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PubMed1976

[Adrenoleukodystrophy. Clinical-pathologic case history and literature review].

This article presents the clinical and pathological history of a 10-year-old boy with adrenoleukodystrophy as well as a tabular survey of 17 additional cases of which the necropsy records were published in the literature. So far as the case of adrenoleukodystrophy directly observed by the authors themselves is concerned, commencement of the disease was in the seventh year of life, with symptoms of Addison's disease and diffuse inflammatory cerebral sclerosis being observed at about the same time. The cerebral disease manifested itself as a progressive pseudobulbar and pyramidal tract symptomatology and as a progressive cerebral psychosyndrome reminiscent of an endocrinal psychosyndrome. Morphologically, the adrenoleukodystrophy was characterized by severe dystrophy of the cortex of the suprarenal gland and the brain are considered the points of action of a still unknown noxa.e suprarenal gland as well as by extensive sudanophilic processes of decomposition in the cerebromedullary substance, putamen, pallidum, and thalamus. Striated cells and cytoplasmic filamentous inclusions observed in the brain and suprarenal glands in a number of cases reported in the literature were not found by the present authors. The cortex of th

Addison Disease↗

PubMed1982

Neonatal adrenoleukodystrophy: clinical, pathologic, and biochemical delineation of a syndrome affecting both males and females.

We describe the detailed clinical, pathologic, and biochemical features of brother and sister with the neonatal onset form of adrenoleukodystrophy, together with evidence of the biochemical defect. When compared with reports of previous cases, it becomes clear that this is a newly described clinical entity with remarkable uniformity of signs and very different from the usual childhood form. Some pathologic features are shared, including the morphologic abnormality of the adrenal in both neonatal and childhood forms, but deposition of abnormally metabolized lipids is more systemic and widespread in the neonatal form. The biochemistry of the disease is presented in both children and parents. Plasma values of long-chain fatty acid C26:0 are 0.328 +/- 0.18 micrograms/ml in a control population and 0.381 +/- 0.312 micrograms/ml in the father and mother. Values for C26:0 in the plasma of childhood adrenoleukodystrophy are 1.62 +/- 0.87 micrograms/ml and in our two cases, 2.79 micrograms/ml in the male, 1.83 micrograms/ml in the female. The basic biochemical defect appears to be a diminished capacity to oxidize these fatty acids leading to accumulation in cholesterol esters. Fatty acid oxidation to CO2 by cultured skin fibroblasts was 51% of control value for stearic acid, 5% for lignoceric acid in the male, and 39% of control value for stearic acid, 5% for lignoceric acid in the female. The genetics of this disease is different; whereas childhood adrenoleukodystrophy is X-linked, the neonatal onset form affects males and females equally and is most probably autosomally recessive in inheritance.

Adrenal Glands↗

PubMed1984

Increased intracranial pressure in adrenoleukodystrophy.

Increased intracranial pressure developed as a terminal event in a 5-year-old boy with adrenoleukodystrophy. The CSF protein concentration was 420 mg/dL. Computed tomography showed extensive areas of decreased density in the posterior cerebral white matter. At autopsy, brain weight exceeded the expected value by 20%, and white matter water content was 87.6% (expected value, 72.5%). In rare instances, brain edema may contribute to the development of increased intracranial pressure in adrenoleukodystrophy.

Adrenoleukodystrophy↗

PubMed1986

Magnetic resonance imaging compared with computed tomography in adrenoleukodystrophy.

Adrenoleukodystrophy was diagnosed in two siblings and confirmed by analysis of very-long-chain fatty acids in skin fibroblasts. Both boys had computed tomograms (CTs) and magnetic resonance imaging (MRI) of the brain. In the most severely affected child, the CT and MRI examinations were both abnormal, but in the other child, the CT was mildly abnormal but the MRI was unequivocally abnormal. This suggests that MRI is more sensitive than CT in detecting the acute demyelinating changes of adrenoleukodystrophy and, in conjunction with very-long-chain fatty acid analysis, should be useful in screening unaffected or mildly affected siblings of patients with this disease.

Adolescent↗

PubMed1986

Neonatal adrenoleukodystrophy: new cases, biochemical studies, and differentiation from Zellweger and related peroxisomal polydystrophy syndromes.

Eight new cases of autopsy-confirmed or suspected neonatal adrenoleukodystrophy (NALD) are presented together with new biochemical data on very-long-chain fatty acids (VLCFA) and plasmalogens and a review of all previously published cases. The clinical, biochemical, and histopathologic abnormalities characteristic of this newly recognized form of adrenoleukodystrophy are analyzed in detail and compared to the principal characteristics of the similar disorder, the cerebrohepatorenal syndrome of Zellweger (ZS). Using strict pathologic criteria for the diagnosis of NALD, we find that, despite many clinical resemblances, NALD and the ZS are distinguishable on the basis of histology and peroxisomal biochemistry. Patients with NALD demonstrate adrenal atrophy, systemic infiltration by abnormal lipid-laden macrophages, and elevations of saturated VLCFA. In contrast, patients with ZS have chondrodysplasia, glomerulocystic disease of the kidney, central nervous system dysmyelination, and elevations of unsaturated as well as saturated VLCFA, but they lack adrenal atrophy. We conclude that NALD and the ZS probably represent at least two different genetic defects.

Abnormalities, Multiple↗

PubMed1992

Sparse hair and multiple endocrine disorders in two women heterozygous for adrenoleukodystrophy.

We describe two sisters (40 and 42 years old) heterozygous for adrenoleukodystrophy who have multiple endocrine disorders. In addition to the characteristic neurological symptoms, the younger patient has Addison disease and primary hypothyroidism attributable to autoimmune thyroiditis, and the older one has Graves disease. Both patients have loss of body hair and sparse scalp hair, which have not been reported previously in women heterozygous for adrenoleukodystrophy. After the institution of glucocorticoid replacement therapy, the younger sister, who has adrenal insufficiency, has shown unexpected neurological improvement.

Addison Disease↗

PubMed2002

Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation.

Skewing of X inactivation may contribute to the manifestation of symptoms in adrenoleukodystrophy carriers. We observed highly skewed X inactivation in 32% of 22 symptomatic and asymptomatic carriers but not in 7 related and 35 unrelated controls. Skewing of X inactivation correlated with clinical neurological scores but not with the extent of very long-chain fatty acid accumulation. Transcript analysis in cultured fibroblasts revealed that skewing could occur both in favor of the mutant and the wild-type allele. Adrenoleukodystrophy carriers are more susceptible to develop skewing of X inactivation in favor of the mutant allele being associated with the manifestation of symptoms.

Adolescent↗

PubMed1985

Identification of the inflammatory cells in the central nervous system of patients with adrenoleukodystrophy.

Adrenoleukodystrophy is a disorder of long-chain fatty acid metabolism associated with adrenal cortical insufficiency and central nervous system demyelination. The central nervous system disease is unusual in that it is abrupt in onset and accompanied by a considerable infiltration of mononuclear inflammatory cells. To determine the nature of these inflammatory cells, immunocytochemical staining was carried out on the mononuclear cells in the brain and cerebrospinal fluid of patients with adrenoleukodystrophy. Monoclonal antibodies to T lymphocytes (T11), the helper/inducer (T4) and cytotoxic/suppressor (T8) subsets of T lymphocytes, B lymphocytes (B1), and monocyte/macrophages (M1 or esterase) were used. Mononuclear cells in the perivascular cuffs of autopsy material from 4 patients were, on average, 59% T cells, 34% T4 cells, 16% T8 cells, 24% B cells, and 11% monocyte/macrophages. Cerebrospinal fluid from 8 of 10 patients had increased IgG concentrations. Mononuclear cells in the cerebrospinal fluid of 6 patients with active disease were, on average, 61% T cells, 40% T4 cells, 16% T8 cells, 3% B cells, and 18% monocyte/macrophages. This distribution of cells is similar to that found in the central nervous system during a cellular immune response and suggests the possibility that one component of this disease is immunologically mediated.

Adolescent↗

PubMed1987

Linkage of adrenoleukodystrophy to a polymorphic DNA probe.

Linkage studies between X-linked adrenoleukodystrophy and a cloned deoxyribonucleic acid fragment (St14), which detects polymorphisms in the distal end of the long arm of the X chromosome (Xq27-28), have shown no recombination in six families. The lod score for these data (and another kindred reported earlier is 13.766 at recombination fraction (theta) = 0.0. These data permit assignment of adrenoleukodystrophy carrier status in family members at risk, supplementing the chemical measurement of very-long-chain fatty acids.

Adrenoleukodystrophy↗

PubMed1994

Multislice proton magnetic resonance spectroscopic imaging in X-linked adrenoleukodystrophy.

Multislice proton magnetic resonance spectroscopic imaging permits metabolic analysis of brain tissue in vivo by data acquisition in four oblique axial slices, each 15-mm thick and divided into 0.8-ml single-volume elements. We applied this technique to the systematic study of 25 patients with adrenoleukodystrophy: 3 with the severe childhood or adult cerebral form of the disease, 5 with adrenomyeloneuropathy, 12 with no demonstrable neurological involvement, and 5 women heterozygous for adrenoleukodystrophy who had some degree of neurological disability. Abnormalities on magnetic resonance spectroscopic imaging included a reduction in N-acetyl aspartate, an increase in choline-containing compounds, and at times, an increase in lactate. Five patients showed abnormalities in the presence of normal-appearing magnetic resonance images, and in 8 other patients the alterations on spectroscopic images were more severe than those demonstrable by magnetic resonance imaging. Correlation with clinical course suggests that an increase in the choline-containing compounds is associated with an active demyelinative process, whereas such compounds are not elevated in lesions that are stable. We conclude that magnetic resonance spectroscopic imaging is a more sensitive indicator of early neurological involvement than is magnetic resonance imaging, and that the character of abnormalities detected by the former technique may serve as a gauge of the degree of activity of the demyelinating process and as a guide to the selection and evaluation of therapeutic approaches.

Adolescent↗

PubMed1994

Very long chain fatty acids in X-linked adrenoleukodystrophy brain after treatment with Lorenzo's oil.

The fatty acid composition of postmortem brain and liver from an adrenoleukodystrophy patient whose diet was supplemented with Lorenzo's oil (glycerol trioleate and glycerol trierucate) for 9 months was determined. The diet depressed plasma and liver saturated very long chain fatty acids (24:0 and 26:0) and increased plasma and liver erucic (22:1) and nervonic (24:1) acids. The levels of plasma linoleic (18:2 n-6), eicosopentaenoic (20:5 n-3), and docosahexaenoic (22:6 n-3) acids were also reduced, while the biochemical marker for essential fatty acid deficiency (20:3 n-9) was markedly increased in liver. However, we were unable to detect any corresponding changes in brain indicating that little erucic acid crossed the blood-brain barrier. Our findings suggest that dietary supplementation with Lorenzo's oil is of limited value in correcting the accumulation of saturated very long chain fatty acids in the brain of patients with adrenoleukodystrophy.

Adolescent↗

PubMed1994

Phenotypic heterogeneity of an adult form of adrenoleukodystrophy in monozygotic twins.

We describe genetically proven monozygotic twins with the adult form of adrenoleukodystrophy with significant phenotypic heterogeneity. Myeloneuropathy was common to both patients, but cognitive impairment and affective symptoms with extensive demyelination in the brain were prominent in the older twin, while adrenal insufficiency was predominant in the younger twin. The younger twin, however, exhibited affective symptoms similar to those displayed by his elder twin 10 years later. These findings suggest that nongenetic factors are important in determining the phenotypic variation of adrenoleukodystrophy gene.

Adrenoleukodystrophy↗

PubMed1997

Adrenoleukodystrophy protein-deficient mice represent abnormality of very long chain fatty acid metabolism.

We have generated a line of mice deficient in adrenoleukodystrophy protein (ALDP) by gene targeting in order to clarify the pathophysiology of adrenoleukodystrophy (ALD). ALDP-deficient male and female mice appeared normal clinically at least up to 12 months. Western blot analysis showed the absence of ALDP in the brain, spinal cord, lung, and kidney and normal expression of PMP70 in the liver, lung, and kidney. The amounts of C26:0 increased by 73-240% in the brain, spinal cord, lung, and kidney. beta-Oxidation of very long chain fatty acids (VLCFA) in cultured hepatocytes and fibroblasts was reduced to 35-50% of normal. Light and electron microscopy did not show demyelination in the brain, spinal cord, and peripheral nerve. Thus, the deficiency of ALDP in mice impairs the peroxisomal fatty acid beta-oxidation but does not duplicate the clinical and pathological abnormalities of the human ALD. These observations suggest that the accumulation of VLCFA alone is not sufficient to cause demyelination in the nervous system.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMed2000

Novel acyl-CoA synthetase in adrenoleukodystrophy target tissues.

X-linked adrenoleukodystrophy (X-ALD) is a neurodegenerative disorder characterized by demyelination of white matter. The X-ALD gene product adrenoleukodystrophy protein (ALDP) is expressed broadly among various tissues. However, deficiency of functional ALDP exclusively impairs brain, adrenal gland, and testis. Thus, loss of ALDP function is assumed to involve inactivation of a putative mediating factor that functions in a tissue-specific manner. Here we cloned a mouse cDNA encoding a novel protein, Lipidosin, that possesses long-chain acyl-CoA synthetase (LCAS) activity. Lipidosin is expressed exclusively in mouse brain, adrenal gland, and testis, which are affected by X-ALD. LCAS activity of Lipidosin was diminished by mutation of conserved amino acids within the AMP-binding domain. Mutation of the Drosophila homologue of Lipidosin has been reported to cause neuronal degeneration. Thus, Lipidosin may mediate the link between ALDP dysfunction and the impairment of fatty acid metabolism in X-ALD.

Adrenoleukodystrophy↗

PubMed1996

Structure and location of the murine adrenoleukodystrophy gene.

X-linked adrenoleukodystrophy (ALD) is a degenerative neurological disease characterized by the accumulation of very long chain fatty acids in various tissues and demyelination of the central nervous system. The human gene responsible for the disease encodes a membrane-bound ATP-binding transporter protein that is located in peroxisomes. We isolated the mouse adrenoleukodystrophy gene, determined its structure, and mapped it both cytogenetically and genetically. The mouse gene is very similar in structure to the human gene, consisting of 10 exons arranged over a 22-kb genomic region. We localized it in band B of the mouse X chromosome by fluorescence in situ hybridization analysis and, using a new microsatellite repeat polymorphism, determined the map location as 47 cM from the X centromere. We found evidence for other sequences in the mouse genome related to the 3' end of Aldgh. This study paves the way for the construction of gene-targeting plasmids that may be used to develop an animal model of ALD.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMed2000

Characterization of the adrenoleukodystrophy-related (ALDR, ABCD2) gene promoter: inductibility by retinoic acid and forskolin.

The adrenoleukodystrophy-related gene (ALDR, ABCD2) is a candidate modifier gene and a potential therapeutic target for X-linked adrenoleukodystrophy (ALD), a severe neurodegenerative disease. The ALDR gene is the closest homologue of the ALD gene, which encodes a peroxisomal ABC transporter involved in the catabolism of very-long-chain fatty acids. Administration of fenofibrate upregulates ALDR expression in rodent liver. As a step toward understanding ALDR transcriptional regulation, the mouse and human 5' regions were characterized. The human and mouse genes share a 500-bp conserved region that contains potential Sp1- and AP-2-binding sites but no TATA box. Analysis of the 5'-flanking region of ALDR using a luciferase reporter system revealed that 1.3 kb of human or mouse 5'-upstream region has functional promoter activity. In these transfection experiments, promoter activity of both human and mouse genes could be upregulated by 9-cis-retinoic acid and forskolin, while no effect of PPARalpha could be detected.

ATP Binding Cassette Transporter, Subfamily D↗

PubMed1999

Two novel missense mutations causing adrenoleukodystrophy in Italian patients.

The authors present two new missense mutations in exon 1 of the adrenoleukodystrophy (ALD) gene. The first, a C813T transition, results in the substitution Pro143 Ser in the third putative transmembrane domain of the adrenoleukodystrophy protein (ALDP) in an adult onset case. The second, a de novo C709T transition, results in a substitution Ser 108 Leu between the second and the third putative transmembrane segments, in a childhood case.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMedDate not supplied

Evaluation of pharmacological induction of fatty acid beta-oxidation in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is an inherited neurometabolic disorder associated with elevated levels of saturated unbranched very-long-chain fatty acids (VLCFA; C > 22:0) in plasma and tissues, and reduced VLCFA beta-oxidation in fibroblasts, white blood cells, and amniocytes from X-ALD patients. The X-ALD gene (ABCD1) at Xq28 encodes the adrenoleukodystrophy protein (ALDP) that is related to the peroxisomal ATP-binding cassette (ABCD) transmembrane half-transporter proteins. The function of ALDP is unknown and its role in VLCFA accumulation unresolved. Previously, our laboratory has shown that sodium 4-phenylbutyrate (4PBA) treatment of X-ALD fibroblasts results in increased peroxisomal VLCFA beta-oxidation activity and increased expression of the X-ALD-related protein, ALDRP, encoded by the ABCD2 gene. In this study, the effect of various pharmacological agents on VLCFA beta-oxidation in ALD mouse fibroblasts is tested. 4PBA, styrylacetate and benzyloxyacetate (structurally related to 4PBA), and trichostatin A (functionally related to 4PBA) increase both VLCFA (peroxisomal) and long-chain fatty acid [LCFA (peroxisomal and mitochondrial)] beta-oxidation. Isobutyrate, zaprinast, hydroxyurea, and 5-azacytidine had no effect on VLCFA or LCFA beta-oxidation. Lovastatin had no effect on fatty acid beta-oxidation under normal tissue culture conditions but did result in an increase in both VLCFA and LCFA beta-oxidation when ALD mouse fibroblasts were cultured in the absence of cholesterol. The effect of trichostatin A on peroxisomal VLCFA beta-oxidation is shown to be independent of an increase in ALDRP expression, suggesting that correction of the biochemical abnormality in X-ALD is not dependent on pharmacological induction of a redundant gene (ABCD2). These studies contribute to a better understanding of the role of ALDP in VLCFA accumulation and may lead to the development of more effective pharmacological therapies.

Adrenoleukodystrophy↗