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PubMed1997

Involvement of the pontomedullary corticospinal tracts: a useful finding in the diagnosis of X-linked adrenoleukodystrophy.

PURPOSE: To determine whether pontomedullary corticospinal tract involvement is a common and specific finding of adrenoleukodystrophy on MR images. METHODS: MR images of 10 patients with biochemically proved adrenoleukodystrophy who were examined during the last 6 years were reviewed retrospectively to determine the frequency of corticospinal tract involvement in the medulla, pons, mesencephalon, internal capsules, and corona radiata. MR images of 10 patients with other leukodystrophies (three with Krabbe disease, two with Alexander disease, two with metachromatic leukodystrophy, two with Pelizaeus-Merzbacher disease, and one with Canavan disease) were reviewed with specific attention to the pontomedullary corticospinal tracts. RESULTS: Medullary and pontine corticospinal tract involvement was present in eight of the 10 patients with adrenoleukodystrophy. Mesencephalic and internal capsular involvement was present in three patients. The coronal radiata portion of the corticospinal tracts was not involved in any of the 10 patients. No pontomedullary corticospinal tract involvement was identified in any of the 10 patients with other leukodystrophies. The difference in the frequency of pontomedullary corticospinal tract involvement between the two groups was highly significant. CONCLUSION: Pontomedullary corticospinal tract involvement is a common finding in adrenoleukodystrophy and is unusual in other leukodystrophies. Awareness of this finding can facilitate the radiologic diagnosis of this disease and may expedite management of affected patients.

Child↗

PubMed1987

Adrenoleukodystrophy: dietary oleic acid lowers hexacosanoate levels.

Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination, adrenal insufficiency, and accumulation of saturated very-long-chain fatty acids (VLFA), particularly hexacosanoate (C26:0). We treated 5 patients with adrenoleukodystrophy (3 males and 2 symptomatic female carriers) for 6 months with a diet enriched in oleic acid (C18:1) and moderately restricted in C26:0. Elevated plasma and erythrocyte levels of C26:0 decreased in a time-dependent manner during treatment. Total plasma C26:0 concentration was lowered by 50 +/- 9% (p less than 0.01); it became normal in the female carriers. The total erythrocyte level of C26:0 decreased (44 +/- 5%; p less than 0.001) into the normal range in all patients. Significant decreases were noted in the saturated VLFA composition of plasma and erythrocyte sphingomyelin and erythrocyte phosphatidylcholine during dietary treatment. In general, decreases in saturated VLFA levels were accompanied by increases in monounsaturated VLFA levels, while total VLFA values did not change. This novel approach to the treatment of adrenoleukodystrophy, in which there is an exchange of monounsaturated VLFA for the more toxic saturated VLFA, may prove clinically beneficial in this disorder.

Adrenoleukodystrophy↗

PubMed1993

Visual evoked potentials in adrenoleukodystrophy: a trial with glycerol trioleate and Lorenzo oil.

Adrenoleukodystrophy is an X-linked metabolic disorder with very-long-chain fatty acid (VLCFA) accumulation and multifocal nervous system demyelination, often with early involvement of visual pathways. Dietary therapy with glycerol trioleate and glycerol trierucate (Lorenzo oil) diminishes VLCFA levels. In a study of patients with the adrenomyeloneuropathy phenotype of adrenoleukodystrophy, we used pattern-reversal visual evoked potentials to evaluate visual pathways before and after treatment. Of 108 patients tested, all 26 women and 68 of the 82 men had normal potentials at baseline. Seventy patients were retested at 1 year, at which time VLCFA levels were markedly diminished. Of them, the responses in the 10 men who showed abnormalities at baseline remained abnormal; the latencies in 4 men with initially normal responses became abnormal. No patients improved. There were no correlations between disease duration prior to treatment, baseline P100 latencies, VLCFA levels, or the change in P100 latencies and VLCFA levels after dietary treatment for 1 year. Pattern-reversal visual evoked potentials were abnormal in 17% of the men with adrenoleukodystrophy, and there was no evidence that reduction of VLCFA levels improved or retarded visual pathway demyelination.

Adolescent↗

PubMed1996

Cerebral adrenoleukodystrophy (ALD) in only one of monozygotic twins with an identical ALD genotype.

We report on monozygotic twins with different clinical phenotypes of X-linked adrenoleukodystrophy. At the age of 10 years both boys were neurologically asymptomatic. The first cranial magnetic resonance examination showed normal findings in the first twin and parietooccipital demyelination in the second. The latter developed behavioral problems 9 months later, followed by visual impairment and gait ataxia. His cranial magnetic resonance image at the age of 11 years showed progressive demyelination. In contrast, neurological status and magnetic resonance images remained normal in the first twin. The same point mutation in exon 8 of the adrenoleukodystrophy gene (C2203T) was detected in both boys. All genotype examinations were consistent with the diagnosis of monozygotic twins, suggesting that some nongenetic factors may be important for different adrenoleukodystrophy phenotypes.

Adrenoleukodystrophy↗

PubMed1993

Adrenoleukodystrophy: overlapping deletions point to a gene location in Xq28.

Adrenoleukodystrophy is a lethal X-linked neurodegenerative disorder which maps close to the red/green color pigment gene cluster in Xq28. We have reported a broad spectrum of color pigment gene changes in adrenoleukodystrophy patients, indicating that the genes may be quite close together. We now have used anonymous DNA probes centromeric to the color pigment gene cluster to analyze patients from 59 adrenoleukodystrophy kindreds. All patients showed normal hybridization using probe Fr9, 30 kb centromeric to the color pigment genes. However, using probe Fr11, 100 kb further centromeric, we found overlapping deletions in 2 patients. We isolated conventional and cosmid genomic clones encompassing 24 kb surrounding Fr11; the clones and map derived from this region localize the telomeric ends of the two deletions to distinct positions 8 kb apart. These overlapping deletions implicate this specific region as a likely site for the ALD gene.

Adrenoleukodystrophy↗

PubMed1997

cDNA cloning and mRNA expression of the human adrenoleukodystrophy related protein (ALDRP), a peroxisomal ABC transporter.

We have cloned the cDNA containing the complete coding region of the human adrenoleukodystrophy related (ALDR) gene. The 2220-bp open reading frame encodes a 740-amino-acid polypeptide with a predicted molecular weight of 83.3 kDa. The human ALDR protein displays high similarity (62.8% identical amino acid residues) to the human adrenoleukodystrophy (ALD) gene. Analysis of ALDR expression revealed the presence of ALDR mRNA in a variety of human tissues, predominantly in brain and heart. This expression pattern is different from all other known peroxisomal ABC-transporters. Defects in the ALD gene are the primary cause of adrenoleukodystrophy, a demyelinating disorder of the central nervous system. The ALD protein (ALDP) and the ALDR gene product are peroxisomal membrane proteins belonging to the superfamily of transporters containing an ATP-binding cassette (ABC-transporters). All known peroxisomal ABC-transporters represent only one-half of a functional transporter. They are expected to form dimers either as a homodimer or as a heterodimer. ALDRP is a potential dimerization partner of ALDP or other peroxisomal ABC-transporters. The ALDR gene is a candidate for a modifier gene, accounting for the strikingly varying clinical courses of ALD observed even within a family.

ATP Binding Cassette Transporter, Subfamily D↗

PubMed1985

Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease: plasma changes and skin fibroblast phytanic acid oxidase.

Cerebro-hepato-renal (Zellweger) syndrome, adrenoleukodystrophy, and Refsum's disease patients can be divided into at least five distinct groups, according to the nature of their plasma changes and their fibroblast phytanic acid oxidase activities. The biochemical changes in the plasma vary from an increase in a single metabolite or group of structurally related metabolites, such as in X-linked adrenoleukodystrophy (ALD) and classical Refsum's disease, to an increase in a number of structurally distinct metabolites, as in neonatal ALD/Zellweger syndrome, and infantile Refsum's disease. All patients, with the exception of those with the X-linked form of adrenoleukodystrophy are deficient in phytanic acid oxidase activity. The great similarity observed in neonatal adrenoleukodystrophy/Zellweger syndrome and infantile Refsum's disease suggests that the basic biochemical lesion in each may be similar or at least closely related.

Adrenoleukodystrophy↗

PubMed1987

Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy.

Three patients affected by infantile Refsum disease are described with mental retardation, minor facial dysmorphia, chorioretinopathy, sensorineural hearing deficit, hepatomegaly, failure to thrive and hypocholesterolaemia. Initially, only an accumulation of phytanic acid was thought to be present. More recent findings showed a biochemical profile very similar to that found in classical Zellweger syndrome or neonatal adrenoleukodystrophy. Morphologically typical peroxisomes were absent in the liver. All three disorders are associated with multiple peroxisomal dysfunction. Because of these similarities pertinent clinical data of our three patients are compared with those of reported patients diagnosed as having infantile Refsum disease, neonatal adrenoleukodystrophy or Zellweger syndrome who survived for several years. Attention is drawn to the difference in severity of clinical features, ranging from infantile Refsum's disease to neonatal adrenoleukodystrophy and, finally, to Zellweger syndrome.

Adrenoleukodystrophy↗

PubMed1983

Adrenoleukodystrophy-cerebello-brainstem dominant case.

A case of adrenoleukodystrophy was studied morphologically and biochemically. The patient was a 28-year-old man with no family history of adrenoleukodystrophy. His neurologic symptoms were cerebellar ataxia, spastic paraplegia, pseudo-bulbar palsy, and a minimal visual disturbance, with neither adrenal nor hypogonadal symptoms. The morphological and biochemical findings in this case are identical with those in typical adrenoleukodystrophy, but the topographical distribution of the lesions is distinctly different. The changes selectively affect the white matter in the cerebellum and brain stem in contrast to minimal involvement of the occipital white matter.

Adrenoleukodystrophy↗

PubMed1996

MRI of adrenoleukodystrophy involving predominantly the cerebellum and brain stem.

A case of adult-onset adrenoleukodystrophy involving predominantly the cerebellum and brain stem is described. The patient was a 30-year-old man with no family history of adrenoleukodystrophy. His neurological symptoms were progressive cerebellar ataxia and spastic paraparesis. CT showed atrophy of the cerebellum and brain stem. MRI disclosed lesions, enhancing partially with gadolinium, in the dentate nuclei and the pyramidal tracts from the internal capsule to the brain stem. The biochemical findings were compatible with typical adrenoleukodystrophy, but the distribution of the lesions on MRI was distinctly different. After steroid administration, the patient's symptoms improved slightly and contrast enhancement of the lesions was markedly reduced.

Adrenoleukodystrophy↗

PubMed1986

Plasmalogen deficiency in cultured skin fibroblasts from neonatal adrenoleukodystrophy.

The plasmalogen ratio (defined as area ratio of lysophosphatidylethanolamine to the diacyl form of phosphatidylethanolamine) was investigated in cultured skin fibroblasts from neonatal adrenoleukodystrophy (N = 4) and X-linked recessive (N = 3) in addition to Zellweger syndrome (N = 3) because plasmalogen was reported to be reduced in Zellweger syndrome. The ratio was markedly decreased in all cases of Zellweger syndrome studied and in three of the four cases of neonatal adrenoleukodystrophy, whereas it was normal in the X-linked cases. This is the first documentation of a plasmalogen deficiency in neonatal adrenoleukodystrophy.

Adrenoleukodystrophy↗

PubMedDate not supplied

Neonatal adrenoleukodystrophy presenting as infantile progressive spinal muscular atrophy.

Two siblings with neonatal adrenoleukodystrophy are described. The signs and laboratory data documenting infantile progressive spinal muscular atrophy included the initial presentation of 1 sibling with neonatal adrenoleukodystrophy. These patients indicate that neonatal adrenoleukodystrophy should be considered in the differential diagnosis of infantile progressive spinal muscular atrophy.

Adrenoleukodystrophy↗

PubMed1994

CSF findings in adrenoleukodystrophy: correlation between measures of cytokines, IgG production, and disease severity.

The childhood-onset cerebral form of adrenoleukodystrophy has a devastating neurologic prognosis. Unfortunately, there is no early method of distinguishing it from the more benign forms of adrenoleukodystrophy, such as adrenomyeloneuropathy. To evaluate the manner in which this disease entity may be reflected in the cerebrospinal fluid, we studied a consecutive series of 19 patients, all with biochemically proved adrenoleukodystrophy. total protein, immunoglobulin production, cytokine levels, and cerebrospinal fluid pressure were measured. In this single sample of cerebrospinal fluid, a significant correlation existed between clinical stage of the illness and cerebrospinal fluid myelin basic protein. No correlation existed with total protein, cytokines, or measures of immunoglobulin production.

Adolescent↗

PubMed2006

Mutational analyses of Taiwanese kindred with X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy is a neurodegenerative disorder with highly variable clinical presentation, including the childhood cerebral form, adult form adrenomyeloneuropathy, and Addison disease. The biochemical hallmark of the disorder is the accumulation of saturated very long chain fatty acids in all tissues and body fluids. This accumulation results from mutations in the ABCD1 gene localized to Xq28. Using polymerase chain reaction and direct sequencing of deoxyribonucleic acid, we identified five novel mutations, including a microdeletion (1624 del ATC), a splicing site mutation (intervening sequence 1 [IVS1] -2a>c), and three missense mutations (1172 T>C, 1520 G>A, and 1754 T>C), from Taiwanese kindred with X-linked adrenoleukodystrophy. A polymorphism involving a single nucleotide deletion in the intervening sequence 5 (IVS5 -6 del c) of the ABCD1 gene, previously misattributed as a mutation in the Chinese population, was also identified. The dinucleotide deletion (1415 del AG) mutation common in Japan and Western countries was not found as frequently in the Chinese and Taiwanese populations. Instead, a higher mutation frequency was observed in exon 6 of the ABCD1 gene among Japanese, Chinese, and Taiwanese kindred with X-linked adrenoleukodystrophy, representing a potential mutational hotspot for future mutational screening among these Asian populations.

ATP Binding Cassette Transporter, Subfamily D, Mem↗

PubMed2003

Evaluation of the therapeutic potential of PPARalpha agonists for X-linked adrenoleukodystrophy.

Adrenoleukodystrophy protein (ABCD1), a peroxisomal membrane protein, is mutated in patients affected by X-linked adrenoleukodystrophy (X-ALD). Adrenoleukodystrophy-related protein (ABCD2) is the closest relative of ABCD1. Pharmacological induction of ABCD2 gene expression has been proposed as a novel therapy strategy for X-ALD. Fibrates induce peroxisome proliferation and Abcd2 expression in rodent liver. Here we evaluate the possibility of using peroxisome proliferator-activated receptor alpha (PPARalpha) agonists for pharmacological induction of ABCD2 expression. In the liver of PPARalpha-deficient mice, both the constitutive and the fenofibrate-inducible Abcd2 gene expression was found to be PPARalpha-dependent. In the brain, PPARalpha-deficiency has no effect on Abcd2 expression. In mice orally treated with the novel, highly selective, and potent PPARalpha agonists GW 7647, GW 6867, and tetradecylthioacetic acid, Abcd2 expression was induced in liver and adrenal glands, but not in brain and testis. None of four putative PPREs identified in the 5(')-flanking DNA and in intron 1 of the Abcd2 gene conferred fibrate response in luciferase reporter assays. Thus, although fibrate-mediated Abcd2 induction is PPARalpha-dependent, it appears to be an indirect mechanism. Within the mouse Abcd2 promoter, a putative sterol regulatory element (SRE) similar in sequence and position to the characterized SRE sequence of the human ABCD2 promoter, was identified. A PPARalpha dependent induction of the sterol regulatory-binding protein 2 (SREBP2) and a down-regulation of SREBP1c mRNA levels could be demonstrated after fenofibrate treatment of mice. Our results suggest that the PPARalpha agonist-mediated induction of Abcd2 expression seems to be indirect and possibly mediated by SREBP2.

ATP Binding Cassette Transporter, Subfamily D↗

PubMed1983

Ocular histopathologic and biochemical studies of the cerebrohepatorenal syndrome (Zellweger's syndrome) and its relationship to neonatal adrenoleukodystrophy.

The eyes of three infants with cerebrohepatorenal disease (Zellweger's syndrome) who died demonstrated ganglion cell loss, gliosis of the nerve fiber layer and optic nerve, optic atrophy, and changes resembling those of retinitis pigmentosa in the retina and pigment epithelium. Ultrastructural examination showed bileaflet inclusions identical to those seen in neonatal adrenoleukodystrophy in the pigment epithelium and in pigmented macrophages, but these were absent in the cornea. Biochemical analysis of tissues demonstrated an excessive amount of very-long-chain fatty acids in the ocular tissues, an abnormality also found in adrenoleukodystrophy. These histopathologic and biochemical results demonstrated that the cerebrohepatorenal syndrome and neonatal adrenoleukodystrophy are similar in regard to ocular abnormalities and the presence of saturated very-long-chain fatty acids.

Adrenoleukodystrophy↗

PubMed1988

Direct demonstration that the deficient oxidation of very long chain fatty acids in X-linked adrenoleukodystrophy is due to an impaired ability of peroxisomes to activate very long chain fatty acids.

A method was developed to prepare peroxisome-enriched fractions depleted of microsomes and mitochondria from cultured skin fibroblasts. The method consists of differential centrifugation of a postnuclear supernatant followed by density gradient centrifugation on a discontinuous Metrizamide gradient. The activity of hexacosanoyl-CoA synthetase was subsequently measured in postnuclear supernatants and peroxisome-enriched fractions prepared from cultured skin fibroblasts from control subjects and patients with X-linked adrenoleukodystrophy. Whereas the hexacosanoyl-CoA synthetase activity in postnuclear supernatants of X-linked adrenoleukodystrophy fibroblasts was only slightly decreased (77.8 +/- 4.4% of control (n = 15], enzyme activity was found to be much more markedly reduced in peroxisomal fractions isolated from the mutant fibroblasts (19.6 +/- 6.7% of control (n = 5]. This is a direct demonstration that the defect in X-linked adrenoleukodystrophy is at the level of a deficient ability of peroxisomes to activate very long chain fatty acids, as first suggested by Hashmi et al. [Hashmi, M., Stanley, W. and Singh, I. (1986) FEBS Lett. 86, 247-250].

Adrenoleukodystrophy↗

PubMed2000

Long-term effect of bone-marrow transplantation for childhood-onset cerebral X-linked adrenoleukodystrophy.

BACKGROUND: The childhood-onset cerebral form of X-linked adrenoleukodystrophy, a demyelinating disorder of the central nervous system, leads to a vegetative state and death within 3-5 years once clinical symptoms are detectable. The hypothesis to be tested was whether bone-marrow transplantation can over an extended period of time halt the inexorable progressive demyelination and neurological deterioration. METHODS: 12 patients with childhood onset of cerebral X-linked adrenoleukodystrophy have been followed for 5-10 years after bone-marrow transplantation. Magnetic resonance imaging (MRI), neurological, neuropsychological, electrophysiological, and plasma very-long-chain fatty acid (VLCFA) measurements were used to evaluate the effect of this treatment. FINDINGS: MRI showed complete reversal of abnormalities in two patients and improvement in one. One patient showed no change from baseline to last follow-up. All eight patients who showed an initial period of continued demyelination stabilised and remained unchanged thereafter. Motor function remained normal or improved after bone-marrow transplantation in ten patients. Verbal intelligence remained within the normal range for 11 patients. Performance (non-verbal) abilities were improved or were stable in seven patients. Decline in performance abilities followed by stability occurred in five patients. Plasma VLCFA concentrations decreased by 55% and remained slightly above the upper limits of normal. INTERPRETATION: 5-10-year follow-up of 12 patients with childhood-onset cerebral X-linked adrenoleukodystrophy shows the long-term beneficial effect of bone marrow transplantation when the procedure is done at an early stage of the disease.

Adrenoleukodystrophy↗