Handbook of Clinical Neurology, Vol.

204 (3rd series)

Inherited White Matter Disorders and Their Mimics
D.S. Lynch and H. Houlden, Editors
https://doi.org/10.1016/B978-0-323-99209-1.00022-3
Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.

Chapter 8

Adrenoleukodystrophy
MARC ENGELEN1,2⁎, STEPHAN KEMP3, AND FLORIAN EICHLER4

1
Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children’s Hospital, Amsterdam UMC,
Vrije Universiteit, Amsterdam, The Netherlands
2
Amsterdam Neuroscience, Cellular & Molecular Mechanisms, Vrije Universiteit, Amsterdam, The Netherlands
3
Laboratory for Genetic Metabolic Diseases, Department of Clinical Chemistry, Amsterdam University Medical Centers,
University of Amsterdam, Amsterdam, The Netherlands
4
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States

Abstract
X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder caused by mutations in the ABCD1 gene
and characterized by impaired very long-chain fatty acid beta-oxidation. Clinically, male patients develop
adrenal failure and progressive myelopathy in adulthood, although the age of onset and rate of progression
are highly variable. In addition, 40% of male patients develop a leukodystrophy (cerebral ALD) before the
age of 18 years. Women with ALD also develop myelopathy, but generally at a later age than men and with
slower progression. Adrenal failure and leukodystrophy are exceedingly rare in women. Allogeneic hema-
topoietic cell transplantation (HCT), or more recently autologous HCT with ex vivo lentivirally transfected
bone marrow, halts the leukodystrophy. Unfortunately, there is no curative treatment for the myelopathy.
In this chapter, clinical spectrum of ALD is discussed in detail.

et al., 1964). Based on these observations, Blaw sug-

INTRODUCTION
gested the possibility of an inborn error of metabolism
In medicine, it is easy to forget the work done by previous and introduced the descriptive term “melanodermic type
generations. Many disease entities were already described leukodystrophy” or “adrenoleukodystrophy” (Blaw et al.,
and classified in the 19th and 20th centuries, long before 1964; Blaw, 1970). More than a decade later, it was found
the pathophysiology or the underlying genetic cause was that ALD was indeed a metabolic disorder characterized
identified. Adrenoleukodystrophy (ALD) is no exception, by the accumulation of saturated very long-chain fatty
and reports of the first cases can be identified in papers acids (VLCFAs; C22), mostly C26:0 (Igarashi et al.,
from the late 19th and early 20th centuries (Heubner, 1976). ALD could therefore be classified as one of
1897; Ceni, 1899; Haberfeld and Spieler, 1910). These the peroxisomal disorders, specifically a single-enzyme
initial reports concern the most severe end of the clinical deficiency causing impaired VLCFA beta-oxidation
spectrum and described boys with progressive and fatal (Singh et al., 1981). The identification of a diagnostic
leukodystrophy, while the association with adrenal biomarker (lipid inclusions in tissue from patients and
failure was also noted (Siemerling and Creutzfeldt, later plasma total C26:0 and C26/C22 ratio) meant
1922), but considered coincidental. In the 1960s, more many more cases were reported and an expansion
observations were published on the occurrence of of the clinical spectrum to include adult-onset patients
adrenal failure and leukodystrophy in boys, and analysis with spinal cord disease but no leukodystrophy
of affected families suggested an X-linked inheritance (Budka et al., 1976; Schaumburg et al., 1977). This chapter
pattern (Fanconi et al., 1963; Blaw et al., 1964; Dubois describes available diagnostic tests and the clinical
⁎
Correspondence to: Marc Engelen, MD, PhD, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands. Tel: +31-20-7329167,
E-mail: [email protected]
134 M. ENGELEN ET AL.
features of ALD as currently understood. The pathology of severity in affected individuals, as reviewed by Engelen
ALD is reviewed in detail elsewhere in the Handbook of and Kemp (Engelen et al., 2012; Kemp et al., 2016).
Clinical Neurology (Volume 182, Chapter 18). Although ALD was traditionally described as presenting
with different “phenotypes,” it is more correct to view it
DIAGNOSING as a progressive neurodegenerative disorder in which
ADRENOLEUKODYSTROPHY symptoms become apparent and worsen over a lifetime
(Kemp et al., 2016). Separating distinct phenotypes
In 1976, it became apparent that ALD is characterized by
can be considered somewhat misleading, since this
accumulation of saturated VLCFAs, and a diagnostic test
suggests a static disease while patients often move from
was developed, i.e., a plasma VLCFA assay (total C26:0
one phenotype to another. For instance, “Addison-only”
and C26:0/C22:0 ratio) (Moser et al., 1981). Plasma
patients will also develop spinal cord disease and remain
VLCFAs are always abnormal in boys and men with
susceptible to convert to cerebral ALD (Geel et al., 2001;
ALD, but only in about 85% of women with ALD
de Beer et al., 2014; Kemp et al., 2016).
(Moser et al., 1999; Engelen et al., 2014). False-positive
measurements are possible in nonfasted plasma samples.
More recently, C26:0-lysophosphatidylcholine (C26:0- Adrenal failure in ALD
LPC) in dried blood spots showed superior sensitivity Adrenal failure is common in boys and men with ALD
for confirming ALD in women (Huffnagel et al., 2017) and often symptoms of adrenal failure are the first symp-
and more recently plasma (Jaspers et al., 2020). It might toms (Moser et al., 2000; Huffnagel et al., 2018b). About
also be less susceptible to dietary fluctuations and may 60% of male patients develop adrenocortical insuffi-
therefore show fewer false-positive results, but this still ciency before the age of 18 years, and lifetime prevalence
requires formal evaluation. Mutation analysis of the is estimated to be about 80% (Huffnagel et al., 2018b).
ABCD1 gene remains the gold standard for diagnosis, There are therefore patients who will not develop clinical
and more than 1300 unique mutations have been reported adrenal failure, and it seems that patients who have nor-
(http://www.adrenoleukodystrophy.info/). In the age of mal adrenal failure at the age of 45 years are at low risk to
whole exome sequencing, and more recently newborn develop this symptom. Adrenocortical failure has been
screening (NBS), it now happens that variants of described in women with ALD but is rare (el-Deiry
unknown significance (VUS) in ABCD1 are detected et al., 1997).
in very young individuals. Functional assays in skin
fibroblasts can be informative in these cases, although Testicular failure in ALD
some variants that cause slightly abnormal biochemistry
between the control and ALD range are difficult to Although there are extensive histopathologic changes in
classify (van de Stadt et al., 2021). the testes of affected men (Powers and Schaumburg,
In case a VUS is identified in a woman and no male 1981) and endocrinological abnormalities have been
probands are available for analysis, this can be especially described during life (with increased levels of follicle-
challenging, but recently a technique was described for stimulating hormone [FSH] and luteinizing hormone
this situation (Schackmann et al., 2016). In the United [LH] and decreased levels of testosterone), virtually all
States, NBS for ALD has been implemented in several men with ALD develop normal sexual characteristics
states (Kemper et al., 2017), based on the detection of (Assies et al., 1997). It is therefore debatable how clini-
increased C26:0-lysoPC in dried blood spots (Hubbard cally relevant these changes are. There is some literature
et al., 2009). The Netherlands followed in 2023, and on erectile dysfunction in men with ALD, but this is
more countries are considering expanding their NBS pro- usually caused by myelopathy and not low testosterone
grams with ALD (Albersen et al., 2023). Of note, in the (van der Stadt et al., manuscript submitted). The fact that
United States, both male and female infants are screened, fertility is generally not affected in men with ALD would
while in the Netherlands the choice was made to identify support this observation.
only male patients, because only male patients develop
treatable complications in childhood. Ethical consider- The leukodystrophy of ALD
ations and a proposal for follow-up if NBS screening is
The earliest descriptions of ALD are boys affected by the
positive for ALD are extensively discussed by Barendsen
leukodystrophy of ALD (cerebral ALD) (for instance,
and coauthors (Albersen et al., 2023).
Haberfeld and Spieler, 1910). Onset has never been
described before the age of 2 years and seems to peak
CLINICAL FEATURES OF
in boys of elementary school age (Moser et al., 2000).
ADRENOLEUKODYSTROPHY
Over the past decades, it has become clear that adult
The study of the natural history of ALD over recent men can also develop cerebral ALD (Geel et al., 2001;
decades has revealed an enormous spectrum of disease de Beer et al., 2014). It has been estimated that
 ADRENOLEUKODYSTROPHY 135
2021). Symptoms are initially nonspecific (with behavioral
changes causing difficulty at school or work) that in the
absence of an ALD family history are often considered
due to ADHD or other psychiatric disorders. As lesions
progress, focal deficits become more manifest, such as
pyramidal tract signs, central visual deficits, auditory
agnosia, and more. Epileptic seizures can occur in
advanced disease but generally are not as prominent as
in neurodegenerative gray matter diseases. Eventually,
patients become bedridden and require gastrostomy tube
feeding. Death occurs 2–3 years after symptom onset
due to complications like pneumonia (Moser et al.,
2000). Although cerebral ALD has been described in
women, it is exceedingly rare (see for instance, Powers
et al., 1987).

The spinal cord disease and peripheral

neuropathy of ALD
The onset of the spinal cord disease of ALD is highly
variable but is rare before the third decade of life in
men and the fifth decade of life in women (Engelen
et al., 2014). Penetrance is virtually 100% in men, and
Fig. 8.1. MRI scan of the leukodystrophy of ALD. Typical is a
90% in women (Engelen et al., 2014; Huffnagel et al.,
lesion originating in the splenium of the corpus callosum,
2018a, 2019), but age of onset and rate of progression
extending in the parieto-occipital white matter. Progressive
lesions show gadolinium enhancement just beyond the leading are highly variable. Symptoms progress over years (men)
edge of the lesion. In the top row T2-weighted image of an or even decades women (Huffnagel et al., 2018a, 2019).
early lesion (left) and advanced lesion (right). In the bottom Although symptoms are of course not specific to ALD,
row corresponding T1-weighted images after administration a few points can be made. Signs of dorsal column dys-
of gadolinium. As is apparent in the bottom left image gadolin- function are an early sign, and vibration sense in the
ium enhancement can be subtle. hallux is diminished or absent on neurologic examination
often before patients experience clear symptoms.
Sensory ataxia is a major component of the gait disorder.
30%–40% of male patients develop cerebral ALD before
Signs of pyramidal tract dysfunction are prominent later
the age of 18 years and that the lifetime prevalence of
in the disease course, with spasticity and paresis (Budka
cerebral ALD is about 60% (de Beer et al., 2014) (Fig.
et al., 1976; Schaumburg et al., 1977). Urinary urge
8.1). It is not known what determines the occurrence
incontinence usually occurs (progressing to complete
of cerebral ALD in some patients but not others
bladder dysfunction), as well as fecal incontinence (for
(Kemp et al., 2016). It is likely that this is determined
unclear reasons, this seems to affect women more than
by both (largely unknown) modifier genes and epige-
men) (Engelen et al., 2014). Another striking clinical fea-
netic/environmental factors (Richmond et al., 2020).
ture in men is thin hair and early balding, sometimes
For instance, it is well documented that (severe) head
already in the third decade, but this has not been exten-
trauma can precipitate the onset of cerebral ALD, as well
sively studied.
as stroke (Raymond et al., 2010; de Beer et al., 2014).
Cerebral lesions detectable on MRI of the brain precede
TREATMENT OF ALD
the onset of symptoms by months or maybe even a year
(Liberato et al., 2019). Lesions on MRI are quantified Although the first attempts in the 1980s were not
with the Loes scoring system, ranging from 0 (no encouraging, allogeneic hematopoietic cell transplanta-
ALD-related abnormalities) to a maximum of 34 (Loes tion (HCT) is now an established treatment option for
et al., 1994). Usually, the disease course of cerebral cerebral ALD (Miller et al., 2011). However, after suc-
ALD is relentlessly progressive over months to years. cessful transplantation, lesions progress for 6–12 months
However, brain lesions can also spontaneously halt, and before stabilizing (Miller et al., 2011). This means that
the prevalence of arrested cerebral ALD is recently esti- the outcome is poor unless performed in an early stage
mated to be 12.4% of cases of cerebral ALD (Mallack with a low lesion load. It is generally accepted that in
et al., 2020). However, arrested lesions can re-activate advanced cases, with a Loes score of 9 or higher, HCT
and progress again, even after many years (Carlson et al., is no longer an option (Miller et al., 2011). More recent
136 M. ENGELEN ET AL.
studies suggest that even with a Loes score of 4.5 or is significantly shortened. However, boys and men
higher, cognitive outcome is poor (Pierpont et al., who are diagnosed in a presymptomatic stage (either
2018). The pattern of MRI abnormalities (frontal vs because of positive family history or NBS) can choose
occipital) also affects the outcome (Gupta et al., 2021). to be monitored for these complications and have a very
It is now well established that HCT is also effective in high probability of reaching adulthood in excellent
adults with cerebral ALD. Like in children, the prognosis clinical condition. Although all men develop myelopathy
is better with low Loes scores. In addition, it should only in adulthood, life expectancy does not seem to be signif-
be considered in those without severe myelopathy (i.e., icantly reduced (personal observation), unless cerebral
ambulatory and no indwelling urinary catheter) because ALD develops in males with severe myelopathy not
otherwise transplant-related mortality is very high (K€ uhl eligible for HCT (Kemp et al., 2016). Women with
et al., 2017). Unfortunately, those without a family ALD are considered to have a normal life expectancy,
history of ALD—that are diagnosed based on signs or although this has not been formally studied (personal
symptoms of cerebral ALD—are usually too advanced observation).
to be eligible for HCT. For this reason, NBS is being
implemented in the United States and other countries CONCLUSIONS
(Kemper et al., 2017; Albersen et al., 2023). Although
The clinical spectrum and natural history of ALD are
the major reason for screening is to identify boys at risk
now well described, but many questions remain about
for cerebral ALD, an added benefit is the possibility to
the exact pathophysiology. Although the genetic and
also monitor for the onset of adrenal failure. The latter
resulting biochemical defect were identified decades
has been challenging without screening as presenting
ago, it is still not well understood how VLCFA accumu-
symptoms are not specific and poorly recognized
lation causes degeneration of the adrenals, the long tracts
(Eng and Regelmann, 2019). As stated previously,
in the spinal cord, and leukodystrophy in a subset of
symptoms develop only when the lesion load is already
patients. Some pieces of the puzzle have been solved,
relatively high. Since at this time onset of cerebral
but a unifying theory still eludes us. Fortunately, great
lesions cannot be predicted, affected boys undergo reg-
strides are being made in clinical trial readiness and gene
ular follow-ups with MRI scans (Engelen et al., 2022).
therapy treatment is being planned in the next few years,
Considering the still considerable morbidity and
which could mean treatment is on the horizon even
mortality associated with allogeneic HCT, preventive
before we fully understand these diseases at a cellular
treatment before the onset of cerebral ALD is not an
level.
option. Since the lifetime prevalence of cerebral ALD
is estimated to be about 60% (de Beer et al., 2014), this
REFERENCES
would result in considerable iatrogenic harm. In addi-
tion, there is evidence that HCT does not prevent the Albersen M, Beek SL, Dijkstra IME et al. (2023). Sex-specific
onset of spinal cord disease (van Geel et al., 2015). newborn screening for X-linked adrenoleukodystrophy.
Unfortunately, this means that currently intensive mon- J Inherit Metab Dis 46: 116–128. https://doi.org/10.1002/
itoring and at times burdensome follow-up are still nec- jimd.12571.
Assies J, Gooren L, Geel B et al. (1997). Signs of testicular
essary (Engelen et al., 2022). Of note, ex vivo lentiviral
insufficiency in adrenomyeloneuropathy and neurologi-
gene therapy has recently made it possible to use the
cally asymptomatic X-linked adrenoleukodystrophy: a
boys’ own cells for gene addition, thus avoiding graft retrospective study. Int J Androl 20: 315–321. https://doi.
vs host and engraftment problems (Eichler et al., org/10.1046/j.1365-2605.1997.00066.x.
2017). While this procedure seems safer than traditional Blaw M (1970). Melanodermic type leukodystrophy
HCT, there are still some concerns about long-term safety (adreno-leukodystrophy), American Elsevier Publishing
and efficacy. There are no disease-modifying treatments Co128–133.
available for spinal cord disease at this time. Treatment Blaw M, Osterberg K, Kozak P et al. (1964).
remains supportive only. Sudanophilic leukodystrophy and adrenal cortical atrophy.
Arch Neurol 11: 626–631. https://doi.org/10.1001/archneur.
1964.00460240058008.
PROGNOSIS OF ALD Budka H, Sluga E, Heiss W (1976). Spastic paraplegia
associated with Addison’s disease: adult variant of adreno-
Boys and men without a positive family history of ALD
leukodystrophy. J Neurol 213: 237–250. https://doi.org/
have an increased mortality risk if they present with an 10.1007/bf00312873.
Addison crisis. Also, those presenting with signs and Carlson AM, Huffnagel IC, Verrips A et al. (2021). Five men
symptoms of cerebral ALD are virtually never diagnosed with arresting and relapsing cerebral adrenoleukodystro-
in a disease stage where they are still eligible for HCT phy. J Neurol 268: 936–940. https://doi.org/10.1007/
(Engelen et al., 2022). In these cases, life expectancy s00415-020-10225-7.
 ADRENOLEUKODYSTROPHY 137
Ceni C (1899). Uber einen interessanten Fall von gliomatoser adrenoleukodystrophy. Mol Genet Metab 122: 209–215.
infiltration bei der Grosshirnhemisphare. Arch Psychiatr https://doi.org/10.1016/j.ymgme.2017.10.012.
Nervenkr 31: 809–819. Huffnagel IC, van Ballegoij WJC, van Geel BM et al. (2018a).
de Beer M, Engelen M, van Geel BM (2014). Frequent occur- Progression of myelopathy in males with adrenoleuko-
rence of cerebral demyelination in adrenomyeloneuropa- dystrophy: towards clinical trial readiness. Brain 142:
thy. Neurology 83: 2227–2231. https://doi.org/10.1212/ 334–343. https://doi.org/10.1093/brain/awy299.
wnl.0000000000001074. Huffnagel IC, Laheji FK, Aziz-Bose R et al. (2018b). The
Dubois R, Loeb H, Perier O et al. (1964). Addison’s disease natural history of adrenal insufficiency in X-linked adreno-
and Schilder’s diffuse sclerosis. Helv Paediatr Acta 19: leukodystrophy: an international collaboration. J Clin
528–555. Endocrinol Metab 104: 118–126. https://doi.org/10.1210/
Eichler F, Duncan C, Musolino PL et al. (2017). jc.2018-01307.
Hematopoietic stem-cell gene therapy for cerebral adreno- Huffnagel IC, Dijkgraaf MGW, Janssens GE et al. (2019).
leukodystrophy. New Engl J Med 377: 1630–1638. https:// Disease progression in women with X-linked adrenoleuko-
doi.org/10.1056/nejmoa1700554. dystrophy is slow. Orphanet J Rare Dis 14: 30. https://doi.
el-Deiry SS, Naidu S, Blevins LS et al. (1997). Assessment of org/10.1186/s13023-019-1008-6.
adrenal function in women heterozygous for adrenoleuko- Igarashi M, Schaumburg H, Powers J et al. (1976). Fatty acid
dystrophy. J Clin Endocrinol Metab 82: 856–860. abnormality in adrenoleukodystrophy. J Neurochem 26:
Eng L, Regelmann MO (2019). Early onset primary adrenal 851–860.
insufficiency in males with adrenoleukodystrophy: case Jaspers YRJ, Ferdinandusse S, Dijkstra IME et al. (2020).
series and literature review. J Pediatr. https://doi.org/ Comparison of the diagnostic performance of C26:0-
10.1016/j.jpeds.2019.04.021. lysophosphatidylcholine and very long-chain fatty acids
Engelen M, Kemp S, Visser M et al. (2012). X-linked adreno- analysis for peroxisomal disorders. Front Cell Dev Biol 8:
leukodystrophy (X-ALD): clinical presentation and guide- 690. https://doi.org/10.3389/fcell.2020.00690.
lines for diagnosis, follow-up and management. Orphanet Kemp S, Huffnagel IC, Linthorst GE et al. (2016).
J Rare Dis 7: 51. https://doi.org/10.1186/1750-1172-7-51. Adrenoleukodystrophy–neuroendocrine pathogenesis and
Engelen M, Barbier M, Dijkstra I et al. (2014). X-linked redefinition of natural history. Nat Rev Endocrinol 12:
adrenoleukodystrophy in women: a cross-sectional cohort 606–615. https://doi.org/10.1038/nrendo.2016.90.
study. Brain 137: 693–706. https://doi.org/10.1093/brain/ Kemper AR, Brosco J, Comeau AM et al. (2017).
awt361. Newborn screening for X-linked adrenoleukodystrophy:
Engelen M, van Ballegoij WJC, Mallack EJ et al. (2022). evidence summary and advisory committee recommenda-
International recommendations for the diagnosis and tion. Genet Med 19: 121–126. https://doi.org/10.1038/
management of patients with adrenoleukodystrophy: a gim.2016.68.
consensus-based approach. Neurology 99: https://doi.org/ K€uhl J-S, Suarez F, Gillett GT et al. (2017). Long-term
10.1212/wnl.0000000000201374. outcomes of allogeneic haematopoietic stem cell trans-
Fanconi A, Prader A, Isler W et al. (1963). Morbus Addison plantation for adult cerebral X-linked adrenoleukodystro-
mit X-chromosomaler Vererbung. Helv Paediatr Acta phy. Brain 140: 953–966. https://doi.org/10.1093/brain/
18: 480–501. awx016.
Geel B, Bezman L, Loes D et al. (2001). Evolution of pheno- Liberato AP, Mallack EJ, Aziz-Bose R et al. (2019). MRI brain
types in adult male patients with X-linked adrenoleukodys- lesions in asymptomatic boys with X-linked adrenoleuko-
trophy. Ann Neurol 49: 186–194. dystrophy. Neurology 92: e1698–e1708. https://doi.org/
Gupta AO, Nascene DR, Shanley R et al. (2021). Differential 10.1212/wnl.0000000000007294.
outcomes for frontal versus posterior demyelination in Loes DJ, Hite S, Moser H et al. (1994). Adrenoleukodystrophy:
childhood cerebral adrenoleukodystrophy. J Inherit Metab a scoring method for brain MR observations. AJNR Am
Dis. https://doi.org/10.1002/jimd.12435. J Neuroradiol 15: 1761–1766.
Haberfeld W, Spieler F (1910). Zur diffusen Hirn- Mallack EJ, van de Stadt S, Caruso PA et al. (2020). Clinical
Ruckenmarksklerose im Kindesalter. Dt Z Nervheilk 40: and radiographic course of arrested cerebral adrenoleuko-
436–463. dystrophy. Neurology 94: e2499–e2507. https://doi.org/
Heubner O (1897). Uber diffuse Hirnsclerose. Charite Ann 22: 10.1212/wnl.0000000000009626.
298–310. Miller W, Rothman S, Nascene D et al. (2011). Outcomes
Hubbard WC, Moser AB, Liu AC et al. (2009). Newborn after allogeneic hematopoietic cell transplantation for
screening for X-linked adrenoleukodystrophy (X-ALD): childhood cerebral adrenoleukodystrophy: the largest
validation of a combined liquid chromatography-tandem single-institution cohort report. Blood 118: 1971–1978.
mass spectrometric (LC-MS/MS) method. Mol Genet https://doi.org/10.1182/blood-2011-01-329235.
Metab 97: 212–220. https://doi.org/10.1016/j.ymgme. Moser H, Moser A, Frayer K et al. (1981).
2009.03.010. Adrenoleukodystrophy: increased plasma content of
Huffnagel IC, van de Beek M-C, Showers AL et al. saturated very long chain fatty acids. Neurology 31:
(2017). Comparison of C26:0-carnitine and C26:0- 1241–1249. https://doi.org/10.1212/wnl.31.10.1241.
lysophosphatidylcholine as diagnostic markers in Moser A, Jones D, Raymond G et al. (1999). Plasma
dried blood spots from newborns and patients with and red blood cell fatty acids in peroxisomal disorders.
138 M. ENGELEN ET AL.
Neurochem Res 24: 187–197. https://doi.org/10.1023/ biochemical testing in the era of advanced genetics.
a:1022549618333. Mol Genet Metab 118: 123–127. https://doi.org/10.1016/
Moser H, Loes D, Melhem E et al. (2000). X-linked adrenoleu- j.ymgme.2016.03.009.
kodystrophy: overview and prognosis as a function of Schaumburg H, Powers J, Raine C et al. (1977).
age and brain magnetic resonance imaging abnormality. Adrenomyeloneuropathy: a probable variant of adrenoleu-
A study involving 372 patients. Neuropediatrics 31: kodystrophy. II. General pathologic, neuropathologic, and
227–239. https://doi.org/10.1055/s-2000-9236. biochemical aspects. Neurology 27: 1114–1119. https://doi.
Pierpont EI, McCoy E, King KE et al. (2018). Post-transplant org/10.1212/wnl.27.12.1114.
adaptive function in childhood cerebral adrenoleukodys- Siemerling E, Creutzfeldt H (1922). Bronzekrankheit und
trophy. Ann Clin Transl Neurol 5: 252–261. https://doi. sklerosierende encephalomyelitis. Arch Psychiatr Nervenkr
org/10.1002/acn3.526. 68: 217–244.
Powers JM, Schaumburg HH (1981). The testis in adreno- Singh I, Moser HW, Moser AB et al. (1981).
leukodystrophy. Am J Pathol 102: 90–98. Adrenoleukodystrophy: impaired oxidation of long chain
Powers JM, Moser HW, Moser AB et al. (1987). Pathologic fatty acids in cultured skin fibroblasts and adrenal cortex.
findings in adrenoleukodystrophy heterozygotes. Arch Biochem Biophys Res Commun 102: 1223–1229. https://
Pathol Lab Med 111: 151–153. doi.org/10.1016/s0006-291x(81)80142-8.
Raymond G, Seidman R, Monteith T et al. (2010). Head trauma van de Stadt SIW, Mooyer PAW, Dijkstra IME et al.
can initiate the onset of adreno-leukodystrophy. J Neurol (2021). Biochemical studies in fibroblasts to interpret
Sci 290: 70–74. https://doi.org/10.1016/j.jns.2009.11.005. variants of unknown significance in the ABCD1 gene.
Richmond PA, van der Kloet F, Vaz FM et al. (2020). Genes (Basel) 12: 1930. https://doi.org/10.3390/
Multi-omic approach to identify phenotypic modifiers genes12121930.
underlying cerebral demyelination in X-linked adrenoleu- van Geel BM, Poll-The BT, Verrips A et al. (2015).
kodystrophy. Front Cell Dev Biol 8: 520. https://doi.org/ Hematopoietic cell transplantation does not prevent mye-
10.3389/fcell.2020.00520. lopathy in X-linked adrenoleukodystrophy: a retrospective
Schackmann MJA, Ofman R, van Geel BM et al. (2016). study. J Inherit Metab Dis 38: 359–361. https://doi.org/
Pathogenicity of novel ABCD1 variants: the need for 10.1007/s10545-014-9797-1.