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At least 127 records · Page 7Linked to original sources
PubMed2002

Atypical X-linked adrenoleukodystrophy: new MRI observations with FLAIR, magnetization transfer contrast, diffusion MRI, and proton spectroscopy.

An 11-year-old boy with an atypical form of X-linked adrenoleukodystrophy is reported predominantly involving the frontal lobes, and later spreading to temporal lobes. Magnetization transfer contrast T1-weighted, and FLAIR images without intravenous paramagnetic contrast medium, clearly identified the leading edge of a central necrotic zone, as well as a splenial lesion. Zonal differences were identified on ADC maps of an echo-planar diffusion MRI sequence that the ADC value of central zone (2.06 x 10(-3) mm(2)/sec) was higher than that of the peripheral zone (1.67 x 10(-3) mm(2)/sec). On proton spectroscopy, besides changes in the peaks of NAA, choline, and myoinositol, prominent peaks between 0.9 and 1.4 ppm were shown belonging to macromolecules, probably to very long chain fatty acids, a diagnostic feature of adrenoleukodystrophy. In addition, a distinct and prominent glycine peak was observed at 3.50 ppm, reflecting excitotoxic brain damage.

Adrenoleukodystrophy↗
PubMed1998

Transient visual symptoms as the initial manifestation of childhood adrenoleukodystrophy.

We report two patients with transient visual symptoms after an acute illness (hypoglycemia and head trauma) who went on to develop a progressive neurodegenerative disease (adrenoleukodystrophy). This report supports the suggestion that environmental factors play a role in the initial expression of the disease and reviews atypical visual manifestations of adrenoleukodystrophy. Proper diagnosis and institution of early treatment before the catastrophic deterioration typical of its natural history requires a high degree of suspicion.

Adrenoleukodystrophy↗
PubMed2002

Unrelated allogeneic bone marrow transplant in adrenoleukodystrophy using CD34+ stem cell selection.

Adrenoleukodystrophy is an inherited disease characterized by progressive neurodegeneration with rapid deterioration to a vegetative state. Of the treatment modalities tried to date, BMT is the only one with the potential for cure. However, the high rate of morbidity and mortality associated with allogeneic transplant makes it necessary to try out novel measures to improve the outcome in these patients. We report here a case where we used CD34+ stem cell selection for allogeneic unrelated-donor BMT in a patient with adrenoleukodystrophy.

Adrenoleukodystrophy↗
PubMed2003

Reversible posterior leukoencephalopathy syndrome in a child with cerebral X-linked adrenoleukodystrophy treated with cyclosporine after bone marrow transplantation.

Reversible posterior leukoencephalopathy syndrome (RPLS) was described by Hinchey and colleagues in 1996. The disorder occurs predominantly in patients with acute hypertension and/or on pharmacological immunosuppression. We report a 6-year-old male with cerebral X-linked adrenoleukodystrophy who received an HLA-matched unrelated bone marrow transplant (BMT). Cyclosporine was used as graft-versus-host disease prophylaxis. At 55 days post-BMT, his cyclosporine concentrations were high for several days and the concentration was still high on day 70 (353 microg/L). He presented 83 days post-BMT with new onset of headache, lethargy, acute visual loss and focal seizures. He was not hypertensive. MRI of the head revealed signal changes that now extended more peripherally into the subcortical and cortical regions of the occipital and temporal lobes. The patient's cyclosporine was stopped for 5 days. The patient's vision returned to normal and his headaches and lethargy resolved with no further seizures 3 weeks later. Follow-up MRI of the head 2 months later showed almost complete resolution of the cortical signal abnormalities. It is important to consider RPLS in patients with cerebral adrenoleukodystrophy who present with acute neurological deterioration. Attention to the pattern of white matter and the presence of cortical grey matter involvement on neuroimaging is important for the diagnosis. When appropriate management is initiated, that is controlling hypertension when present and discontinuing or reducing the dose of offending immunosuppressive agents, the acute neurological symptoms will usually resolve.

Adrenoleukodystrophy↗
PubMedDate not supplied

Exon organisation of the mouse gene encoding the Adrenoleukodystrophy related protein (ALDRP).

ALDR is one of the four genes encoding an ATP Binding Cassette (ABC) hemi-transporter of the peroxisomal membrane so far identified in mammalian cells. The best known of these is X-ALD, whose dysfunction has been causally associated with X-linked adrenoleukodystrophy. ALDR and X-ALD protein product are closely related and we show here that this striking conservation is maintained at the genomic level. Although extending to a larger genomic region, the organisation of the mouse ALDR gene mirrors exactly that of X-ALD. This supports further the hypothesis that among the four known peroxisomal ABC hemi-transporters ALDRP is the most likely candidate as a modifier contributing to the phenotypic variability of X-linked adrenoleukodystrophy.

ATP Binding Cassette Transporter, Subfamily D↗
PubMed1995

PXA1, a possible Saccharomyces cerevisiae ortholog of the human adrenoleukodystrophy gene.

The adrenoleukodystrophy protein (ALDp) is an ATP-binding cassette (ABC) transporter in the human peroxisome membrane. It is defective in X chromosome-linked adrenoleukodystrophy (ALD), a neurodegenerative disorder with impaired peroxisomal oxidation of very long chain fatty acids. We report cloning and characterization of PXA1, a yeast gene encoding a protein (Pxa1p) exhibiting high similarity to ALDp. Disruption of PXA1 results in impaired growth on oleic acid and reduced ability to oxidize oleate. Pxa1p is peroxisome associated; however, in the PXA1 mutant yeast, as in ALD cells, peroxisomes are morphologically intact. Disruption of a second yeast gene, YKL741, which encodes a more distantly related ALDp homolog (Yk174p), in either wild-type or PXA1 mutant yeast, results in a growth phenotype identical to that of the PXA1 mutant. This result suggests that Yk1741p and Pxa1p may be subunits of the same transporter. Sequence analysis of Pxa1p, ALDp, and related ABC transporters reveals a possible fatty acid binding domain and a 14-amino acid EAA-like motif, previously described only in prokaryotes. Because of the similarities in sequence and function, we propose that Pxa1p is the Saccharomyces cerevisiae ortholog of ALDp.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed1997

A mouse model for X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with impaired beta-oxidation of very long chain fatty acids (VLCFAs) and reduced function of peroxisomal very long chain fatty acyl-CoA synthetase (VLCS) that leads to severe and progressive neurological disability. The X-ALD gene, identified by positional cloning, encodes a peroxisomal membrane protein (adrenoleukodystrophy protein; ALDP) that belongs to the ATP binding cassette transporter protein superfamily. Mutational analyses and functional studies of the X-ALD gene confirm that it and not VLCS is the gene responsible for X-ALD. Its role in the beta-oxidation of VLCFAs and its effect on the function of VLCS are unclear. The complex pathology of X-ALD and the extreme variability of its clinical phenotypes are also unexplained. To facilitate understanding of X-ALD pathophysiology, we developed an X-ALD mouse model by gene targeting. The X-ALD mouse exhibits reduced beta-oxidation of VLCFAs, resulting in significantly elevated levels of saturated VLCFAs in total lipids from all tissues measured and in cholesterol esters from adrenal glands. Lipid cleft inclusions were observed in adrenocortical cells of X-ALD mice under the electron microscope. No neurological involvement has been detected in X-ALD mice up to 6 months. We conclude that X-ALD mice exhibit biochemical defects equivalent to those found in human X-ALD and thus provide an experimental system for testing therapeutic intervention.

Adrenoleukodystrophy↗
PubMed2002

Functional characterization of the adrenoleukodystrophy protein (ALDP) and disease pathogenesis.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder characterized by abnormal accumulation of saturated very long chain fatty acids in tissues and body fluids with predominance in brain white matter and adrenal cortex. The clinical phenotype is highly variable ranging from the severe childhood cerebral form to asymptomatic persons. The responsible ALD gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal integral membrane protein that is a member of the ATP-binding cassette (ABC) transporter protein family. The patient gene mutations are heterogeneously distributed over the functional domains of ALDP. The extreme variability in clinical phenotype, even within one affected family, indicates that besides the ALD gene mutations other factors strongly influence the clinical phenotype. To understand the cell biology and function of mammalian peroxisomal ABC transporters and to determine their role in the pathogenesis of X-ALD we developed a system for expressing functional ABC protein domains in fusion with the maltose binding protein. Wild type and mutant fusion proteins of the nucleotide-binding fold were overexpressed, purified, and characterized by photoaffinity labeling with 8-azido ATP or 8-azido GTP and a coupled ATP regenerating enzyme assay for ATPase activity. Our studies provide evidence that peroxisomal ABC transporters utilize ATP to become a functional transporter and that ALD gene mutations alter peroxisomal transport function. The established disease model will be used further to study the influence of possible disease modifier proteins on ALDP function.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2005

Decreased expression of ABCD4 and BG1 genes early in the pathogenesis of X-linked adrenoleukodystrophy.

Childhood cerebral adrenoleukodystrophy (CCER), adrenomyeloneuropathy (AMN) and AMN with cerebral demyelination (AMN-C) are the main phenotypic variants of X-linked adrenoleukodystrophy (ALD). It is caused by mutations in the ABCD1 gene encoding a half-size peroxisomal transporter that has to dimerize to become functional. The biochemical hallmark of ALD is the accumulation of very-long-chain fatty acids (VLCFA) in plasma and tissues. However, there is no correlation between the ALD phenotype and the ABCD1 gene mutations or the accumulation of VLCFA in plasma and fibroblast from ALD patients. The absence of genotype-phenotype correlation suggests the existence of modifier genes. To elucidate the mechanisms underlying the phenotypic variability of ALD, we studied the expression of ABCD1, three other peroxisomal transporter genes of the same family (ABCD2, ABCD3 and ABCD4) and two VLCFA synthetase genes (VLCS and BG1) involved in VLCFA metabolism, as well as the VLCFA concentrations in the normal white matter (WM) from ALD patients with CCER, AMN-C and AMN phenotypes. This study shows that: (1) ABCD1 gene mutations leading to truncated ALD protein are unlikely to cause variation in the ALD phenotype; (2) accumulation of saturated VLCFA in normal-appearing WM correlates with ALD phenotype and (3) expression of the ABCD4 and BG1, but not of the ABCD2, ABCD3 and VLCS genes, tends to be correlated with the severity of the disease, acting early in the pathogenesis of ALD.

ATP-Binding Cassette Transporters↗
PubMed1995

Regional cerebral blood flow measurement using Tc-99m HMPAO SPECT in a patient with adrenoleukodystrophy.

Regional cerebral blood flow (rCBF) measurement using Tc-99m HMPAO angiography and SPECT was performed in a patient with adrenoleukodystrophy. The whole brain CBF showed great reduction to 31 ml/100 g/min as compared with an age-matched normal value of 45.9 ml/100 g/min. rCBF showed extremely decreased values of approximately 28 and 10 ml/100 g/min in bilateral frontal cortex and white matter respectively. The SPECT scan provided useful information on gray matter involvement to MRI findings of widespread white matter lesions. This quantitative nuclear medicine technique may contribute to pathophysiologic evaluation of adrenoleukodystrophy complementary with MRI.

Adrenoleukodystrophy↗
PubMed1999

Case studies: psychological test findings for two children with X-linked adrenoleukodystrophy.

Psychological evaluations were performed on two children with X-linked adrenoleukodystrophy. Case histories are presented that describe the natural history of the disorder and its symptom patterns, some of which mirror psychiatric disorders of childhood. Psychological evaluation test scores for both boys are displayed in a table, and commonalities and differences are discussed. Findings are reviewed to expedite the referral process for a definitive diagnosis. Guidelines are provided regarding the differential diagnosis of adrenoleukodystrophy and other neurodegenerative disorders of childhood from the more prevalent disorders of behavior and learning that may present in a developmental clinic. Finally, recommendations for psychological interventions with the affected child and family members are provided.

Adrenoleukodystrophy↗
PubMed1995

Adrenoleukodystrophy.

The main advances concerning adrenoleukodystrophy have been in the fields of genetics and therapy. Abnormalities in the 'putative gene' reported in 1993 have been confirmed. Mutations in this gene have been demonstrated in all of the 80 adrenoleukodystrophy families studied so far in various parts of the world. The same unusual dinucleotide deletion was present in approximately 20% of families. The remaining deletions involved nearly all parts of the gene and in most instances were unique in each family. There was no correlation between the phenotype and the nature or location of the mutation. Follow-up of patients treated with Lorenzo's Oil suggests that this therapy does not alter the course of the illness in symptomatic patients. However, dietary therapy started before the development of symptoms may reduce the frequency and severity of subsequent neurological disability.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed2004

Voiding dysfunction in x-linked adrenoleukodystrophy: symptom score and urodynamic findings.

PURPOSE: Adrenoleukodystrophy is an x-linked genetic disorder characterized by the breakdown of the myelin sheath surrounding nerve cells in the brain and progressive dysfunction of the adrenal gland with 6 possible phenotypes. Lower urinary tract symptoms affect the quality of life of these patients but only sporadic cases have been previously studied by urodynamics. We report to our knowledge the first series in the literature looking at the prevalent pattern. MATERIALS AND METHODS: A total of 14 children and adults 8 to 53 years old (average age 30) with different phenotypes were referred for evaluation. Of the patients 6 had adrenomyeloneuropathy without cerebral involvement (C-) 3 had the adult cerebral form, 3 had the childhood cerebral form, 1 had cerebral involvement (C+) and 1 was asymptomatic. All patients were submitted to a screening protocol, consisting of the self-administered short form questionnaire International Conference on Incontinence Questionnaire-Short Form (ICIQ-SF) and a 3-day voiding diary. Patients were divided in group 1-no urinary symptoms, ICIQ-SF score 0 and no further investigation (3); group 2-frequency/urgency, ICIQ-SF score 1 to 5, uroflowmetry and post-voiding residual urine (4); and group 3-voiding symptoms and incontinence, ICIQ-SF score greater than 5, standard urodynamic examination (7). RESULTS: A neurogenic overactive bladder was the prevalent urodynamic finding (6 of 7 patients), while hypocontractility was found in 1 case. CONCLUSIONS: Vesicosphincteric dysfunction can be explained by spinal and/or cerebral involvement in the different neurological forms of adrenoleukodystrophy. Attempts at treatment with anticholinergics and neuromodulation in 4 of our patients provided temporary benefit with clear subjective amelioration of symptoms and improved quality of life.

Adolescent↗
PubMed1990

Urinary dicarboxylic acids in X-linked adrenoleukodystrophy.

The urinary excretion of dicarboxylic acids in X-linked adrenoleukodystrophy (X-ALD) was studied. The dicarboxylic acid profile in X-ALD did not show any specific pattern, unlike Zellweger syndrome and neonatal adrenoleukodystrophy. Medium-chain dicarboxylic acids with an even number of carbon atoms (adipic, suberic, sebacic) and an odd number of carbon atoms (pimelic, azelaic) were excreted within the normal ranges. Dicarboxylic acids with more than 10 carbon atoms were not found. These findings may be due to the normal beta-oxidation system of dicarboxylic acids in X-ALD.

Adolescent↗
PubMed1987

Can head injury influence the site of demyelination in adrenoleukodystrophy?

Adrenoleukodystrophy is an inherited disorder, in which there is degeneration of white matter of the central nervous system. The disorder presents classically in males during the first decade, and although early clinical features may be asymmetrical, radiological and pathological features are essentially generalised. Two boys are reported with proven adrenoleukodystrophy, who at first had focal clinical and radiological features, with the foci in the region of local trauma. This raises the possibility that a local insult may have precipitated or hastened the degenerative process.

Adolescent↗
PubMed1986

Neonatal adrenoleukodystrophy.

Nine cases of neonatal adrenoleukodystrophy are described. All patients had abnormal facial features, moderate to severe hypotonia, hepatomegaly, and retinitis pigmentosa. The clinical course was rapidly progressive in six cases and more protracted in three others. Biological signs of adrenal insufficiency were present in five cases. CT scan showed a demyelinating process in four patients. Trilamellar inclusions were found in the liver of four cases and dark and complex lipidic inclusions in three other cases. In the three necropsied patients there was severe alteration of the white matter involving particularly the cerebellum in two cases. Gyral and cytoarchitectonic disturbances were absent in all three cases. Increased plasma levels of very long chain fatty acids (8/8), phytanic acid (7/8) and bile fluid trihydroxycoprostanic acid (2/4) confirmed the deficiency of multiple peroxisomal enzymes. Clinical, histopathological and biochemical findings of these nine cases are compared to those reported in other neonatal adrenoleukodystrophy cases and to those of other neonatal peroxisomal disorders, that is cerebro-hepato-renal syndrome of Zellweger and infantile Refsum's disease.

Adrenal Cortex↗
PubMed1987

Adrenoleukodystrophy in a mother and son.

A 6 year old boy died from a degenerative brain disease which was clinically and pathologically typical of adrenoleukodystrophy. Shortly before his disease became manifest his 28 year old mother had presented with similar symptoms, and subsequently died. Her brain showed almost identical features including the presence of pathognomonic ultrastructural inclusions. The accumulation of very long chain fatty acids in cerebral white matter as well as high hexacosanoic to docosanoic acid (C26:22) ratios, substantiated the diagnosis in both cases. This is one of the few documented cases of adrenoleukodystrophy in an adult female, and is almost certainly an example of clinical manifestation of this X-linked inherited disease in a carrier.

Adrenoleukodystrophy↗
PubMed1990

MR imaging appearance of childhood adrenoleukodystrophy with auditory, visual, and motor pathway involvement.

Childhood adrenoleukodystrophy is an X chromosome-linked disorder characterized by progressive demyelination of cerebral white matter and adrenal insufficiency. Magnetic resonance (MR) imaging was performed in 15 patients with symptomatic disease and three with presymptomatic disease. MR imaging findings were abnormal only in symptomatic patients. Major sites of disease were the occipital, parietal, and temporal lobes, with all patients showing involvement of occipital lobes, optic radiations, and splenium of the corpus callosum. Follow-up images obtained in four patients demonstrated a posterior-to-anterior progression of disease. Correlation of results from MR imaging with those from evoked potential studies indicated that MR imaging was the method of choice for detecting demyelination of visual, auditory, and motor systems in adrenoleukodystrophy.

Adrenoleukodystrophy↗