Adrenoleukodystrophy
For the autosomal recessive, neonatal onset disease, see nificantly higher incidence in any specific ethnic groups.
Neonatal adrenoleukodystrophy
Adrenoleukodystrophy (/-ˌlu-koʊ-ˈdis-trə-fiː/; also
known as X-linked adrenoleukodystrophy, ALD,
X-ALD, Siemerling–Creutzfeldt disease or bronze
Schilder disease) is a disease linked to the X chromo-
some. It is a result of fatty acid buildup caused by the
relevant enzymes not functioning properly, which then
causes damage to the myelin sheathes of the nerves,
resulting in seizures and hyperactivity. Other side
effects include problems with speaking, listening and
understanding verbal instructions.
In more detail, it is a disorder of peroxisomal fatty acid
beta oxidation which results in the accumulation of very
long chain fatty acids in tissues throughout the body. The
most severely affected tissues are the myelin in the central
nervous system, the adrenal cortex and the Leydig cells
in the testes. Clinically, ALD is a heterogeneous dis-
order, presenting with several distinct phenotypes, and
no clear pattern of genotype-phenotype correlation. As
an X-linked disorder, ALD presents most commonly in
males, however approximately 50% of heterozygote fe-
males show some symptoms later in life. Approximately
two-thirds of ALD patients will present with the child-
hood cerebral form of the disease, which is the most se-
vere form. It is characterized by normal development
1.1
in early childhood, followed by rapid degeneration to a
vegetative state. The other forms of ALD vary in terms
of onset and clinical severity, ranging from adrenal in-
sufficiency to progressive paraparesis in early adulthood 1.2
(this form of the disease is typically known as adreno-
myeloneuropathy).
ALD is caused by mutations in ABCD1, a gene located
on the X chromosome that codes for ALD, a peroxiso-
mal membrane transporter protein. The exact mechanism
of the pathogenesis of the various forms of ALD is not
known. Biochemically, individuals with ALD show very
high levels of unbranched, saturated, very long chain fatty
acids, particularly cerotic acid (26:0). The level of cerotic
acid in plasma does not correlate with clinical presenta-
tion. Treatment options for ALD are limited. Dietary
treatment is with Lorenzo’s oil. For the childhood cere-
bral form, stem cell transplant and gene therapy are op-
tions if the disease is detected early in the clinical course.
Adrenal insufficiency in ALD patients can be success-
fully treated. ALD is the most common peroxisomal in-
born error of metabolism, with an incidence estimated
between 1:18,000 and 1:50,000. It does not have a sig-
1
1 Signs and symptoms
ALD can present in different ways. The different pre-
sentations are complicated by the pattern of X-linked re-
cessive inheritance. There have been seven phenotypes
described in males with ABCD1 mutations and five in
females.[1] Initial symptoms in boys affected with the
childhood cerebral form of ALD include emotional in-
stability, hyperactivity and disruptive behavior at school.
Older patients affected with the cerebral form will
present with similar symptoms. Untreated, cerebral
ALD is characterized by progressive demyelination lead-
ing to a vegetative state and death.[2] Adult males with
an adrenomyeloneuropathy presentation typically present
initially with muscle stiffness, paraparesis and sexual
dysfunction.[3] All patients with clinically recognized
ALD phenotypes are at risk for adrenal insufficiency.[2]
There is no reliable way to predict which form of the
disease an affected individual will develop, with multiple
phenotypes being demonstrated within families.[4] Onset
of adrenal insufficiency is often the first symptom, ap-
pearing as early as two years of age.[3]
Male adrenoleukodystrophy pheno-
types
Female adrenoleukodystrophy pheno-
types
2 Diagnosis
The clinical presentation of ALD can vary greatly, mak-
ing diagnosis difficult. With the variety of phenotypes,
clinical suspicion of ALD can result from a variety of dif-
ferent presentations. Symptoms vary based on the disease
phenotype, and even within families or between twins.[4]
When ALD is suspected based on clinical symptoms, the
initial testing usually includes plasma very long chain fatty
acid (VLCFA) determination using gas chromatography-
mass spectrometry. The concentration of unsaturated
VLCFA, particularly 26 carbon chains is significantly el-
evated in males with ALD, even prior to the develop-
ment of other symptoms.[5] Confirmation of ALD af-
ter positive plasma VLCFA determination usually in-
volves molecular genetic analysis of ABCD1. In females,
2 5 TREATMENT

where plasma VLCFA measurement is not always con- typically avoid the most severe manifestations of the dis-
clusive (some female carriers will have normal VLCFA ease, but often become symptomatic later in life.[1] Al-
in plasma),[5] molecular analysis is preferred, particularly though, the detection of an ABCD1 mutation identifies an
in cases where the mutation in the family is known.[1][3] individual who is affected with a form of ALD, however
Although the clinical phenotype is highly variable among there is no genotype - phenotype correlation.[12] Within a
affected males, the elevations of VLCFA are present in family, there will often be several different phenotypes,
all males with an ABCD1 mutation.[3] despite the presence of the same causative mutation. In
Because the characteristic elevations associated with one case, a family with six affected members displayed
five different phenotypes.[1] There are no common mu-
ALD are present at birth, well before any symptoms are
apparent, there have been methods developed[6][7] in the tations that cause ALD, most are private or familial. Al-
most 600[3] different mutations have been identified, ap-
interests of including it in newborn screening programs.[8]
One of the difficulties with ALD as a disease included proximately half are missense mutations, one quarter are
frameshifts, with in-frame deletions and splicing defects
in universal newborn screening is the difficulty in pre-
dicting the eventual phenotype that an individual will ex- making up the remainder.[1] The incidence of new muta-
press. The accepted treatment for affected boys present- tions in ALD (those occurring spontaneously, rather than
ing with the cerebral childhood form of the disease is a being inherited from a carrier parent) is estimated at ap-
bone marrow transplant, a procedure which carries signif- proximately 4.1%, with the possibility that these are due
icant risks.[2][9] However, because most affected males to germline mosaicism.[3]
will demonstrate adrenal insufficiency, early discovery
and treatment of this symptom could potentially prevent
complications and allow these patients to be monitored 4 Pathogenesis
for other treatment in the future, depending on the pro-
gression of their disease.[8] The exact cause for the varied collection of symptoms
The Loes score is a rating of the severity of abnormal- found in the different ALD phenotypes is not clear. The
ities in the brain found on MRI. It ranges from 0 to 34, white matter of the brain, the Leydig cells of the testes
based on a point system derived from the location and ex- and the adrenal cortex are the most severely affected
[1]
tent of disease and the presence of atrophy in the brain, systems. The excess VLCFA can be detected in al-
either localized to specific points or generally through- most all tissues of the body, despite the localization of
[1]
out the brain. A Loes score of 0.5 or less is classified symptoms. Successful treatment of the demyelination
as normal, while a Loes score of 14 or greater is consid- process that affects the brain with either stem cell trans-
ered severe. It was developed by neuroradiologist Daniel plant or gene therapy does not immediately normalize
[9]
J. Loes MD and is an important tool in assessing disease the VLCFA levels in body tissues. The levels of VL-
progression and the effectiveness of therapy. [10] CFA can be normalized by treatment with Lorenzo’s oil,
but this does not alter the progression of the disease.[2]
It is unclear whether the accumulation of VLCFA is as-
sociated with the pathogenesis of the disease in a spe-
3 Genetics cific way, or if it is a biochemical phenotype, useful for
identification.[1]
Xq28
ABCD1 gene in
X-chromosome 5 Treatment
Xq21.31
Xp22.32

Xp11.22
Xp22.12
Xp21.1

Xq13.2

Xq22.2

Xq27.1
Xq25

5.1 Dietary therapy

Xq21.33
Xq21.1
Xp11.3
Xp22.2

Xp21.3

Xq27.3
Xq26.2
Xq12

Xq23

Initial attempts at dietary therapy in ALD involved re-

stricting the intake of very-long chain fatty acids (VL-
CFA). Dietary intake is not the only source for VLCFA in
the body, as they are also synthesized endogenously. This
ALD is caused by mutations in ABCD1, located at dietary restriction did not impact the levels of VLCFA
Xq28 and demonstrates X-linked recessive inheritance. in plasma and other body tissues.[2] After the realization
The gene ABCD1 encodes a peroxisomal membrane that endogenous synthesis was an important contribution
transporter which is responsible for transporting very to VLCFA in the body, efforts at dietary therapy shifted
long chain fatty acid substrate into the peroxisomes for to inhibiting these synthetic pathways in the body. The
degradation.[11] Mutations in this gene that interfere with parents of Lorenzo Odone, a boy with ALD, spearheaded
this process cause this syndrome. efforts to develop a dietary treatment to slow the progres-
Males with an ABCD1 mutation are hemizygous, as they sion of the disease. They developed a mixture of unsatu-
only have a single X chromosome. Female carriers will rated fatty acids (glycerol trioleate and glyceryl trierucate

in a 4:1 ratio), known as Lorenzo’s oil that inhibits elon-
gation of saturated fatty acids in the body.[2][9] Supple-
mentation with Lorenzo’s oil has been found to normalize
the VLCFA concentrations in the body, although its ef-
fectiveness at treating the cerebral manifestations of the
disease is still controversial and unproven.[13] Trials with
Lorenzo’s oil have shown that it does not stop the neuro-
logical degradation in symptomatic patients, nor does it
improve adrenal function.[2]
5.2 Transplant
While dietary therapy has been shown to be effective
to normalize the very-long chain fatty acid concentra-
tions in the plasma of individuals with ALD, allogeneic
hematopoietic stem cell transplants are the only treatment
that can stop the demyelination that is the hallmark of
the cerebral forms of the disease.[9] In order to be ef-
fective, the transplant must be done at an early stage of
the disease; if the demyelination has progressed, trans-
plant can worsen the outcome, and increase the rate of de-
cline. While transplants have been shown to be effective
at halting the demyelination process in those presenting
with the childhood cerebral form of ALD, follow-up of
these patients has shown that it does not improve adrenal
function.[14]
5.3 Gene therapy
For patients where an appropriate match for a transplant
cannot be found, there have been investigations into the
use of gene therapy. Appropriate vectors are selected
and modified to express wild type ABCD1, which is then
transplanted into the patients using a similar procedure as
for a bone marrow or stem cell transplant.[9] Gene therapy
has only been tried on a small number of patients, mainly
in France. These patients were only considered for gene
therapy after there was no HLA match for a traditional
transplant. In two reported cases, the gene therapy was
successful, with a resolution of the demyelination pro-
cess up to two years after the procedure. Although the
gene therapy was successful in resolving the neurological
symptoms, plasma VLCFA levels remained elevated.[9]
5.4 Adrenal insufficiency
Treatment of the adrenal insufficiency that can accom-
pany any of the common male phenotypes of ALD does
not resolve any of the neurological symptoms. Hormone
replacement is standard for ALD patients demonstrating
adrenal insufficiency.[15] Adrenal insufficiency does not
resolve with successful transplant; most patients still re-
quire hormone replacement.[14]
3
6 Epidemiology
ALD has not been shown to have an increased incidence
in any specific country or ethnic group. In the United
States, the incidence of affected males is estimated at
1:21,000. Overall incidence of hemizygous males and
carrier females is estimated at 1:16,800.[3] The reported
incidence in France is estimated at 1:22,000.[1]
7 See also
• Lorenzo’s Oil
8 References
[1] Moser, Hugo W.; Smith, Kirby D.; Watkins, Paul A.;
Powers, James; Moser, Ann (2001). “131. X-Linked
Adrenoleukodystrophy”. In Scriver, C.W.; Beaudet, A.L.;
Sly, W.S.; Valle, D.; Childs, B.; Kinzler, K.W.; Vogel-
stein, B. Metabolic and Molecular Bases of Inherited Dis-
ease. 2 (8th ed.). New York: McGraw Hill. ISBN 0-07-
136320-3.
[2] Berger, J.; Gärtner, J. (2006). “X-linked adrenoleukodys-
trophy: Clinical, biochemical and pathogenetic
aspects”. Biochimica et Biophysica Acta (BBA) -
Molecular Cell Research. 1763 (12): 1721–32.
doi:10.1016/j.bbamcr.2006.07.010. PMID 16949688.
[3] Steinberg, S. J.; Moser, A. B.; Raymond, G. V.; Pagon,
R. A.; Bird, T. D.; Dolan, C. R.; Stephens, K.; Adam,
M. P. (1993). “X-Linked Adrenoleukodystrophy”. PMID
20301491.
[4] "#300100 - Adrenoleukodystrophy”. Johns Hopkins Uni-
versity. Retrieved 2012-06-27.
[5] Moser, A. B.; Kreiter, N.; Bezman, L.; Lu, S.;
Raymond, G. V.; Naidu, S.; Moser, H. W. (1999).
“Plasma very long chain fatty acids in 3,000 peroxi-
some disease patients and 29,000 controls”. Annals
of Neurology. 45 (1): 100–110. doi:10.1002/1531-
8249(199901)45:1<100::aid-art16>3.0.co;2-u. PMID
9894883.
[6] Sandlers, Y.; Moser, A. B.; Hubbard, W. C.; Kratz, L.
E.; Jones, R. O.; Raymond, G. V. (2012). “Combined
extraction of acyl carnitines and 26:0 lysophosphatidyl-
choline from dried blood spots: Prospective newborn
screening for X-linked adrenoleukodystrophy”. Molec-
ular Genetics and Metabolism. 105 (3): 416–420.
doi:10.1016/j.ymgme.2011.11.195. PMID 22197596.
[7] Hubbard, W. C.; Moser, A. B.; Liu, A. C.; Jones,
R. O.; Steinberg, S. J.; Lorey, F.; Panny, S. R.;
Vogt Jr, R. F.; MacAya, D.; Turgeon, C. T.; Tor-
torelli, S.; Raymond, G. V. (2009). “Newborn screen-
ing for X-linked adrenoleukodystrophy (X-ALD): Val-
idation of a combined liquid chromatography–tandem
4 9 EXTERNAL LINKS

mass spectrometric (LC–MS/MS) method”. Molec- • Adrenoleukodystrophy at DMOZ

ular Genetics and Metabolism. 97 (3): 212–220.
doi:10.1016/j.ymgme.2009.03.010. PMID 19423374. • adrenoleukodystrophy at NINDS

[8] Raymond, G. V.; Jones, R. O.; Moser, A. B. (2007). • Images of ALD at USUHS
“Newborn screening for adrenoleukodystrophy: Implica-
tions for therapy”. Molecular diagnosis & therapy. 11 (6): • Adrenoleukodystrophy at National Center for
381–384. doi:10.1007/BF03256261. PMID 18078355. Biotechnology Information

[9] Cartier, N.; Aubourg, P. (2009). “Hematopoietic Stem

Cell Transplantation and Hematopoietic Stem Cell Gene
Therapy in X-Linked Adrenoleukodystrophy”. Brain
Pathology. 20 (4): 857–862. doi:10.1111/j.1750-
3639.2010.00394.x. PMID 20626747.

[10] Loes, Daniel J.; Hite, S; Moser, H; Stillman, A E; Shapiro,

E; Lockman, L; Latchaw, R E; Krivit, W (October 1994).
“Adrenoleukodystrophy: a scoring method for brain MR
observations”. American Journal of Neuroradiology. 15
(9): 1761–1766. PMID 7847225. Retrieved January 17,
2013.

[11] Hung KL, Wang JS, Keng WT, Chen HJ, Liang
JS, Ngu LH, Lu JF (2013). “Mutational analy-
ses on X-linked adrenoleukodystrophy reveal a novel
cryptic splicing and three missense mutations in the
ABCD1 gene”. Pediatr Neurol. 49: 185–190.
doi:10.1016/j.pediatrneurol.2013.04.021.

[12] Smith, K. D.; Kemp, S.; Braiterman, L. T.; Lu, J.

F.; Wei, H. M.; Geraghty, M.; Stetten, G.; Bergin,
J. S.; Pevsner, J.; Watkins, P. A. (1999). “X-linked
adrenoleukodystrophy: Genes, mutations, and pheno-
types”. Neurochemical research. 24 (4): 521–535.
doi:10.1023/A:1022535930009. PMID 10227685.

[13] Moser, H. W.; Moser, A. B.; Hollandsworth, K.; Brere-

ton, N. H.; Raymond, G. V. (2007). ""Lorenzo’s oil” ther-
apy for X-linked adrenoleukodystrophy: Rationale and
current assessment of efficacy”. Journal of molecular neu-
roscience : MN. 33 (1): 105–113. doi:10.1007/s12031-
007-0041-4. PMID 17901554.

[14] Petryk, A.; Polgreen, L. E.; Chahla, S.; Miller, W.; Or-
chard, P. J. (2012). “No evidence for the reversal of
adrenal failure after hematopoietic cell transplantation in
X-linked adrenoleukodystrophy”. Bone Marrow Trans-
plantation. 47 (10): 1377–8. doi:10.1038/bmt.2012.33.
PMID 22388279.

[15] Poll-The, B.; Engelen, M. (2012). “Peroxisomal

Leukoencephalopathy”. Seminars in Neurology. 32 (1):
42–50. doi:10.1055/s-0032-1306385. PMID 22422205.

9 External links
• ALD Life
• European Leukodystrophy Foundation
• Fight ALD
• March of Dimes Foundation
• United Leukodystrophy Foundation
 5

10 Text and image sources, contributors, and licenses

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• Adrenoleukodystrophy Source: https://en.wikipedia.org/wiki/Adrenoleukodystrophy?oldid=748277071 Contributors: Mav, Timo
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