i(3)so3-galactosylceramide and Adrenoleukodystrophy

A 4-year old boy died of diffuse disseminated sclerosis (DDS) of the brain and was found to have also pseudoarylsulfatase A deficiency (PASAD) with about 20% residual arylsulfatase A (ASA) and cerebroside sulfatase (CS) activity. The reexamination of lipids did not show any sulfatide accumulation in the patient's organ extracts. Although the residual CS activity in the patient's extracts was clearly demonstrable only after partial purification, it was concluded that this activity protects organ tissues from sulfatide accumulation in PASAD, since in sulfatide lipidosis (metachromatic leukodystrophy, MLD) no residual CS activity was detectable. The study of residual ASA activity in the patient's fibroblasts by gel electrofocusing resulted in an almost normal enzyme microheterogeneity. However, the detailed study of the brain galactolipids in the patient revealed an elevated ratio of sulfatide/galactocerebroside content, despite the decrease of both lipids. In tissues of other patients with severe demyelinating diseases different from DDS and MLD, this galactolipid ratio was also found to be increased, especially in three patients with adrenoleukodystrophy. A general mechanism of this anomaly in severe demyelination is considered.

Topics: Adolescent; Adrenoleukodystrophy; Adult; Brain; Cerebroside-Sulfatase; Child; Child, Preschool; Diffuse Cerebral Sclerosis of Schilder; Female; Galactolipids; Galactosylceramides; Glycolipids; Humans; Infant; Leukodystrophy, Metachromatic; Male; Middle Aged; Multiple Sclerosis; Sulfoglycosphingolipids

Different portions with or without demyelination or degeneration of formalin-fixed brain tissues of a patient with adrenoleukodystrophy and a control subject were applied to analyses of lipids, particularly sphingolipids and cholesteryl ester. Demyelinated area of the white matter in the occipital lobe showed marked decrease in cerebroside and sulfatide except for sphingomyelin and, conversely an accumulation of cholesteryl ester, whereas un-demyelinated white matter in the frontal lobe showed no abnormalities in lipids. Abnormalities of lipids in degenerated lateral nuclei of the thalamus were not so remarkable as the demyelinated white matter, whereas apparently normal dorsomedial nuclei of the thalamus showed no abnormalities in lipids. With regard to the fatty acid composition of abnormal lipids in the demyelinated white matter, all sphingolipids of cerebroside, sulfatide, and sphingomyelin showed remarkable reduction of their longer chain fatty acids and, conversely a significant increment of shorter chain fatty acids. However, these fatty acids in the degenerated lateral nuclei of the thalamus were not so different from those in the undemyelinated and apparently normal areas as well as in control brain. The fatty acids of cholesteryl ester contained mainly C18:1 and C16 acids, and very long chain fatty acids, namely fatty acids with chain length more than 22 carbons, by about 22% of the total fatty acids. In view of the analytical results of the fatty acid composition of brain lipids, it was inconceivable that this ALD patient brain showed especially the accumulation of very long chain fatty acids, and that the biochemical defect in this disease was related to the abnormal oxidation of very long chain fatty acids in peroxisomes. However, the neuropathological findings of demyelination, reactive astrocytosis, and massive infiltration of foam cells well correlated with the abnormalities in myelin lipids and the accumulation of cholesteryl ester. Also, the lower values of urinary 17-ketosteroid and 17-hydroxycorticosteroid suggested that the failure of ACTH to stimulate corticoid secretion seemed to indicate the relationship between the adrenocortical insufficiency and the affected areas of the central nervous system.

Topics: Adrenoleukodystrophy; Adult; Brain; Cerebrosides; Cholesterol Esters; Diffuse Cerebral Sclerosis of Schilder; Fatty Acids; Humans; Lipid Metabolism; Male; Olivopontocerebellar Atrophies; Sphingolipids; Sphingomyelins; Spinocerebellar Degenerations; Sulfoglycosphingolipids

The patient was a 27-year-old man who developed spastic quadriplegia and cerebral disorders. Initial signs were gait disturbance, spastic paraplegia, and sphincter disturbance; these occurred when he was 21. Upon autopsy, the white matter of the brain and spinal cord showed diffuse demyelination, and the adrenal glands and right testis were atrophic. Cytoplasmic striations seen by light microscopy and trilamellar inclusions seen by electron microscopy were found in ballooned adrenocortical cells. Trilamellar inclusions were also observed in macrophages of the affected cerebral white matter. Biochemical analysis disclosed a high ratio (0.27) of hexacosanoic acid (C26:0) to docosanoic acid (C22:0) in cerebrosides and sulfatides of the cerebrum. The histological features as well as the result of biochemical analysis were those of classical adrenoleukodystrophy. However, the time of the onset of clinical signs and the duration of the disease were different in the present case from classical adrenoleukodystrophy. The case presented here was diagnosed as adrenoleukomyeloneuropathy, which is a variant of adrenoleukodystrophy.

Topics: Adrenoleukodystrophy; Adult; Autopsy; Cerebrosides; Diffuse Cerebral Sclerosis of Schilder; Fatty Acids; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Microscopy, Electron; Spinal Cord; Sulfoglycosphingolipids

Leukodystrophies are disorders affecting primarily oligodendroglial cells or myelin. Another necessary criteria for defining a leukodystrophy is that the disorder has to be of endogenous origin with a pattern compatible with genetic transfer of a metabolic defect. The clinical criterion of a steadily progressive deterioration of function must also be included. Much of the material presented during the conference related to three leukodystrophies from which subclasses with a relatively uniform clinical presentation can be distinguished and about which a considerable body of consistent biochemical information is available. These disorders are metachromatic leukodystrophy (MLD), globoid leukodystrophy (GLD, also referred to as Krabbe's disease) and adrenoleukodystrophy (ALD). Discussion was focused to the pathophysiology of the more prevalent "classical" subclass of each of these disorders; discussion of clinical variants was in the context of what we could learn about the more prevalent form. Finally, because of time restraints, most of the discussion on the final day was centered around MLD. This clinical disorder was used as a starting point for discussion of questions both specific to MLD as well as those questions common to all leukodystrophies. The discussion of GLD and ALD was more restricted and only points relevant to those specific leukodystrophies were discussed. Information from the presentation not dealing directly with these human disorders is also summarized.

Topics: Adrenoleukodystrophy; Animals; Child; Diffuse Cerebral Sclerosis of Schilder; DNA, Recombinant; Fatty Acids; Galactosylceramidase; Genes, Recessive; Humans; Leukodystrophy, Globoid Cell; Leukodystrophy, Metachromatic; Mice; Mice, Neurologic Mutants; Mutation; Myelin Proteins; Psychosine; Sulfoglycosphingolipids

Adrenoleukodystrophy (ALD) is an X-linked progressive neurological disorder characterized by the accumulation of saturated very-long-chain fatty acids (C24 to C30) in lipids, especially cholesterol esters of the brain white matter and adrenal cortex. In the present study we have investigated the localization of accumulated cholesterol esters in brain white matter. During isolation of purified myelin membrane from regions of active demyelination, significant enrichment in cholesterol ester was found in two fractions, mainly in a low-density floating fraction and to a lesser degree in the purified myelin preparation. The fatty acid composition of cholesterol esters from both the ALD floating and myelin fractions was enriched approximately 10-fold in saturated very-long-chain fatty acids (greater than or equal to C24) compared with control preparations.

Topics: Adrenoleukodystrophy; Brain Chemistry; Cerebrosides; Cholesterol Esters; Diffuse Cerebral Sclerosis of Schilder; Glycolipids; Humans; Lipids; Microscopy, Electron; Myelin Sheath; Phospholipids; Sphingomyelins; Sulfoglycosphingolipids