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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 Therapeutische Strategien bei


hereditary disorder due to mutations of the ABCD1 Adrenoleukodystrophie
gene, which encodes a peroxisomal transport protein
necessary for very long-chain fatty acid degradation Zusammenfassung Adrenoleukodystrophie (ALD) ist
(VLCFA). Toxic accumulation thereof is associated eine X-chromosomale Erbkrankheit, die auf Muta-
with a proinflammatory state and eventual cell death tionen des ABCD1-Gens basiert. Dieses codiert für
in multiple tissues. ALD may manifest either as ein peroxisomales Transportprotein, welches zur me-
a fatal, rapidly progressive demyelinating disease in tabolischen Degradation überlangkettiger Fettsäu-
boys and adult men, or as a slowly progressive adult- ren notwendig ist. Bei Dysfunktion können diese
onset long-tract myelopathy along with peripheral akkumulieren und führen zu einem proinflamma-
neuropathy. Our understanding of manifold mecha- torischen Zustand sowie schließlich zum Zelltod in
nisms implicated in the disease pathology is currently vielen Geweben. ALD kann sich bei männlichen Kin-
incomplete, as neither genotype–phenotype corre- dern und Erwachsenen als rasch fortschreitende,
lation nor the trigger for cerebral disease has been tödliche, demyelinisierende Erkrankung der weißen
described. Therapy objectives are therefore broadly Substanz manifestieren oder als langsam fortschrei-
aimed at correcting either the gene mutation or down- tende Myelopathie der langen Bahnen des Rücken-
stream molecular effects, such as oxidative stress. Ad- marks mit peripherer Neuropathie und Beginn im
vancements in disease detection, including the newly Erwachsenenalter. Die molekularen Mechanismen
implemented newborn screening in the US and imag- der Krankheit sind nicht zur Gänze geklärt, da weder
ing modalities, allow for more timely intervention die Genotyp-Phänotyp-Korrelationen noch zerebra-
in the form of hematopoietic stem cell transplanta- le Krankheitsauslöser bekannt sind. Therapieansätze
tion (HSCT), which may only be performed in early konzentrieren sich daher darauf, die Genmutation
cerebral disease states. oder die daraus abgeleiteten molekularen Effekte wie
oxidativen Stress zu kompensieren. Neue Diagnose-
Keywords Leukoencephalopathies · Therapeutics · methoden wie das in den USA neuimplementierte
Demyelinating Diseases · Hematopoietic Stem Cell Neugeborenenscreening oder neuere bildgebende
Transplantation 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
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 219


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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
Fig. 1 Deficiency of ABCD1 peroxisome protein function re- damage, mitochondrial dysfunction, immunological
sults in very long-chain fatty acid (VLCFA) accumulation, which response, and eventual cell death [17]. In adrenocor-
leads to mitochondrial dysfunction, oxidative stress, membrane tical cell culture, a decrease in adrenocorticotropic-
function disruption, demyelination, and cell death hormone(ACTH)-stimulated cortisol release has been
shown [52].
Introduction Brain tissue lesions taken from autopsies sug-
gest microglial involvement in demyelinating lesions,
The disease entity X-linked adrenoleukodystrophy while injections of lysophosphatidylcholine (lyso-PC)
(ALD) was first coined in 1970, referencing ear- (C24:0) into cerebral white matter initiates a simi-
lier associations of adrenocortical insufficiency with lar pattern of microglial activation and concomitant
leukodystrophy [21]. ALD is proposed to have pre- apoptosis [12]. In the spinal cord of the ABCD1-
viously fallen into the loosely defined collective of deficient mouse, dysregulation of oxidative phospho-
demyelinating disorders “Addison-Schilder disease” rylation and mitochondrial function were shown in
[14]. The first unique histological hallmarks de- tandem with protein synthesis and cytokine signaling
scribed lipid and lamellar inclusions in the adrenal pathway dysfunction [45], as indicated in Fig. 1. Lipid
gland, testis, and peripheral nerve [41]. Electron mi- peroxidation is indicated by high levels of N-mal-
croscopic identification of very long-chain fatty acids ondialdehyde-lysine, an end product of lipoxidation,
(VLCFA) within these inclusions [22] confirmed early described as early as 3.5 months of age in the mouse
suspicions of a metabolic disorder concerning both spine, well before neurological or behavioral deficits
brain and adrenal gland. The establishment of VLCFA can be shown [17]. Treatment of ABCD1-deficient
levels as a biomarker for diagnosis and the discovery mice with an antioxidant cocktail containing N-acetyl-
of the responsible ABCD1 gene’s peroxisomal function cysteine, alpha lipoic acid, and alpha tocopherol have
in VLCFA homeostasis [35] have collectivized a host shown a reversal of oxidative damage and locomotor
of divergent phenotypes under the ALD entity [53]. In impairment [29].
light of recent advancements in understanding of the
disease process, this review aims to provide insight to ALD patients may shift between phenotypes
diagnostic, surveillance, and treatment paradigms.
No genotype–phenotype correlation has been de-
ALD is the most common peroxisomal disease scribed in X-ALD: studies of monozygotic twins have
shown different clinical phenotypes between siblings
The ABCD1 gene located on the X chromosome en- [24], more pronounced deletions or frameshift mu-
codes the peroxisomal protein ABCD1 (previously tations may even lead to milder phenotypes [47],
ALDP), an adenosine-triphosphate(ATP)-binding cas- and patients may progress through multiple pheno-
sette (ABC), subfamily D, member 1. ABCD1 is known types [23]. A few mutations do show some residual
to mediate the transport of VLCFA Coenzyme A (CoA) ABCD1 function, which may influence the severity of
esters into the peroxisome for degradation of en- phenotypes [38]: However, the only environmental
dogenous fatty acids [3, 39]. Mutations which lead factor known to induce a phenotypic shift is trau-
to ABCD1 dysfunction result in accumulation of VL- matic brain injury, which may lead to the rapidly
CFAs in the nervous system, adrenal glands, testes, progressive inflammatory form, cerebral ALD (cALD).
and blood of all ALD phenotypes. Most patients ac- Onset of cALD peaks during early childhood in boys
quire the defective ABCD1 allele from one parent; between 4–8 years (30–40% of all males). It is impor-
however, up to 19% of cases report de novo muta- tant to note that prior to disease onset, these children
tions [53, 54]. Estimates of mutation prevalence from develop normally and do not exhibit any neurode-
newly implemented newborn screening programs [43] velopmental issues. The second cALD peak occurs in

220 Therapeutic strategies in adrenoleukodystrophy K


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adolescent or young adult years (approximately 20%), successfully compensated by medication therapy; ul-
with the probability of cALD onset decreasing over timately, however, up to half of male X-ALD patients
time. show mineralocorticoid dysfunction [26]. Whilst an
elevated level of VLCFAs (C26:0 and C24:0) may rep-
Cerebral ALD leads to complete disability within resent standard biomarkers for the diagnosis of ALD,
4 years levels between all male ALD phenotypes are constant.

cALD is a rapidly progressive demyelinating disease, ALD heterozygotes


often initially seen in the corpus callosum progressing
outwards with confluent lesion areas in both hemi- Heterozygote female carriers of the ABCD1 mutation
spheres [28] Imaging of the lesion correlates well with often develop AMN-like symptoms [37]. The inci-
neurologic decline, leading, in most cases to total dence of AMN in heterozygous women is suspected
disability in two years or death within 4 years. Pre- to be up to 65% by the age of 60 [13] and the pre-
sentation in childhood may manifest as behavioral sentation is similar to that of AMN men. Psychiatric
or cognition impairment via declining school perfor- problems are very common in this population. Cere-
mance. Devastating focal neurological deficits also bral ALD is extremely rare in women and is likely due
appear, ranging from motor dysfunction including to skewed X-inactivation [15].
spastic paresis, dysarthria and dysphagia to sensory
agnosia and epilepsy. Patients lose mobility, the ability Diagnosis and newborn screening
to speak and understand language and are ultimately
unable to move or communicate, requiring full time Clinical presentation or magnetic resonance imag-
nursing. Rarely, some well cared for individuals may ing (MRI) abnormalities may lead to suspicion of
remain in this state for many years [13, 34]. ALD. Biochemical testing for elevated plasma VLCFAs
should be performed and, when positive, this shows
Adrenomyeloneuropathy eventually develops in a significantly elevated homogenous distribution, re-
all male patients gardless of phenotype: the total concentration of
C26:0, the ratio of C26:0 to C22:0, or C24:0 to C22:0
Patients who do not develop signs of cerebral disease may be used [53].
will go on to show signs of myelopathy with concor- The development and implementation of newborn
dant axonal peripheral neuropathy shown by elec- screening marks a substantial milestone for ALD [43],
trophysiological testing [50]. In addition to adrenal by ensuring timely diagnosis and consequent moni-
dysfunction, this dying-back axonopathy of the spinal toring of patients. Early detection of cerebral disease
cord, adrenomyeloneuropathy (AMN), manifests in all and early initiation of hormone replacement therapy
male patients, symptoms appearing in the third and to avoid adrenal crises may improve early mortal-
fourth decades of life. These are typically progressive ity. High-throughput screening via C26:0 lysophos-
spastic paraparesis, sensory ataxia, sphincter dysfunc- phatidylcholine assessment from dried blood spots
tion, and impotence, sometimes accompanied by pain and tandem mass spectrometry have been estab-
[34]. Scalp hair is usually thin and sparse, showing lished for newborn screening in the state of New
balding signs at an early age [42]. Among the individu- York in the United States, with similar programs see-
als with AMN, disease severity and rate of progression ing implementation in California, Connecticut, and
is highly variable. At our center, we have followed Massachusetts [51].
several men into their 60s and 70s with very minor
deficits. AMN patients may go on to develop cerebral Imaging studies as disease monitoring tools
disease. One retrospective series showed 20% of AMN
patients developed cALD over a period of 10 years A significant number of neuroimaging studies have
[48]. These individuals show cognitive decline, often been conducted in ALD as measures of disease pro-
initially recognized by families, friends, or work col- gression. MRI findings have been shown to either pre-
leagues, and psychiatric symptoms, which are more date cerebral disease or appear simultaneously with
common in adult cALD and may mimic psychosis and symptomatic onset. T2-weighted hyperintensity of
schizophrenia [18]. Disease progression and neuro- the posterior white matter is the most common pat-
logical decline are similar, albeit slightly slower and tern (80%), while others present with frontal periven-
less well studied as compared to the childhood cere- tricular (5–20%) or projection fiber (5–20%) patterns
bral disease. [28]. A 34-point MRI score was proposed by Loes et al.
in 1994, based on location, extent of involvement,
Other phenotypes and the presence of focal or global atrophy [27], and
is now the gold standard for determining cALD dis-
An Addison-only phenotype may be seen at a young ease severity and viability for the therapeutic option
age before cerebral or myelopathy onset, initially af- of hematopoietic stem cell transplantation (described
fecting only glucocorticoid function which may be later). A very early stage of disease may be a score be-

K Therapeutic strategies in adrenoleukodystrophy 221


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

222 Therapeutic strategies in adrenoleukodystrophy K


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described using these methods. Involvement of the Hematopoietic stem cell transplantation arrests
genu of the corpus callosum suggests that pathologi- cALD progression
cal processes are not confined to the long tracts of the
spinal cord [10]; supporting evidence has been shown An initial attempt at HSCT in the 1980s failed, with
using MRS, which also detected cerebral biochemical retrospective Loes scoring of the patient’s MRI well
abnormalities in AMN patients [9]. above 8. In a second attempt at an earlier stage of
Magnetization transfer-weighted MRI (MTw) allows demyelination, symptoms continued to progress af-
high-resolution quantitative assessment of spinal cord ter HSCT, yet halted after 18 months. Two decades
white matter by analysis of the exchange of radiofre- later, the patient is described as showing regular MRI
quency-irradiated protons between a semisolid pool imaging findings and no clinical signs of AMN [8].
and freely moving fluids. MTw hyperintensities were Currently, HSCT is the gold standard for cALD
shown in the lateral and dorsal column of all AMN with a Loes score below 8, with multiple series con-
patients and were significantly higher than in het- firming arrest of neuroinflammatory demyelination
erozygotes, in whom, in turn, these were significantly some 12 to 18 months after the procedure [2, 30].
higher than in control subjects [16]. Interestingly, this This is believed to be due to the time required for
method has been shown to correlate well with the ex- bone marrow-derived brain microglia to replace their
panded disability status scale (EDSS) and quantita- ABCD1 deficient predecessors [7], although the de-
tive sensory motor function studies [16]. This imag- tailed mechanism is not known. In the ABCD1 mouse
ing methodology has been proposed as an outcome model, HSCT has not been shown to correct total
measure in assessment of therapies in AMN. brain VLCFA levels; however, the model does not
develop cerebral demyelination. While HSCT arrests
Therapeutic approaches demyelination in ALD patients, improvement of mi-
croglial peroxisome function or reduction of VLCFA
Boys diagnosed with ALD should undergo a compre- levels have not been described as a result of HSCT. [7,
hensive clinical evaluation, including genetic coun- 8]. Therefore, whether microglia function is corrected
seling provided for the family. Endocrine evaluation by HSCT has yet to be shown. One limitation of HSCT
is imperative, with serum ACTH and cortisol evalu- in ALD may be ameliorated by timely recognition of
ation recommended every 6 months [51]. Adrenal cerebral involvement following newborn screening di-
monitoring is recommended for patients both with agnosis. In adult cALD, a more subtle demyelination
and without adrenal insufficiency; primal adrenal in- and symptom onset coupled with less frequent MRI
sufficiency monitoring should be appropriate to their follow-up complicates a timely indication for HSCT.
clinical and therapeutic regimen. Adrenal hormone Development of phenotype-specific biomarkers may
therapy should commence if abnormal ACTH or cor- greatly ameliorate the selection process for appro-
tisol levels develop. Patient education and timely de- priate HSCT candidates. Mortality rates in children
tection and management may be lifesaving [43, 46]. (5–20%) [32] and adults (20–40%) with “reasonable”
Surveillance for asymptomatic boys should be es- HLA-matched unrelated donor graft, full myeloab-
pecially vigilant in detecting signs of cerebral disease. lation, and cyclophosphamide and busulfan therapy
Yearly neurological evaluation and brain MRI from are dependent on the severity of disease progression.
6 until 30 months is recommended; thereafter, MRIs Additionally, graft-versus-host disease and prolonged
should be performed every 6 months until age 10 immune deficiency are associated with HSCT. Pa-
and once yearly from 10 to 18 years [51]. Currently, tients with cerebral disease should be recommended
no clear guidelines exist on neuroimaging in adults. for HSCT if the current Loes score is 9 or less and if
However, based on anecdotal reports of successful performance IQ is greater than 80 [30]. It is impor-
hematopoietic stem cell transplantation in adults, tant to note that in a recent series of five patients,
we recommend endocrine and MRI monitoring in who received HSCT up to two decades previously and
asymptomatic adulthood on an annual basis. were followed up, three out of five showed signs of
The only currently available standard therapy is myelopathy in adulthood [49].
hematopoietic stem cell transplantation in boys with
cerebral ALD. There is currently no disease-alter- Lorenzo’s oil
ing treatment to slow or prevent onset of chronic
myelopathy in AMN; the only therapeutic options are Lorenzo’s oil is a combination comprising a 4:1 mix
for symptomatic support. Medication and regular of oleic and erucic acids, which, when combined with
physical therapy may help with progressive spasticity. a fat-restricted diet, normalizes plasma VLCFA levels.
Collecting quantitative data on the natural progres- Lorenzo’s oil was shown to be ineffective in halting
sion of AMN will assist in progression comparisons progression in a series of open-label trials [1], but may
for future clinical trials. 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.

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Gene therapeutic strategies AMN Board in Europe. These involve patient orga-
nizations and, as a platform, aim to facilitate high-
Autologous HSCT may represent a potential alter- quality investigation of unresolved questions. Bench-
native to allogeneic HSCT. Using a lentiviral vector, to-bedside investigation would be facilitated by the
ABCD1-corrected transplanted CD34+ cell (equiva- development of a better mouse model, as the genera-
lents) in knock out mice have shown a replacement tion of translation data for assessing therapy efficacy
of 20–25% of brain microglial cells [5], though the in mouse is limited to myelopathy-related behavioral
mouse model shows no cerebral disease. Two allo- outcomes and biochemical parameters. Investigat-
geneic transplantation candidate patients for whom ing differences between ALD phenotypes may assist
no match was found underwent successful autol- in the development of more adequate biomarkers
ogous HSCT with lentiviral vectors [7]. Here, pe- for the assessment of potential therapies and in un-
ripheral CD34+ cells were collected following gran- derstanding the as yet unknown trigger for cerebral
ulocyte colony-stimulating factor mobilization and disease.
transduced with an HIV-1-based lentiviral vector
Acknowledgements The authors would like to thank the
expressing the human ALD cDNA. Following full Myelin Project, the Brian’s Hope Foundation, and the ALD
myeloablation and busulfan/cyclophosphamide im- families for their continuous support and commitment.
munosuppression, the autologous transplantation
saw hematological recovery after 2 weeks, stabiliza- Conflict of interest B.R. Turk, A.B. Moser, and A. Fatemi de-
clare that they have no competing interests.
tion of corrected ALD protein expression in peripheral
blood granulocytes after 16 months, and demyelina-
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