Chapter 131

### Abstract

1. The term adrenoleukodystrophy (ALD) is used to describe two genetically determined disorders that cause varying degrees of malfunction of the adrenal cortex and nervous system myelin, and are characterized by abnormally high levels of very long chain fatty acids (VLCFA) in tissues and body fluids.

2. Two types of ALD must be distinguished. One type is X-linked (MIM 300100), with the biochemical abnormality apparently confined to very long chain fatty acid metabolism, and normal peroxisome structure. The second type has an autosomal recessive mode of inheritance, is referred to as neonatal adrenoleukodystrophy (MIM 202370), and resembles the Zellweger cerebrohepatorenal syndrome (MIM 214100) in that the number and size of peroxisomes are diminished and the function of at least five peroxisomal enzymes is impaired. This chapter is concerned with X-linked ALD (X-ALD). Neonatal ALD is discussed in Chap. 129.

3. The incidence of males with X-ALD is estimated to lie between 1:20,000 and 1:50,000 of the total population, and appears to be the same in most ethnic groups. There are several distinct phenotypes. Approximately 35 percent of patients have the childhood cerebral form. Affected boys develop normally until 4 to 8 years of age, and then suffer dementia and a progressive neurologic deficit that leads to a vegetative state. More than 90 percent of these have adrenal insufficiency. In approximately 35 to 40 percent of patients, the disorder presents in young adulthood as a slowly progressive paraparesis with sphincter disturbances that involves the long tracts in the spinal cord mainly and is referred to as adrenomyeloneuropathy (AMN). Adrenal insufficiency is present in two-thirds of these patients. Less common phenotypes include adrenal insufficiency without nervous system involvement, progressive cerebral dysfunction in adults, a syndrome that resembles olivopontocerebellar degeneration, and persons who are asymptomatic. The various phenotypes commonly occur within the same kindred. Twenty percent of female heterozygotes develop overt neurologic disturbances that resemble those of adrenomyeloneuropathy. Up to 50 percent of heterozygotes have mild neurologic abnormalities, but overt adrenal insufficiency is rare.

4. Tissues and body fluids of patients with X-ALD contain abnormally high levels of unbranched saturated very long chain fatty acids, particularly hexacosanoate (C26:0). This excess is most striking in the cholesterol ester and ganglioside fractions of affected brain white matter and adrenal cortex, but is present to varying degrees in virtually all tissues and body fluids.

5. The very long chain fatty acid accumulation is associated with an impaired capacity for their degradation, a reaction that normally takes place in the peroxisome. The defect results in an impaired capacity to form the coenzyme-A derivative of very long chain fatty acids in the peroxisome, a reaction which is catalyzed by very long chain acyl-CoA synthetases (VLCS).

6. The gene for X-ALD has been mapped to Xq28. It codes for a peroxisomal membrane protein with homology to the ATP-binding cassette (ABC) transporter superfamily of proteins. The X-ALD protein (ALDP) is closely related to three other peroxisomal membrane ABC proteins. One of these, ALDRP, has 66 percent ...

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