GLYCEROL-TRIERUCATE THERAPY OF ADRENOLEUKODYSTROPHY

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The key biochemical abnormality in X-linked adrenoleukodystrophy (ALD) is the accumulation of saturated very long chain fatty acids (VLCFA) in tissues and body fluids, due to a genetic defect of a peroxisomal enzyme that normally degrades these substances. ALD affects mainly the adrenal cortex, nervous system white matter and testis. While the endocrine deficits can be helped by steroid replacement, the neurological disability cannot be treated and often leads to severe disability and premature death. Neurological involvement ranges from rapid cerebral demyelination with mean age of onset at age 7.2 + 1.7 (SD) years, to much more slowly progressive spinal cord and peripheral nerve involvement in adults (adrenomyeloneuropathy). Our laboratory conducts a national program for the diagnosis of X-linked ALD and peroxisomal disorders, and through this program has identified more than 700 males with X-linked ALD, by far the largest group of patients with this disorder anywhere. Recent studies have demonstrated that a new dietary approach can normalize the levels of saturated VLCFA in the plasma of patients with ALD within 2-4 weeks. The regimen involves the oral administration of a glycerol trierucate (GTE) oil together with certain other dietary modifications. Diagnosis ALD can be achieved in the early postnatal period (as well as prenatally), at least several years before the onset of neurological disability in untreated patients. The striking biochemical effect of the new regimen for the first time offers the opportunity to test whether early normalization of saturated VLCFA can prevent or ameliorate the neurological disability in ALD. The proposed study has three components: 1) a double- blinded trial involving adults with adrenomyeloneuropathy and neurologically involved ALD heterozygotes; 2) a prevention trial for neurologically asymptomatic boys with the biochemical defect of ALD; and 3) a study of neurologically symptomatic boys in whom the rate of neurological progression will be compared with that in more than 100 untreated childhood ALD patients who had previously been diagnosed in our laboratory.