Therapeutic effects of docosahexaenoic acid ethyl ester in patients with generalized peroxisomal disorders

Generalized peroxisomal disorders are severe congenital diseases that invol ve the central nervous system, leading to severe psychomotor retardation, r etinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristicall y, plasmalogen synthesis and beta-oxidation of very-long-chain fatty acids (VLCFAs) are affected. We found that patients with generalized peroxisomal disorders have a profound brain deficiency of docosahexaenoic acid (DHA; 22 :6n-3) and low DHA concentrations in all tissues and the blood. Given the f undamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therap eutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl eater (DHA-EE) because of its high degre e of purity at daily oral doses of 100-500 mg. This article summarizes the results of treatment of 13 patients with DHA-EE, with some follow-up eviden ce of clinical improvement. Supplementation with DHA-EE normalized blood DH A values within a few weeks. Plasmalogen concentrations increased in erythr ocytes in most patients and after DHA concentrations were normalized, amoun ts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal i n most cases. From a clinical viewpoint, most patients showed improvement i n vision, liver function, muscle tone, and social contact. In 3 patients, n ormalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progr essing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recom mended, not only to alleviate symptoms in patients with life-threatening di seases, but also to clarify remaining questions regarding the role of DHA i n health and disease.