Patients with the
cerebrohepatorenal syndrome of Zellweger lack peroxisomes and certain peroxisomal
enzymes such as
dihydroxyacetone phosphate acyltransferase in their tissues. Deficiency of this
enzyme, which is necessary for
glycerol ether lipid synthesis, provides a biochemical method for recognizing patients with subtle manifestations of
Zellweger syndrome and suggests the utility of exogenous
ether lipid precursors as a therapeutic strategy for these children. We describe the results of
glycerol ether lipid supplementation to two children, one with classic
Zellweger syndrome and 9% of control fibroblast
dihydroxyacetone phosphate acyltransferase activity, and one with mild facial manifestations, wide
sutures,
hypotonia, developmental delay,
hepatomegaly, peripheral
retinal pigmentation, and 50% of control fibroblast
dihydroxyacetone phosphate acyltransferase activity. An increase in erythrocyte
plasmalogen levels following
therapy was clearly demonstrated in the milder patient, and neither patient showed evidence of toxicity. Evaluation of
therapy by comparison to the usual
clinical course of
Zellweger syndrome was not helpful because of the variability and incomplete documentation of 90 previously reported cases. The literature survey did provide criteria for classic
Zellweger syndrome, which include
hypotonia with or without deformation of limbs, large fontanels and split
sutures, prominent forehead, flattened facial profile with hypoplastic supraorbital ridges, anteverted nares, highly arched palate,
cryptorchidism or labial hypoplasia,
hepatomegaly or elevated liver
enzymes, peripheral pigmentation of the retina, renal cortical
cysts, and characteristic neuropathology involving decreased myelinization, abnormal neuronal migration, and sudanophilic macrophages. Less severe patients, as exemplified by our case 2 and others from the literature, will not have all the classic features and can be recognized only by a growing panel of biochemical indicators. Our patient studies illustrate the complexity of designing comprehensive
therapy for Zellweger-like conditions, suggest other diseases that may involve peroxisomal alterations, and emphasize the need for multicenter, collaborative studies to evaluate biochemical heterogeneity and
therapy of
peroxisomal disorders.