RESUMO
X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency, and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro- and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN, and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro-inflammatory cytokines IL-1ß, IL-2, IL-8, and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5, and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflammatory cytokines in asymptomatic and AMN patients and negative correlation between anti-inflammatory cytokine and C24:0/C22:0 ratio in AMN patients. The present work yields experimental evidence that there is an inflammatory imbalance associated Th1, (IL-2, IL-6, and IFN-γ), Th2 (IL-4 and IL-10), and macrophages response (TNF-α and IL-1ß) in the periphery of asymptomatic and AMN patients, and there is correlation between VLCFA plasmatic levels and inflammatory mediators in X-ALD. Furthermore, we might also speculate that the increase of plasmatic cytokines in asymptomatic patients could be considered an early biomarker of brain damage and maybe also a predictor of disease progression.
Assuntos
Adrenoleucodistrofia/imunologia , Citocinas/sangue , Macrófagos/imunologia , Células Th1/imunologia , Adolescente , Adrenoleucodistrofia/sangue , Adulto , Criança , Pré-Escolar , Ácidos Graxos/sangue , Humanos , Lactente , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-2/sangue , Interleucina-4/sangue , Interleucina-5/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/sangue , Adulto JovemRESUMO
Primary adrenal failure (PAF) can be congenital or acquired. X-linked adrenoleukodystrophy (ALD-X), produced by the mutation of the ABDC1 gene (Xq28), that leads to the plasma accumulation of very long chain fatty acids, is one of the congenital diseases associated to adrenal destruction. We report a 7 years old boy with fast progression of right strabismus and general symptoms as weariness, weakness and mucosal and skin pigmentation. A brain magnetic resonance image showed a leukoencephalopathy, characteristic of ALD-X. Low plasma cortisol, high ACTH levels and lack of response to ACTH test, confirmed the diagnosis of primary adrenal insufficiency. High plasma levels of C26:0 fatty acids, and C24/22, C26/22 ratios confirmed ALD-X.
Assuntos
Humanos , Masculino , Criança , Adrenoleucodistrofia/diagnóstico , Doença de Addison/etiologia , Doença de Addison/tratamento farmacológico , Ácidos Graxos/sangue , Adrenoleucodistrofia/complicações , Adrenoleucodistrofia/sangue , Anti-Inflamatórios/uso terapêutico , Cérebro/patologia , Estrabismo/etiologia , Insuficiência Adrenal/etiologia , Insuficiência Adrenal/tratamento farmacológico , Imageamento por Ressonância MagnéticaRESUMO
X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterized by deficient beta-oxidation of saturated very long chain fatty acids (VLCFA). The consequent accumulation of these fatty acids in different tissues and in biological fluids is associated with a progressive central and peripheral demyelination, as well as with adrenocortical insufficiency and hypogonadism. Seven variants of this disease have been described, cerebral childhood being the most frequent. The recommended therapy consists of the use of the glyceroltrioleate/glyceroltrierucate mixture known as Lorenzo's Oil (LO), combined with a VLCFA-poor diet, but only in asymptomatic patients will this treatment prevent the progression of the symptomatology. In the present study we evaluated the biochemical course of patients with cerebral childhood (CCER) and asymptomatic clinical forms of X-ALD treated with LO associated with a VLCFA-restricted diet. We observed that hexacosanoic acid plasma concentrations and hexacosanoic/docosanoic ratio were significantly reduced in CCER patients during treatment when compared with diagnosis. Hexacosanoic acid plasma level was significantly reduced when compared with that at diagnosis and achieved the normal levels only in asymptomatic patients under LO treatment. In asymptomatic patients the magnitude of hexacosanoic acid decrease was higher than that of the CCER patients. These results show the good biochemical response of LO treatment in asymptomatic X-ALD patients. It is possible to suppose that this could be correlated with the prevention of the appearance of neurological signals in this group of patients treated with LO.
Assuntos
Adrenoleucodistrofia/sangue , Adrenoleucodistrofia/dietoterapia , Ácidos Erúcicos/uso terapêutico , Ácidos Graxos/sangue , Trioleína/uso terapêutico , Adrenoleucodistrofia/psicologia , Criança , Dieta , Combinação de Medicamentos , Ácidos Graxos/metabolismo , Feminino , Humanos , Hipercinese/etiologia , Hipercinese/psicologia , Deficiências da Aprendizagem/etiologia , Deficiências da Aprendizagem/psicologia , Masculino , Convulsões/etiologia , Convulsões/psicologiaRESUMO
OBJECTIVE: Plasma assay for very long-chain fatty acids has made it possible to perform large-scale screening of at-risk individuals to identify asymptomatic patients with X-linked adrenoleukodystrophy (X-ALD). We evaluated the burden of undiagnosed adrenal insufficiency in 49 such patients (age, 4.5 +/- 3.5 years). STUDY DESIGN: Serum adrenocorticotropic hormone (ACTH) and standard-dose ACTH stimulation test were performed at the baseline and followed prospectively until initiation of adrenal replacement therapy (follow-up, 2 +/- 1.7 years). RESULTS: At baseline, 39 (80%) patients had impaired adrenal function, serum ACTH levels were elevated in 34 (69%) patients, and ACTH stimulation test was abnormal in 21(43%) patients. There was a moderate association between Serum ACTH and age at baseline, ( r = 0.32, P = .05). By the end of follow-up, 86% of patients had borderline or overt adrenal insufficiency (age of onset, 4.8 +/- 3.7 years). CONCLUSIONS: We detected a high prevalence of unrecognized adrenocortical insufficiency in asymptomatic boys with X-ALD. It is known to be a frequent cause of morbidity and can be prevented by careful monitoring, early identification of impaired adrenal reserve, and timely initiation of therapy. It manifests early and before onset of neurologic symptoms, suggesting X-ALD as a candidate disorder for neonatal screening.
Assuntos
Insuficiência Adrenal/sangue , Insuficiência Adrenal/etiologia , Hormônio Adrenocorticotrópico/sangue , Adrenoleucodistrofia/sangue , Adrenoleucodistrofia/complicações , Ácidos Graxos/sangue , Adrenoleucodistrofia/diagnóstico , Pré-Escolar , Humanos , Masculino , Estudos ProspectivosRESUMO
X-linked adrenoleukodystrophy (X-ALD) is a hereditary disorder of peroxisomal metabolism biochemically characterized by the accumulation of very long chain fatty acids (VLCFA), particularly hexacosanoic acid (C26:0) and tetracosanoic acid (C24:0) in different tissues and in biological fluids. The disease is clinically characterized by central and peripheral demyelination and adrenal insufficiency, which is closely related to the increased concentrations of these fatty acids. However, the mechanisms underlying the brain damage in X-ALD are poorly known. Considering that free radical generation is involved in various neurodegenerative disorders, like Parkinson disease, multiple sclerosis and Alzheimer's disease, in the present study we evaluated various oxidative stress parameters, namely chemiluminescence, thiobarbituric acid reactive species (TBA-RS), total radical-trapping antioxidant potential (TRAP), and total antioxidant reactivity (TAR) in plasma of X-ALD patients, as well as the activities of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) in erythrocytes and fibroblasts from these patients. It was verified a significant increase of plasma chemiluminescence and TBA-RS, reflecting induction of lipid peroxidation, as well as a decrease of plasma TAR, indicating a deficient capacity to rapidly handle an increase of reactive species. We also observed a significant increase of erythrocytes GPx activity and of catalase and SOD activities in fibroblasts from the patients studied. It is therefore proposed that oxidative stress may be involved in pathophysiology of X-ALD.
Assuntos
Adrenoleucodistrofia/fisiopatologia , Estresse Oxidativo/fisiologia , Adrenoleucodistrofia/sangue , Adulto , Antioxidantes/metabolismo , Catalase/sangue , Células Cultivadas , Criança , Eritrócitos/enzimologia , Eritrócitos/metabolismo , Radicais Livres/metabolismo , Glutationa Peroxidase/sangue , Humanos , Superóxido Dismutase/sangue , Substâncias Reativas com Ácido Tiobarbitúrico/análiseRESUMO
OBJECTIVES: To determine the biochemical and clinical effects of intravenous arginine butyrate in X-linked Adrenoleukodystrophy (X-ALD). STUDY DESIGN: Arginine butyrate was intravenously infused over a 4-month period in a patient with the rapid cerebral form of X-ALD. Very long chain fatty acids (VLCFA), complete blood counts, and serum chemistries were monitored, and serial MRI of the brain and clinical neurologic examinations were performed. RESULTS: All blood chemical and hematologic values remained within the normal range for age throughout the therapy. After completion of the first day of infusion, the C 26:0 value fell from 1.01 microg/mL to 0.445 microg/mL, which is below the mean value for an X-ALD heterozygote. Throughout the remainder of the trial, all C26:0 levels fell below the mean -1 SD for X-ALD hemizygotes (mean, 1.18 microg/mL, 1 SD = 0.53), ranging from 0.321 to 0.565 microg/mL. Despite reduction of the plasma VLCFA, the patient continued to deteriorate neurologically. CONCLUSIONS: Intravenous arginine butyrate resulted in a rapid decrease in plasma VLCFA but no effect on the neurologic progression of the disease in this patient. Additional studies are needed to determine minimum effective dosage and interval, what proportion of patients respond, and whether the agent can prevent neurologic degeneration.
Assuntos
Adrenoleucodistrofia/tratamento farmacológico , Arginina/análogos & derivados , Arginina/uso terapêutico , Butiratos/uso terapêutico , Proteínas Repressoras , Proteínas de Saccharomyces cerevisiae , Adrenoleucodistrofia/sangue , Arginina/administração & dosagem , Butiratos/administração & dosagem , Criança , Coenzima A Ligases/sangue , Feminino , Humanos , Infusões IntravenosasRESUMO
Blood cell and plasma lipid classes and their fatty acids were analyzed in a child with X-linked adrenoleukodystrophy. The increase in saturated fatty acids with very long chains typical of this disease occurred almost exclusively in sphingomyelin. In this lipid, the proportion of lignoceric (24:0) and hexacosanoic (26:0) acids increased while that of 18:0, 20:0, and 24:1 decreased. In the rest of the lipid classes, but especially in cholesteryl esters and triacylglycerols, the proportion of linoleate (18:2) decreased while that of oleate (18:1) increased. In glycerophospholipids, polyunsaturated fatty acids such as 20:4n-6, 22:5n-6, and 22:6n-3 were reduced while their immediate precursors, 20:3n-6, 22:4n-6, and 22:5n-3, respectively, were relatively increased, suggesting a defect in fatty acid desaturation mechanisms. Although less pronounced, a similar trend of changes was seen in the patient's mother; in both, all alterations were more marked in serum than in blood cells.
Assuntos
Adrenoleucodistrofia/sangue , Ácidos Graxos/sangue , Fosfolipídeos/sangue , Cromossomo X , Adrenoleucodistrofia/genética , Criança , Ácidos Graxos Insaturados/sangue , Ligação Genética , Humanos , Ácido Linoleico , Ácidos Linoleicos/sangue , Masculino , Ácido Oleico , Ácidos Oleicos/sangue , Esfingomielinas/sangueRESUMO
OBJECTIVE: To use the technique of complementation analysis to help define genotype and classify patients with clinical manifestations consistent with those of the disorders of peroxisome assembly, namely the Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP). STUDY DESIGN: Clinical findings, peroxisomal function, and complementation groups were examined in 173 patients with the clinical manifestations of these disorders. RESULTS: In 37 patients (21%), peroxisome assembly was intact and isolated deficiencies of one of five peroxisomal enzymes involved in the beta-oxidation of fatty acids or plasmalogen biosynthesis were demonstrated. Ten complementation groups were identified among 93 patients (54%) with impaired peroxisome assembly and one of three phenotypes (ZS, NALD, or IRD) without correlation between complementation group and phenotype. Forty-three patients (25%) had impaired peroxisome assembly associated with the RCDP phenotype and belonged to a single complementation group. Of the 173 patients, 10 had unusually mild clinical manifestations, including survival to the fifth decade or deficits limited to congenital cataracts. CONCLUSIONS: At least 16 complementation groups, and hence genotypes, are associated with clinical manifestations of disorders of peroxisome assembly. The range of phenotype is wide, and some patients have mild involvement.
Assuntos
Adrenoleucodistrofia/genética , Microcorpos/genética , Fenótipo , Doença de Refsum/genética , Síndrome de Zellweger/genética , Aciltransferases/deficiência , Adrenoleucodistrofia/sangue , Adrenoleucodistrofia/enzimologia , Adulto , Células Cultivadas , Criança , Ácidos Graxos , Feminino , Teste de Complementação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Refsum/sangue , Doença de Refsum/enzimologia , Síndrome de Zellweger/sangue , Síndrome de Zellweger/enzimologiaRESUMO
The concentrations of very long chain fatty acids in plasma and cultured skin fibroblasts were studied in 96 women who were obligate heterozygotes for X-linked adrenoleukodystrophy, in 34 women who were mothers of single probands with ALD, and in 32 normal women of comparable age. Discriminant analysis was used to develop a classification function for the plasma values. With this function, plasma values in 88% of the women who were obligate heterozygotes for ALD and 77% of the mothers of single probands were identified as abnormal. With subsequent inclusion of the fibroblast assay data, abnormal plasma values were found in 93% of the obligate heterozygotes.