As to the biochemical abnormality, Moser and coworkers (1984) demonstrated a fivefold increase of very-long-chain fatty acids, particularly hexacosanoic acid, in the plasma and cultured skin fibroblasts from 35 patients with Zellweger disease. A similar abnormality was found in cultured amniocytes of women at risk of bearing a child with Zellweger disease, thus permitting prenatal diagnosis. The findings of Moser and colleagues (1984) are in keeping with current notions about the basic abnormality in Zellweger syndrome, namely, that it is caused by a lack of liver peroxisomes (oxidase-containing, membrane-bound cytoplasmic organelles), in which the very-long-chain fatty acids are normally oxidized (Goldfischer et al).
Currently, a spectrum of at least 12 disorders of peroxisomal function is recognized, all of them characterized by deficiencies in the peroxisomal enzyme of fatty-acid oxidation. The most common form of Zellweger syndrome is due to a mutation in PEX1. However, the most widely recognized peroxisomal disorders are adrenoleukodystrophy and Refsum disease, but the Zellweger cerebrohepatorenal syndrome can be considered a prototype. Each variant can be identified by its characteristic profile of elevated longand very-long-chain fatty acids, and the specific diagnosis can be confirmed by enzymology of cultured fibroblasts or amniocytes. Several of them become manifest at a later age and are discussed further on. For an authoritative discussion of peroxisomal biogenesis, the reader is referred to the article by Gould and Valle.
The Oculocerebrorenal (Lowe) Syndrome
Here the mode of inheritance is probably X-linked recessive, although sporadic cases have been reported in girls. The abnormal gene is located on chromosome Xq25.26. The clinical abnormalities comprise bilateral cataracts (which may be present at birth), glaucoma, large eyes with megalocornea and buphthalmos, corneal opacities and blindness, pendular nystagmus, hypotonia and absent or depressed tendon reflexes, corticospinal signs without paralysis, slow movements of the hands, tantrums and aggressive behavior, high-pitched cry, occasional seizures, and psychomotor regression. Later the frontal bones become prominent and the eyes sunken. The characteristic biochemical abnormality is a renal tubular acidosis, and death is usually from renal failure. Additional laboratory findings include demineralization of bones and typical rachitic deformities, anemia, metabolic acidosis, and generalized aminoaciduria. The neuropathologic changes are nonspecific; inconstant atrophy and poor myelination have been described in the brain and tubular abnormalities in the kidneys. The primary genetic defects are in the gene encoding inositol polyphosphate phosphatase of the Golgi complex. The main diagnostic distinction is from Zellweger disease. Treatment programs include antiepileptic medication, correction of electrolyte disorders, and removal of cataracts.
Menkes Disease (Kinkyor Steely-Hair Disease; Trichopoliodystrophy, ATP7A Mutation)