4 Journal of Neurology, Neurosurgery, and Psychiatry 1997;63:4–14 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

REVIEW

X linked : clinical presentation, diagnosis, and therapy

Björn M van Geel, Johanna Assies, RonaldJAWanders, Peter G Barth

Abstract that has its onset in adulthood, was first X linked adrenoleukodystrophy (X-ALD) reported in 1976.4 Now, at least six diVerent is an inherited disorder of peroxisomal phenotypes are recognised.5 Not only men are metabolism, biochemically characterised aVected: in the early 1980s it was shown that by accumulation of saturated very long female carriers are at risk for developing chain fatty acids. Accumulation of these neurological deficits as well.6 fatty acids is associated with cerebral In 1976 the accumulation of saturated very demyelination, peripheral abnor- long chain fatty acids (VLCFAs) in brain lipids malities, and adrenocortical and testicu- and adrenal cortex of patients with X-ALD was lar insuYciency. The lowest estimated reported.78 In 1980 raised concentrations of birth incidence is one per 100 000. At least VLCFAs were shown in cultured skin 9 10 six phenotypes can be distinguished, of fibroblasts and in 1981 in plasma, thus Department of which the two most frequent are child- providing a reliable biochemical diagnostic Neurology, Academic hood cerebral ALD and adrenomyelo- test. In 1984 a defect in peroxisomal metabo- Medical Center, 11 neuropathy. The X-ALD gene has been lism was suggested, and shortly thereafter the University of defective enzyme activity in peroxisomal Amsterdam, PO Box identified, but thus far no relation between â-oxidation of VLCFAs was discovered.12 13 In 22700, 1100 DE genotype and phenotype has been found. 14 Amsterdam, the Diagnosis is relatively easy and can be 1981 the X-ALD locus was mapped to Xq28, Netherlands confirmed reliably, and prenatal testing is and in 1993 the gene predisposing for X-ALD B M van Geel 15 possible in aVected families. Several was identified. therapeutic options, some with promising Nevertheless, many physicians are still unfa- Departments of miliar with X-ALD and its many facets. Psychiatry and perspectives, are available. Neurologists

Although the disease is rare, the estimated http://jnnp.bmj.com/ Internal Medicine and other physicians seem not to be 51617 J Assies familiar with the many facets of X-ALD. birth incidence is at least one per 100 000. Early identification is mandatory, as untreated In this review, the clinical presentation, Department of Clinical patients with adrenocortical insu ciency need the relative frequencies of the diVerent Y Biochemistry, steroid hormone substitution therapy. Genetic phenotypes, and the diagnostic and thera- Academic Medical counselling should be performed, and prenatal Center, University of peutic options are presented. diagnosis is possible and desired in aVected Amsterdam, PO Box 18 22700, 1100 DE families. Dietary treatment with “Lorenzo’s (J Neurol Neurosurg Psychiatry 1997;63:4–14) 19

Amsterdam, the oil” can be considered, particularly in male on September 28, 2021 by guest. Protected copyright. Netherlands patients without neurological symptoms, and RJAWanders Keywords: adrenoleukodystrophy; adrenomyeloneu- ropathy; very long chain fatty acids; cerebral demyelination in boys may be halted or reversed by marrow transplantation.20 Departments of Furthermore, may become a seri- Neurology and 21 22 Pediatrics, Academic More than seven decades have passed since ous therapeutic option in the near future. Medical Center, Siemerling and Creutzfeldt reported a seven The aim of this review is to familiarise University of year old previously healthy boy with a bronzed neurologists and other physicians with the Amsterdam, PO Box skin, behavioural abnormalities, , clinical presentation of X-ALD and the diag- 22700, 1100 DE 1 nostic and therapeutic options. Amsterdam, the and spasticity of the lower limbs. Within Netherlands months he became tetraplegic, developed dys- P G Barth arthria and , and died six months after presentation. Postmortem examination dis- Clinical manifestations Correspondence to: Dr B M van Geel, closed atrophy of the adrenal cortex and diffuse HEMIZYGOTES Department of Neurology, cerebral sclerosis. In 1963 an X linked mode The classification of the diVerent phenotypes Academic Medical Center, of inheritance was suggested,2 and in the of X-ALD is somewhat arbitrary, and based on University of Amsterdam, mid-1970s the term adrenoleukodystrophy the age of onset and the organs principally PO Box 22700, 1100 DE 3 Amsterdam, the Netherlands. was coined for this mysterious disorder. aVected. At present, at least six variants can be Apparently only boys were aVected by the distinguished (table).5 The two most frequent Received 9 December 1996 disease, now known as X linked adrenoleuko- phenotypes, that account for about 80% of all and in revised form 11 February 1997 dystrophy (X-ALD). Adrenomyeloneuropathy cases, are childhood cerebral ALD and Accepted 14 February 1997 (AMN), a more indolent phenotypic variant adrenomyeloneuropathy.5162324 The delay X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy 5 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

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

Pre- or asymptomatic Addison ALD CCALD AdolCALD ACALD AMN only Relative frequencies (%) 4-10 31-57 1-3 25-46 8-14 Age at onset of − < 10 10-21 > 21 > 18; frequent >2 neurological 3rd-4th decade symptoms Behavioural disturbances − + + + − − Impaired cognition − + + Frequent − − Pyramidal tract − Eventually, not Eventually, not Frequent Present by − involvement initially initially definition Cerebral MRI Absent or Extensive in Extensive in Extensive in Internal capsule Absent or abnormalities mild* occipital or occipital or occipital or basal ganglia, mild* frontal frontal myelin frontal myelin mesencephalon, pons Polyneuropathy − − Rare Possible Sensorimotor, − mostly axonal Abnormal evoked − VEP, BAEP VEP, BAEP VEP (not BAEP, SEP Sometimes potentials (not initially) (not initially) initially), BAEP BAEP sometimes SEP sometimes SEP Impaired endocrine − ADinmost ADinmost ADinmost ADand AD by function hypogonadism in definition most Abnormal neuropsychological examination − + + Frequent − − Progression − Rapidly, rarely Rapidly, rarely Rapidly, Slowly, sometimes − slowly slowly sometimes rapidly slowly

− = Absent; + = present; * = depending on definition; CCALD = childhood cerebral ALD; AdolCALD = adolescent cerebral ALD; ACALD = adult cerebral ALD; AMN = adrenomyeloneuropathy; VEP = visual evoked potential; BAEP = brainstem auditory evoked potential; SEP = somatosensory evoked potential; AD = adrenocortical insuYciency (Addison’s disease).

between onset and diagnosis may be long, par- and impaired auditory discrimination. The ticularly in probands.25 course is relentlessly progressive, and seizures, About two thirds of the male patients with spastic tetraplegia, and become neurological dysfunction also have overt or manifest within months. Figure 2 shows a typi- subclinical adrenocortical insuYciency (Addi- cal patient with CCALD. Most patients die son’s disease).26 This may precede, accompany, within two to three years after the onset of or follow the onset of neurological symptoms. neurological symptoms.5 However, some pa- Virtually all aVected men have manifest or tients survive longer, albeit in a persistent veg- subclinical testicular insuYciency (Assies et al, etative state. In 80% of patients with CCALD, unpublished data), and many have typical, cerebral MRI typically shows extensive demy-

scanty scalp hair (fig 1). elination in the occipital periventricular white http://jnnp.bmj.com/ matter (fig 3).29 The early symptoms of Childhood cerebral ALD CCALD are often attributed to an attention Childhood cerebral ALD (CCALD) is charac- deficit disorder or hyperactivity. Before the terised by rapidly progressive cerebral advent of reliable diagnostic tests and MRI, demyelination.27 28 The onset is between 3 and metachromatic , ceroid lipofus- 10 years of age. Frequent early neurological cinosis, globoid cell leukodystrophy (Krabbe’s symptoms are behavioural disturbances, poor disease), and subacute sclerosing panencepha- school performance, deterioration of vision, litis were sometimes diagnosed instead of on September 28, 2021 by guest. Protected copyright. CCALD.5

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).

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 Figure 1 The typical scanty scalp hair that can be seen in all phenotypes. This patient onset of neurological symptoms in this pheno- with AMN developed the hair pattern during adolescence. type usually occurs in the third and fourth 6 van Geel, Assies, Wanders, Barth J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

Figure 3 Cerebral T2 weighted MRI of an 8 year old boy Figure 2 A 7 year old boy with CCALD. Until the age of with impaired visual acuity and seizures due to CCALD. 6 years psychomotor development was normal. At the age of The extensive damage inflicted on the occipital 6 impaired auditory discrimination was noted. Shortly periventricular is evident. Three of his therafter his vision became impaired and he developed maternal uncles died before the age of 10, but his mother seizures and a spastic tetraparesis as shown in this had normal VLCFAs in plasma and skin fibroblasts and photograph. He died two years after the onset of somehow had understood that she could not be a neurological symptoms. heterozygote. Retrospectively, his first neurological symptoms consisted of divergent strabism for which he was operated on decade.16 36 Neurological deficits are primarily twice. He died at the age of 10 years (MRI courtesy of Dr EL Mooyaart, University Hospital, Groningen, the due to myelopathy, and to a lesser extent to Netherlands.) neuropathy.42837 Patients gradually develop a spastic paraparesis, often in combination with disturbed vibration sense in the legs and void- indeed. However, we examined a 78 year old ing disturbances. About 50% of men with biochemically aVected man with adrenocortical AMN show mild to moderate cerebral involve- insuYciency who, considering his age, had a normal neurological examination and a normal ment on MRI, and in some the abnormalities http://jnnp.bmj.com/ in white matter may resemble the demyelina- cerebral MRI. tion seen in CCALD; the spinal cord is often atrophic.38 39 Nerve conduction studies and Asymptomatic or presymptomatic patients EMG are compatible with a predominantly Some patients, in particular those identified by axonal, sensorimotor polyneuropathy.40 41 Life family screening, may neither have expectancy is probably normal, unless patients neurological nor endocrinological abnormali- additionally develop cerebral demyelination, or ties, even in the presence of mild cerebral 48 when adrenocortical insuYciency is not recog- involvement as evidenced by MRI or MR on September 28, 2021 by guest. Protected copyright. nised and remains untreated. In many patients spectroscopy.49 Although there is no consensus, with AMN neurological diseases such as we regard these patients as presymptomatic or chronic progressive and asymptomatic, and consider a patient sympto- hereditary spastic paraparesis were initially matic once the neurological examination or diagnosed.52542 neuropsychological tests disclose abnormali- ties. The risk for asymptomatic patients to The “Addison only” phenotype develop neurological symptoms is high. How- Some patients have isolated adrenocortical dys- ever, some patients may remain asymptomatic 50 function (Addison’s disease), manifested by into their 60s. , hypotension, and diVuse or focal bronz- ing of the skin. Laboratory studies in these Atypical presentations patients show raised plasma concentrations of Very rarely, patients with X-ALD display adrenocorticotrophin (ACTH), often in combi- symptoms resembling olivoponto-cerebellar nation with lowered cortisol concentrations in atrophy51–53 or spinocerebellar degeneration.54 plasma, or inadequate cortisol increases after Unilateral neurological deficits do not exclude ACTH stimulation. Several studies have dis- X-ALD.55 It has been suggested that head closed that a variable, though possibly substan- injury can precipitate or accelerate cerebral tial percentage (4% to 63%) of patients with demyelination.55 56 Addison’s disease in fact may have the “Addison Powers and Schaumburg reported that the only” phenotype of X-ALD.24 43–47 The risk for first symptoms of X-ALD may be caused by developing neurological involvement is very high gonadal insuYciency.57 In a series of 26 adult X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy 7 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

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.

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 http://jnnp.bmj.com/ the cervical spinal canal, whereas X-ALD remained unnoticed. Exceptionally, heterozygotes may develop Figure 4 Dramatic metamorphosis of a healthy 6 year old boy into a demented and 62–64 spastic 17 year old adolescent. The initial diagnosis was myoclonus epilepsy, but rapidly progressive cerebral demyelination. retrospectively AdolCALD was diagnosed after one of his cousins had died from CCALD. In an interview with members of an aVected family, we learned that a Dutch girl developed patients with X-ALD, we found four men with bronzing of her skin and neurological symp- only signs of hypogonadism (Assies , et al toms attributable to cerebral demyelination on September 28, 2021 by guest. Protected copyright. unpublished data). and died at the age of 14 years. Overt adrenocortical dysfunction in female 62 65 PHENOTYPIC VARIABILITY AMONG AFFECTED carriers has been reported, but in general 26 KINDREDS adrenocortical function is normal. The scanty In 178 kindreds Moser et al found only cerebral scalp hair in most male patients can also be variants in 30%, only AMN in 20%, and both found in heterozygotes.66 CCALD and AMN in 50%.5 In 15 Dutch kin- dreds, we found only CCALD in 20%, only Epidemiology AMN in 40%, and both cerebral variants and X-ALD is considered by many to be very rare, 16 AMN in 40%. So it is possible that in a fam- although neither prevalence nor incidence are ily with AMN, someone will develop CCALD, exactly known. The disease is found among all and vice versa. Even siblings may have different races and on all continents. For The Nether- 58 59 phenotypes. lands we estimated a frequency of at least one in 100 000 male births, and a prevalence of at 16 17 HETEROZYGOTES least one in 200 000. Surveys in France and As many as 20% to 50% of all heterozygotes in the United States5 showed a similar fre- may show neurological symptoms resembling quency. those of AMN.16 50 The onset usually is in the Aubourg et al24 and Moser et al36 reported in fourth decade, symptoms are milder, and the the early 1990s that the variants dominated by progression is slower than in the patients with cerebral demyelination prevailed (more than AMN. On cerebral MRI abnormalities in white 50% of all cases) in France and the United 8 van Geel, Assies, Wanders, Barth J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

States. We reported that AMN is the predomi- incorporated in the peroxisomal membrane.74 nant phenotype (46% of all cases), at least in Its precise function remains to be determined, The Netherlands.16 Moser et al assumed that but it is somehow involved in the activation of ascertainment bias might have influenced the VLCFAs or the import of these fatty acids into results in previous reports, and that the Dutch .75 phenotypic distribution may be more precise.67 Worldwide, patients with X-ALD have mu- Indeed, the rapidly progressive variants of tations in the X-ALD gene,76–79 by contrast with X-ALD prompt extensive investigations such healthy controls.77 Often, a 2 bp deletion in as cerebral MRI and analysis of VLCFAs, exon 5 is found.77 79 80 So far, no correlation was whereas the more indolent variants such as found between genotype and phenotype.76–79 AMN or the “Addison only” phenotype are An autosomal modifier gene has been often overlooked or misdiagnosed. The thor- suggested,36 81 but so far has not been identi- ough screening of aVected Dutch kindreds has fied. Surprisingly, a variation in phenotypic been facilitated by the small area of The Neth- expression has even been found in mono- erlands, the high density of population, the zygotic twins,82 83 suggesting that non-genetic insurance level of nearly 100%, and the decen- factors may also be involved in the varying tralisation and accessability of healthcare facili- phenotypic expression. ties. Indeed, over the past years the relative fre- quencies of CCALD and AMN in France and Pathological findings the United States are shifting towards the Abnormalities are particularly found in the Dutch percentages (P Aubourg, HW Moser, central and peripheral nervous system, testis, personal communications). and adrenal cortex.42728378485 Characteristic are the lamellar cytoplasmic inclusions in brain Biochemical abnormalities macrophages, Schwann cells, Leydig cells, and In 1976, the first report appeared on the char- adrenocortical cells. These lamellar inclusions acteristic accumulation of saturated un- consist of cholesterol esterified with VLCFAs.8 branched very long chain fatty acids (VL- Postmortem examination in the cerebral CFAs), in particular hexacosanoic acid variants of X-ALD shows widespread periven- (C26:0).7 This accumulation is due to an tricular demyelination and cavitation, most impaired capacity to -oxidise these fatty acids. â severe in the occipital region, with sparing of As very long chain fatty acyl-CoA esters were the U fibres and cerebral cortex, and perivascu- metabolised in peroxisomes, it was reasoned lar lymphocytic infiltrates.28 86 Peripheral nerve that the defect was at the level of the very long abnormalities are uncommon and minimal in chain acyl-CoA synthetase (or ligase). The comparison with the cerebral lesions. -oxidation of VLCFAs occurs exclusively in â In AMN, mainly the spinal cord and, to a peroxisomes.11–13 68 69 lesser extent, peripheral are aVected. Peroxisomes are intracellular organelles that Perivascular lymphocytic infiltrates may be are present in virtually every cell, except for the found, but they are much less prominent than mature erythrocyte.70 71 Their abundance and in CCALD. It is suggested that, by contrast size vary from tissue to tissue: they are promi- with the cerebral variants with their character- nent in liver and kidney, but relatively rare in http://jnnp.bmj.com/ istic severe demyelination, AMN in fact is a the nervous system. The biochemical reactions distal axonopathy with secondary degeneration that occur in peroxisomes are many, the most of myelin in the most distant part of the important being the aforementioned axons.28 â-oxidation of VLCFAs, biosynthesis of plasm- alogens and bile acids, and glyoxylate detoxification.72 Peroxisomal disorders are ten- Pathogenesis tatively subdivided into three distinct groups.73 The accumulation of VLCFAs has long been

In group I, peroxisomal biogenesis is impaired held responsible for damage inflicted to the on September 28, 2021 by guest. Protected copyright. and peroxisomes are virtually absent (for nervous system, testis, and adrenal cortex. An example, and neonatal excess of VLCFAs may be toxic to adrenocor- adrenoleukodystrophy). In group II, peroxi- tical cells.28 The incorporation of abnormal somes are present, but multiple peroxisomal amounts of VLCFA laden lipids in the functions are lost (for example, rhizomelic membranes of cultured human adrenocortical chondrodysplasia punctata). The most fre- cells influenced the response to ACTH quent , X-ALD, belongs stimulation.87 to group III in which only one peroxisomal However, the exact mechanisms by which function is deficient. the nervous system is damaged remain to be unravelled. It is hypothesised that immune Genetics mechanisms are involved in the cerebral In 1981 X-ALD was linked to the long arm of variants of X-ALD: perivascular mononuclear the (Xq28).14 It took 12 years accumulations compatible with a cellular to identify the X-ALD gene.15 It spans 21 kb, immune response are found in active brain contains 10 exons, and encodes a protein of lesions in CCALD and AdolCALD,86 and CSF 745 amino acids with significant homology to examination showed a raised IgG index in the peroxisomal membrane protein PMP-70, about 30% of patients with CCALD and belonging to the “ATP binding casette” super- AdolCALD.27 86 88 A two stage scheme has been family of transporters. Monoclonal antibodies suggested: at first there is degradation of myelin were raised against this X-ALD protein due to its instability by an excess of VLCFAs, (ALDP), and it was shown that the ALDP is followed by an inflammatory reaction that X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy 9 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

destroys the myelin.28 89 By contrast with the Immunofluorescence studies in cultured cerebral variants of X-ALD, inflammatory skin fibroblasts or leucocytes may aid in the infiltrates are scarce in AMN.37 identification heterozygous females, in particu- Thus far there is no evidence that the sever- lar when VLCFA concentrations in plasma and ity of the biochemical defect, as measured by fibroblasts are normal. In 70% to 80% of the the plasma concentration of VLCFAs, ac- aVected kindreds aVected boys and men lack counts for the phenotypic variability.5 How- ALDP immunoreactivity in cultured skin ever, a correlation between impairment of fibroblasts or leucocytes; female carriers in nerve conduction and VLCFAs was recently these kindreds show a mixture of positive and found.41 negative immunoreactivity.79 96 97 Mutational analysis is another option once a certain mutation has been shown in an affected Diagnosis family.76 However, this technique is very The discovery that VLCFAs, particularly laborious, and, to our knowledge, not yet hexacosanoic acid, are raised in cultured skin carried out routinely. fibroblasts,990 plasma,10 erythocytes,91 and leucocytes,92 led to reliable and relatively PRENATAL DIAGNOSIS simple biochemical diagnostic tests becoming Prenatal diagnosis has been performed by available. Most laboratories measure the abso- VLCFA analysis in cultured amniotic fluid lute concentration of C26:0 as well as the 101 102 73 cells and cultured chorionic villus cells. So C24:0/C22:0 and C26:0/C22:0 ratios. DNA far, there have been two reports of false linkage analysis has also been used for postna- 93–95 negative test results of a VLCFA assay in tal and prenatal diagnosis, and after the cultured chorionic villus cells.103 104 DNA link- identification of the X-ALD gene, mutational age analysis with the DXS52 DNA probe is analysis became available. Monoclonal anti- also possible.94 95 Recently, prenatal diagnosis bodies have been raised against ALDP, and by means of mutational analysis was may facilitate the diagnosis in people at 105 79 96 97 reported. risk. False negative and false positive results both have far reaching consequences. In the first a POSTNATAL DIAGNOSIS boy may develop CCALD, and in the second a Biochemical assays pregnancy might be needlessly terminated. In virtually all male patients with X-ALD the Therefore, the most reliable diagnostic proce- plasma concentrations of C26:0 and the dures should be used. Unfortunately, muta- C24:0/C22:0 and C26:0/C22:0 ratios are tional analysis is not yet routinely available. clearly increased: in 0.1% of aVected males the plasma C26:0 is borderline normal or mildly DIAGNOSTIC STRATEGY increased, but the ratios are abnormal.5 In gen- When X-ALD is suspected, the first diagnostic eralised peroxisomal disorders (for example, step consists of analysis of VLCFAs in plasma. the Zellweger syndrome and neonatal adreno- An abnormal test result should always be leukodystrophy) the concentrations of VL- followed by a repeat assay in another sample to

CFAs are raised as well, but both the pattern of exclude problems such as sample mix up. If the http://jnnp.bmj.com/ the VLCFAs and the clinical presentation test results are abnormal and peroxisomal dis- diVer widely from X-ALD. Analysis of VL- orders with neonatal onset are excluded (for CFAs in cultured skin fibroblasts is also example, Zellweger syndrome or neonatal possible.990 In addition, the oxidation rate of adrenoleukodystrophy),106 the patient has a VLCFAs in skin fibroblasts can be measured.13 biochemical defect consistent with X-ALD. We Nevertheless, plasma concentrations of perform VLCFA assays in cultured skin C26:0 at the upper limit of normal, but fibroblasts in all probands and in females at risk

certainly not abnormally increased, have re- for heterozygosity. on September 28, 2021 by guest. Protected copyright. cently been reported in two male patients.98 99 If the patient is the proband, or if a mutation In these patients diagnosis was finally estab- has not yet been shown in a kindred, lished by elevated concentrations of VLCFAs mutational analysis is desirable. The presence in cultured skin fibroblasts, and abnormal of ALDP in skin fibroblasts or leucocytes plasma VLCFA concentrations in one of the should be investigated, as abnormal ALDP mothers. expression on immunoflurescence staining In a study conducted in 96 obligate female may eventually aid in the identification of het- carriers, the combined results of VLCFA con- erozygotes. centrations in plasma and skin fibroblasts were 100 abnormal in 93%. Consequently, about 5% Therapy to 10% of female carriers have false negative After the discovery of increased concentrations test results. This is probably due to the of VLCFAs in blood and other tissues of compensatory function of their non-aVected X patients with X-ALD, several dietary treat- chromosomes. ments were developed. Bone marrow trans- plantation and immunosuppressive therapies Other tests are currently investigated. DNA linkage analysis with the DXS52 marker Before reviewing these, we emphasise that can be used, in particular for the identification the adrenocortical insuYciency, found in most of heterozygotes, when the necessary relatives patients with X-ALD, if left untreated, may be are available, and when it is informative at the lethal. Therefore, the adrenocortical function, X-ALD locus.93 94 either measured by plasma ACTH and cortisol 10 van Geel, Assies, Wanders, Barth J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

concentrations, or by the rise in cortisol after neurological symptoms in asymptomatic ACTH stimulation,107 should be tested in all males. The side eVects encountered have been aVected male patients at regular intervals, relatively mild, and lacking other therapeutic unless they are already on steroid hormone options for asyptomatic or presymptomatic substitution therapy. males, we continue to prescribe the GTO and GTE products to neurologically asymptomatic DIETARY THERAPY patients, and those symptomatic patients al- After the finding that orally administered ready treated who prefer to adhere to the diet. C26:0 reached the brain of a terminally ill We no longer recommend the use of “Loren- patient with CCALD,108 it was reasoned that zo’s oil” to the parents of patients with the VLCFA accumulation was at least in part CCALD, and newly diagnosed diagnosed of dietary origin. However, a diet reducing the patients with AMN, and symptomatic female intake of products rich in VLCFAs failed to carriers. lower plasma concentrations.109 Later, an ex- cess of VLCFA biosynthesis was shown in skin fibroblasts obtained from patients with BONE MARROW TRANSPLANTS X-ALD.110 111 (C18:1), a monoun- Postmortem examinations of the brain of saturated , was shown to competi- patients with the cerebral variants of X-ALD tively inhibit the fatty acid elongation system, have shown perivascular mononuclear infil- 28 86 thus interfering with the biosynthesis of trates compatible with an immune reaction. VLCFAs.111 With the combination of fat This inflammatory reaction has been linked to restriction and oral supplementation with glyc- excess of VLCFAs in myelin lipids in the region eroltrioleate (oleic acid in triglyceride form, or of the brain where demyelination takes 86 89 126 GTO) it was possible to reduce plasmaVLCFA place. On the assumption that brain concentrations by about 50%.112 113 After glyc- macrophages of patients with X-ALD are erol trierucate ( (C22:1) in triglycer- unable to remove and degrade the VLCFAs, ide form, GTE) was added, a dramatic and that the inflammatory reaction is thus con- lowering of the plasma concentration of C26:0 tinued, brain macrophages derived from the was noted: in most patients C26:0 concentra- bone marrow from a donor with normal tions normalised within a month.114 The 4:1 peroxisomal function might halt the cerebral combination of the GTO and GTE oils demyelination. became known as “Lorenzo’s oil”, as a tribute In 1984 the results of the first bone marrow to Lorenzo Odone, a boy with CCALD, whose transplant (BMT) in X-ALD were reported.127 parents helped to develop the dietary A121⁄2 year old boy with cerebral abnormali- treatment.19 Trials with “Lorenzo’s oil” were ties showed no improvement of his clinical sta- started worldwide, and hundreds of patients tus, and died of an adenovirus infection 141 were—and still are—treated. days after transplantation. In 1990 the first Because of the dramatic progression of the reversal of neurological and neuroradiological cerebral variants of X-ALD, the impressive manifestations was reported in an 8 year old biochemical eVect, the relatively few patients, boy with CCALD.128 Six years after BMT he is

and the considerable phenotypic variability, still alive and well: his cerebral MRI, cognitive http://jnnp.bmj.com/ open studies were preferred to randomised, function, and neurological examination are placebo controlled, and double blinded stud- normal, despite mildly raised plasma VLCFAs ies. This has complicated the evaluation of the (P Aubourg, personal communication). eYcacy of the treatment tremendously. Results Worldwide, some 200 bone marrow trans- of the dietary treatment thus far have been dis- plants have been performed in patients with the appointing. “Lorenzo’s oil” did not halt the intention to treat storage diseases, including neurological progression in the cerebral forms CCALD and AdolCALD and other 23 36 115 116 20 of X-ALD. This may be explained by . Apart from the boy pre- on September 28, 2021 by guest. Protected copyright. the failure of the dietary oil to reach the sented by Aubourg in 1990,128 bone marrow brain.117 118 Nevertheless, a retrospective analy- transplantation was shown to reverse or stabilise sis of the eYcacy of Lorenzo’s oil in patients abnormalities on cerebral MRI129 and may result with CCALD indicated that there was slight in stability of mental ability.130 Correction of but significant slowing of progression of symp- increased plasma VLCFAs before transplanta- toms and delay of death.119 In 14 men with tion has been advocated, as this seems to AMN and five symptomatic female carriers, improve the survival of the procedure.20 Analysis “Lorenzo’s oil” failed to induce a neurological by Moser of data supplied by Krivit, Aubourg benefit.120 Furthermore, endocrine function and others, showed that up to January 1996 52 did not improve in five patients with AMN.121 patients underwent a bone marrow transplant On the other hand, side eVects such as throm- (HW Moser, personal communication). Nine- bocytopenia were often found,122–125 fortunately teen patients, mostly those with severe not resulting in a haemorrhagic diathesis. In neurological symptoms, died because of the several Dutch patients, we have found platelet transplant procedure or neurological progres- counts below 40 × 109/l, which increased again sion. The 33 patients who survived in general after the intake of the GTO and GTE products had mild to moderate neurological involvement, was reduced or discontinued. and two thirds of them showed stabilisation or Although no beneficial eVect of “Lorenzo’s improvement after the procedure. According to oil” was noted in patients with neurological Krivit et al the donor may even be a hetero- symptoms thus far, we cannot conclude that zygous sister, and because of new techniques to “Lorenzo’s oil“ does not postpone the onset of purify donor cells, a bone marrow transplant X linked adrenoleukodystrophy: clinical presentation, diagnosis, and therapy 11 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.63.1.4 on 1 July 1997. Downloaded from

should be considered in all instances, even if understanding of the disease has led to several there is no related match.20 therapeutic options. Because a bone marrow transplant may be In addition to the biochemical diagnostic indicated in X-ALD, we perform HLA-typing tests, mutational analysis is possible, and in a family once a patient at risk for developing abnormal ALDP immunoreactivity in skin cerebral demyelination has been identified. In fibroblasts or leucocytes may aid in the identi- The Netherlands,a bone marrow transplant is fication of patients with X-ALD, in particular only performed when a suitable donor, prefer- female carriers. ably an HLA identical sibling, is available and The results of dietary treatment with when cerebral involvement is mild, as may be “Lorenzo’s oil” so far have been disappointing; evidenced by abnormalities on neurological however, neurologically asymptomatic patients and neuropsychological examination. So far, may still benefit. Bone marrow transplants have bone marrow transplants have been given to a therapeutic potential, but should only be per- two Dutch boys, one with progressive demyeli- formed in patients with mild cerebral involve- nation of the corpus callosum, and one with ment who have a suitable donor. It must not be impending cerebral demyelination. There were forgotten that adrenocortical insufficiency may no serious complications, and at one and two be the only manifestation of X-ALD, and that it years after engraftment, their plasma C26:0 has to be treated with steroid hormone substi- concentrations are mildly raised, and both the tution. neurological and neuropsychological examin- Retroviral mediated gene transfer corrected ation are normal. VLCFA metabolism for several months in cul- tured skin fibroblasts obtained from patients 139 OTHER THERAPEUTIC INTERVENTIONS with X-ALD. Therefore, it is hoped—and Plasmapheresis lowered VLCFA concentra- feasible—that in the near future gene therapy tions, but did not alter the progressive may become available for those aVected by this course.131 Clofibrate and L- were not severely disabling and potentially lethal 21 22 eVective.109 disease. Because of the severe inflammatory reaction in the brain of patients with CCALD,86 89 126 there have been several attempts to suppress This report was financially supported by grant 28-1942 from the Praeventiefonds, the Hague, The Netherlands. We thank the this reaction. Immunosuppression with cyclo- patients and their relatives who permitted us to use their photo- phosphamide, alone or in combination with graphs for scientific publications and presentations. We are very grateful to M Vermeulen and J Stam for their critical reading prednisone, failed to prevent neurological pro- and helpful suggestions. gression in CCALD.132 133 There are conflicting reports on the eYcacy of treatment with intravenous immunoglobu- 1 Siemerling E, Creutzfeldt HG. Bronzekrankheit und sclero- lins (IVIgs). An arrest of neurological dysfunc- sierende Encephalomyelitis (DiVuse Sklerose). Archiv für Psychiatrie 1923;68:217–44. tion lasting 18 months was seen in a patient 2 Fanconi A, Prader A, Isler W, Luthy F, Siebenmann R. 134 with AdolCALD. On the other hand, in a Morbus Addison mit X-chromosomaler Vererbung. Hel- vetica Paediatrica Acta 1963;18:480–501. recent report no diVerences were shown 3 Blaw ME. Melanodermic type leukodystrophy (adreno- between the progression of cerebral demyelina- leukodystrophy). In: Vinken PJ, et al. Handbook of clinical http://jnnp.bmj.com/ neurology. Vol 10. 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Fatty acid abnormality in adrenoleu- cebo controlled trial with â-interferon in kodystrophy. J Neurochem 1976;26:851–60. patients withCCALD is now underway in the 8 Johnson AB, Schaumburg HH, Powers JM. Histochemical 137 characteristics of the striated inclusions of adrenoleukodys- United States. Recently German investiga- trophy. J Histochem Cytochem 1976;24:725–30. 9 Moser HW, Moser AB, Kawamura N, et al. tors found neurological deterioration and pro- Adrenoleukodystrophy: elevated C26 fatty acid in cultured gression of cerebral lesions in three boys with skin fibroblasts. Ann Neurol 1980;7:542–9. CCALD despite treatment with -interferon.138 10 Moser HW, Moser AB, Frayer KK, et al. â Adrenoleukodystrophy: increased plasma content of satu- rated very long chain fatty acids. Neurology 1981;31:1241– 6. 11 Singh I, Moser AE, Goldfischer S, Moser HW. 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NEUROLOGICAL STAMP

Georg Agricola (1490-1555) Georg Agricola, a younger contemporary of Paracelsus whose real name was Georg Bauer, and who was born in Saxony, Germany, is often regarded as the father of modern mineralology. He studied philology and then went to Italy where he graduated in medicine in 1525. On returning to Germany he was appointed physician in Joachimsthal, the centre of a rich mining area. Later in 1530 he was appointed historiographer of Prince Maurice of Saxony and in 1533 city physician to Chemnitz, another well known mining town. Here he occupied himself with medical, mathematical, theological, and historical studies, but particularly with mineralology. His greatest work De re metallica was published in 1556 the year after his death. The book has a unique distinction of having been translated and edited in 1912 by Herbert Hoover, President of the United States and his wife, Lou Henry http://jnnp.bmj.com/ Hoover. Agricola acknowledged a very old belief that an emerald worn on an amulet or ring averted epilepsy. He stated that the emerald fights with epilepsy as with a deadly enemy. If the stone was stronger than the disease, it remained whole; if, however, it was conquered by the disease it broke into several parts. Philatelically he was honoured in 1955 on the 400th on September 28, 2021 by guest. Protected copyright. anniversary of his death by East Germany as a mineralolo- gist and scholar (Stanley Gibbons No E240, Scott No 271). L F HAAS