Protective effect of N-acetyl-L-cysteine and rosuvastatin against oxidative stress in fibroblasts from asymptomatic patients with X-ALD: a preliminary study

Introduction: Several studies in the literature have evaluated the role of oxidative stress and adjuvant therapies for X-linked adrenoleukodystrophy (X-ALD). Here, we investigated whether n-acetyl-L-cysteine (NAC) and rosuvastatin (RSV) could influence the generation of reactive species, redox status and nitrative stress in fibroblasts from asymptomatic patients with X-ALD. Methods: Skin biopsy samples were cultured and treated for 2 hours (37 °C) with NAC and RSV. Results: X-ALD fibroblasts generated high levels of reactive oxygen species. These levels were significantly lower in fibroblasts treated with NAC and RSV relative to untreated samples. The X-ALD fibroblasts from asymptomatic patients also had higher catalase activity, and only NAC was able to increase enzyme activity in the samples. Conclusions: Our results indicated that NAC and RSV were able to improve oxidative stress parameters in fibroblasts from asymptomatic patients with X-ALD, showing that adjuvant antioxidant therapy may be a promising treatment strategy for asymptomatic patients with this disease. (AU)

X-linked adrenoleukodystrophy in brazil: a case series / Adrenoleucodistrofia ligada ao x no brasil: uma série de casos

ABSTRACT Objective: To describe patients with different phenotypes of X-linked adrenoleukodystrophy: pre-symptomatic, cerebral demyelinating inflammatory adrenoleukodystrophy, adrenomyeloneuropathy and adrenal insufficiency only. Methods: Specific data related to epidemiology, phenotype, diagnosis and treatment of 24 patients with X-linked adrenoleukodystrophy were collected. A qualitative cross-sectional and descriptive-exploratory analysis was performed using medical records from a reference center in Neuropediatrics in Curitiba, Brazil, as well as an electronic questionnaire. Results: The majority (79%) of patients had cerebral demyelinating inflammatory adrenoleukodystrophy, presenting aphasia, hyperactivity and vision disorders as the main initial symptoms. These symptoms appeared, on average, between six and seven years of age. There was a mean delay of 11 months between the onset of symptoms/signs and the diagnosis. Patients sought diagnosis mainly with neuropediatricians, and the main requested tests were dosage of very long chain fatty acids and brain magnetic resonance. Conclusions: All phenotypes of X-linked adrenoleukodystrophy, except for myelopathy in women, were presented in the studied population, which mainly consisted of children and adolescents. Prevalent signs and symptoms registered in the literature were observed. Most of the patients with cerebral demyelinating inflammatory adrenoleukodystrophy were not diagnosed in time for hematopoietic stem cell transplantation.

RESUMO Objetivo: Descrever pacientes com diferentes formas de adrenoleucodistrofia ligada ao X: pré-sintomática, adrenoleucodistrofia inflamatória desmielinizante cerebral, adrenomieloneuropatia e insuficiência adrenal primária. Métodos: Dados específicos relacionados a epidemiologia, fenótipo, diagnóstico e tratamento de 24 pacientes com adrenoleucodistrofia ligada ao X foram coletados. Realizou-se análise qualitativa, transversal e descritivo-exploratória, utilizando prontuários de um centro de referência em neuropediatria de Curitiba, Brasil, além de um questionário eletrônico. Resultados: A maioria (79%) dos pacientes manifestou adrenoleucodistrofia inflamatória desmielinizante cerebral, apresentando afasia, hiperatividade e distúrbios da visão como principais sintomas iniciais, que apareceram, em média, entre seis e sete anos de idade. Houve um atraso médio de 11 meses entre o início das manifestações e o diagnóstico. Os pacientes procuraram diagnóstico principalmente com neuropediatras, e os principais exames solicitados foram dosagem de ácidos graxos de cadeia muito longa e a ressonância magnética de crânio. Conclusões: Todos os fenótipos da adrenoleucodistrofia ligada ao X, exceto mielopatia em mulheres, foram apresentados na amostra estudada, composta principalmente de crianças e adolescentes. Foram observados sinais e sintomas prevalentes na literatura. A maioria dos pacientes com adrenoleucodistrofia inflamatória desmielinizante cerebral não recebeu diagnóstico em tempo hábil para a realização de transplante de medula óssea.

Haploidentical allogenetic hematopoietic stem cell transplantation for X-linked adrenoleukodystrophy / 北京大学学报(医学版)

OBJECTIVE@#X-linked adrenoleukodystrophy (ALD) is a severe inherited disorder leading to rapid neurological deterioration and premature death. Allogeneic hematopoietic stem cell transplantation (HSCT) is still the only treatment that halts the neurologic symptoms in ALD. However, many patients lack suitable human leukocyte antigen (HLA) matched related donors and must rely on alternative donors for a source of stem cells. The purpose of this study was to explore the outcomes of haploidentical allogeneic stem cell transplantation for ALD patients.@*METHODS@#Between December 2014 and December 2018, eight children with ALD lacking HLA matched related or unrelated donors were treated with haploidentical allogeneic hematopoietic stem cell transplantation. The patients received conditioning regimen with busulfan 9.6 mg/kg, cyclophosphamide 200 mg/kg and fludarabine 90 mg/m2. Graft-versus-host disease (GVHD) prophylaxis consisted of anti-human thymocyte globulin, cyclosporine A, mycophenolate mofetil and short course of methotrexate.@*RESULTS@#All the 8 children received allogeneic stem cell transplants from their fathers. The median age of the recipients was 8 (range: 5-12) years. The median age of the donors was 36 (range: 32-40) years. All the recipients received granulocyte colony-stimulating factor (G-CSF) mobilized bone marrow and peripheral blood-derived stem cells. The median number of total mononuclear cells dose and CD34+ dose was 10.89 (range: 9.40-12.16)×108/kg and 7.06 (range: 0.74-7.80)×106/kg, respectively. Neutrophil engraftment occurred a median of 11 days (range:8-13 days) after transplantation. Platelet engraftment occurred a median of 10 days (range:8-12 days) after transplantation. All the patients achieved complete donor chimerism at the time of engraftment. Four patients had grades II-IV acute GVHD and 1 had chronic graft-versus-host disease. No severe chronic GVHD occurred. Among all the children, 2 had cytomegalovirus (CMV) DNAemia and 2 Epstein-Barr virus (EBV) DNAemia. Overall, seven of them survived and had no major complications related to transplantation. One died of cerebral hernia after epilepsy 125 days after transplantation.@*CONCLUSION@#The preliminary observation demonstrates that haploidentical allogeneic stem cell transplantation with this novel regimen could successfully achieve full donor chimerism in ALD patients. According to our experience, haploidentical allogeneic hematopoietic stem cell transplantation is safe and feasible in the treatment of X-linked adrenoleukodystrophy.

Adrenoleucodistrofia: reporte de caso / Adrenoleukodystrophy: case report

Se reporta el caso de un adulto afectado con enfermedad de Addison debido a una patología poco frecuente en nuestro medio, como es la adrenoleucodistrofia. Se describen las manifestaciones clínicas de insuficiencia suprarrenal con alteraciones del sistema central y periférico, así como las típicas lesiones en los estudios de neuroimágenes.

We report the case of an adult affected with AddisonÆs disease due to a rare condition in our country, such as adrenoleukodystrophy. It is described the clinical manifestations of adrenal insufficiency with impaired central and peripheral nervous system and the typical lesions in neuroimaging studies.

X-Linked adrenoleukodystrophy the Saudi Experience

To evaluate the clinical, biochemical, neuroradiological, and neurophysiological findings of patients with X-linked adrenoleukodystrophy. Retrospective study evaluating the data of 10 X-linked adrenoleukodystrophy patients diagnosed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. The common presenting symptoms were deterioration in school performance, vision and hearing, behavioral changes, and seizures. Eight patients survived 1-4 years and one patient 12 years after the initial presentation, while one patient expired. Six patients had the childhood form, 3 had the adolescent form and one had the adrenomyeloneuropathy form. Six are in an advanced stage of the disease and 3 have mild to moderate spasticity. All except 2 manifested moderate to severe dementia with variable degrees of visual loss. Decreased hearing and features of adrenal insufficiency were seen in 7 patients. Very long chain fatty acids were significantly increased in seven and mildly elevated in 2 patients, however the C26 to C22 ratio was increased in all. The characteristic high-signal intensity of parieto-occipital white matter on brain magnetic resonance imaging T2-weighted images was observed in all patients. Two patients had functional study of the brain, which showed hypometabolic activity in gray and white matter of the occipital lobes. Various neurophysiological abnormalities were detected. The response to different treatment modalities was not promising. The disease is more common than had been previously recognized due to phenotypic variability and a wide spectrum of presentations. This report describes various aspects of this disorder and emphasizes the importance of early identification and treatment of asymptomatic but biochemically affected individuals, since all current therapeutic approaches are disappointing if overt neurological abnormalities have been already developed

Primer caso documentado en Venezuela de adrenoleucodistrofia ligada al cromosoma X / Documented case first in Venezuela of adrenoleukodystrophy thick X chromosome

La adrenoleucodistrofia ligada al cromosoma X (xALD) es un trastorno del metabólismo de los ácidos grasos de cadena muy larga (AGCML) que origina su acumulación en múltiples tejidos y plasma, lo que provoca disfunción del sistema nervioso y las glándulas suprarrenales. Se han descrito seis formas clínicas: Cerebral de la niñez, cerebral de la adolescencia, cerebral de la edad adulta, adrenomieloneuropatía, Addison solo y asintomática. Se presenta el caso de un paciente xALD de forma cerebral de la niñez, quien inicia en forma lenta y progresiva a la edad de 9 años deterioro neurológico dado por: diagrafía, dismetría, trastorno de la marcha, bradilalia, y disartria, acompañados por hipertonía generalizada, con daño de las funciones cognitivas y motoras, concomitantemente imágenes características en la RMN, cortisol normal y AGML elevados en plasma, lo cual confirma el diagnóstico. Conclusión: la xALD es una enfermedad recientemente descrita, de fácil diagnostico. En Venezuela sólo se ha diagnósticado clínicamente. En el paciente descrito se confirmo bioquímicamente la enfermedad en el Instituto Kennedy Krieger, EE.UU

Insuficiência adrenal primária está freqüentemente associada à adrenoleucodistrofia em crianças / Primary adrenal insufficiency is usually associated to adrenoleukodystrophy in children

Adrenoleucodistrofia (ALD) é uma doença desmielinizante do sistema nervoso central freqüentemente associada à insuficiência adrenal (IA) primária. Devido a um defeito genético, näo ocorre a oxidaçäo dos ácidos graxos saturados de cadeia muito longa (AGSCML), os quais se acumulam na forma de ésteres de colesterol na substância branca cerebral e no córtex adrenal. O fenótipo mais comum da ALD é a forma cerebral (cerca de 45 por cento) que se desenvolve em indivíduos do sexo masculino entre 5 e 12 anos. A IA primária pode ser a única manifestaçäo do distúrbio em 6 a 8 por cento dos casos. Apresentamos dois irmäos, 8 e 5 anos, masculinos, portadores de adrenoleucodistrofia ligada ao X, associada à insuficiência adrenal primária. O propósito iniciou com mudança comportamental e alteraçöes cognitivas há dois anos. A avaliaçäo já apresentava dismielinizaçäo importante do sistema nervoso central, com déficit neurológico e escurecimento de pele. Os exames laboratoriais e de imagem evidenciaram níveis plasmáticos elevados de AGSCML, IA primária (aumento do ACTH, diminuiçäo da resposta do cortisol ao estímulo com ACTH e elevaçäo da atividade plasmática da renina) e acometimento cerebral. Concomitantemente, foi avaliado o irmäo do propósito, o qual era assintomático. Devido aos níveis de AGSCML, o paciente estava sendo tratado com o óleo de Lorenzo há um ano. Apesar deste tratamento, evoluiu com IA primária, sem outras manifestaçöes neurológicas de ALD. Relatamos o caso de dois irmäos portadores de ALD associada à IA primária.

Insuficiencia supra-renal na infancia associada a severas alteracoes do sistema nervoso central: relato de um caso de adrenoleucodistrofia / Supra-renal failure in infancy associated with severe alterations of central nervous system: a adrenoleukodystrophy case report

E apresentado um caso de adrenoleucodistrofia (ALD), doenca metabolica hereditaria ligada ao sexo e caracterizada por alteracoes no metabolismo de acidos graxos de cadeia muito longa (Very Long-Chain Fatty Acids - VLCFA), manifestando-se clinicamente por insuficiencia adrenal e anormalidades neurologicas progressivas. Sao discutidas a forma de apresentacao da doenca e o seu diagnostico, sendo enfatizada a importancia de ter-se presente a possibilidade de ALD em criancas portadoras de doenca de Addison, porque trata-se de molestia sujeita a intervencao terapeutica, com prevencao e ate regressao dos disturbios neurologicos