Mutation in the MICOS subunit gene APOO (MIC26) associated with an X-linked recessive mitochondrial myopathy, lactic acidosis, cognitive impairment and autistic features.

BACKGROUND: Mitochondria provide ATP through the process of oxidative phosphorylation, physically located in the inner mitochondrial membrane (IMM). The mitochondrial contact site and organising system (MICOS) complex is known as the 'mitoskeleton' due to its role in maintaining IMM architecture. APOO encodes MIC26, a component of MICOS, whose exact function in its maintenance or assembly has still not been completely elucidated. METHODS: We have studied a family in which the most affected subject presented progressive developmental delay, lactic acidosis, muscle weakness, hypotonia, weight loss, gastrointestinal and body temperature dysautonomia, repetitive infections, cognitive impairment and autistic behaviour. Other family members showed variable phenotype presentation. Whole exome sequencing was used to screen for pathological variants. Patient-derived skin fibroblasts were used to confirm the pathogenicity of the variant found in APOO. Knockout models in Drosophila melanogaster and Saccharomyces cerevisiae were employed to validate MIC26 involvement in MICOS assembly and mitochondrial function. RESULTS: A likely pathogenic c.350T>C transition was found in APOO predicting an I117T substitution in MIC26. The mutation caused impaired processing of the protein during import and faulty insertion into the IMM. This was associated with altered MICOS assembly and cristae junction disruption. The corresponding mutation in MIC26 or complete loss was associated with mitochondrial structural and functional deficiencies in yeast and D. melanogaster models. CONCLUSION: This is the first case of pathogenic mutation in APOO, causing altered MICOS assembly and neuromuscular impairment. MIC26 is involved in the assembly or stability of MICOS in humans, yeast and flies.

Brazilian consensus recommendations on the diagnosis and treatment of autoimmune encephalitis in the adult and pediatric populations.

BACKGROUND: Autoimmune encephalitis (AIE) is a group of inflammatory diseases characterized by the presence of antibodies against neuronal and glial antigens, leading to subacute psychiatric symptoms, memory complaints, and movement disorders. The patients are predominantly young, and delays in treatment are associated with worse prognosis. OBJECTIVE: With the support of the Brazilian Academy of Neurology (Academia Brasileira de Neurologia, ABN) and the Brazilian Society of Child Neurology (Sociedade Brasileira de Neurologia Infantil, SBNI), a consensus on the diagnosis and treatment of AIE in Brazil was developed using the Delphi method. METHODS: A total of 25 panelists, including adult and child neurologists, participated in the study. RESULTS: The panelists agreed that patients fulfilling criteria for possible AIE should be screened for antineuronal antibodies in the serum and cerebrospinal fluid (CSF) using the tissue-based assay (TBA) and cell-based assay (CBA) techniques. Children should also be screened for anti-myelin oligodendrocyte glucoprotein antibodies (anti-MOG). Treatment should be started within the first 4 weeks of symptoms. The first-line option is methylprednisolone plus intravenous immunoglobulin (IVIG) or plasmapheresis, the second-line includes rituximab and/or cyclophosphamide, while third-line treatment options are bortezomib and tocilizumab. Most seizures in AIE are symptomatic, and antiseizure medications may be weaned after the acute stage. In anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, the panelists have agreed that oral immunosuppressant agents should not be used. Patients should be evaluated at the acute and postacute stages using functional and cognitive scales, such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Modified Rankin Scale (mRS), and the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSION: The present study provides tangible evidence for the effective management of AIE patients within the Brazilian healthcare system.

ANTECEDENTES: Encefalites autoimunes (EAIs) são um grupo de doenças inflamatórias caracterizadas pela presença de anticorpos contra antígenos neuronais e gliais, que ocasionam sintomas psiquiátricos subagudos, queixas de memória e distúrbios anormais do movimento. A maioria dos pacientes é jovem, e o atraso no tratamento está associado a pior prognóstico. OBJETIVO: Com o apoio da Academia Brasileira de Neurologia (ABN) e da Sociedade Brasileira de Neurologia Infantil (SBNI), desenvolvemos um consenso sobre o diagnóstico e o tratamento da EAIs no Brasil utilizando a metodologia Delphi. MéTODOS: Um total de 25 especialistas, incluindo neurologistas e neurologistas infantis, foram convidados a participar. RESULTADOS: Os especialistas concordaram que os pacientes com critérios de possíveis EAIs devem ser submetidos ao rastreio de anticorpos antineuronais no soro e no líquido cefalorraquidiano (LCR) por meio das técnicas de ensaio baseado em tecidos (tissue-based assay, TBA, em inglês) e ensaio baseado em células (cell-based assay, CBA, em inglês). As crianças também devem ser submetidas ao rastreio de de anticorpo contra a glicoproteína da mielina de oligodendrócitos (anti-myelin oligodendrocyte glycoprotein, anti-MOG, em inglês). O tratamento deve ser iniciado dentro das primeiras 4 semanas dos sintomas, sendo as opções de primeira linha metilprednisolona combinada com imunoglobulina intravenosa (IGIV) ou plasmaférese. O tratamento de segunda linha inclui rituximabe e ciclofosfamida. Bortezomib e tocilizumab são opções de tratamento de terceira linha. A maioria das crises epilépticas nas EAIs são sintomáticas, e os fármacos anticrise podem ser desmamadas após a fase aguda. Em relação à encefalite antirreceptor de N-metil-D-aspartato (anti-N-methyl-D-aspartate receptor, anti-NMDAR, em inglês), os especialistas concordaram que agentes imunossupressores orais não devem ser usados. Os pacientes devem ser avaliados na fase aguda e pós-aguda mediante escalas funcionais e cognitivas, como Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Modified Rankin Scale (mRS), e Clinical Assessment Scale in Autoimmune Encephalitis (CASE). CONCLUSãO: Esta pesquisa oferece evidências tangíveis do manejo efetivo de pacientes com EAIs no sistema de saúde Brasileiro.

GABAA receptor encephalitis associated with human parvovirus B19 virus infection: Case report.

RATIONALE: Human parvovirus B19 (B19) infection can produce a spectrum of clinical syndromes, including neurological manifestations, most notably encephalitis. Although symptoms suggestive of autoimmune disease in patients with B19 infection have been previously described, a clear association of autoimmune encephalitis with B19 infection has yet to be established. PATIENT CONCERNS: We describe the case of a 6-year-old boy who was hospitalized due to status epilepticus, which evolved to super-refractory status epilepticus that was only mildly responsive to anticonvulsant drugs. DIAGNOSIS: A cerebrospinal fluid study identified slight pleocytosis and B19 positivity. A subsequent autoimmunity cerebrospinal fluid study revealed the presence of anti-γ-aminobutyric acid type A (GABAA) receptor antibodies. INTERVENTIONS: After pulse therapy with methylprednisolone and continuous therapy with prednisolone with cyclosporine, the patient experiencing seizure persistence with disordered motor function manifestations and only minor improvement in consciousness, and so, plasmapheresis was performed. With continued immunosuppressive treatments with cyclosporine and prednisolone, the patient's clinical picture showed progressive improvement, with good control of seizures. Although the patient tolerated withdrawal of the anticonvulsant drugs well, he developed seizures when corticosteroid therapy withdrawal was attempted, so was started on azathioprine. OUTCOMES: After immunosuppressive therapy, the patient evolved with complete remission of symptoms, normal neurological examination and age-appropriate neuropsychomotor development. LESSONS: The present case characteristics, together with previous findings, support the hypothesis that autoimmunity may be triggered by extensive antigen release due to degeneration of infected neurons. This case highlights the importance of early clinical suspicion and treatment.

Acute Childhood Viral Encephalitis in Southern Brazil.

BACKGROUND: Viral meningoencephalitis is highly heterogeneous, varying by geographic location. The aim of this study was to characterize the etiology and reporting the clinical findings and outcome of viral encephalitis in children in southern Brazil. METHODS: A cross-Sectional study was conducted at Hospital Pequeno Príncipe, Curitiba, Brazil, between January 2013 and December 2017. It included patients younger than 18 years, who fulfilled the criteria: altered mental status as a major criteria and 2 or more minor criteria (1) fever, (2) seizures, (3) focal neurologic findings, (4) central system fluid white cell count of ≥5 cells/mm, (5) abnormal brain imaging, and/or (6) electroencephalogram abnormalities. RESULTS: Viral meningoencephalitis was diagnosed in 270 children, with median age of 2 years (interquartile range: 0-4), The etiology of viral meningoencephalitis was confirmed in 47% of patients. Enterovirus (18%) was the major cause of encephalitis in Southern Brazilian children, and a high prevalence of Epstein-Barr virus (6%) was demonstrated. Most patients presented with fever (81%), followed by vomiting (50%), focal neurologic findings (46%), seizures (31%) and headache (30%). Few abnormalities were detected on electroencephalograms and brain magnetic resonance images. On discharge from hospital, symptoms resolved completely in 87% of children. Sequelae were mainly observed in patients with focal neurologic symptoms (P<0.001), presence of seizures (P<0.001) and electroencephalogram abnormalities (P=0.024). CONCLUSIONS: Enterovirus was the major cause of encephalitis. Etiologic agent of encephalitis seems to be influenced by the local virologic pattern. A poor outcome was identified in patients with seizures, focal neurologic findings and electroencephalogram abnormalities.

MUCOPOLYSACARIDOSIS TYPE IIIB MISDIAGNOSED AS AN AUTISTIC SPECTRUM DISORDER: A CASE REPORT AND LITERATURE REVIEW.

OBJECTIVE: To report a rare case of mucopolysaccharidosis IIIB in a pediatric patient, with emphasis on the description of the clinical manifestations and the early diagnosis. CASE DESCRIPTION: A 14-year-old male patient, who presented regression of neuropsychomotor development since his three years and six months old, with speech loss and frequent falls, evolving with behavioral changes, with agitation and aggressiveness. Although being diagnosed with autism, there was no response to the established treatment; he was subsequently submitted to metabolic investigation, which lead to the diagnosis of Mucopolysaccharidosis IIIB. COMMENTS: Identifying a metabolic disorder requires connecting multiple signs and symptoms, as well as eliminating other apparent causes. MPS IIIB is a diagnostic challenge, particularly in the early stages and in the absence of a family history of the disease.

Mucopolysacaridosis type iiib misdiagnosed as an autistic spectrum disorder: a case report and literature review / Mucopolissacaridose tipo iii b mal diagnosticada como transtorno de espectro autista: relato de caso e revisão de literatura

ABSTRACT Objective: To report a rare case of mucopolysaccharidosis IIIB in a pediatric patient, with emphasis on the description of the clinical manifestations and the early diagnosis. Case description: A 14-year-old male patient, who presented regression of neuropsychomotor development since his three years and six months old, with speech loss and frequent falls, evolving with behavioral changes, with agitation and aggressiveness. Although being diagnosed with autism, there was no response to the established treatment; he was subsequently submitted to metabolic investigation, which lead to the diagnosis of Mucopolysaccharidosis IIIB. Comments: Identifying a metabolic disorder requires connecting multiple signs and symptoms, as well as eliminating other apparent causes. MPS IIIB is a diagnostic challenge, particularly in the early stages and in the absence of a family history of the disease.

RESUMO Objetivo: Relatar o caso raro de um paciente pediátrico com mucopolissacaridose III B, com ênfase na descrição de manifestações clínicas. Descrição do caso: Paciente masculino de 14 anos que, a partir dos 3 anos e 6 meses de idade, apresentou regressão do desenvolvimento neuropsicomotor, com perda da fala e quedas frequentes, evoluindo com alterações comportamentais, agitação e agressividade. Diagnosticado como autista, não obteve resposta ao tratamento estabelecido, sendo posteriormente submetido à investigação metabólica, que evidenciou o diagnóstico de mucopolissacaridose III B. Comentários: A identificação de um distúrbio metabólico exige conectar vários sinais e sintomas, além de eliminar outras causas aparentes. A mucopolissacaridose III B é um desafio diagnóstico, particularmente nos estágios iniciais e na ausência de história familiar da doença.

The role of human adenoviruses type 41 in acute diarrheal disease in Minas Gerais after rotavirus vaccination

Abstract Human adenovirus species F (HAdV-F) type 40 and 41 are commonly associated with acute diarrheal disease (ADD) across the world. Despite being the largest state in southeastern Brazil and having the second largest number of inhabitants, there is no information in the State of Minas Gerais regarding the role of HAdV-F in the etiology of ADD. This study was performed to determine the prevalence, to verify the epidemiological aspects of infection, and to characterize the strains of human adenoviruses (HAdV) detected. A total of 377 diarrheal fecal samples were obtained between January 2007 and August 2011 from inpatient and outpatient children of age ranging from 0 to 12 years. All samples were previously tested for rotavirus, norovirus, and astrovirus, and 314 of 377 were negative. The viral DNA was extracted, amplified using the polymerase chain reaction and the HAdV-positive samples were sequenced and phylogenetically analyzed. Statistical analyses were performed using the Chi-square test (p < 0.05), considering two conditions: the total of samples tested (377) and the total of negative samples for the remaining viruses tested (314). The overall prevalence of HAdV was 12.47% (47/377); and in 76.60% (36/47) of the positive samples, this virus was the only infectious agent detected. The phylogenetic analysis of partial sequences of 32 positive samples revealed that they all clustered with the HAdV-F type 41. The statistical analysis showed that there was no correlation between the onset of the HAdV infection and the origin of the samples (inpatients or outpatients) in the two conditions tested: the total of samples tested (p = 0.598) and the total of negative samples for the remaining viruses tested (p = 0.614). There was a significant association in the occurrence of infection in children aged 0–12 months for the condition 1 (p = 0.030) as well as condition 2 (p = 0.019). The occurrence of infections due to HAdV did not coincide with a pattern of seasonal distribution. These data indicate the significant involvement of HAdV-F type 41 in the etiology of ADD in Minas Gerais, which demonstrates the importance of other viral agents in the development of the disease after the introduction of rotavirus vaccine immunization.

Perfil das usuárias de um banco de leite humano, em Juiz de Fora, MG / Characteristics of mothers attended at a human milk bank, in Juiz de Fora, MG

Com objetivo de conhecer o perfil socioeconômico das mães usuárias do Banco de Leite Humano (BLH) de Juiz de Fora, MG, assim como suas motivações e demandas, quando na busca pelos serviços oferecidos pela institui- ção, realizou-se uma pesquisa transversal, aplicada, de objetivo exploratório, realizada no BLH, na qual foram avaliados 47 binômios mãe-filhos que buscaram o serviço. A maioria das mães era casada, possuía nível médio ou superior, emprego com direitos trabalhistas e realizou o pré- -natal, em serviço de saúde privado. O aleitamento materno exclusivo foi adotado pela maioria dos binômios (62%) e orientado por profissionais de saúde em 66%. Houve baixa prevalência de procura pelo BLH por usuárias de serviço público (23%). A procura ao BLH foi motivada por problemas associados ao aleitamento, em sua maioria (85,1%). Assim, o estudo indica como ação importante para as equipes das unidades de Atenção Primária intensificar a orientação à população de gestantes e puérperas em direção à busca aos serviços do BLH, tanto como forma de promoção do aleitamento materno e apoio ao mesmo nessa população, quanto para possível captação de doadoras.

To identify the socioeconomic profile of the mothers who sought care at the Human Milk Bank, in Juiz de Fora, MG, as well as their motivations and needs when seeking the services offered by the institution. A cross-sectional, applied, exploratory study was conducted at the milk bank, where 47 mother-child pairs who sought the Milk bank services were assessed. It was noted that the majority of the mothers were married, had a secondary or higher level of education, had a job with labor rights, and had done prenatal care in a private health service. Exclusive breastfeeding was adopted by most of the motherchild pairs analyzed (62%), mostly guided by health care professionals (66%). There was a low prevalence of mothers seeking milk bank care by users of the public service (23%). The demand for the milk bank was mostly motivated by problems associated with breastfeeding (85.1%). Thus the study shows that teams of primary care units should intensify their guidance to expectant and post-partum mothers to seek out the milk bank services, both to promote breastfeeding in this population and to identify potential human milk donors.

A iatrogenia como desdobramento da relação médico-paciente: [revisão] / Iatrogenesis as an implication of patient-physician relationship: [review]

JUSTIFICATIVA E OBJETIVOS: Entende-se por iatrogenia qualquer intervenção da equipe de saúde, seja ela correta ou equivocada, justificada ou não, que resulte em alguma lesão para ao bem estar do paciente. Nesse sentido, a própria relação médico-paciente seria uma possível fonte de desdobramentos caracteristicamente iatrogênicos no nível emocional, plenos em consequências. No presente estudo, busca-se entender esses desdobramentos observando a relação entre alguém que necessita de cuidados com o outro que se propõe a cuidar, utilizando-se para tanto os conceitos de regressão e transferência, a partir das teorias do psicanalista Donald W. Winnicott referentes às funções da mãe quanto ao cuidado primário dedicadas ao bebê. CONTEÚDO: Destacam-se aspectos da relação primitiva de dependência presentificados no vínculo entre médico e paciente, bem como algumas implicações dos desencontros nas expectativas de um em relação ao outro. CONCLUSÃO: A transferência que o paciente estabelece em relação ao médico contribui para as possibilidades iatrogênicas já inerentes ao vínculo entre os dois. É necessário, portanto, que o profissional atente para a intromissão dessas demandas regressivas, sem negar, tampouco, a possível intromissão de suas próprias questões pessoais. Reconhecer uma e outra interferência a partirde seus sinais é o que o permitirá evitar ou contornar seus piores efeitos iatrogênicos.

BACKGROUND AND OBJECTIVES: Iatrogenesis can be defined as any intervention of the healthcare team, either is itcorrect or misguided, justified or not, resulting in patient's health damage. In this sense, the patient-physician relationship itself would be a possible source of characteristically iatrogenic implications on emotional level, full of consequences. The present study aims to understand these implications by observing the relationship between someone who needs care with another that purports to take care, using the regression and transference concepts, and Donald W. Winnicott's theories concerning themother's role in provide baby's primary care. CONTENTS: It highlights some elements of the primitive dependence relationship between mother and child, which reappears inside the patient-physician bond, as well as some implications of disagreements on the expectations regarding each other. CONCLUSION: The patient-physician relationship is endowed with an iatrogenic potential derived from its transferencial elements. Therefore, the professional must be aware of the regressive demands that meddle in the therapeutic relationship, and recognize them from their signals without denying also the interference resulting from their own personal issues, allowing, in avoiding interference from both sources, prevent its worst iatrogenic effects.

Uso e compreensão da medicina alternativa e complementar pela população de Juiz de Fora / Usage and comprehension of alternative and complementary medicine by the population of Juiz de Fora

Medicina alternativa e complementar (MAC) é o conjunto de diversos sistemas, práticas e produtos médicos e de atenção à saúde que não se consideram, atualmente, parte da medicina convencional. A Organização Mundial de Saúde estimula o uso dessas práticas nos sistemas de saúde de forma integrada à medicina alopática, preconizando o desenvolvimento de políticas que obedeçam a requisitos de segurança, eficácia, qualidade, uso racional e acesso. Buscamos obter um perfil de usuários da MAC da população de Juiz de Fora, o conhecimento, práticas adotadas em seus tratamentos de doença e suas crenças. Nossa amostra contemplou 495 participantes (0,1% da população). Utilizamos entrevista estruturada com dezoito perguntas. Como resultados principais: forma de conhecimento: 52,5% obtiveram informações de familiares, 59,8% de amigos, 74,3% pela televisão e 49,5% de revistas e jornais. Apenas 41,4% foram informados por um profissional de saúde. 64,20% afirmam que o médico nunca questiona a respeito desse assunto. Terapias de maior interesse de uso: massagem (35%) e terapias corporais (37,9%). Medicina antroposófica foi a menos escolhida: somente 10,9% possuíam algum interesse em usá-la, 0,4% declararam que não gostariam de utilizar nenhuma terapia. A maior taxa de rejeição foi para acupuntura (17,3%), seguida de práticas religiosas (13,3%). Concluímos que é necessário abordar esse tema durante a formação médica, visto a grande utilização. Ao acompanhar a tendência desse usuário, o médico poderá melhor intervir e orientar, visando minimizar complicações na saúde do seu paciente. É interessante investigar o conhecimento e compreensão dos médicos em relação à adoção de tratamentos da MAC.

Alternative and Complementary Medicine (ACM) consists in a group of systems, practices and medical products not currently accepted as part of conventional medicine. The World Health Organization stimulates its usage in addition to allopathic medicine, advising the development of policies which are safe, efficient, rational and accessible. Our objective was to obtain a profile of ACM users in the population of Juiz de Fora, the knowledge and practices applied to the treatment of their illnesses and their belief. We used a structured questionnaire containing eighteen questions, answered by 495 people (0, 1% of the city’s population). Our results: On how to get information of MAC: 52,5% of the participants received it from family members, 59,8% from friends, 74,3% from television, 49,5% from newspapers and magazines. Only 41,4% received the information from a health professional. 64,2% affirm that physicians never discuss the issue. On alternative and complementary treatments that raise more interest: massage (35%), body therapies (37, 9%). Anthroposophic Medicine was the least chosen option: 10, 9% of the participants had some interest on it. 0, 4% would not want to make use of any alternative therapy. The highest rejection rates are to acupuncture (17, 3%), and religious practices (13, 3%). Conclusion: It is necessary to deal with this issue along the physician’s academical studies, due to its wide usage. By considering the tendency, physicians will be able to better interfere and guide treatments, minimizing possible complications in the patient’s health conditions. The physician’s knowledge and comprehension related to Alternative and Complementary Medicine should be investigated.