[Clinical and biochemical characteristics of atypical variants of multiple sclerosis]. / Kliniko-biokhimicheskie kharakteristiki atipichnykh variantov rasseiannogo skleroza.

AIM: To study the clinical and biochemical features of atypical variants of multiple sclerosis (MS) (tumefactive demyelination (TD), Balo's concentric sclerosis (BCS)) and acute disseminated encephalomyelitis (ADEM)). MATERIAL AND METHODS: Forty-two patients were studied, including 32 patients with atypical variants of MS (6 patients with BCS and 26 patients with TD) and 10 patients with ADEM. The control group included 20 healthy volunteers. Clinical characteristics and EDSS scores were evaluated. Antibodies to aquaporin 1 (AQP1-IgG), aquaporin 4 (AQP4-IgG), antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) and aquaporin 1 (AQP1) in serum and cerebrospinal fluid (CSF) were detected using ELISA. RESULTS AND CONCLUSION: BCS and TD occurred both in isolation and comorbid with MS (in 50% of cases with BCS, 50% of cases with TD). Atypical symptoms of MS were detected in 50% of cases of CFS, 15.4% of cases of PD. The levels of CSF cytosis and CSF protein were not significantly different between the groups. The levels of AQP1-IgG, AQP4-IgG, AQP1, MOG-IgG in serum with BCS, TD and ADEM were significantly higher than in the control group. No significant differences were found between atypical variants of MS. A correlation between a high level of MOG-IgG and the EDSS score in BCS was shown. MOG-IgG may have a pathogenetic significance in BCS. Further studies of AQP1-IgG, AQP4-IgG and MOG-IgG in patients with atypical variants of MS are needed.

Anti-aquaporin-4 antibody-seronegative NMO spectrum disorder with Baló's concentric lesions.

A 34-year-old woman developed simultaneous bilateral severe optic neuritis and subsequent myelitis. Two months after the first attack, she developed a headache and dysesthesia in the left arm. Brain magnetic resonance imaging revealed multiple hyperintense lesions in the white matter of the right hemisphere, some of which were Baló-like concentric lesions. Our diagnosis was neuromyelitis optica spectrum disorder with Baló's concentric sclerosis (BCS), although the patient was negative for anti-aquaporin-4 (anti-APQ4) antibodies. Our case suggests that Baló's concentric sclerosis overlaps with neuromyelitis optica spectrum disorder and that this overlapping is caused by a mechanism that does not involve anti-AQP4 antibodies.

Improved determination of very-long-chain fatty acids in plasma and cultured skin fibroblasts: applications to the diagnosis of peroxisomal disorders.

Current techniques for the determination of very-long-chain fatty acids from biological samples require laborious procedures including solvent extraction of lipids, purification, hydrolysis, derivatization, purification of derivatized fatty acids by thin-layer chromatography and finally gas chromatographic analysis. A comparison was made between such a procedure based on solvent extraction and a method based on a recently developed direct one-step transesterification reaction. The latter method proved to be much faster and led to higher recoveries of all individual very-long-chain fatty acids from both plasma and skin fibroblasts. The assay proved to be very convenient in the diagnosis of genetically determined disorders in which very-long-chain fatty acids accumulate in tissues and body fluids. Because of its simplicity and speed and because it can be performed with as little as 100 microliters of plasma, the method can be recommended as a valuable screening procedure for peroxisomal disorders.

Very long-chain fatty acids in erythrocyte membrane phospholipids in adrenoleukodystrophy.

Mass fragmentography was used to analyze the very long-chain fatty acid (VLCFA) composition of erythrocyte membrane phospholipids. The VLCFA content decreased in the order sphingomyelin (SM), phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The tetracosanoic acid (C24:0) and hexacosanoic acid (C26:0) content of both SM and PC in patients with adrenoleukodystrophy (ALD) were significantly higher than those in controls. The VLCFA content of PE was too small, in comparison with those of SM, to be accurately determined.

Plasma polyenoic very-long-chain fatty acids in peroxisomal disease: biochemical discrimination of Zellweger's syndrome from other phenotypes.

The plasma of patients with inherited defects in peroxisomal biogenesis (ie, Zellweger's syndrome, infantile Refsum's disease, and neonatal adrenoleukodystrophy) shows evidence of a disturbance in the metabolism of saturated and monoenoic fatty acids with carbon chain lengths greater than 22 (VLCFA). Zellweger's syndrome plasma alone contains, in addition, increased amounts of a number of n-6 polyenoic VLCFA including 24:5, 26:5, 28:5, 30:5, and 30:6 fatty acids. These fatty acids facilitate the biochemical discrimination of Zellweger's syndrome from other related phenotypes.

Large molecular weight ACTH immunoactivity in a patient with adrenoleukomyeloneuropathy.

Very high ACTH immunoactivity was measured in a patient with adrenoleukomyeloneuropathy. The basal adrenocortical function was hyperactive, whereas the response to exogenous ACTH was depressed. Most of the ACTH immunoactivity was a large molecule (55,000 daltons), which weakly stimulated steroidogenesis of adrenocortical cells in vitro, but inhibited the binding of 125I-iodoACTH to the cells and suppressed ACTH-induced steroid production. Abnormalities in the pituitary-adrenal axis in adrenoleukomyeloneuropathy have been considered to be solely attributable to destruction of the adrenal cortex. In the current case, however, large molecular weight ACTH immunoactivity is present and might have some role in the adrenocortical dysfunction.

Adult adrenoleucodystrophy with hypercortisolemia.

A 39-year-old male showed rapid progression of cerebral white matter involvement after 8 years' duration of adrenomyeloneuropathy. Increased ratio of C:26 to C:22 in the fatty acid composition of sphyngomyelin in the blood and needle-like cytoplasmic inclusions in the biopsied peripheral nerve were indicative of adrenoleucodystrophy or adrenoleucomyeloneuropathy. Plasma ACTH levels were extremely elevated, but most of ACTH immunoactivity was eluted at the molecular weight of 55000. Plasma cortisol levels were initially within normal range and were elevated in the final stage. Possible mechanism of elevated ACTH in this disorder was briefly discussed.

Adrenoleukodystrophy: fatty acid analysis of total glycerophospholipids in erythrocyte membranes.

The saturated fatty acids released from the erythrocyte membranes of four patients with adrenoleukodystrophy (ALD) and 14 diseased controls were analyzed by high performance liquid chromatography. The ratios of C26:0 to other saturated fatty acids in ALD were higher than those of diseased controls, and neither false-positive nor false-negative samples were observed. These results suggest that a study of fatty acids of total glycerophospholipids in erythrocyte membranes by high performance liquid chromatography is a useful diagnostic method of ALD.

Capillary gas-liquid chromatographic-mass spectrometric measurement of very long chain (C22 to C26) fatty acids in microliter samples of plasma.

In order to quantify accurately the plasma content of very long chain fatty acids, we have developed a selected ion monitoring gas-liquid chromatographic-mass spectrometric micromethod which allows all of these acids (22:0, 24:1, 24:0, 26:1, and 26:0) to be determined simultaneously in the same 0.5-ml plasma sample; 17:0 and 27:0 fatty acids are used as assay internal standards. For plasma samples in the range equivalent to the various very long chain fatty acid physiological concentrations, assay precision was +/- 2%. The present method has been successfully applied to the biological recognition of patients with adrenoleukodystrophy, their heterozygote relatives, and of cerebro-hepato-renal syndrome and neonatal adrenoleukodystrophy.

Childhood form of adrenoleukodystrophy in the sucking infant.

The childhood form of adrenoleukodystrophy (ALD) in a sucking infant was discovered before the appearance of clinical symptoms. C24:0/C22:0 and C26:0/C22:0 ratios in umbilical cord plasma were significantly higher so that very long-chain saturated fatty acid-restricted milk was given. Ultrastructural study on biopsied rectal mucosa revealed rectilinear and/or curved electron-lucent clefts in the histiocytes at 3 months of age, which were also recognized in the elder brother and another boy with symptoms of ALD. However, magnetic resonance imaging and T1 and T2 values were within the normal range in cerebral gray matter, cerebral white matter, caudate nucleus, internal capsule, and thalamus.

Determination of C20-C30 fatty acids by reversed-phase chromatographic techniques: an efficient method to quantitate minor fatty acids in serum of patients with adrenoleukodystrophy.

An analytical method for the determination of saturated very long chain (VLC) fatty acids in the serum has been devised. Free fatty acids obtained after hydrolysis of total lipid extracts were converted into p-bromophenacyl esters. The derivatives were purified in two sequential steps by clean-up on C18 reversed-phase cartridge and fractionation by reversed-phase thin-layer chromatography (TLC), and then quantitated by high performance liquid chromatography (HPLC) analysis. This technique provides a reliable and alternative method for the biochemical identification of patients and carriers of an inherited metabolic disease characterized by the accumulation of saturated VLC fatty acids (C24-C26) such as Adrenoleukodystrophy (ALD). In four cases of diagnosed ALD the fatty acid composition of serum total lipids was dramatically enriched in saturated VLC fatty acids compared to controls. The ratio of hexacosanoic acid (C26:0) to docosanoic acid (C22:0) in ALD patients was approximately six-fold higher than that of healthy controls or patients affected by metabolic or neurological disorders other than ALD.

Hyperpipecolic acidemia in neonatal adrenoleukodystrophy.

Serum pipecolic acid was measured in patients with neonatal adrenoleukodystrophy (NALD), sex-linked ALD, and the cerebrohepatorenal syndrome of Zellweger. Pipecolic acid was elevated, often markedly, in most of the patients with NALD but in none of those with X-linked ALD or adrenomyeloneuropathy, or in normal adults and children, or children with cirrhosis or other neurodegenerative disorders. The demonstration of elevated serum pipecolic acid in NALD adds to the previously recognized elevation of very-long-chain fatty acids (another Zellweger syndrome sign) and suggests that generalized peroxisomal dysfunction may be a characteristic of NALD as it appears to be of Zellweger syndrome, which diseases share some clinical characteristics. The nosologic significance of these findings is discussed.

Membrane microviscosity is increased in the erythrocytes of patients with adrenoleukodystrophy and adrenomyeloneuropathy.

Adrenoleukodystrophy (ALD) and adrenomyeloneuropathy (AMN) are related X-linked disorders characterized by adrenal, gonadal, and nervous system dysfunction. While the pathologic finding common to these tissues appears to be the accumulation of excessive amounts of very long chain fatty acids, the mechanism leading to functional impairment in these tissues is unclear. Measurements of fluorescence polarization (P), using the lipid probe diphenylhexatriene, demonstrate a highly significant increase in the microviscosity of erythrocyte membranes in affected patients (P = 0.286 +/- 0.012) vs. normals (P = 0.239 +/- 0.020). Analyses of these membranes by gas-liquid chromatography revealed 1.9-, 1.6-, and 1.3-fold increases above normal values in the C25:0, C26:0, and C27:0 fatty acids, respectively. These observations are compatible with previously obtained data in animals that correlate membrane microviscosity with the number of hormone receptors in target tissues. The present data support the thesis that a decrease in responsiveness to trophic hormones in ALD and AMN is secondary to changes in the membrane microviscosity of the target tissues and suggest a mechanism by which adrenal and gonadal failure occur in such patients.

Adrenoleukodystrophy: increased plasma content of saturated very long chain fatty acids.

With a new method we measured the saturated very long chain fatty acids in the plasma of adrenoleukodystrophy (ALD) hemizygotes, ALD heterozygotes, and controls. ALD hemizygotes showed increased levels of hexacosanoate (C26 fatty acid) which represented 0.081 +/- 0.0066% (SEM) of total fatty acids, compared to 0.015 +/- 0.0032% in the controls. C25, C24, and C23 fatty acids were also increased, but the C22 and C20 fatty acids were normal. C26 levels were also increased in most ALD heterozygotes, with a mean level 0.057 +/- 0.0063% of total fatty acids. The technique can be used for diagnosis and carrier identification, and in the evaluation of therapy.

Plasma corticotrophin levels in addison-schilder's disease.

Raised plasma immunoreactive corticotrophin (ACTH) levels were found in five boys with the sex-linked disorder progressive leucodystrophy associated with adrenal insufficiency (Addison-Schilder's disease) and in a symptom-free brother of one of them. Similar ACTH concentrations were found using two antisera, one against the N-terminal part of the ACTH molecule and the other against the C-terminal part. In one patient the circulating ACTH had normal biological activity as measured using the cytochemical ACTH bioassay. Immunoreactive beta/-melanocyte-stimulating hormone was also determined in one patient and found to be raised.