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X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy

Abstract

X linked adrenoleukodystrophy (X-ALD) is an inherited disorder of peroxisomal metabolism, biochemically characterised by accumulation of saturated very long chain fatty acids. Accumulation of these fatty acids is associated with cerebral demyelination, peripheral nerve abnormalities, and adrenocortical and testicular insufficiency. The lowest estimated birth incidence is one per 100 000. At least six phenotypes can be distinguished, of which the two most frequent are childhood cerebral ALD and adrenomyeloneuropathy. The X-ALD gene has been identified, but thus far no relation between genotype and phenotype has been found. Diagnosis is relatively easy and can be confirmed reliably, and prenatal testing is possible in affected families. Several therapeutic options, some with promising perspectives, are available. Neurologists and other physicians seem not to be familiar with the many facets of X-ALD. In this review, the clinical presentation, the relative frequencies of the different phenotypes, and the diagnostic and therapeutic options are presented.

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More than seven decades have passed since Siemerling and Creutzfeldt reported a seven year old previously healthy boy with a bronzed skin, behavioural abnormalities, dysphagia, and spasticity of the lower limbs.1 Within months he became tetraplegic, developed dysarthria and seizures, and died six months after presentation. Postmortem examination disclosed atrophy of the adrenal cortex and diffuse cerebral sclerosis. In 1963 an X linked mode of inheritance was suggested,2 and in the mid-1970s the term adrenoleukodystrophy was coined for this mysterious disorder.3 Apparently only boys were affected by the disease, now known as X linked adrenoleukodystrophy (X-ALD). Adrenomyeloneuropathy (AMN), a more indolent phenotypic variant that has its onset in adulthood, was first reported in 1976.4Now, at least six different phenotypes are recognised.5Not only men are affected: in the early 1980s it was shown that female carriers are at risk for developing neurological deficits as well.6

In 1976 the accumulation of saturated very long chain fatty acids (VLCFAs) in brain lipids and adrenal cortex of patients with X-ALD was reported.7 8 In 1980 raised concentrations of VLCFAs were shown in cultured skin fibroblasts9 and in 1981 in plasma,10 thus providing a reliable biochemical diagnostic test. In 1984 a defect in peroxisomal metabolism was suggested,11 and shortly thereafter the defective enzyme activity in peroxisomal β-oxidation of VLCFAs was discovered.12 13 In 1981 the X-ALD locus was mapped to Xq28,14 and in 1993 the gene predisposing for X-ALD was identified.15

Nevertheless, many physicians are still unfamiliar with X-ALD and its many facets. Although the disease is rare, the estimated birth incidence is at least one per 100 000.5 16 17 Early identification is mandatory, as untreated patients with adrenocortical insufficiency need steroid hormone substitution therapy. Genetic counselling should be performed, and prenatal diagnosis is possible and desired in affected families.18 Dietary treatment with “Lorenzo’s oil”19 can be considered, particularly in male patients without neurological symptoms, and cerebral demyelination in boys may be halted or reversed by bone marrow transplantation.20 Furthermore, gene therapy may become a serious therapeutic option in the near future.21 22 The aim of this review is to familiarise neurologists and other physicians with the clinical presentation of X-ALD and the diagnostic and therapeutic options.

Clinical manifestations

HEMIZYGOTES

The classification of the different phenotypes of X-ALD is somewhat arbitrary, and based on the age of onset and the organs principally affected. At present, at least six variants can be distinguished (table).5 The two most frequent phenotypes, that account for about 80% of all cases, are childhood cerebral ALD and adrenomyeloneuropathy.5 16 23 24 The delay between onset and diagnosis may be long, particularly in probands.25

Clinical characteristics of the different phenotypes of X-ALD in hemizygotes

About two thirds of the male patients with neurological dysfunction also have overt or subclinical adrenocortical insufficiency (Addison’s disease).26 This may precede, accompany, or follow the onset of neurological symptoms. Virtually all affected men have manifest or subclinical testicular insufficiency (Assies et al, unpublished data), and many have typical, scanty scalp hair (fig 1).

Figure 1

The typical scanty scalp hair that can be seen in all phenotypes. This patient with AMN developed the hair pattern during adolescence.

Childhood cerebral ALD

Childhood cerebral ALD (CCALD) is characterised by rapidly progressive cerebral demyelination.27 28 The onset is between 3 and 10 years of age. Frequent early neurological symptoms are behavioural disturbances, poor school performance, deterioration of vision, and impaired auditory discrimination. The course is relentlessly progressive, and seizures, spastic tetraplegia, and dementia become manifest within months. Figure 2 shows a typical patient with CCALD. Most patients die within two to three years after the onset of neurological symptoms.5 However, some patients survive longer, albeit in a persistent vegetative state. In 80% of patients with CCALD, cerebral MRI typically shows extensive demyelination in the occipital periventricular white matter (fig3).29 The early symptoms of CCALD are often attributed to an attention deficit disorder or hyperactivity. Before the advent of reliable diagnostic tests and MRI, metachromatic leukodystrophy, ceroid lipofuscinosis, globoid cell leukodystrophy (Krabbe’s disease), and subacute sclerosing panencephalitis were sometimes diagnosed instead of CCALD.5

Figure 2

A 7 year old boy with CCALD. Until the age of 6 years psychomotor development was normal. At the age of 6 impaired auditory discrimination was noted. Shortly therafter his vision became impaired and he developed seizures and a spastic tetraparesis as shown in this photograph. He died two years after the onset of neurological symptoms.

Figure 3

Cerebral T2 weighted MRI of an 8 year old boy with impaired visual acuity and seizures due to CCALD. The extensive damage inflicted on the occipital periventricular white matter is evident. Three of his maternal uncles died before the age of 10, but his mother had normal VLCFAs in plasma and skin fibroblasts and somehow had understood that she could not be a heterozygote. Retrospectively, his first neurological symptoms consisted of divergent strabism for which he was operated on twice. He died at the age of 10 years (MRI courtesy of Dr EL Mooyaart, University Hospital, Groningen, the Netherlands.)

Adolescent cerebral ALD

Adolescent cerebral ALD (AdolCALD) occurs much less often. The symptoms and progression are similar to those of CCALD, but the onset is between 10 and 21 years of age (fig 4).

Figure 4

Dramatic metamorphosis of a healthy 6 year old boy into a demented and spastic 17 year old adolescent. The initial diagnosis was myoclonus epilepsy, but retrospectively AdolCALD was diagnosed after one of his cousins had died from CCALD.

Adult cerebral ALD (ACALD)

Very rarely, cerebral demyelination occurs in adult hemizygotes and causes symptoms as seen in CCALD.30-35 These patients may be misdiagnosed as having paranoid psychosis, schizophrenia, or other psychiatric disorders. The illness may progress rapidly.

Adrenomyeloneuropathy (AMN)

At least in The Netherlands, AMN (fig 5) is the most common phenotype of X-ALD.16 The onset of neurological symptoms in this phenotype usually occurs in the third and fourth decade.16 36 Neurological deficits are primarily due to myelopathy, and to a lesser extent to neuropathy.4 28 37Patients gradually develop a spastic paraparesis, often in combination with disturbed vibration sense in the legs and voiding disturbances. About 50% of men with AMN show mild to moderate cerebral involvement on MRI, and in some the abnormalities in white matter may resemble the demyelination seen in CCALD; the spinal cord is often atrophic.38 39 Nerve conduction studies and EMG are compatible with a predominantly axonal, sensorimotor polyneuropathy.40 41 Life expectancy is probably normal, unless patients additionally develop cerebral demyelination, or when adrenocortical insufficiency is not recognised and remains untreated. In many patients with AMN neurological diseases such as chronic progressive multiple sclerosis and hereditary spastic paraparesis were initially diagnosed.5 25 42

Figure 5

This 44 year old man with AMN shows a posture resulting from a slowly progressive spastic paraparesis with an onset 15 years earlier. He also shows the typical scanty scalp hair.

The “Addison only” phenotype

Some patients have isolated adrenocortical dysfunction (Addison’s disease), manifested by fatigue, hypotension, and diffuse or focal bronzing of the skin. Laboratory studies in these patients show raised plasma concentrations of adrenocorticotrophin (ACTH), often in combination with lowered cortisol concentrations in plasma, or inadequate cortisol increases after ACTH stimulation. Several studies have disclosed that a variable, though possibly substantial percentage (4% to 63%) of patients with Addison’s disease in fact may have the “Addison only” phenotype of X-ALD.24 43-47 The risk for developing neurological involvement is very high indeed. However, we examined a 78 year old biochemically affected man with adrenocortical insufficiency who, considering his age, had a normal neurological examination and a normal cerebral MRI.

Asymptomatic or presymptomatic patients

Some patients, in particular those identified by family screening, may neither have neurological nor endocrinological abnormalities, even in the presence of mild cerebral involvement as evidenced by MRI48 or MR spectroscopy.49 Although there is no consensus, we regard these patients as presymptomatic or asymptomatic, and consider a patient symptomatic once the neurological examination or neuropsychological tests disclose abnormalities. The risk for asymptomatic patients to develop neurological symptoms is high. However, some patients may remain asymptomatic into their 60s.50

Atypical presentations

Very rarely, patients with X-ALD display symptoms resembling olivoponto-cerebellar atrophy51-53 or spinocerebellar degeneration.54 Unilateral neurological deficits do not exclude X-ALD.55 It has been suggested that head injury can precipitate or accelerate cerebral demyelination.55 56

Powers and Schaumburg reported that the first symptoms of X-ALD may be caused by gonadal insufficiency.57 In a series of 26 adult patients with X-ALD, we found four men with only signs of hypogonadism (Assies et al, unpublished data).

PHENOTYPIC VARIABILITY AMONG AFFECTED KINDREDS

In 178 kindreds Moser et al found only cerebral variants in 30%, only AMN in 20%, and both CCALD and AMN in 50%.5 In 15 Dutch kindreds, we found only CCALD in 20%, only AMN in 40%, and both cerebral variants and AMN in 40%.16 So it is possible that in a family with AMN, someone will develop CCALD, and vice versa. Even siblings may have different phenotypes.58 59

HETEROZYGOTES

As many as 20% to 50% of all heterozygotes may show neurological symptoms resembling those of AMN.16 50 The onset usually is in the fourth decade, symptoms are milder, and the progression is slower than in the patients with AMN. On cerebral MRI abnormalities in white matter are found in about 20% of the heterozygotes.39

Often, chronic progressive multiple sclerosis is suspected initially in symptomatic carriers.25 50 60 61 In The Netherlands, at least one female carrier underwent a cervical laminectomy because of suspected stenosis of the cervical spinal canal, whereas X-ALD remained unnoticed.

Exceptionally, heterozygotes may develop rapidly progressive cerebral demyelination.62-64 In an interview with members of an affected family, we learned that a Dutch girl developed bronzing of her skin and neurological symptoms attributable to cerebral demyelination and died at the age of 14 years.

Overt adrenocortical dysfunction in female carriers has been reported,62 65 but in general adrenocortical function is normal.26 The scanty scalp hair in most male patients can also be found in heterozygotes.66

Epidemiology

X-ALD is considered by many to be very rare, although neither prevalence nor incidence are exactly known. The disease is found among all races and on all continents. For The Netherlands we estimated a frequency of at least one in 100 000 male births, and a prevalence of at least one in 200 000.16 Surveys in France17 and in the United States5 showed a similar frequency.

Aubourg et al 24 and Moser et al 36 reported in the early 1990s that the variants dominated by cerebral demyelination prevailed (more than 50% of all cases) in France and the United States. We reported that AMN is the predominant phenotype (46% of all cases), at least in The Netherlands.16 Moser et al assumed that ascertainment bias might have influenced the results in previous reports, and that the Dutch phenotypic distribution may be more precise.67 Indeed, the rapidly progressive variants of X-ALD prompt extensive investigations such as cerebral MRI and analysis of VLCFAs, whereas the more indolent variants such as AMN or the “Addison only” phenotype are often overlooked or misdiagnosed. The thorough screening of affected Dutch kindreds has been facilitated by the small area of The Netherlands, the high density of population, the insurance level of nearly 100%, and the decentralisation and accessability of healthcare facilities. Indeed, over the past years the relative frequencies of CCALD and AMN in France and the United States are shifting towards the Dutch percentages (P Aubourg, HW Moser, personal communications).

Biochemical abnormalities

In 1976, the first report appeared on the characteristic accumulation of saturated unbranched very long chain fatty acids (VLCFAs), in particular hexacosanoic acid (C26:0).7 This accumulation is due to an impaired capacity to β-oxidise these fatty acids. As very long chain fatty acyl-CoA esters were metabolised in peroxisomes, it was reasoned that the defect was at the level of the very long chain acyl-CoA synthetase (or ligase). The β-oxidation of VLCFAs occurs exclusively in peroxisomes.11-13 68 69

Peroxisomes are intracellular organelles that are present in virtually every cell, except for the mature erythrocyte.70 71 Their abundance and size vary from tissue to tissue: they are prominent in liver and kidney, but relatively rare in the nervous system. The biochemical reactions that occur in peroxisomes are many, the most important being the aforementioned β-oxidation of VLCFAs, biosynthesis of plasmalogens and bile acids, and glyoxylate detoxification.72 Peroxisomal disorders are tentatively subdivided into three distinct groups.73 In group I, peroxisomal biogenesis is impaired and peroxisomes are virtually absent (for example, Zellweger syndrome and neonatal adrenoleukodystrophy). In group II, peroxisomes are present, but multiple peroxisomal functions are lost (for example, rhizomelic chondrodysplasia punctata). The most frequent peroxisomal disorder, X-ALD, belongs to group III in which only one peroxisomal function is deficient.

Genetics

In 1981 X-ALD was linked to the long arm of the X chromosome (Xq28).14 It took 12 years to identify the X-ALD gene.15 It spans 21 kb, contains 10 exons, and encodes a protein of 745 amino acids with significant homology to the peroxisomal membrane protein PMP-70, belonging to the “ATP binding casette” superfamily of transporters. Monoclonal antibodies were raised against this X-ALD protein (ALDP), and it was shown that the ALDP is incorporated in the peroxisomal membrane.74 Its precise function remains to be determined, but it is somehow involved in the activation of VLCFAs or the import of these fatty acids into peroxisomes.75

Worldwide, patients with X-ALD have mutations in the X-ALD gene,76-79 by contrast with healthy controls.77 Often, a 2 bp deletion in exon 5 is found.77 79 80 So far, no correlation was found between genotype and phenotype.76-79 An autosomal modifier gene has been suggested,36 81 but so far has not been identified. Surprisingly, a variation in phenotypic expression has even been found in monozygotic twins,82 83 suggesting that non-genetic factors may also be involved in the varying phenotypic expression.

Pathological findings

Abnormalities are particularly found in the central and peripheral nervous system, testis, and adrenal cortex.4 27 28 37 84 85 Characteristic are the lamellar cytoplasmic inclusions in brain macrophages, Schwann cells, Leydig cells, and adrenocortical cells. These lamellar inclusions consist of cholesterol esterified with VLCFAs.8

Postmortem examination in the cerebral variants of X-ALD shows widespread periventricular demyelination and cavitation, most severe in the occipital region, with sparing of the U fibres and cerebral cortex, and perivascular lymphocytic infiltrates.28 86 Peripheral nerve abnormalities are uncommon and minimal in comparison with the cerebral lesions.

In AMN, mainly the spinal cord and, to a lesser extent, peripheral nerves are affected. Perivascular lymphocytic infiltrates may be found, but they are much less prominent than in CCALD. It is suggested that, by contrast with the cerebral variants with their characteristic severe demyelination, AMN in fact is a distal axonopathy with secondary degeneration of myelin in the most distant part of the axons.28

Pathogenesis

The accumulation of VLCFAs has long been held responsible for damage inflicted to the nervous system, testis, and adrenal cortex. An excess of VLCFAs may be toxic to adrenocortical cells.28The incorporation of abnormal amounts of VLCFA laden lipids in the membranes of cultured human adrenocortical cells influenced the response to ACTH stimulation.87

However, the exact mechanisms by which the nervous system is damaged remain to be unravelled. It is hypothesised that immune mechanisms are involved in the cerebral variants of X-ALD: perivascular mononuclear accumulations compatible with a cellular immune response are found in active brain lesions in CCALD and AdolCALD,86 and CSF examination showed a raised IgG index in about 30% of patients with CCALD and AdolCALD.27 86 88 A two stage scheme has been suggested: at first there is degradation of myelin due to its instability by an excess of VLCFAs, followed by an inflammatory reaction that destroys the myelin.28 89 By contrast with the cerebral variants of X-ALD, inflammatory infiltrates are scarce in AMN.37

Thus far there is no evidence that the severity of the biochemical defect, as measured by the plasma concentration of VLCFAs, accounts for the phenotypic variability.5 However, a correlation between impairment of nerve conduction and VLCFAs was recently found.41

Diagnosis

The discovery that VLCFAs, particularly hexacosanoic acid, are raised in cultured skin fibroblasts,9 90plasma,10 erythocytes,91 and leucocytes,92 led to reliable and relatively simple biochemical diagnostic tests becoming available. Most laboratories measure the absolute concentration of C26:0 as well as the C24:0/C22:0 and C26:0/C22:0 ratios.73 DNA linkage analysis has also been used for postnatal and prenatal diagnosis,93-95 and after the identification of the X-ALD gene, mutational analysis became available. Monoclonal antibodies have been raised against ALDP, and may facilitate the diagnosis in people at risk.79 96 97

POSTNATAL DIAGNOSIS

Biochemical assays

In virtually all male patients with X-ALD the plasma concentrations of C26:0 and the C24:0/C22:0 and C26:0/C22:0 ratios are clearly increased: in 0.1% of affected males the plasma C26:0 is borderline normal or mildly increased, but the ratios are abnormal.5 In generalised peroxisomal disorders (for example, the Zellweger syndrome and neonatal adrenoleukodystrophy) the concentrations of VLCFAs are raised as well, but both the pattern of the VLCFAs and the clinical presentation differ widely from X-ALD. Analysis of VLCFAs in cultured skin fibroblasts is also possible.9 90 In addition, the oxidation rate of VLCFAs in skin fibroblasts can be measured.13

Nevertheless, plasma concentrations of C26:0 at the upper limit of normal, but certainly not abnormally increased, have recently been reported in two male patients.98 99 In these patients diagnosis was finally established by elevated concentrations of VLCFAs in cultured skin fibroblasts, and abnormal plasma VLCFA concentrations in one of the mothers.

In a study conducted in 96 obligate female carriers, the combined results of VLCFA concentrations in plasma and skin fibroblasts were abnormal in 93%.100 Consequently, about 5% to 10% of female carriers have false negative test results. This is probably due to the compensatory function of their non-affected X chromosomes.

Other tests

DNA linkage analysis with the DXS52 marker can be used, in particular for the identification of heterozygotes, when the necessary relatives are available, and when it is informative at the X-ALD locus.93 94

Immunofluorescence studies in cultured skin fibroblasts or leucocytes may aid in the identification heterozygous females, in particular when VLCFA concentrations in plasma and fibroblasts are normal. In 70% to 80% of the affected kindreds affected boys and men lack ALDP immunoreactivity in cultured skin fibroblasts or leucocytes; female carriers in these kindreds show a mixture of positive and negative immunoreactivity.79 96 97

Mutational analysis is another option once a certain mutation has been shown in an affected family.76 However, this technique is very laborious, and, to our knowledge, not yet carried out routinely.

PRENATAL DIAGNOSIS

Prenatal diagnosis has been performed by VLCFA analysis in cultured amniotic fluid cells101 and cultured chorionic villus cells.102 So far, there have been two reports of false negative test results of a VLCFA assay in cultured chorionic villus cells.103 104 DNA linkage analysis with the DXS52 DNA probe is also possible.94 95 Recently, prenatal diagnosis by means of mutational analysis was reported.105

False negative and false positive results both have far reaching consequences. In the first a boy may develop CCALD, and in the second a pregnancy might be needlessly terminated. Therefore, the most reliable diagnostic procedures should be used. Unfortunately, mutational analysis is not yet routinely available.

DIAGNOSTIC STRATEGY

When X-ALD is suspected, the first diagnostic step consists of analysis of VLCFAs in plasma. An abnormal test result should always be followed by a repeat assay in another sample to exclude problems such as sample mix up. If the test results are abnormal and peroxisomal disorders with neonatal onset are excluded (for example, Zellweger syndrome or neonatal adrenoleukodystrophy),106 the patient has a biochemical defect consistent with X-ALD. We perform VLCFA assays in cultured skin fibroblasts in all probands and in females at risk for heterozygosity.

If the patient is the proband, or if a mutation has not yet been shown in a kindred, mutational analysis is desirable. The presence of ALDP in skin fibroblasts or leucocytes should be investigated, as abnormal ALDP expression on immunoflurescence staining may eventually aid in the identification of heterozygotes.

Therapy

After the discovery of increased concentrations of VLCFAs in blood and other tissues of patients with X-ALD, several dietary treatments were developed. Bone marrow transplantation and immunosuppressive therapies are currently investigated.

Before reviewing these, we emphasise that the adrenocortical insufficiency, found in most patients with X-ALD, if left untreated, may be lethal. Therefore, the adrenocortical function, either measured by plasma ACTH and cortisol concentrations, or by the rise in cortisol after ACTH stimulation,107 should be tested in all affected male patients at regular intervals, unless they are already on steroid hormone substitution therapy.

DIETARY THERAPY

After the finding that orally administered C26:0 reached the brain of a terminally ill patient with CCALD,108 it was reasoned that the VLCFA accumulation was at least in part of dietary origin. However, a diet reducing the intake of products rich in VLCFAs failed to lower plasma concentrations.109 Later, an excess of VLCFA biosynthesis was shown in skin fibroblasts obtained from patients with X-ALD.110 111 Oleic acid (C18:1), a monounsaturated fatty acid, was shown to competitively inhibit the fatty acid elongation system, thus interfering with the biosynthesis of VLCFAs.111 With the combination of fat restriction and oral supplementation with glyceroltrioleate (oleic acid in triglyceride form, or GTO) it was possible to reduce plasma VLCFA concentrations by about 50%.112 113 After glycerol trierucate (erucic acid (C22:1) in triglyceride form, GTE) was added, a dramatic lowering of the plasma concentration of C26:0 was noted: in most patients C26:0 concentrations normalised within a month.114 The 4:1 combination of the GTO and GTE oils became known as “Lorenzo’s oil”, as a tribute to Lorenzo Odone, a boy with CCALD, whose parents helped to develop the dietary treatment.19 Trials with “Lorenzo’s oil” were started worldwide, and hundreds of patients were—and still are—treated.

Because of the dramatic progression of the cerebral variants of X-ALD, the impressive biochemical effect, the relatively few patients, and the considerable phenotypic variability, open studies were preferred to randomised, placebo controlled, and double blinded studies. This has complicated the evaluation of the efficacy of the treatment tremendously. Results of the dietary treatment thus far have been disappointing. “Lorenzo’s oil” did not halt the neurological progression in the cerebral forms of X-ALD.23 36 115 116 This may be explained by the failure of the dietary oil to reach the brain.117 118Nevertheless, a retrospective analysis of the efficacy of Lorenzo’s oil in patients with CCALD indicated that there was slight but significant slowing of progression of symptoms and delay of death.119 In 14 men with AMN and five symptomatic female carriers, “Lorenzo’s oil” failed to induce a neurological benefit.120 Furthermore, endocrine function did not improve in five patients with AMN.121 On the other hand, side effects such as thrombocytopenia were often found,122-125 fortunately not resulting in a haemorrhagic diathesis. In several Dutch patients, we have found platelet counts below 40 × 109/l, which increased again after the intake of the GTO and GTE products was reduced or discontinued.

Although no beneficial effect of “Lorenzo’s oil” was noted in patients with neurological symptoms thus far, we cannot conclude that “Lorenzo’s oil“ does not postpone the onset of neurological symptoms in asymptomatic males. The side effects encountered have been relatively mild, and lacking other therapeutic options for asyptomatic or presymptomatic males, we continue to prescribe the GTO and GTE products to neurologically asymptomatic patients, and those symptomatic patients already treated who prefer to adhere to the diet. We no longer recommend the use of “Lorenzo’s oil” to the parents of patients with CCALD, and newly diagnosed diagnosed patients with AMN, and symptomatic female carriers.

BONE MARROW TRANSPLANTS

Postmortem examinations of the brain of patients with the cerebral variants of X-ALD have shown perivascular mononuclear infiltrates compatible with an immune reaction.28 86 This inflammatory reaction has been linked to excess of VLCFAs in myelin lipids in the region of the brain where demyelination takes place.86 89 126 On the assumption that brain macrophages of patients with X-ALD are unable to remove and degrade the VLCFAs, and that the inflammatory reaction is thus continued, brain macrophages derived from the bone marrow from a donor with normal peroxisomal function might halt the cerebral demyelination.

In 1984 the results of the first bone marrow transplant (BMT) in X-ALD were reported.127 A 12½ year old boy with cerebral abnormalities showed no improvement of his clinical status, and died of an adenovirus infection 141 days after transplantation. In 1990 the first reversal of neurological and neuroradiological manifestations was reported in an 8 year old boy with CCALD.128 Six years after BMT he is still alive and well: his cerebral MRI, cognitive function, and neurological examination are normal, despite mildly raised plasma VLCFAs (P Aubourg, personal communication).

Worldwide, some 200 bone marrow transplants have been performed in patients with the intention to treat storage diseases, including CCALD and AdolCALD and other leukodystrophies.20 Apart from the boy presented by Aubourg in 1990,128 bone marrow transplantation was shown to reverse or stabilise abnormalities on cerebral MRI129 and may result in stability of mental ability.130 Correction of increased plasma VLCFAs before transplantation has been advocated, as this seems to improve the survival of the procedure.20 Analysis by Moser of data supplied by Krivit, Aubourg and others, showed that up to January 1996 52 patients underwent a bone marrow transplant (HW Moser, personal communication). Nineteen patients, mostly those with severe neurological symptoms, died because of the transplant procedure or neurological progression. The 33 patients who survived in general had mild to moderate neurological involvement, and two thirds of them showed stabilisation or improvement after the procedure. According to Krivit et al the donor may even be a heterozygous sister, and because of new techniques to purify donor cells, a bone marrow transplant should be considered in all instances, even if there is no related match.20

Because a bone marrow transplant may be indicated in X-ALD, we perform HLA-typing in a family once a patient at risk for developing cerebral demyelination has been identified. In The Netherlands,a bone marrow transplant is only performed when a suitable donor, preferably an HLA identical sibling, is available and when cerebral involvement is mild, as may be evidenced by abnormalities on neurological and neuropsychological examination. So far, bone marrow transplants have been given to two Dutch boys, one with progressive demyelination of the corpus callosum, and one with impending cerebral demyelination. There were no serious complications, and at one and two years after engraftment, their plasma C26:0 concentrations are mildly raised, and both the neurological and neuropsychological examination are normal.

OTHER THERAPEUTIC INTERVENTIONS

Plasmapheresis lowered VLCFA concentrations, but did not alter the progressive course.131 Clofibrate and L-carnitine were not effective.109

Because of the severe inflammatory reaction in the brain of patients with CCALD,86 89 126 there have been several attempts to suppress this reaction. Immunosuppression with cyclophosphamide, alone or in combination with prednisone, failed to prevent neurological progression in CCALD.132 133

There are conflicting reports on the efficacy of treatment with intravenous immunoglobulins (IVIgs). An arrest of neurological dysfunction lasting 18 months was seen in a patient with AdolCALD.134 On the other hand, in a recent report no differences were shown between the progression of cerebral demyelination in six patients with CCALD or AdolCALD treated with IVIg, and six who did not receive IVIg.135

Similarities between the inflammation found in the cerebral forms of CCALD and multiple sclerosis and the effect of β-interferon on the MRI abnormalities in multiple sclerosis136 led to an increasing interest in the possible treatment of CCALD with β-interferon. A placebo controlled trial with β-interferon in patients withCCALD is now underway in the United States.137 Recently German investigators found neurological deterioration and progression of cerebral lesions in three boys with CCALD despite treatment with β-interferon.138

Concluding remarks

X-ALD is probably underdiagnosed as not everyone is aware of the relatively high incidence and the clinical presentations of the different phenotypes of X-ALD, in particular those variants with only mild or no neuroinvolvement. It is important to recognise X-ALD and its many facets, as it is an inherited disease and may result in severe disability or death. Although the pathogenesis of X-ALD is still not completely understood, much progress has been made in its diagnosis, and our better understanding of the disease has led to several therapeutic options.

In addition to the biochemical diagnostic tests, mutational analysis is possible, and abnormal ALDP immunoreactivity in skin fibroblasts or leucocytes may aid in the identification of patients with X-ALD, in particular female carriers.

The results of dietary treatment with “Lorenzo’s oil” so far have been disappointing; however, neurologically asymptomatic patients may still benefit. Bone marrow transplants have a therapeutic potential, but should only be performed in patients with mild cerebral involvement who have a suitable donor. It must not be forgotten that adrenocortical insufficiency may be the only manifestation of X-ALD, and that it has to be treated with steroid hormone substitution.

Retroviral mediated gene transfer corrected VLCFA metabolism for several months in cultured skin fibroblasts obtained from patients with X-ALD.139 Therefore, it is hoped—and feasible—that in the near future gene therapy may become available for those affected by this severely disabling and potentially lethal disease.21 22

Acknowledgments

This report was financially supported by grant 28-1942 from the Praeventiefonds, the Hague, The Netherlands. We thank the patients and their relatives who permitted us to use their photographs for scientific publications and presentations. We are very grateful to M Vermeulen and J Stam for their critical reading and helpful suggestions.

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