Abstract
Generalized peroxisomal disorders are severe congenital diseases that involve the central nervous system, leading to severe psychomotor retardation, retinopathy, liver disease, and early death. In these disorders, peroxisomes are not normally formed and their enzymes are deficient. Characteristically, 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 fundamental role of DHA in neuronal and retinal membranes, a DHA deficiency of this magnitude might be pathogenic. Thus, we studied the possible therapeutic effect of normalizing DHA concentrations in patients with peroxisomal disorders. We chose the DHA ethyl ester (DHA-EE) because of its high degree 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 evidence of clinical improvement. Supplementation with DHA-EE normalized blood DHA values within a few weeks. Plasmalogen concentrations increased in erythrocytes in most patients and after DHA concentrations were normalized, amounts of VLCFAs decreased in plasma. Liver enzymes returned almost to normal in most cases. From a clinical viewpoint, most patients showed improvement in vision, liver function, muscle tone, and social contact. In 3 patients, normalization of brain myelin was detected by magnetic resonance imaging. In 3 others, myelination improved. In a seventh patient, myelination is progressing at a normal rate. These results suggest a fundamental role of DHA in the pathogenesis of Zellweger syndrome. DHA therapy is thus strongly recommended, not only to alleviate symptoms in patients with life-threatening diseases, but also to clarify remaining questions regarding the role of DHA in health and disease.
Highlights
Microbodies or peroxisomes are single membrane-bound organelles, 0.2–1 m in diameter, that are distributed ubiquitously in most cells in nature
We discovered a dramatic deficiency of docosahexaenoic acid (DHA; 22:6nϪ3) in the brain, retina, liver, kidneys, and blood of patients with peroxisomal disorders [24,25,26]
In a 3-y-old girl in whom treatment was initiated late, DHA ethyl ester (DHA-EE) could be given for only 6 wk [29]
Summary
Microbodies or peroxisomes are single membrane-bound organelles, 0.2–1 m in diameter, that are distributed ubiquitously in most cells in nature. A difference between mitochondrial and peroxisomal -oxidation is that the former requires carnitine for the passage of fatty acids across the inner mitochondrial membrane; in the latter, carnitine only facilitates the output of the -oxidation end products. Another difference relates to the enzymes involved in the -oxidation cycle. The double bond in the fatty acyl group is hydrated and dehydrogenated in the second and third -oxidation steps by 2 different enzymes (a hydratase and a dehydrogenase) In peroxisomes, these same reactions are catalyzed by a single, bifunctional enzyme
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