main topic
Wien Med Wochenschr (2017) 167:219–226
DOI 10.1007/s10354-016-0534-2
Therapeutic strategies in adrenoleukodystrophy
Bela R. Turk · Ann B. Moser · Ali Fatemi
Received: 20 September 2016 / Accepted: 2 December 2016 / Published online: 10 May 2017
© Springer-Verlag Wien 2016
Summary Adrenoleukodystrophy (ALD) is an X-linked
hereditary disorder due to mutations of the ABCD1
gene, which encodes a peroxisomal transport protein
necessary for very long-chain fatty acid degradation
(VLCFA). Toxic accumulation thereof is associated
with a proinflammatory state and eventual cell death
in multiple tissues. ALD may manifest either as
a fatal, rapidly progressive demyelinating disease in
boys and adult men, or as a slowly progressive adult-
onset long-tract myelopathy along with peripheral
neuropathy. Our understanding of manifold mecha-
nisms implicated in the disease pathology is currently
incomplete, as neither genotype–phenotype corre-
lation nor the trigger for cerebral disease has been
described. Therapy objectives are therefore broadly
aimed at correcting either the gene mutation or down-
stream molecular effects, such as oxidative stress. Ad-
vancements in disease detection, including the newly
implemented newborn screening in the US and imag-
ing modalities, allow for more timely intervention
in the form of hematopoietic stem cell transplanta-
tion (HSCT), which may only be performed in early
cerebral disease states.
Keywords Leukoencephalopathies · Therapeutics ·
Demyelinating Diseases · Hematopoietic Stem Cell
Transplantation
B. R. Turk · A. B. Moser · A. Fatemi ()
Kennedy Krieger Institute, Johns Hopkins Medical
Institutions, The Moser Center for Leukodystrophies,
Baltimore, USA
fatemi@kennedykrieger.org
K Therapeutic strategies in adrenoleukodystrophy
Therapeutische Strategien bei
Adrenoleukodystrophie
Zusammenfassung Adrenoleukodystrophie (ALD) ist
eine X-chromosomale Erbkrankheit, die auf Muta-
tionen des ABCD1-Gens basiert. Dieses codiert für
ein peroxisomales Transportprotein, welches zur me-
tabolischen Degradation überlangkettiger Fettsäu-
ren notwendig ist. Bei Dysfunktion können diese
akkumulieren und führen zu einem proinflamma-
torischen Zustand sowie schließlich zum Zelltod in
vielen Geweben. ALD kann sich bei männlichen Kin-
dern und Erwachsenen als rasch fortschreitende,
tödliche, demyelinisierende Erkrankung der weißen
Substanz manifestieren oder als langsam fortschrei-
tende Myelopathie der langen Bahnen des Rücken-
marks mit peripherer Neuropathie und Beginn im
Erwachsenenalter. Die molekularen Mechanismen
der Krankheit sind nicht zur Gänze geklärt, da weder
die Genotyp-Phänotyp-Korrelationen noch zerebra-
le Krankheitsauslöser bekannt sind. Therapieansätze
konzentrieren sich daher darauf, die Genmutation
oder die daraus abgeleiteten molekularen Effekte wie
oxidativen Stress zu kompensieren. Neue Diagnose-
methoden wie das in den USA neuimplementierte
Neugeborenenscreening oder neuere bildgebende
Verfahren erlauben einen frühzeitigeren Therapiebe-
ginn durch hämatopoetische Stammzelltransplanta-
tion, die möglicherweise nur in den Anfangsstadien
der Krankheit durchgeführt werden kann.
Schlüsselwörter Leukoencephalopathien · Thera-
pien · Demyelinisierende Erkrankungen · Hematopoi-
etische Stammzelltransplantation
219
 main topic
Fig. 1 Deficiency of ABCD1 peroxisome protein function re-
sults in very long-chain fatty acid (VLCFA) accumulation, which
leads to mitochondrial dysfunction, oxidative stress, membrane
function disruption, demyelination, and cell death
Introduction
The disease entity X-linked adrenoleukodystrophy
(ALD) was first coined in 1970, referencing ear-
lier associations of adrenocortical insufficiency with
leukodystrophy [21]. ALD is proposed to have pre-
viously fallen into the loosely defined collective of
demyelinating disorders “Addison-Schilder disease”
[14]. The first unique histological hallmarks de-
scribed lipid and lamellar inclusions in the adrenal
gland, testis, and peripheral nerve [41]. Electron mi-
croscopic identification of very long-chain fatty acids
(VLCFA) within these inclusions [22] confirmed early
suspicions of a metabolic disorder concerning both
brain and adrenal gland. The establishment of VLCFA
levels as a biomarker for diagnosis and the discovery
of the responsible ABCD1 gene’s peroxisomal function
in VLCFA homeostasis [35] have collectivized a host
of divergent phenotypes under the ALD entity [53]. In
light of recent advancements in understanding of the
disease process, this review aims to provide insight to
diagnostic, surveillance, and treatment paradigms.
ALD is the most common peroxisomal disease
The ABCD1 gene located on the X chromosome en-
codes the peroxisomal protein ABCD1 (previously
ALDP), an adenosine-triphosphate(ATP)-binding cas-
sette (ABC), subfamily D, member 1. ABCD1 is known
to mediate the transport of VLCFA Coenzyme A (CoA)
esters into the peroxisome for degradation of en-
dogenous fatty acids [3, 39]. Mutations which lead
to ABCD1 dysfunction result in accumulation of VL-
CFAs in the nervous system, adrenal glands, testes,
and blood of all ALD phenotypes. Most patients ac-
quire the defective ABCD1 allele from one parent;
however, up to 19% of cases report de novo muta-
tions [53, 54]. Estimates of mutation prevalence from
newly implemented newborn screening programs [43]
220 Therapeutic strategies in adrenoleukodystrophy
in the United States suggest a rate of 1:15,500 males
(22 ALD males in 340,000 newborns screened to date),
which is higher than previous retrospective large-
scale estimates of hemizygote females at 1:42,000 and
1:16,800 combined male and female [4].
Biochemistry and pathology
VLCFAs are extremely hydrophobic with an extraordi-
narily slow rate of desorption from biological mem-
branes and are thought to cause disruptive effects
on structure, stability, and function when integrated
into cell membranes [34, 40]. In vivo studies have
shown increased levels of oxidative stress in tissues
showing accumulation of VLCFA, leading to protein
damage, mitochondrial dysfunction, immunological
response, and eventual cell death [17]. In adrenocor-
tical cell culture, a decrease in adrenocorticotropic-
hormone(ACTH)-stimulated cortisol release has been
shown [52].
Brain tissue lesions taken from autopsies sug-
gest microglial involvement in demyelinating lesions,
while injections of lysophosphatidylcholine (lyso-PC)
(C24:0) into cerebral white matter initiates a simi-
lar pattern of microglial activation and concomitant
apoptosis [12]. In the spinal cord of the ABCD1-
deficient mouse, dysregulation of oxidative phospho-
rylation and mitochondrial function were shown in
tandem with protein synthesis and cytokine signaling
pathway dysfunction [45], as indicated in Fig. 1. Lipid
peroxidation is indicated by high levels of N-mal-
ondialdehyde-lysine, an end product of lipoxidation,
described as early as 3.5 months of age in the mouse
spine, well before neurological or behavioral deficits
can be shown [17]. Treatment of ABCD1-deficient
mice with an antioxidant cocktail containing N-acetyl-
cysteine, alpha lipoic acid, and alpha tocopherol have
shown a reversal of oxidative damage and locomotor
impairment [29].
ALD patients may shift between phenotypes
No genotype–phenotype correlation has been de-
scribed in X-ALD: studies of monozygotic twins have
shown different clinical phenotypes between siblings
[24], more pronounced deletions or frameshift mu-
tations may even lead to milder phenotypes [47],
and patients may progress through multiple pheno-
types [23]. A few mutations do show some residual
ABCD1 function, which may influence the severity of
phenotypes [38]: However, the only environmental
factor known to induce a phenotypic shift is trau-
matic brain injury, which may lead to the rapidly
progressive inflammatory form, cerebral ALD (cALD).
Onset of cALD peaks during early childhood in boys
between 4–8 years (30–40% of all males). It is impor-
tant to note that prior to disease onset, these children
develop normally and do not exhibit any neurode-
velopmental issues. The second cALD peak occurs in
K

adolescent or young adult years (approximately 20%),
with the probability of cALD onset decreasing over
time.
Cerebral ALD leads to complete disability within
4 years
cALD is a rapidly progressive demyelinating disease,
often initially seen in the corpus callosum progressing
outwards with confluent lesion areas in both hemi-
spheres [28] Imaging of the lesion correlates well with
neurologic decline, leading, in most cases to total
disability in two years or death within 4 years. Pre-
sentation in childhood may manifest as behavioral
or cognition impairment via declining school perfor-
mance. Devastating focal neurological deficits also
appear, ranging from motor dysfunction including
spastic paresis, dysarthria and dysphagia to sensory
agnosia and epilepsy. Patients lose mobility, the ability
to speak and understand language and are ultimately
unable to move or communicate, requiring full time
nursing. Rarely, some well cared for individuals may
remain in this state for many years [13, 34].
Adrenomyeloneuropathy eventually develops in
all male patients
Patients who do not develop signs of cerebral disease
will go on to show signs of myelopathy with concor-
dant axonal peripheral neuropathy shown by elec-
trophysiological testing [50]. In addition to adrenal
dysfunction, this dying-back axonopathy of the spinal
cord, adrenomyeloneuropathy (AMN), manifests in all
male patients, symptoms appearing in the third and
fourth decades of life. These are typically progressive
spastic paraparesis, sensory ataxia, sphincter dysfunc-
tion, and impotence, sometimes accompanied by pain
[34]. Scalp hair is usually thin and sparse, showing
balding signs at an early age [42]. Among the individu-
als with AMN, disease severity and rate of progression
is highly variable. At our center, we have followed
several men into their 60s and 70s with very minor
deficits. AMN patients may go on to develop cerebral
disease. One retrospective series showed 20% of AMN
patients developed cALD over a period of 10 years
[48]. These individuals show cognitive decline, often
initially recognized by families, friends, or work col-
leagues, and psychiatric symptoms, which are more
common in adult cALD and may mimic psychosis and
schizophrenia [18]. Disease progression and neuro-
logical decline are similar, albeit slightly slower and
less well studied as compared to the childhood cere-
bral disease.
Other phenotypes
An Addison-only phenotype may be seen at a young
age before cerebral or myelopathy onset, initially af-
fecting only glucocorticoid function which may be
K Therapeutic strategies in adrenoleukodystrophy
main topic
successfully compensated by medication therapy; ul-
timately, however, up to half of male X-ALD patients
show mineralocorticoid dysfunction [26]. Whilst an
elevated level of VLCFAs (C26:0 and C24:0) may rep-
resent standard biomarkers for the diagnosis of ALD,
levels between all male ALD phenotypes are constant.
ALD heterozygotes
Heterozygote female carriers of the ABCD1 mutation
often develop AMN-like symptoms [37]. The inci-
dence of AMN in heterozygous women is suspected
to be up to 65% by the age of 60 [13] and the pre-
sentation is similar to that of AMN men. Psychiatric
problems are very common in this population. Cere-
bral ALD is extremely rare in women and is likely due
to skewed X-inactivation [15].
Diagnosis and newborn screening
Clinical presentation or magnetic resonance imag-
ing (MRI) abnormalities may lead to suspicion of
ALD. Biochemical testing for elevated plasma VLCFAs
should be performed and, when positive, this shows
a significantly elevated homogenous distribution, re-
gardless of phenotype: the total concentration of
C26:0, the ratio of C26:0 to C22:0, or C24:0 to C22:0
may be used [53].
The development and implementation of newborn
screening marks a substantial milestone for ALD [43],
by ensuring timely diagnosis and consequent moni-
toring of patients. Early detection of cerebral disease
and early initiation of hormone replacement therapy
to avoid adrenal crises may improve early mortal-
ity. High-throughput screening via C26:0 lysophos-
phatidylcholine assessment from dried blood spots
and tandem mass spectrometry have been estab-
lished for newborn screening in the state of New
York in the United States, with similar programs see-
ing implementation in California, Connecticut, and
Massachusetts [51].
Imaging studies as disease monitoring tools
A significant number of neuroimaging studies have
been conducted in ALD as measures of disease pro-
gression. MRI findings have been shown to either pre-
date cerebral disease or appear simultaneously with
symptomatic onset. T2-weighted hyperintensity of
the posterior white matter is the most common pat-
tern (80%), while others present with frontal periven-
tricular (5–20%) or projection fiber (5–20%) patterns
[28]. A 34-point MRI score was proposed by Loes et al.
in 1994, based on location, extent of involvement,
and the presence of focal or global atrophy [27], and
is now the gold standard for determining cALD dis-
ease severity and viability for the therapeutic option
of hematopoietic stem cell transplantation (described
later). A very early stage of disease may be a score be-
221
 main topic

Fig. 2 Cranial MRI of cere-

bral adrenoleukodystrophy.
a shows typical diffuse pos-
terior white matter hyperin-
tensity. b shows gadolinium
contrast agent enhance-
ment borders of the same
lesion. c shows white matter
hyperintensities in the au-
ditory pathway, visual path-
wayandtemporal whitemat-
ter. White arows indicate the
lateral geniculate body and
optic radiation. Black arrow
indicates the brachium of the
inferior colliculus. d shows
white matter hyperinten-
sities in the brain stem and
temporal white matter. Black
arrow indicates lateral lem-
nicus

low 4, early stage between 4 and 8, late stage 9 to 13,
and advanced disease above 13. Loes score, when
combined with the pattern of lesion involvement, age
of the patient, and absence or presence of contrast
enhancement, allows prediction of lesion progression
[28] (Fig. 2).
AMN patients typically show diffuse spinal cord
atrophy, mainly in the thoracic regions (90%), while
a faint bilateral T2 hyperintensity of the corticospinal
tract, up to the level of the capsula interna, is often
seen (80%) [25]. Image findings for heterozygote fe-
male carriers are more heterogeneous, with a series
of 76 patients showing abnormalities consistent with
cerebral ALD in less than 5% [15], which is contrary to
earlier broader electrophysiological methods propos-
ing cerebral processes in 80% of carriers [44].
Contrast agent and advanced imaging tech-
niques as biomarkers
Gadolinium enhancement in MRI studies shows en-
hancement in active lesion zones [31]. Postmortem
studies have correlated these to zones of active de-
myelination, macrophage infiltration, and avid in-
flammatory response [36].
More advanced imaging techniques, such as pro-
ton magnetic resonance spectroscopic (MRS) imaging
and diffusion tensor imaging (DTI), show changes in
metabolite levels and water diffusion parameters [11].
N-acetylaspartate (NAA) is believed to be of neuronal
axonal origin in the mature brain [6], and its decrease
in patients with all ALD phenotypes may be due to ei-
ther axonal loss or dysfunction. Elevated choline lev-
els seen in cerebral ALD are associated with instances
of demyelination. MRS imaging has been able to show
low NAA and high choline levels in white matter as
a first sign of metabolic impairment, preceding MRI
changes in ALD [11].
A high directionality and organization of white
matter, stemming from the directional morphology of
myelinated axons, is quantified by a higher relative
fractional anisotropy (FA) using DTI. A decrease in FA
is shown in central cALD lesion areas [11]. In pure
AMN, occult cerebral abnormalities have also been

222 Therapeutic strategies in adrenoleukodystrophy K


described using these methods. Involvement of the
genu of the corpus callosum suggests that pathologi-
cal processes are not confined to the long tracts of the
spinal cord [10]; supporting evidence has been shown
using MRS, which also detected cerebral biochemical
abnormalities in AMN patients [9].
Magnetization transfer-weighted MRI (MTw) allows
high-resolution quantitative assessment of spinal cord
white matter by analysis of the exchange of radiofre-
quency-irradiated protons between a semisolid pool
and freely moving fluids. MTw hyperintensities were
shown in the lateral and dorsal column of all AMN
patients and were significantly higher than in het-
erozygotes, in whom, in turn, these were significantly
higher than in control subjects [16]. Interestingly, this
method has been shown to correlate well with the ex-
panded disability status scale (EDSS) and quantita-
tive sensory motor function studies [16]. This imag-
ing methodology has been proposed as an outcome
measure in assessment of therapies in AMN.
Therapeutic approaches
Boys diagnosed with ALD should undergo a compre-
hensive clinical evaluation, including genetic coun-
seling provided for the family. Endocrine evaluation
is imperative, with serum ACTH and cortisol evalu-
ation recommended every 6 months [51]. Adrenal
monitoring is recommended for patients both with
and without adrenal insufficiency; primal adrenal in-
sufficiency monitoring should be appropriate to their
clinical and therapeutic regimen. Adrenal hormone
therapy should commence if abnormal ACTH or cor-
tisol levels develop. Patient education and timely de-
tection and management may be lifesaving [43, 46].
Surveillance for asymptomatic boys should be es-
pecially vigilant in detecting signs of cerebral disease.
Yearly neurological evaluation and brain MRI from
6 until 30 months is recommended; thereafter, MRIs
should be performed every 6 months until age 10
and once yearly from 10 to 18 years [51]. Currently,
no clear guidelines exist on neuroimaging in adults.
However, based on anecdotal reports of successful
hematopoietic stem cell transplantation in adults,
we recommend endocrine and MRI monitoring in
asymptomatic adulthood on an annual basis.
The only currently available standard therapy is
hematopoietic stem cell transplantation in boys with
cerebral ALD. There is currently no disease-alter-
ing treatment to slow or prevent onset of chronic
myelopathy in AMN; the only therapeutic options are
for symptomatic support. Medication and regular
physical therapy may help with progressive spasticity.
Collecting quantitative data on the natural progres-
sion of AMN will assist in progression comparisons
for future clinical trials.
K Therapeutic strategies in adrenoleukodystrophy
main topic
Hematopoietic stem cell transplantation arrests
cALD progression
An initial attempt at HSCT in the 1980s failed, with
retrospective Loes scoring of the patient’s MRI well
above 8. In a second attempt at an earlier stage of
demyelination, symptoms continued to progress af-
ter HSCT, yet halted after 18 months. Two decades
later, the patient is described as showing regular MRI
imaging findings and no clinical signs of AMN [8].
Currently, HSCT is the gold standard for cALD
with a Loes score below 8, with multiple series con-
firming arrest of neuroinflammatory demyelination
some 12 to 18 months after the procedure [2, 30].
This is believed to be due to the time required for
bone marrow-derived brain microglia to replace their
ABCD1 deficient predecessors [7], although the de-
tailed mechanism is not known. In the ABCD1 mouse
model, HSCT has not been shown to correct total
brain VLCFA levels; however, the model does not
develop cerebral demyelination. While HSCT arrests
demyelination in ALD patients, improvement of mi-
croglial peroxisome function or reduction of VLCFA
levels have not been described as a result of HSCT. [7,
8]. Therefore, whether microglia function is corrected
by HSCT has yet to be shown. One limitation of HSCT
in ALD may be ameliorated by timely recognition of
cerebral involvement following newborn screening di-
agnosis. In adult cALD, a more subtle demyelination
and symptom onset coupled with less frequent MRI
follow-up complicates a timely indication for HSCT.
Development of phenotype-specific biomarkers may
greatly ameliorate the selection process for appro-
priate HSCT candidates. Mortality rates in children
(5–20%) [32] and adults (20–40%) with “reasonable”
HLA-matched unrelated donor graft, full myeloab-
lation, and cyclophosphamide and busulfan therapy
are dependent on the severity of disease progression.
Additionally, graft-versus-host disease and prolonged
immune deficiency are associated with HSCT. Pa-
tients with cerebral disease should be recommended
for HSCT if the current Loes score is 9 or less and if
performance IQ is greater than 80 [30]. It is impor-
tant to note that in a recent series of five patients,
who received HSCT up to two decades previously and
were followed up, three out of five showed signs of
myelopathy in adulthood [49].
Lorenzo’s oil
Lorenzo’s oil is a combination comprising a 4:1 mix
of oleic and erucic acids, which, when combined with
a fat-restricted diet, normalizes plasma VLCFA levels.
Lorenzo’s oil was shown to be ineffective in halting
progression in a series of open-label trials [1], but may
prevent cerebral disease, as shown in an open-label
study [33]. A larger placebo-controlled trial in men
and women with pure AMN was discontinued due to
adverse reactions in the control group.
223
 main topic
Gene therapeutic strategies
Autologous HSCT may represent a potential alter-
native to allogeneic HSCT. Using a lentiviral vector,
ABCD1-corrected transplanted CD34+ cell (equiva-
lents) in knock out mice have shown a replacement
of 20–25% of brain microglial cells [5], though the
mouse model shows no cerebral disease. Two allo-
geneic transplantation candidate patients for whom
no match was found underwent successful autol-
ogous HSCT with lentiviral vectors [7]. Here, pe-
ripheral CD34+ cells were collected following gran-
ulocyte colony-stimulating factor mobilization and
transduced with an HIV-1-based lentiviral vector
expressing the human ALD cDNA. Following full
myeloablation and busulfan/cyclophosphamide im-
munosuppression, the autologous transplantation
saw hematological recovery after 2 weeks, stabiliza-
tion of corrected ALD protein expression in peripheral
blood granulocytes after 16 months, and demyelina-
tion arrest after 14 months [5].
Newer vectors, such as the recombinant adeno-as-
sociated virus (rAAV) have also seen successful imple-
mentation in ALD gene delivery in vitro and in vivo,
normalizing VLCFA ratios in mouse models both in
brain and spine [20].
Other therapeutics
Anecdotally, a number of AMN patients have reported
improvement of gait and activity with dalfampridine;
however, no systemic studies have been performed in
ALD or AMN.
Exercise therapy is also being investigated in fe-
males with AMN. As of yet, the authors are not aware
of published data indicating a benefit of exercise ther-
apy.
A current trial with antioxidant therapy is ongoing
in Spain, as a reduction of oxidative stress and resul-
tant damage has been shown in the mouse model. No
results are yet available from the human trial.
Thyromimetics have been shown to increase ABCD2
(ALD-related protein) function in vitro [19] and are
currently being discussed as potential therapeutics
for ALD.
Blocking central nervous system (CNS) infiltration
of systemic monocytes using natalizumab has also
been discussed as a potential strategy for cerebral
ALD, yet anecdotal reports from France have failed to
show any benefits.
Future outlook
Newborn screening and improved surveillance meth-
ods will allow earlier detection of cerebral disease
onset and collection of data on natural disease pro-
gression. Compiling and sharing these data between
multiple centers has been facilitated by new con-
sortia; ALD Connect in the USA and the European
224 Therapeutic strategies in adrenoleukodystrophy
AMN Board in Europe. These involve patient orga-
nizations and, as a platform, aim to facilitate high-
quality investigation of unresolved questions. Bench-
to-bedside investigation would be facilitated by the
development of a better mouse model, as the genera-
tion of translation data for assessing therapy efficacy
in mouse is limited to myelopathy-related behavioral
outcomes and biochemical parameters. Investigat-
ing differences between ALD phenotypes may assist
in the development of more adequate biomarkers
for the assessment of potential therapies and in un-
derstanding the as yet unknown trigger for cerebral
disease.
Acknowledgements The authors would like to thank the
Myelin Project, the Brian’s Hope Foundation, and the ALD
families for their continuous support and commitment.
Conflict of interest B.R. Turk, A.B. Moser, and A. Fatemi de-
clare that they have no competing interests.
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