diagnosed with extended oligoarticular JIA, and received naproxen and methotrexate subsequently replaced by leflunomide. At 11 years old, he was diagnosed with aseptic meningitis, followed by a partial motor seizure with secondary generalization. Brain magnetic resonance imaging (MRI) and electroencephalogram showed diffuse disorganization of the brain electric activity and leflunomide was suspended. Seven days later, the patient presented acute ocular pain, loss of acuity for color, blurred vision, photophobia, redness and short progressive visual loss in the right eye. A fundoscopic exam detected unilateral papilledema without retinal exudates. Orbital MRI suggested right ON. The anti-aquaporin 4 (anti-AQP4) antibody was negative. Pulse therapy with methylprednisolone was administered for five days, and subsequently with prednisone, he had clinical and laboratory improvement. In conclusion, a low prevalence of ON was observed in our JIA population. The absence of anti-AQP4 antibody and the normal brain MRI do not exclude the possibility of demyelinating disease associated with chronic arthritis. Therefore, rigorous follow up is required.

Adherencia a un programa interdisciplinario de rehabilitación respiratoria / Adherence to interdisciplinary pulmonary rehabilitation program

La participación en un Programa de Rehabilitación Respiratoria (PRR) mejora la disnea, la capacidad funcional y la calidad de vida en pacientes con enfermedad respiratoria crónica. Sin embargo, la adherencia a PRR suele ser baja. Se realizó un estudio retrospectivo con el objetivo de identificar variables relacionadas con la adherencia a un PRR ambulatorio en un centro de la Argentina y secundariamente evaluar los resultados en quienes adhirieron. El PRR incluyó una etapa de "adquisición" que consistió en 16 semanas de entrenamiento físico supervisado, dos veces por semana, y clases sobre los beneficios del tratamiento, el uso de los dispositivos de inhalación, cesación tabáquica, reconocimiento de síntomas y manejo de las exacerbaciones, entre otros. Al finalizar el entrenamiento los pacientes fueron re-evaluados. Se consideró "adherencia al PRR" cuando el paciente completó la etapa de adquisición. De 388 pacientes que iniciaron la primera evaluación, 102 (26.3%) adhirieron al PRR. Se utilizó regresión logística múltiple (Forward Stepwise con ingreso de variables con p < 0.10) para identificar factores relacionados con "adherencia al programa". El modelo final fue el siguiente: poseer obra social (OR = 3.99; IC90% = 2.24-7.12), tiempo de viaje al hospital menor de 60 minutos (OR = 2.07; IC90% = 1.37-3.11) e ingreso económico disponible (OR = 2.11; IC90% = 1.03-4.31). Los pacientes que adhirieron al PRR presentaron mejoría significativa en la prueba de marcha de 6 minutos y en la calidad de vida. Los resultados alertan sobre la baja adherencia y su relación con las variables socioeconómicas.

Participation in a Pulmonary Rehabilitation Program (PRP) improves dyspnea, functional capacity and quality of life in patients with chronic respiratory disease. A retrospective study was carried out to identify variables related to compliance in an out patient PRP at an Argentine center and to evaluate the results in compliant patients. The PRP included an "acquisition" stage consisting of 16 weeks of supervised training twice weekly and lectures on treatment benefits, inhalation devices used, smoking cessation, symptoms recognition and flair up management, among others. Patients were reassessed after this stage. Patients completing the acquisition stage were considered PRP compliant. Of 388 patients evaluated for admission 102 (26.3%) complied with PRP. Multiple logistic regression analysis (Forward Stepwise; p < 0.10 to be eligible for entry into the model) was used to identify factors related to "program compliance". The final model was as follows: having health insurance coverage (OR = 3.99; CI90% = 2.24-7.12), commute time under 60minutes (OR = 2.07; CI90% = 1.37-3.11) and financial capacity (OR = 2.11; CI90% = 1.03-4.31). All patients complied with the PRP showed significant improvement in the six-minute walking test and quality of life. The results warn about low compliance and their relationship with socioeconomic variables.

Neurite óptica em paciente com artrite idiopática juvenil / Optic neuritis in juvenile idiopathic arthritis patient

O bloqueio do TNF tem tido sucesso no tratamento de algumas doenças reumáticas, como a espondiloartrite. Relatam-se muitas complicações infecciosas com a terapia anti-TNF, principalmente infecções bacterianas, micobacterianas, virais e fúngicas. A Entamoeba histolytica é um protozoário extracelular que causa principalmente colite e abscesso hepático, sendo que a perfuração intestinal é uma complicação rara, com alta mortalidade. O TNF é considerado o principal mediador da imunidade celular contra a amebíase. Inicialmente, é quimiotático para a E. histolytica, potencializando sua adesão ao enterócito por meio da lectina galactose-inibível, e depois ativando os macrófagos para matarem a ameba pela liberação de NO; assim, o bloqueio do TNF poderia ser prejudicial, aumentando a virulência amebiana. Descreve-se o caso de uma mulher de 46 anos com espondiloartrite que apresentou uma perfuração do colo por colite amebiana invasiva durante uso de anti-TNF.

Optic neuritis (ON) was rarely reported in juvenile idiopathic arthritis (JIA) patients, particularly in those under anti-tumor necrosis factor alpha blockage. However, to our knowledge, the prevalence of ON in JIA population has not been studied. Therefore, 5793 patients were followed up at our University Hospital and 630 (11%) had JIA. One patient (0.15%) had ON and was reported herein. A 6-year-old male was diagnosed with extended oligoarticular JIA, and received naproxen and methotrexate subsequently replaced by leflunomide. At 11 years old, he was diagnosed with aseptic meningitis, followed by a partial motor seizure with secondary generalization. Brain magnetic resonance imaging (MRI) and electroencephalogram showed diffuse disorganization of the brain electric activity and leflunomide was suspended. Seven days later, the patient presented acute ocular pain, loss of acuity for color, blurred vision, photophobia, redness and short progressive visual loss in the right eye. A fundoscopic exam detected unilateral papilledema without retinal exudates. Orbital MRI suggested right ON. The anti-aquaporin 4 (anti-AQP4) antibody was negative. Pulse therapy with methylprednisolone was administered for five days, and subsequently with prednisone, he had clinical and laboratory improvement. In conclusion, a low prevalence of ON was observed in our JIA population. The absence of anti-AQP4 antibody and the normal brain MRI do not exclude the possibility of demyelinating disease associated with chronic arthritis. Therefore, rigorous follow up is required.

É possível desenvolver a autorreflexão no estudante de primeiro ano que atua na comunidade? um estudo preliminar / Is it possible for first year students working in the communityto develop self-reflection? a preliminaryStudy

Numa faculdade com currículo tradicional e predomínio da avaliação cognitiva e somativa, uma nova disciplina, baseada na interação entre universidade, serviços e comunidade (Iusc), para estudantes de Medicina e Enfermagem numa escola de São Paulo, teve por objetivo buscar uma forma de avaliar o desenvolvimento do aluno em habilidades de comunicação e autorreflexão. A avaliação global do aluno em pequenos grupos feita por meio de relatórios escritos e portfólio do grupo não evidenciou a autorreflexão sobre o processo de aprendizagem de alguns estudantes. Foi proposto, então, um estudo piloto com 15 alunos, divididos em dois grupos, selecionados aleatoriamente, que aceitaram desenvolver um portfólio individual e reflexivo. Na análise qualitativa do material, identificou-se a presença de categorias como reflexão sobre a vida estudantil antes do curso universitário escolhido, experiências de vida que levaram à escolha profissional, correlação do aprendizado na disciplina com a prática profissional e capacidade de identificar o crescimento em habilidades de comunicação, mostrando-se eficiente no processo de autorreflexão sobre a aprendizagem.

In a multiprofessional, discipline-based curriculum with cumulative and cognitive assessment, anew discipline based on University-Community Service Interaction (IUSC), for medicine and nursing students at a São Paulo school, aimed at finding a way to evaluate students' development of communication and self-reflection skills. Overall assessment of students in small groups conducted through written reports and group portfolios failed to demonstrate self-reflection on the learning process in some students. A pilot study was therefore proposed, involving 15 students, divided into two randomly-selected groups, who agreed to develop an individual and reflective portfolio. Qualitative analysis of the material outlined categories such as reflection on student life before the chosen university course began, life experiences that led the student to the chosen career, correlation between learning the subject and professional practice and ability to identify their growth in communication skills, indicating an efficient process of self-reflection on their learning.