Docosahexaenoic acid–A new therapeutic approach to peroxisomal‐disorder patients

Abstract

Docosahexaenoic acid (DHA, 22:6 omega 3) is a major constituent of brain membrane phospholipids and photoreceptor cells. Patients with generalized peroxisomal disorders have extremely low levels of DHA in the brain and other tissues. Since a DHA deficiency could explain some basic symptoms in peroxisomal-disorder patients, we tested the possible beneficial effects of DHA in two patients with neonatal adrenoleukodystrophy (NALD). Before the treatment, both patients had very low DHA levels in plasma and erythrocytes. We first gave DHA in the form of fish oil and, in both patients, the rapid increase in red-cell DHA levels indicated that this fatty acid was being absorbed and incorporated into membrane phospholipids very fast. However, a low ratio 22:6 omega 3/22:5 omega 3 was still present in erythrocyte membranes, and the content of 20:5 omega 3 (eicosapentaenoic acid) was too high with the fish oil diet. We then began treatment with pure DHA ethyl ester and, after a few weeks, erythrocyte omega 3 polyunsaturated fatty acids were normal. There was an increase in the 18:0 molecular species of plasmalogens in both patients, most significantly in the child with affected plasmalogen biosynthesis in cultured fibroblasts. In the less severely affected NALD patient, treatment with DHA produced a very significant decrease in the ratios 24:1/22:0 and 26:1/22:0, and this child improved neurologically. The present data suggest that DHA deficiency may be the cause for some of the most characteristic abnormalities in peroxisomal-disorder patients and open new therapeutic possibilities for these patients.

Docosahexaenoic Acid Deficit Is Not a Major Pathogenic Factor in Peroxisome-Deficient Mice

“…In addition, a potential beneficial effect on visual functions and myelination could not be evaluated in the newborn mouse. We did not observe changes either in plasmalogen levels or in C26:0 levels in brain of DHA-treated Zellweger mice, which is in contrast to the findings in DHA-treated Zellweger patients (Martinez et al, 1993). It should be noted that in the patients, plasmalogens and C26:0 were analyzed in erythrocytes and in plasma, respectively, whereas in DHA-treated mice, the phospholipid fraction of the brain was used.…”

“…In several of the Zellweger patients treated with DHA by Martinez (Martinez, 1996;Martinez et al, 1993), the increase of DHA levels was accompanied by an increase of the vinyletherphospholipids (plasmalogens) in erythrocytes and a decrease of C26:0 levels in plasma. Analysis of the brain phospholipid fraction of DHA-treated PEX5 Ϫ/Ϫ mice revealed that the plasmalogen levels were somewhat increased but remained extremely low (Table 1) and that C26:0 accumulated to the same extent as in non-treated PEX5 Ϫ/Ϫ mice (Table 1).…”

Replenishment of docosahexaenoic acid in n-3 fatty acid-deficient fetal rats by intraamniotic ethyl-docosahexaenoate administration

“…Administration of pure ethyl-docosahexae-noate (Et-DHA) to two patients with one of these syndromes, neonatal adrenoleukodystrophy, resulted in almost complete normalization of the biochemical profile and a profound, albeit partial, therapeutic effect (Martinez et al, 1993).…”

Genetic and molecular bases of peroxisome biogenesis disorders

“…Deficiency of DHA is considered to relate to brain and visual dysfunction and abnormal myelination. 54,55 Although 11 human PEX genes have been identified, there are over 20 yeast PEX genes. Novel complementation groups and responsible genes may be elucidated in the near future.…”