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Mitogen-activated protein kinase 8-interacting protein 3 gene (MAPK8IP3) encodes the c-Jun-amino-terminal kinase-interacting protein 3 (JIP3) and is involved in retrograde axonal transport. Heterozygous de novo pathogenic variants in MAPK8IP3 result in a neurodevelopmental disorder with or without brain abnormalities and possible axonal peripheral neuropathy. Whole-exome sequencing was performed on an individual presenting with severe congenital muscle hypotonia of neuronal origin mimicking lethal spinal muscular atrophy. Compound heterozygous rare variants (a splice and a missense) were detected in MAPK8IP3, inherited from the healthy parents. Western blot analysis in a muscle biopsy sample showed a more than 60% decrease in JIP3 expression. Here, we suggest a novel autosomal recessive phenotype of a lower motor neuron disease caused by JIP3 deficiency.
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Atrofia Muscular Espinal , Doenças Musculares , Anormalidades Musculoesqueléticas , Humanos , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Fenótipo , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas Adaptadoras de Transdução de Sinal/genéticaRESUMO
BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.
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Epilepsia , Pós-Menopausa , Feminino , Humanos , Animais , Ratos , Estudos de Casos e Controles , Estudos Prospectivos , Estudos Transversais , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Hormônios Esteroides Gonadais/farmacologia , Hormônios Esteroides Gonadais/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive disease caused by biallelic pathogenic variants in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Acid sphingomyelinase deficiency is characterized by a spectrum of disease and is broadly divided into three types (ASMD type A, ASMD type A/B, and ASMD type B). More than 220 disease-associated SMPD1 variants have been reported, and genotype/phenotype correlations are limited. Here we report the first description of all six diagnosed acid sphingomyelinase deficiency cases in Hungary. Nine SMPD1 variants are present in this cohort, including 3 SMPD1 variants (G247D, M384R, and F572L), which have only been described in Hungarian patients. All described variants are deemed to be pathogenic. Eight of the variants are missense, and one is a frameshift variant. The treatment of an ASMD type A/B patient in this cohort using hematopoietic stem cell transplantation is also detailed. This study may help to support diagnosis, patient genetic counseling, and management of acid sphingomyelinase deficiency.
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INTRODUCTION: Rhabdomyolysis is a syndrome characterized by a rapid necrosis of muscle fibers and the release of muscle-derived metabolic products into the circulatory system. A rare cause of rhabdomyolysis is paraneoplastic polymyositis. CASE PRESENTATION: A 67-year-old man was diagnosed with paraneoplastic polymyositis and rhabdomyolysis caused by hepatocellular carcinoma (HCC). Intravenous steroid was used as a symptomatic therapy for rhabdomyolysis, and the tumour was removed by left hemihepatectomy to treat the underlying cause. After muscle strength gradually improved, steroid therapy was discontinued. The patient was reoperated multiple times due to bleeding and bile leakage. Following the operations, his overall state and muscle strength further improved. Despite that, the patient's condition worsened again, and eventually, he died of candida albicans pneumonia and sepsis. DISCUSSION: HCC is an extremely rare cause of paraneoplastic polymyositis and rhabdomyolysis. Treatment is challenging, as none of the few available case reports record long term survival and less than half of the reports record muscle strength improvement. In our case, the patient was treated with systemic steroid therapy and resection of the tumour. The patient's muscle strength temporarily improved, but subsequently, the patient died. CONCLUSION: Our case confirms the importance of a definitive treatment of HCC, as we achieved a significant improvement in muscle strength by removing the tumour. On the other hand, our paper highlights the dangers of double-sided steroid therapy, which, combined with the essential, effective treatment of rhabdomyolysis, may have contributed to the development of postoperative complications and candida sepsis leading to death.
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BACKGROUND: Marfan syndrome (MFS) is a systemic connective tissue disorder with life-threatening manifestations affecting the ascending aorta. MFS is caused by dominant negative (DN) and haploinsufficient (HI) mutations of the FBN1 gene. Our aim was to identify mutations of MFS patients with high detection rate and to investigate the use of a gene panel for patients with Marfanoid habitus. We also aimed to examine correlations between genotype and cardiovascular manifestations to predict "malignant" mutations. METHODS: 136 individuals were enrolled. In the first phase, next-generation sequencing (NGS) and Sanger sequencing were performed for 57 patients to screen the FBN1 gene, followed by multiplex ligation-dependent probe amplification (MLPA) in negative cases. For repeated negative results, NGS gene panel involving 9 genes was used. In the second phase, 79 patients were tested primarily with the same gene panel, negative samples were tested by MLPA. RESULTS: 84 pathogenic mutations were detected, out of which 78 affected FBN1, 6 non-FBN1 mutations (2 TGFB2, 1 TGFBR2, 2 TGFBR1, 1 SMAD3) are associated with Loeys-Dietz syndrome (LDS). LDS patients had lower systemic score and they were younger, but their aortic involvement did not differ. MLPA detected 4 multi-exon deletions of FBN1 gene, which could not be identified by our first-step screening method. Aortic involvement (aortic dissection and/or dilation) did not differ significantly among HI and DN mutations (p = 0.061). Combined group of HI and DN mutations eliminating a disulphide-bonding cysteine (DN Cys) had significantly higher aortic involvement rate than DN mutations not eliminating a disulphide-bonding cysteine (DN non-Cys) (p < 0.001). Patients with DN Cys required significantly more aortic surgeries than HI and DN non-Cys mutations (p = 0.042 and p = 0.015, respectively). CONCLUSIONS: Due to the relevant number of mutations affecting genes other than FBN1, preferred approach for testing individuals with Marfanoid habitus is using a gene panel rather than single-gene analysis, followed by MLPA for negative samples. DN Cys and HI mutations should be considered as risk factors for aortic involvement. Genetic testing for patients with Marfanoid features and a systemic score under 7 is recommended, as LDS patients may have lower scores, but they may have severe cardiovascular manifestations.
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Síndrome de Loeys-Dietz , Síndrome de Marfan , Aorta , Fibrilina-1/genética , Fibrilinas , Genótipo , Humanos , Síndrome de Marfan/diagnóstico , Síndrome de Marfan/genética , Mutação/genéticaRESUMO
INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a homozygous deletion of the survival motor neuron (SMN) 1 gene. Nusinersen is an antisense oligonucleotide enhancing the production of the SMN protein. It has received approval by the European Medicines Agency (EMA) in 2017, based on the clinical trials demonstrating the effectiveness of nusinersen in several types of SMA. In Hungary, the first patient received nusinersen treatment in April 2018. Our aim is to summarize our experience regarding the efficacy, safety and tolerability of nusinersen in our patients. METHODS: Data were collected retrospectively in all types of SMA patients (type 1-3) starting treatment with nusinersen in Hungary between April 2018 and December 2019. Motor functions were evaluated at baseline, at the fourth and all following injections. RESULTS: By 31st December 2019, nusinersen therapy was initiated in 54 patients at either of the two Hungarian treatment centres. Mean age of the patients at the start of the treatment was 6.3 years (±5,4 range 0.4-17.9). 13 patients are type 1 (mean 0.78 ± 0.27, range 0.4-1.5 yrs), 21 patients are type 2 (mean 4.5 ± 3.3, range 1.3-12 yrs), 23 patients are type 3 (mean 10.9 ± 5.2, range 2.9-17.9 yrs). Fourteen patients had severe scoliosis, four of them underwent spine stabilizing surgery. During the study period 340 injections were administered without any new safety concerns emerging. The data of 38 patients, who had completed the first six treatments, were included in the final statistical analysis. Motor function has improved in most of the children. By the 307th day visit, on average, a 14.9 (±5,1) point improvement was measured on the CHOP INTEND scale in type 1 patients (p = 0.016). All patients with type 1 SMA who performed the motor evaluation (7/10) have improved by more than four (7-21) points. Regarding type 2 patients, a 7.2 (range -2- 17) point increase from baseline (p < 0.001) on the Hammersmith Functional Motor Scale Expanded (HFMSE) and 4.3 (range: 2-9) point increase (p = 0.031) on the Revised Upper Limb Module (RULM) were found. The distance of the 6 min walk test also increased by 33.9 m on average (range -16 - 106), in type 3 patients. CONCLUSION: According to our results nusinersen has the same safety and tolerability profile as in the clinical trials. In a heterogenic patient population of SMA type 1 and 2, nusinersen showed similar efficacy as seen in the pivotal studies. A clinically and statistically significant improvement of motor functions was also detectable in type 3 patients with heterogeneous age distribution.
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Atividade Motora/efeitos dos fármacos , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hungria , Lactente , Masculino , Recuperação de Função Fisiológica/efeitos dos fármacos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Perrault syndrome is a genetically heterogenous, very rare disease, characterized clinically by sensorineural hearing loss, ovarian dysfunction and neurological symptoms. We present the case of a 33 years old female patient with TWNK-associated Perrault syndrome. The TWNK gene is coding the mitochondrial protein Twinkle and currently there are only two reports characterizing the phenotype of TWNK-associated Perrault syndrome. None of these publications reported about special brain MRI alterations and neuropathological changes in the muscle and peripheral nerves. CASE PRESENTATION: Our patients with TWNK-dependent Perrault syndrome had severe bilateral hypoacusis, severe ataxia, polyneuropathy, lower limb spastic paraparesis with pyramidal signs, and gonadal dysgenesis. Psychiatric symptoms such as depression and paranoia were present as well. Brain MRI observed progressive cerebellar hyperintensive signs associated with cerebellar, medulla oblongata and cervical spinal cord atrophy. Light microscopy of the muscle biopsy detected severe neurogenic lesions. COX staining was centrally reduced in many muscle fibers. Both muscle and sural nerve electron microscopy detected slightly enlarged mitochondria with abnormal cristae surrounded by lipid vacuoles. In the sural nerve, dystrophic axons had focally uncompacted myelin lamellae present. Genetic investigation revealed multiple mtDNA deletion and compound heterozygous mutations of the TWNK gene (c.1196 A > G, c.1358 G > A). CONCLUSION: This study demonstrates that TWNK associated Perrault syndrome has a much broader phenotype as originally published. The coexistence of severe hypoacusis, spastic limb weakness, ataxia, polyneuropathy, gonadal dysgensia, hyperintense signals in the cerebellum and the presence of the mtDNA multiple deletion could indicate the impairment of the TWNK gene. This is the first report about pyramidal tract involvement and cerebellar MRI alteration associated with TWNK-related Perrault syndrome.
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DNA Helicases/genética , Disgenesia Gonadal 46 XX/genética , Perda Auditiva Neurossensorial/genética , Proteínas Mitocondriais/genética , Fenótipo , Adulto , Feminino , Disgenesia Gonadal 46 XX/diagnóstico por imagem , Disgenesia Gonadal 46 XX/patologia , Perda Auditiva Neurossensorial/diagnóstico por imagem , Perda Auditiva Neurossensorial/patologia , Humanos , Imageamento por Ressonância Magnética , MutaçãoRESUMO
We describe a family with a novel TNPO3 mutation of limb-girdle muscular dystrophy D2 (or LGMD 1F), a rare muscle disorder with autosomal dominant inheritance, first identified in an Italo-Spanish family where the causative defect has been found to be due to TNPO3 gene mutation, encoding transportin-3 protein (TNPO3). We present the clinical, histopathological and muscle magnetic resonance imaging (MRI) features in two patients, mother and son Hungarian origin, affected by LGMD D2 and correlate their clinical, MRI and histopathological data found in this condition. The affected son presented early pelvic girdle muscle weakness and thin muscles similar to a congenital myopathy; the mother was less compromised and had an LGMD phenotype. Muscle MRI showed a very pronounced lower limb muscle atrophy in both patients. The most relevant change obtained in the child muscle biopsy was a generalized type 1 fibre atrophy. The two patients presented the same mutation, but a different phenotype has been observed in mother and son.
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PURPOSE: Pathogenic variants of the gap junction beta 2 (GJB2) gene are responsible for about 50% of hereditary non-syndromic sensorineural hearing loss (NSHL). In this study, we report mutation frequency and phenotype comparison of different GJB2 gene alterations in Hungarian NSHL patients. METHODS: The total coding region of the GJB2 gene was analyzed with Sanger or NGS sequencing for 239 patients with NSHL and 160 controls. RESULTS: Homozygous and compound heterozygous GJB2 mutations were associated with early onset serious clinical phenotype in 28 patients. In 24 patients, two deletion or nonsense mutations were detected in individuals with mainly prelingual NSHL. In compound heterozygous cases, a combination of deletion and missense mutations associated with milder postlingual NSHL. A further 25 cases harbored single heterozygous GJB2 mutations mainly associated with later onset, milder clinical phenotype. The most common mutation was the c.35delG deletion, with 12.6% allele frequency. The hearing loss was more severe in the prelingual groups. CONCLUSION: The mutation frequency of GJB2 in the investigated cohort is lower than in other European cohorts. The most serious cases were associated with homozygous and compound heterozygous mutations. In our cohort the hearing impairment and age of onset was not altered between in cases with only one heterozygous GJB2 mutation and wild type genotype, which may exclude the possibility of autosomal dominant inheritance. In early onset, severe to profound hearing loss cases, if the GJB2 analysis results in only one heterozygous alteration further next generation sequencing is highly recommended.
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Conexinas/genética , Perda Auditiva Neurossensorial/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos de Coortes , Conexina 26 , Feminino , Frequência do Gene , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Sequência de DNA , Índice de Gravidade de Doença , Adulto JovemRESUMO
The rare, genetically determined group of diseases characterized by pathological accumulation of iron in the central nervous system and progressive, typically movement disorder's symptoms are called NBIA (neurodegeneration with brain iron accumulation). By the rapid development of molecular genetics, it has become apparent that different mutations in numerous genes can lead to pathological cerebral iron accumulation. Simultaneously, it has also been recognized that the age of onset, the symptoms and the prognosis of NBIA disorders are much more diverse than it was previously perceived. To our knowledge, a review article on the most recent clinical data of NBIA has not been published in Hungarian. In the first part of this publication, we survey the general clinical characteristics and the diagnostic algorithm of NBIA diseases and address some considerations for differential diagnostics. In the second part of this review, the particular NBIA disorders are presented in details. The purpose of this article is to provide a clinical overview that may be useful for neurologists, pediatricians and any other medical practitioners interested in this field.
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Encéfalo/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/diagnóstico , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Distúrbios do Metabolismo do Ferro/diagnóstico , Distúrbios do Metabolismo do Ferro/genética , Ferro/metabolismo , Mutação , Distrofias Neuroaxonais/diagnóstico , Distrofias Neuroaxonais/genética , Alopecia/diagnóstico , Alopecia/genética , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/genética , Doenças dos Gânglios da Base/diagnóstico , Doenças dos Gânglios da Base/genética , Encéfalo/patologia , Ceruloplasmina/genética , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Fosfolipases A2 do Grupo VI/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/terapia , Humanos , Hipogonadismo/diagnóstico , Hipogonadismo/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Distúrbios do Metabolismo do Ferro/metabolismo , Distúrbios do Metabolismo do Ferro/terapia , Oxigenases de Função Mista/genética , Distrofias Neuroaxonais/metabolismo , Distrofias Neuroaxonais/terapia , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Doenças Raras/diagnóstico , Doenças Raras/genética , Transferases/genéticaRESUMO
Dynamin2 (DNM2) gene mutations may result in Charcot-Marie-Tooth disease and centronuclear myopathy. Here, we present a patient suffering from cardiomyopathy and centronuclear myopathy with repetitive discharges and mild axonal neuropathy due to DNM2 mutation. Detailed cardiological and neurological examinations, electrophysiological tests, muscle biopsy, and molecular genetic analysis were performed. The patient developed left bundle branch block at age 40 and was fitted with a pacemaker at the age of 43. The patient has severe heart failure, ptosis, strabism, facial and proximal muscle weakness. Electrophysiological investigations found myopathy, complex repetitive discharges, and axonal neuropathy. Skeletal muscle biopsy detected centronuclear myopathy and cytochrome C oxidase (COX) negative fibers. Genetic analysis detected a pathogenic c.1105C>T (p.R369W) DNM2 gene mutation and heteroplasmic multiple mitochondrial DNA (mtDNA) deletion. Our data broadens the phenotypic spectrum of DNM2 mutations. The presence of the multiple mtDNA deletions may provide new aspects to understanding the pathogenesis of multisystemic symptoms in patients with DNM2 mutations.
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Cardiomiopatias/genética , DNA Mitocondrial/genética , Dinaminas/genética , Mutação , Miopatias Congênitas Estruturais/genética , Southern Blotting , Cardiomiopatias/fisiopatologia , Dinamina II , Eletrofisiologia , Feminino , Humanos , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/fisiopatologia , Reação em Cadeia da Polimerase , Deleção de SequênciaRESUMO
Focusing on the benefits of patients with rare disease the authors analysed the aspects of orphan medicines financed in the frame of the Hungarian social insurance system in 2012 in order to make the consumption more rational, transparent and predictable. Most of the orphan drugs were financed in the frame of compassionate use by the reimbursement system. Consequently, a great deal of crucial problems occurred in relation to the unconventional subsidized method, especially in the case of the highest cost enzyme replacement therapies. On the base of the findings, proposals of the authors are presented for access to orphan drugs, fitting to the specific professional, economical and ethical aspects of this unique field of the health care system. The primary goal is to provide a suitable subsidized method for the treatment of rare disease patients with unmet medical needs. The financial modification of orphans became indispensible in Hungary. Professionals from numerous fields dealing with rare disease patients' care expressed agreement on the issue. Transforming the orphan medicines' financial structure has been initiated according to internationally shared principles.
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Custos de Medicamentos , Terapia de Reposição de Enzimas/economia , Financiamento Governamental , Produção de Droga sem Interesse Comercial/economia , Doenças Raras/tratamento farmacológico , Doenças Raras/economia , Ensaios de Uso Compassivo/economia , Doença de Fabry/tratamento farmacológico , Doença de Fabry/economia , Financiamento Governamental/legislação & jurisprudência , Financiamento Governamental/métodos , Financiamento Governamental/organização & administração , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/economia , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/economia , Necessidades e Demandas de Serviços de Saúde , Humanos , Hungria , Cobertura do Seguro , Seguro Saúde , Mucopolissacaridose I/tratamento farmacológico , Mucopolissacaridose I/economia , Mucopolissacaridose II/tratamento farmacológico , Mucopolissacaridose II/economiaRESUMO
Increasing number of evidences support the role of glycosylation in the evolution of autoimmunity. We examined carbohydrate-reactive natural autoantibodies systematically for the first time in patients with autoimmune myasthenia gravis. Antibodies reactive to glycosaminoglycans were measured with CovaLink ELISA in the sera of 59 myasthenia patients as well as in 54 healthy controls. We used the GlycoChip carbohydrate array to characterize individual carbohydrate recognition patterns. Chondroitin-sulphate C and anti-α-mannose-specific IgG levels were significantly elevated in myasthenia patients. Unexpectedly, we found that immunosuppressants increased the levels of the protective IgM glycosaminoglycan-reactive natural antibodies demonstrating a new role for these agents in immunoregulation.
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Autoanticorpos/sangue , Glicosaminoglicanos/imunologia , Imunossupressores/imunologia , Miastenia Gravis/sangue , Adulto , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Receptores Colinérgicos/imunologiaRESUMO
Cerebrotendinous xanthomatosis is a rare neurodegenerative disease characterized by the accumulation of cholesterol and cholestanol in the brain and the tendons caused by mutations of the gene encoding sterol 27-hydroxylase (CYP27A1), which is involved in bile acid synthesis. The diagnosis is often missed and delayed because of the variable clinical presentation of the disease. Blood testing for cerebrotendinous xanthomatosis is routinely performed using gas chromatography-mass spectrometry measurement of elevated cholestanol level, and the diagnosis is confirmed by molecular genetic analysis. Early recognition and initiation of chenodeoxycholic acid therapy with hydoxymethylglutarylCoenzyme-A reductase inhibitors is critical to prevent irreversible neurological damage and permanent disability. The authors summarize the current knowledge about the pathomechanism, laboratory diagnosis and therapeutic options of cerebrotendinous xanthomatosis.
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Ácido Quenodesoxicólico/uso terapêutico , Colestanotriol 26-Mono-Oxigenase/genética , Colestanol/metabolismo , Colesterol/metabolismo , Xantomatose Cerebrotendinosa/diagnóstico , Xantomatose Cerebrotendinosa/metabolismo , Encéfalo/metabolismo , Colestanol/sangue , Colesterol/sangue , Técnicas de Laboratório Clínico , Diagnóstico Precoce , Cromatografia Gasosa-Espectrometria de Massas , Regulação Enzimológica da Expressão Gênica , Testes Genéticos/economia , Saúde Global , Humanos , Hungria/epidemiologia , Recém-Nascido , Triagem Neonatal , Doenças Raras , Tendões/metabolismo , Xantomatose Cerebrotendinosa/tratamento farmacológico , Xantomatose Cerebrotendinosa/enzimologia , Xantomatose Cerebrotendinosa/genética , Xantomatose Cerebrotendinosa/fisiopatologiaRESUMO
The authors report a case of rare chloroquine cardiotoxicity mimicking connective tissue disease heart involvement in a 56-year-old woman with mixed connective tissue disease (MCTD) manifested suddenly as third degree A-V block with QT(c) interval prolongation and short torsade de pointes runs ultimately degenerating into ventricular fibrillation. Immunological tests suggested an MCTD flare, implying that cardiac arrest had resulted from myocardial involvement by MCTD. However, QT(c) prolongation is not a characteristic of cardiomyopathy caused by connective tissue disease, unless anti-Ro/SSA positivity is present, but that was not the case. Therefore, looking for another cause of QT(c) prolongation the possibility of chloroquine cardiotoxicity emerged, which the patient had been receiving for almost two years in supramaximal doses. Biopsy of the deltoid muscle was performed, because in chloroquine toxicity, specific lesions are present both in the skeletal muscle and in the myocardium, and electron microscopy revealed the accumulation of cytoplasmic curvilinear bodies, which are specific to antimalarial-induced myocyte damage and are absent in all other muscle diseases, except neuronal ceroid lipofuscinosis. Thus, the diagnosis of chloroquine cardiotoxicity was established. It might be advisable to supplement the periodic ophthalmological examination, which is currently the only recommendation for patients on long-term chloroquine therapy, with ECG screening.
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Cloroquina/efeitos adversos , Doenças do Tecido Conjuntivo/induzido quimicamente , Doenças do Tecido Conjuntivo/diagnóstico , Cardiopatias/diagnóstico , Coração/efeitos dos fármacos , Cloroquina/uso terapêutico , Doenças do Tecido Conjuntivo/fisiopatologia , Diagnóstico Diferencial , Feminino , Coração/fisiopatologia , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Humanos , Pessoa de Meia-IdadeRESUMO
ABSTRACT: The currently hyped expectation of personalized medicine is often associated with just achieving the information technology led integration of biomolecular sequencing, expression and histopathological bioimaging data with clinical records at the individual patients' level as if the significant biomedical conclusions would be its more or less mandatory result. It remains a sad fact that many, if not most biomolecular mechanisms that translate the human genomic information into phenotypes are not known and, thus, most of the molecular and cellular data cannot be interpreted in terms of biomedically relevant conclusions. Whereas the historical trend will certainly be into the general direction of personalized diagnostics and cures, the temperate view suggests that biomedical applications that rely either on the comparison of biomolecular sequences and/or on the already known biomolecular mechanisms have much greater chances to enter clinical practice soon. In addition to considering the general trends, we exemplarily review advances in the area of cancer biomarker discovery, in the clinically relevant characterization of patient-specific viral and bacterial pathogens (with emphasis on drug selection for influenza and enterohemorrhagic E. coli) as well as progress in the automated assessment of histopathological images. As molecular and cellular data analysis will become instrumental for achieving desirable clinical outcomes, the role of bioinformatics and computational biology approaches will dramatically grow. AUTHOR SUMMARY: With DNA sequencing and computers becoming increasingly cheap and accessible to the layman, the idea of integrating biomolecular and clinical patient data seems to become a realistic, short-term option that will lead to patient-specific diagnostics and treatment design for many diseases such as cancer, metabolic disorders, inherited conditions, etc. These hyped expectations will fail since many, if not most biomolecular mechanisms that translate the human genomic information into phenotypes are not known yet and, thus, most of the molecular and cellular data collected will not lead to biomedically relevant conclusions. At the same time, less spectacular biomedical applications based on biomolecular sequence comparison and/or known biomolecular mechanisms have the potential to unfold enormous potential for healthcare and public health. Since the analysis of heterogeneous biomolecular data in context with clinical data will be increasingly critical, the role of bioinformatics and computational biology will grow correspondingly in this process.
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Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/etiologia , Leucoencefalopatias/complicações , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/etiologia , Adulto , Idade de Início , Neoplasias do Sistema Nervoso Central/patologia , Feminino , Humanos , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/epidemiologia , Leucoencefalopatias/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Imageamento por Ressonância Magnética , Anamnese , Fatores de TempoRESUMO
Autoimmune myasthenia gravis is a T-cell-dependent, antibody-mediated, rare neuromuscular disorder. Interleukin-4, acting via interleukin-4 receptor alpha, plays a pivotal role in B-cell differentiation and antibody production and has been implicated to influence disease progression in experimental autoimmune myasthenia gravis. Polymorphisms of the interleukin-4 receptor alpha gene have been shown to be associated with various autoimmune diseases. We compared the distribution of three polymorphisms of the interleukin-4 receptor alpha gene (S503P, rs1805015, Q576R, rs1801275, I75V, rs1805010), all affecting interleukin-4 signaling, in two cohorts of myasthenia gravis patients with ethnically matched controls. Although the distribution of the S503P and Q576R polymorphisms did not differ significantly between the groups, the frequency of the GG rare homozygote genotype of the I75V polymorphism was significantly higher in patients with myasthenia gravis. Our data suggest that the reduced responsiveness to interleukin-4 because the I75V polymorphism may contribute to the pathogenesis of myasthenia gravis.
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Miastenia Gravis/genética , Polimorfismo Genético , Receptores de Interleucina-4/genética , População Branca/genética , Adolescente , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Feminino , Genética Populacional , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/imunologia , Miastenia Gravis/fisiopatologiaAssuntos
Fármacos Neuromusculares/uso terapêutico , Doenças Neuromusculares/genética , Doenças Neuromusculares/imunologia , Algoritmos , Autoimunidade , Tomada de Decisões , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Epigênese Genética , Predisposição Genética para Doença , Doença de Depósito de Glicogênio Tipo II/diagnóstico , Doença de Depósito de Glicogênio Tipo II/tratamento farmacológico , Doença de Depósito de Glicogênio Tipo II/enzimologia , Humanos , Distrofia Muscular Facioescapuloumeral/diagnóstico , Distrofia Muscular Facioescapuloumeral/genética , Miastenia Gravis/imunologia , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/tratamento farmacológico , Polimiosite/diagnóstico , Polimiosite/terapia , Polineuropatias/imunologiaRESUMO
The authors report the case of a 27-year-old woman with muscle-specific receptor tyrosine kinase antibody positive myasthenia with predominantly ocular and bulbar symptoms. Both edrophonium and low dose (4×30 mg/day) pyridostigmin resulted in cholinergic side effects including fasciculation mainly in the facial and neck muscles, and excessive salivation. The patient responded well to a relatively high dose of chronic corticosteroid treatment (methyprednisolone 64mg/day), but the decrease of the corticosteroid dose below 16 mg/day induced exacerbation of the clinical symptoms. Immunosuppression with azathioprine and methotrexate failed to maintain the clinical improvement. However, plasma exchange was always very effective, and all clinical symptoms improved significantly. The authors conclude that patients with muscle-specific receptor tyrosine kinase antibody positive myasthenia gravis should have an individual treatment protocol differing from those used in patients who do not have this antibody but are positive for acetylcholine-receptor antibody. Identification of the pathogenic antibody in the early stage of myasthenia gravis may help to develop the optimal, individualized treatment strategy, to avoid severe side effects, and to achieve fast improvement.