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X-linked adrenoleukodystrophy (X-ALD) is a frequent but underrecognized cause of primary adrenocortical insufficiency.

BIOCHEMISTRY AND GENETICS OF X-ALD

X-ALD is a genetically determined disorder that involves mainly the white matter and axons of the central nervous system, the adrenal cortex and the testis (1). It is associated with the accumulation of saturated very long chain fatty acids (VLCFA), particularly hexacosanoic (C26:0) and lignoceric (C24:0) acids, due to the impaired capacity to degrade these substances (2), a reaction that normally takes place in the peroxisome (3). The gene that is defective is referred to as ABCD1. It is located at Xq28. It codes for a peroxisomal membrane protein (ALDP) (4) that is a member of the ATP binding cassette (ABC) transport protein family (5). Transfection of X-ALD cell lines with normal ABCD1 restores their capacity to degrade to VLCFA (6), through mechanisms that have not yet been determined (7). More than 400 different mutations have been identified in X-ALD patients (8) and are updated in the website http://www.x-ald.nl). The mode of inheritance of X-ALD is X-linked recessive. The minimum incidence in the United States is estimated to be 1:16,800 (9). X-ALD has been reported in all ethnic groups with approximately the same frequency.

CLINICAL MANIFESTATIONS OF X-ALD

The clinical manifestations of X-ALD are summarized in several recent reviews (1;10-12). The range of clinical expression varies widely. Tables 1a and 1b summarize the principal phenotypes. Approximately 40% of patients have the childhood, adolescent or adult cerebral forms, with the childhood form being the most severe. These phenotypes are rapidly progressive. They are associated with an inflammatory response (13), in which autoimmune mechanisms may play a role (14) and which is associated with characteristic brain MRI (15) and magnetic resonance spectroscopy (16-18). In contrast, adrenomyeloneuropathy (AMN) is a slowly progressive disorder that affects the long tracts of the spinal cord mainly and in which the inflammatory response is absent or mild (19;20). AMN patients may survive to the eighth decade. However, approximately 20-30% of AMN patients later develop progressive cerebral involvement in which the inflammatory response is present (21). Approximately 50% of female heterozygotes develop and AMN like syndrome, but milder, in middle or later life. In our experience all male X-ALD patients develop some degree of neurologic or endocrine abnormality at some time in their life. The various phenotypes often co-occur within the same family. The nature of the mutation or the degree of elevation of plasma VLCFA levels is not predictive of phenotype.

INCIDENCE OF ADRENAL DEFICIENCY IN X-ALD

Correlation between the severity of adrenal and neurological involvement. The incidence of adrenal insufficiency in the various phenotypes is shown in table 1. While many patients have both neurologic involvement and adrenal insufficiency, a considerable nubmer have only or the other. The patients with the "Addison only" phenotype by definition are free of demonstrable neurologic involvement, although many in this category will later become neurologically involved. In 20 of 41 AMN patients studied by Brennemann et al (22) the ACTH stimulation test gave normal results. The incidence of adrenal insufficiency in the patients with the childhood cerebral forms of ALD (79%) appears to be higher than in the AMN patients.

Addison disease is rare in women heterozygous for X-ALD (1% or less), and considerably less frequent than the AMN-like syndrome, which develops in approximately 50% of women in middle age or later. Even though it is rare for heterozygous women to show clinically evident adrenal insufficiency or abnormalities in plasma ACTH level or ACTH stimulation test, postmortem studies have shown abnormalities that resemble those in affected males (23). When more subtle tests of adrenal function, such as the response to ovine corticotropin-releasing-hormone, were performed, subnormal responses were demonstrated in five of eight women whose ACTH stimulation tests were normal (24).

X-ALD appears to be a more frequent cause of Addison's Disease in males than is generally recognized. Lauretti et al (25) found that 5 of 14 male patients, ages 12-45 years, previously diagnosed as having primary adrencortical insufficiency, had abnormally high plasma VLCFA levels and had X-ALD. Jorge et reported X-ALD in ten of 37 patients with idiopathic Addison Disease (27%), and found that the incidence was highest (5 out of 5) in those patients in whom adrenal insufficiency became evident before 7.5 years of age (26). These results have important clinical implications. The diagnosis of X-ALD has profound implications for prognosis, therapy and genetic counseling.

We recommend that screening for X-ALD be carried out in all male patients with idiopathic Addison Disease. The need to do so is particularly great in patients in whom the adrenal insufficiency manifested before 7.5 yeas of age.

Table 2 shows the patterns of adrenal dysfunction in patients with various X-ALD phenotypes. Elevated ACTH levels and impaired cortisol response to ACTH administration are the most frequent finding, but impaired aldosterone response was also observed in one third of the patients.

DIAGNOSIS OF X-ALD

The plasma assay for VLCFA is the most frequently used diagnostic assay. It is reliable for the identification of affected males (27) VLCFA levels are already increased on the day of birth and in untreated patients remain approximately the same throughout life. The assay can be used to identify asymptomatic patients by screening members of the extended family (9). While plasma levels of VLCFA are increased in many women who are heterozygous for X-ALD, false negative results occur in approximately 15 to 20% of obligate heterozygotes (27). Mutation analysis is the most accurate method for the definitive identification of heterozygotes (28). Studies of chorion villus biopsies or amniocytes permit the prenatal identification of affected male fetuses (29).

The diagnosis of X-ALD should be suspected in:

1. Boys with progressive behavioral, cognitive or neurologic disturbances beginning at 3 years of age or later. The initial manifestations resemble those of attention deficit disorder, and even in X-ALD patients may appear to respond to medications such as ritalin. In X-ALD evidence of dementia, spatial disorientation, more serious behavioral disturbances, and difficulty in hearing supervene. Early suspicion and diagnostic studies are recommended, because when the symptom complex is fully characteristic current methods of therapy are no longer effective.
2. Males with Addison's disease in which etiology has not been defined. Since the plasma VLCFA assay is non-invasive, and the practical and genetic implications of the diagnosis of X-ALD are great, we recommend that VLCFA assay be part of the routine initial evaluation of male patients with Addison Disease.
3. Men and women with progressive spastic paraparesis. AMN is often misdiagnosed as multiple sclerosis. The diagnosis of X-ALD should be considered even when there is no clinical or biochemical evidence of adrenal insufficiency. In a series from Germany (22) adrenal function was normal in 20 of 41 men with AMN, and adrenal insufficiency occurs in less than one percent of women with and AMN-like syndrome.
4. Patients in whom adrenal insufficiency occurs in combination with neurologic disability
   (Table 3).
5. Patients who are at genetic risk of having X-ALD on the basis of pedigree. This recommendation is of key importance. Because X-ALD is X-linked recessive, a large number of relatives in the nuclear and extended family are at genetic risk. In one family we screened 174 family members. Bezman et al (9) reported that extended family screening led to the identification of 504 affected males, half of whom were asymptomatic, and of 1,270 heterozygotes. Detection of asymptomatic patients is particularly important, since therapeutic interventions have the greatest chance of success when clinical manifestations are still mild.

PATHOLOGY OF THE ADRENAL GLAND IN X-ALD

In patients with X-ALD the adrenocortical cells, particularly those in the inner fasciculata-reticularis, become ballooned and striated due to the accumulation of lamellae, lamellar-lipid profiles, and fine lipid clefts (34) (Figure 1). Histochemical and biochemical studies make it likely that these lammellae consist of cholesterol esterified with saturated very long chain fatty acids (35;36). The inclusions and strikingly elevated levels of very long chain fatty acids are also demonstrable in the fetal adrenal gland (37). The striated material appears to lead to cell dysfunction atrophy and death of the cells. Whitcomb et al carried out studies of the cortisol response to stimulation with increasing concentrations of ACTH in cultured adrenal cells, and found that this response was impaired when the culture medium contained very long chain fatty acids (Figure 2). Ultimately primary atrophy of the adrenal cortex ensues. Inflammatory cells are rarely involved.

Figure 1.

THERAPY

For those patients with X-ALD who have impaired adrenal function glucocorticoid replacement therapy is mandatory and life-saving. In patients with normal adrenal function at time of first contact, we recommend that adrenal function be monitored yearly. This aspect of the therapy is not infrequently neglected, in part because attention often is focused mainly on the neurologic aspects of the disorder, or because of failure to monitor adrenal function in those patients in whom it was initially normal. We know of at least 10 patients who have died of adrenal crisis, some of whom were neurologically uninvolved. Glucocorticoid replacement requirements are generally the same as those used for other forms of primary adrenal insufficiency. To mimic the diurnal rhythm of physiological cortisol secretion, 25 mg of cortisone acetate or 20 mg hydrocortisone is administered in the early morning with a smaller second dose, 12.5 or 10 mg, respectively, given in the late afternoon. Patients are instructed in a protocol to augment glucocorticoid coverage during stress, provided with parenteral methylprednisone dose for potential use if vomiting prevents oral dosing, and encouraged to use Medic-Alert identification. Not all patients require mineralocorticoid replacement. When postural hypotension, hyponatremia, or hyperkalemia persist in spite of adequate glucocorticoid, fludrocortisone 0.05 mg to 0.1 mg per day is prescribed. While there is one report of substantial improvement of neurologic function when replacement therapy was administered to a patient with AMN (38) the general impression is that adrenal replacement therapy does not alter neurologic progression.

Therapy of the neurologic aspects of X-ALD is a major challenge. Bone marrow transplantation offers the greatest promise at this time. It is recommended for boys and adolescents who show early evidence of cerebral involvement. Here it can lead to long-term stabilization and occasionally improvement in some patients (39;40). The mechanism of this effect is still unclear. Bone marrow cells do express the ABCD1 gene and plasma very long chain fatty acid levels are reduced after bone marrow transplantation. It has been shown that bone marrow-derived cells do enter the brain and that part of the brain microglial cells are bone marrow-derived (41). It may also diminish the brain inflammatory response. Brain MRI abnormalities precede symptoms in patients with the cerebral forms of X-ALD (42). Current strategy is to monitor asymptomatic patients by MRI at 6 months to yearly intervals and consider bone marrow transplantation for those patients in whom the MRI abnormality is advancing and clinical disability is mild. It is not recommended for patients who already have advanced cerebral involvement, because it has not reversed these severe deficits and in some instances may have accelerated disease progression. Bone marrow transplantation carries a high risk. It is not recommended for patients without cerebral involvement because of the high risk and because up to 50% of untreated X-ALD patients never develop cerebral involvement. It has not been tested systematically in AMN because of concern that the risk-benefit ratio may not be favorable, and it is uncertain whether the procedure will affect the non-inflammatory distal axonopathy which is the main pathological feature in AMN (19) and differs from that in the cerebral forms of the disease.

Other therapeutic modalities include dietary therapies with restriction of fat intake and the administration of a mixture of glyceryl trioleate and glyceryl trierucate, also referred to as Lorenzo's Oil (43). This therapy normalizes plasma very long chain fatty acid levels within four weeks, but its therapeutic effects in patients who are already symptomatic has been disappointing (44). An international trial to determine whether administration of the oil to neurologically asymptomatic patients prevents or diminishes subsequent neurological disability is in progress. Lorenzo's Oil therapy does not improve adrenal function (45). Other therapies that are under consideration of being tested are 4-phenylbutyrate (46), Lovastatin (47;48), and gene therapy (49).