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.
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.
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.
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.
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).
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 homology to the protein product of the ALD gene (ALDP) and may have some overlapping function. Mutations in this gene have been identified in all X-ALD patients who have been studied in sufficient detail. More than 200 different mutations have been identified (see www.x-ald.nl). There is no correlation between the nature of the mutation and the phenotype. The X-ALD gene has no homology to known VLCS and the mechanisms by which the gene defect leads to VLCFA accumulation and the phenotypic manifestations have not yet been defined.
The rapidly progressive cerebral forms of X-ALD are associated with an inflammatory response in the brain white matter. A distal axonopathy that involves mainly the long tracts in the spinal cord is the principal abnormality in the more slowly progressive AMN phenotype. Mouse models of X-ALD have been produced by targeted gene disruption. These models have defects of VLCFA metabolism and adrenocortical histological abnormalities that resemble the human disease. They do not have a neurologic phenotype, except for mild changes in advanced age that have some resemblance to AMN.
Diagnosis of X-ALD can be achieved by demonstration of increased levels of VLCFA in plasma. This diagnosis is accurate in males but normal levels occur in 15 percent of female heterozygotes. Thus, molecular analysis is required to exclude heterozygote status. Prenatal diagnosis is achieved by measurements of VLCFA levels in cultured amniocytes and by mutation analysis. Brain magnetic resonance imaging (MRI) studies often provide the first clue to the diagnosis, and are of great value in assessing prognosis, and the selection and evaluation of therapeutic approaches.
Adrenal hormone replacement therapy is effective in correcting the adrenal insufficiency associated with adrenoleukodystrophy, but does not alter the neurologic manifestations. Bone marrow transplantation is the most effective therapy in children and adolescents who show early evidence of cerebral involvement. The procedure carries a high risk and selection of candidates requires careful clinical judgment. It is not recommended for patients who do not show evidence of neurologic involvement, patients whose involvement is already advanced, or for adults with adrenomyeloneuropathy. Many patients have received dietary therapy based on the oral administration of a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, also referred to as Lorenzo's Oil. While this therapy reduces or normalizes VLCFA levels in plasma, it does not appear to alter the rate of disease progression in patients who already have neurologic symptoms. An international multicenter study aimed to determine whether administration of the oil to asymptomatic patients can reduce the frequency and severity of later neurologic involvement is in progress.
Studies in cultured cells and the animal model have suggested two therapeutic approaches based upon lovastatin and 4-phenylbutyrate, which are agents in use for other disease states. Both medications have been reported to increase the capacity of cultured X-ALD cells to metabolize VLCFA. It has been proposed that lovastatin may also reduce the brain inflammatory response. 4-Phenylbutyrate increases the expression of ALDRP and reduces VLCFA levels in the animal model. The clinical efficacy of these agents has not yet been tested. Clinical trials are planned.
At this time, disease prevention represents the most effective method of diminishing the hardship caused by X-ALD. Disease prevention is facilitated by the fact that less than 5 percent of patients have new mutations, so that most patients can be identified by screening extended families. The combination of plasma VLCFA and mutation analysis can identify all hemizygotes and heterozygotes by noninvasive techniques, and prenatal diagnosis can be established securely. This strategy is complicated by the inability to predict disease severity.