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PubMed1987

Adrenoleukodystrophy: correlating MR imaging with CT.

The effect on the brain of the sex-linked recessive form of adrenoleukodystrophy was studied in 40 boys, 4-18 years old. All underwent computed tomography (CT) scanning; six underwent magnetic resonance (MR) imaging. MR showed a high sensitivity in demonstrating white matter disease. Auditory pathway disease was characterized as involvement of the lateral lemniscus and medial geniculate body, and visual pathway disease was characterized by lateral geniculate body, Meyer loop, and optic radiation involvement. Contrast-enhanced CT still proved to have a greater capacity (at this time) to show the active, advancing form of the disease and concomitant calcifications. This large CT series also demonstrated the broad and variable expressions of adrenoleukodystrophy, which allowed the unification of previously described atypical forms of the disease.

Adolescent↗
PubMed1991

Peroxisomal fatty acid beta-oxidation in relation to adrenoleukodystrophy.

X-linked adrenoleukodystrophy is a neurological disease characterized by progressive demyelination with destruction of the white matter, and adrenal insufficiency. Biochemically there is accumulation of very-long-chain fatty acids resulting from an impairment in the peroxisomal oxidation of these fatty acids. In this paper we describe the present state of our knowledge with regard to the organization of the peroxisomal fatty acid oxidation system, with particular emphasis on X-linked adrenoleukodystrophy.

Adrenoleukodystrophy↗
PubMed1989

Adrenoleukodystrophy presenting as spinocerebellar degeneration.

The clinical features of 3 patients from a kindred with adrenoleukodystrophy and the analysis of their plasma sphingomyelin are described. Onset of symptoms was between the ages of 33 and 54 years. Ataxic gait and spasticity were the only symptoms noted during the early stage of the disorder. Dementia and optic atrophy were present in two of the cases. Baseline plasma cortisol was normal, but adrenocorticotropic hormone was elevated. Analysis of plasma sphingomyelin demonstrated an increase in very-long-chain (C24-C26) fatty acid. This study demonstrates that adrenoleukodystrophy may present with spinocerebellar symptoms.

Adrenocorticotropic Hormone↗
PubMed1999

The neuropsychiatry of adult-onset adrenoleukodystrophy.

Adrenoleukodystrophy is an inherited X-linked peroxisomal disorder that preferentially affects the adrenal cortex, testes, and brain and may occur at almost any age. Psychiatric symptomatology is present in many of the adult-onset cases reported in the literature and may be one of the earliest manifestations of the disease. The majority of patients with psychiatric disturbances have signs and symptoms typical of mania. Psychosis and cognitive impairment may also be prominent. Metabolic diseases such as adrenoleukodystrophy are probably underrecognized as a cause of psychiatric illness. Increased awareness of these disorders will lead to accurate diagnosis, appropriate treatment selection, and genetic counseling.

Addison Disease↗
PubMed1986

Medium- and long-chain dicarboxylic aciduria in patients with Zellweger syndrome and neonatal adrenoleukodystrophy.

This study reports that patients with neonatal adrenoleukodystrophy and Zellweger syndrome excrete a very peculiar pattern of organic acids. Dicarboxylic acids with an even number of carbon atoms (adipic, suberic, sebacic, 2- and 3-hydroxy-sebacic, hexadecanedioic), as well as with an odd number of carbon atoms (pimelic, azelaic, un-, tri-, and pentadecanedioic) were found in excess in the urines of six patients with neonatal adrenoleukodystrophy and one with Zellweger syndrome. The accumulation of dicarboxylic acids, reflecting an impairment of their beta-oxidation in mitochondria and/or peroxisomes, thus appears as an additional useful marker of these peroxisomal diseases.

Abnormalities, Multiple↗
PubMed2005

Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients.

BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.

Adolescent↗
PubMed2006

Methionine metabolism and phenotypic variability in X-linked adrenoleukodystrophy.

A combined genotype of polymorphisms of methionine metabolism has been associated with CNS demyelination in methotrexate-treated patients. Within a sample of 86 patients with X-linked adrenoleukodystrophy, this genotype was overrepresented in a subgroup of 15 patients with adrenomyeloneuropathy (AMN) with CNS demyelination (adrenoleukomyeloneuropathy) in comparison to 49 AMN patients without CNS demyelination ("pure" AMN; p = 0.002), suggesting that methionine metabolism might contribute to the phenotypic variability in adrenoleukodystrophy.

Adolescent↗
PubMed1985

Adrenoleukodystrophy: abnormality of "tightly bound" fatty acids in the erythrocyte membrane proteins.

"Tightly bound" and "loosely bound" fatty acids in erythrocyte membranes were analyzed in three patients with adrenoleukodystrophy, three probable carriers, and eight controls. The ratios of C28:0 or C26:0 to C22:0 or C20:0 in the tightly bound fatty acids of three patients were significantly higher than those of controls, and the ratios in two of three probable carriers were higher than those in controls. The ratios of C26:0 to C22:0 or C20:0 in the loosely bound fatty acids of three patients and three probable carriers were also significantly higher than those of controls. Since tightly bound fatty acids in membrane proteins are found not only in erythrocyte membranes but also in myelin proteins, the abnormality of tightly bound fatty acids may be related to the demyelination in adrenoleukodystrophy.

Adolescent↗
PubMed1993

X-linked adrenoleukodystrophy: adult cerebral variant.

We report a unique case of a 43-year-old architect with adult-onset adrenoleukodystrophy who presented primarily with intellectual decline and no evidence of adrenal insufficiency. Serial MRIs taken over a number of months demonstrated the evolution of demyelination starting in the frontal white matter then shifting to the occipital white matter and finally resolving without any therapeutic intervention. Clinically, over this same period of time, the patient's symptoms resolved and he was able to return to work. The proband, his brother, and his nephew were found to have a color-vision defect. Each of these individuals had a red/green gene array that contained a 5' green-red 3' hybrid known to be associated with deutan color-vision defects. The proband's brother and nephew were otherwise normal. The gene that causes adrenoleukodystrophy appears not to be as close to the red/green color vision gene array on the X chromosome as previously reported.

Adrenoleukodystrophy↗
PubMed1995

X-linked adrenoleukodystrophy presenting as neurologically pure familial spastic paraparesis.

The familial spastic paraplegias (FSPs) are heterogeneous neurologic disorders that are known to occur clinically as "pure" or "complicated" forms. Although some of the complicated FSPs have been linked to specific metabolic defects, the pure forms of this disorder remain idiopathic and are considered to be primary system degenerations. We report the case of a 28-year-old man who has evidenced a neurologically pure spastic paraparesis since age twenty-five. Consistent with this diagnosis were the findings of magnetic resonance imaging, which revealed atrophy of the thoracic spinal cord without evidence for white matter disease in the cerebrum, cerebellum, or brainstem. His 32-year-old brother has also evidenced progressive spastic paraparesis since age 30, but his case is confounded by a severe head injury at age 24 that caused a skull fracture and a focal demyelinating lesion of the right frontal lobe. Both patients have had hypogonadism, requiring treatment with testosterone, since age 20. Measurement of plasma levels of very long-chain fatty acids (VLCFA) revealed that both brothers had concentrations diagnostic of adrenoleukodystrophy; their mother had plasma VLCFA levels in the heterozygous range. We conclude that neurologically pure FSP can be an early manifestation of adrenoleukodystrophy and that levels of plasma VLCFA should be determined for all cases of FSP in which X-linked inheritance appears tenable. These considerations may have bearing on the ongoing linkage studies for these disorders.

Adrenoleukodystrophy↗
PubMed2002

Proton MR spectroscopic imaging predicts lesion progression on MRI in X-linked adrenoleukodystrophy.

BACKGROUND: The phenotypic expression of X-linked adrenoleukodystrophy (X-ALD) ranges from the rapidly progressive childhood cerebral form to the milder adrenomyeloneuropathy in adults. It is not possible to predict phenotype by mutation analysis or biochemical assays. Multislice proton MRS imaging (MRSI) has previously detected more extensive brain abnormalities in X-ALD than conventional MRI, which has been suggested to predict impending demyelination. However, the significance of these changes is unclear. OBJECTIVE: The purpose of this study was to determine the long-term sensitivity and specificity of MRSI for disease progression in X-ALD. METHODS: Twenty-five patients with X-ALD were investigated (average age, 15 years; range, 2-43 years) with MRI and proton MRSI at baseline and follow-up MRI over a mean period of 3.5 years. Eight patients had normal MRI findings at baseline and on follow-up (noncerebral group), 11 had abnormal MRI at baseline and no change on follow-up (cerebral nonprogressive group), and 6 had progressive MRI abnormalities (cerebral progressive group). On MRSI, voxels were analyzed in the normal MRI-appearing perilesional white matter, or in the corresponding area in the noncerebral group. RESULTS: The concentration ratio of N-acetylaspartate (NAA) to choline was the most sensitive indicator of disease progression. The average NAA/choline ratio was 5.99 for the noncerebral group, 5.75 for the cerebral nonprogressive group, and 3.74 for the cerebral progressive group (p = 0.002). At a cut-off point of 5.0, the NAA/choline ratio predicted disease progression in all patients with six cerebral progressive disease (sensitivity 100%). The specificity was 83%, the positive predictive value was 66%, and the negative predictive value was 100%. CONCLUSIONS: Multislice proton MRS imaging is able to identify impending or beginning degeneration in white matter that still appears normal on conventional MRI. Multislice proton MRSI may be a suitable technique for the prediction of lesion progression on MRI in X-linked adrenoleukodystrophy.

Adolescent↗
PubMed2004

An unusual case of X-linked adrenoleukodystrophy with auditory processing difficulties as the first and sole clinical manifestation.

X-linked adrenoleukodystrophy (X-ALD) is characterized by demyelination that is associated with a deficient beta-oxidation of very long chain fatty acids. We report the unusual case of a male adult with X-ALD who was diagnosed at the age of 26 by a brain MRI performed because his brother had been diagnosed with a rapidly deteriorating form of X-ALD. His sole symptom was hearing difficulties in the presence of a normal audiogram since childhood. He has remained stable for seven years. Central auditory testing in our patient revealed severe deficits in several auditory processes. These findings correlated with involvement of the auditory pathway at the level of the trapezoid body, and posterior corpus callosum in particular, on his brain MRI. This case highlights not only the need for thorough audiological investigation of the patient who complains of hearing difficulties in the presence of a normal audiogram, but also that audiological investigations could be of value in the phenotypic evaluation of cases with adrenoleukodystrophy.

Acoustic Impedance Tests↗
PubMedDate not supplied

[Cerebral adrenomyeloneuropathy as a late type of adrenoleukodystrophy: case report].

Adrenoleukodystrophy (ALD) is a hereditary disease related to abnormalities in the structure and function of peroxisomes. The nature of disorder arises from defective process of beta-oxidation of very-long-chain fatty acids and their accumulation in various organs. ALD may present as a few phenotypes urologic symptomatology of which depends on proportions of the brain, spinal cord and peripheral nerves affection. Below, we present a case (and its family) of a cerebral type of adrenomyeloneuropathy--a rare form of adrenoleukodystrophy, and discuss its clinical manifestation as well as biochemical, hormonal, electrophysiological, neuropsychological and magnetic resonance imaging (MRI) diagnostics.

Adrenoleukodystrophy↗
PubMed2000

X-linked adrenoleukodystrophy. The Saudi experience.

OBJECTIVES: To evaluate the clinical, biochemical, neuroradiological, and neurophysiological findings of patients with X-linked adrenoleukodystrophy. METHODS: Retrospective study evaluating the data of 10 X-linked adrenoleukodystrophy patients diagnosed at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. RESULTS: 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. CONCLUSION: 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.

Adolescent↗
PubMed2002

Adrenal functions in children with adrenoleukodystrophy.

BACKGROUND: Adrenoleukodystrophy refers to an inherited disorder that mainly affects the adrenal gland, and the nervous system. The most common type is X-linked adrenoleukodystrophy (XALD). The main presenting symptoms are behavioral changes. However, endocrinological manifestations are also important and need to be clarified especially adrenal insufficiency which is a lifethreatening condition that can be prevented. OBJECTIVE: To review the endocrinological and the adrenal functions in X-linked ALD. SUBJECTS AND METHOD: The medical records of four patients diagnosed with ALD at the Endocrinology and Metabolic Unit, Department of Pediatrics, King Chulalongkorn Memorial Hospital between 1998 and 2000 were reviewed. The diagnoses were confirmed by elevated very long chain fatty acid (VLCFA) levels and the typical changes seen on magnetic resonance imaging (MRI) of the brain. The adrenal functions in these patients were studied. RESULTS: All patients presented between 7-11 years of age with learning problems and behavioral changes, without symptoms of adrenal insufficiency such as nausea, vomiting and abdominal pain. However, the physical signs of adrenal insufficiency such as generalized hyperpigmentation particularly on the nipples, skin creases and genitalia were present. The laboratory investigations revealed normal blood sugar and serum electrolytes. The adrenal functions were revealed as follows. Basal ACTH levels were high in 2 cases (290, > 1,250 pg/mL). Basal cortisol level was low in 1 case. ACTH stimulation tests revealed subnormal responses in 3 cases. Magnetic Resonance Imaging of the brain showed white matter degeneration in the occipital area in 2 cases and frontal area in 2 cases. CONCLUSION: Adrenal insufficiency can be detected by laboratory evaluation despite the lack of symptoms, therefore, the adrenal function should be evaluated in X-ALD at diagnosis for proper management.

Adrenal Glands↗
PubMed2003

[Analysis on mutation of adrenoleukodystrophy gene in exon 1 and exon 5].

OBJECTIVE: To elucidate the molecular mechanism of X-linked adrenoleukodystrophy(ALD) in Chinese. METHODS: Polymerase chain reaction in exon 1, exon 5 and their flanking sequences and direct DNA sequencing of ALD gene were performed in four patients, their mothers and twenty normal individuals as controls. RESULTS: A splice mutation was identified in the interface of exon 5 and intron 5 (1875 G-->A). This splice mutation in 5' end of intron 5 might lead to abnormal splice in exon 5 and exon 6 and bring about unstable and abnormal ALD protein; the lignoceryl CoA ligase could not transport very long chain fatty acids (VLCFA) into peroxisome and could not function normally; consequently, defective beta-oxidation of VLCFA in peroxisome could result in an accumulation of VLCFAS in the central nervous system, adrenal gland and blood. CONCLUSION: The splice mutation in 5' end of intron 5 leading to abnormal splice in exon 5 and exon 6 appears to be one of the causes of X-linked recessive adrenoleukodystrophy.

ATP Binding Cassette Transporter, Subfamily D, Mem↗
PubMed1992

[Gadolinium-MRI findings of two adrenoleukodystrophy cases treated with gamma-globulin].

Two cases of adrenoleukodystrophy were reported. We treated them with intravenous gamma-globulin infusion. MRI with gadolinium enhancement was performed before and after the therapy to evaluate the effect of gamma-globulin. Case 1 was a 19-year-old boy, who noticed left hemianopsia when he was 18 years old. Case 2 was a 36-year-old man, who developed ataxic gait and character change when he was 33 years old. Very long chain fatty acids in plasma and RBC membrane were elevated in both cases. On T2-weighted image of MRI, high signal lesions were seen in the white matter of occipital lobe in case 1, cerebellum, internal capsule, and around the corpus callosum in case 2. On T1-weighted image, the rim of every lesion was enhanced by gadolinium infusion. After the gamma-globulin therapy, gadolinium enhancement of the rim remarkably reduced in case 1. No reduction was observed in case 2. MRI findings of case 1 indicate the possibility that gamma-globulin may suppress the inflammation of the adrenoleukodystrophy.

Adrenoleukodystrophy↗
PubMed2003

[Preliminary analysis of mutations in X-linked adrenoleukodystrophy gene(ABCD1) in Chinese patients].

OBJECTIVE: To detect the mutations in exon 6 of ABCD1 gene encoding adrenoleukodystrophy protein(ALDP) in Chinese X-linked adrenoleukodystrophy (ALD MIM 300100) patients. METHODS: Genomic DNA from 14 unrelated patients and two patients' parents with X-linked ALD was extracted using standard procedures from the peripheral blood leukocytes. Polymerase chain reaction (PCR) and DNA direct sequencing were employed to analyze exon 6 of ABCD1 gene. RESULTS: Three mutations in exon 6 were identified in 3 of 14 patients. One mutation was deleted 1 base pair at splice acceptor-site (1489-6 del C). It was not clear what the effect of this mutation is on the ALD protein, maybe induce splicing error. One missense mutation: T1559A(L520Q). These two patients' mothers were heterozygous. The third patient had a mutation: G1548A (L516 L), which is a known polymorphism. It was not a disease causing mutation, so there should be another mutation in this patient. CONCLUSION: For the first time, mutations in ABCD1 are identified in Chinese ALD patients in the mainland of China. No major gene deletion or rearrangement is detected in exon 6. Despite many mutations having been identified in patients with these clinical phenotypes, the genotype-phenotype correlations have not been clarified, suggesting that other genetic or environmental factors may also be involved in determining phenotypic expression in ALD. Two carriers are also confirmed.

ATP Binding Cassette Transporter, Subfamily D, Mem↗