Adult Onset Cerebral X-Linked Adrenoleuokodystrophy in 18 Cases
Health, 2015, 7, 723-728
Published Online June 2015 in SciRes. http://www.scirp.org/journal/health
http://dx.doi.org/10.4236/health.2015.76086
How to cite this paper: Furuhashi, Y. and Ishikawa, M. (2015) Adult Onset Cerebral X-Linked Adrenoleuokodystrophy in 18
Cases. Hea l th, 7, 723-728. http://dx.doi.org/10.4236/health.2015.76086
Adult On s et Cerebral X-Linked
Adrenoleuokodystrophy in 18 Cases
Yuko Furuhashi1*, Masaya Ishikawa2
1Section of Health Care Center, Shizuoka Universit y, Shizuoka, Japan
2Saginuma Kouen Clinic, Kawasaki, Jap an
Email: *furuhashi.yuko@shizuoka.ac.jp
Received 30 April 2015; accepted 13 June 2015; published 17 June 2015
Copyright © 2015 by authors and Scientific Researc h Publishing Inc.
This wor k is licens ed under the Creati ve Commons Attribution International License (CC BY).
http://creativecommons.org/licenses/by/4.0/
Abstract
Adrenoleukody str oph y ( A LD) is an X-linked inhe rited metab olic d iseas e associated wi th the ac-
cumulation of very l ong chai n f at ty ac id s (VLCFA) in the nervous system, ad re n al cor tex , and te ste s .
At least seven phenotype s can be distingu ished, wh ich ar e Ad dison onl y, childhood, adolescent
and adult cerebral ALD, adrenomyelon europ athy (AMN), and s ymp tom ati c or asymptom at ic car-
riers. Children most often develop rapidly a progre ssive cerebral disease, wher e as adults rarely
develop a cereb ral di seas e. The majori ty of adult-onset ALD patient s are AM N. The prog nos is of
ALD remains unpredictable in indi vidual p atients. Fam il y hist ory c an be ve ry in forma tive. The
plasma VLCFA assay pe rm its prec ise diagnosis. Specific chan ges on brai n M agnetic R eso nance Im-
aging ( MRI) c an h ave diag nostic u til i ty. Howev er, th ere is consid era ble overla p amo ng adult-onset
leukodyst rophies . Adult onset form of cerebral X-linked AL D (AOC ALD) is a rare disease. Th e dis-
ease progre sses rapidly with wid esp read d emyel ination of th e cer ebral h emis ph eres. AOCALD is
an important differen tial diagnosis for adults with psychiatric symptoms and progressive cogni-
tive changes. In th is ar ti cl e , we re view on c ase rep ort s of AOC ALD.
Keywords
Adrenoleu kodystr ophy, Adult Onset, Cerebrum, H allu cination , Delusion
1. Introduction
ALD is an X-linked inher ited metabolic disea se associated with very long chain fatty acids (VLCFA) accumula-
tion in the ner vous system, adrenal cortex, and testes [1] [2].
It is caused by a mutation in the ABCD1 gene on chromosome Xq28. A number of different mutations in the
*Corresp onding author.
Y. Furuhashi, M. Ishikawa
724
ABCD1 gene have been reported to be associated wit h X-linked ALD [3]-[10]. The gene product is a perox-
iso mal membrane protein, which belongs to the family of peroxisomal mem b ra n e ABC half-transporter proteins.
The genetic defect leads to decreased peroxisomal α-oxidation of VLCFA and subsequent accumulation of
VLCFA mainly in the central nervous system and adrenal glands as well as in plasma. Accumulation of VLCFA
is associated with progressive central and peripheral demyelination, adrenocortical insufficiency, and hypogo-
nadism. Its prevalence is curr ently esti mated at 1 in 20,000 - 50,000 [11]. The clinical manifestatio ns of ALD
ran ge widely. At least seven phe no t ype s can be distinguished, which are Addison only, childhood, adolescent a nd
adult cerebral ALD, AMN wi th or without cereb r al d emyelination, and symptomatic or asymptomatic carr iers
[12]. Children mos t often develop rapidly a progressive cerebral disease, whereas adults rarely develop a cere-
bral disease. In the most severe phenotype, affected patients develop cerebral demyelination with inflammation
which is rapidly progressive a nd usually fatal within 2 years after onset. Thi s phenotype presents most frequent-
ly in early childho od (childhood cerebral ALD; CCALD), but can also occur in adolescence or adulthood. In
seven phenotypes, two mos t freq ue nt are child ho od cerebral ALD (CCALD) and adrenomyeloneuropathy (AMN)
[13]. Childhood cerebral ALD (CCALD) and AMN account for more than 75% of all X-lin ked ALD [13].
The adrenomyelone uropathy (AMN) phenotype usual ly develops between the 30 years and 50 years of life
and is graduall y progressi ve. AMN represents the core cl inical symptoms in X-linked ALD. The neuro logic
disabilit y is slowly progressive initially. The main sy mptoms of AMN are gait disturbances, adrenal insuffi-
ciency, bladder problems, as well as scarce scalp hair [14]. The neuro logical symptoms are related to a myelo-
neuropathy. Adrenocortical and testicular insufficienc y can occur in isolation (Addison-o nly) , but also in com-
bination with any of the other phenotypes. There is no correlation between the duration or severity of endoc rine
dys function and the severity of the myeloneuropathy. The majority of adult-onset ALD patients are AMN. The
adult onset form of cerebral X-linked ALD (AOCALD) is a rare disease and less than 3% of X-linked patients
present with ALD [13] [14]. The phenotypic presentation of AOCALD is mainly characterized by a gradual de-
velopment of behavi or changes a nd cognit ive dysfunction [2]. The disease progresses r a pidly with widespread
demyelination of the cerebral hemispheres. Hallucinations and delus ions are not common as initial symptoms,
howe ver, we reported the case of AOCALD heralded by auditory hallucinations and delusions [15]. Specific
treatment should be effective at psychiatric stage before the occurrence of irreversible neurol ogical lesions.
General practitioners should bear in mind the importance of performing neurological and radiological ex amin a-
tions on psychiatr ic pa tie nts with chronic illnesses in order to diagnose correctly.
In this article, we present an overvi ew of 18 case reports on AOCALD.
2. Methods
An electronic search of databases was conducted through academic search engine, MEDLINE.
T e r ms were entered for searching in the title and abstract of articles. The search set used the terms “Adreno-
leykodystrophy (ALD)” or “adu lt onset” or “cerebrum” or “case report”.
The search sets included all papers published from January 1995 to January 2015. The search was limited to
journals written in English. The search produced 25 articles. All papers wer e then manually reviewed to ensur e
the studies i nvestigated AOCALD.
3. Results and Discussion
Over View of Reviewed Studies
A total of 18 studies met the c riteria for inclusio n in this review.
The inclusion criteria we re 1) diagnosis of probable X-linked ALD as confirmed by ABCD1 gene or serum
VLCFA, 2) age of onset is older than 20 years old, 3) presence of cerebral demyelination confirmed by brain
MRI or CT (cerebral ALD).
Table 1 provides an overview of the reviewed articles. The average age of cases was 33.4 years old (20 years
old to 62 years old), and all cases were male. In these cases [3]-[10] [15]-[24], the symptomatolog y resembles
childhood cerebral ALD (CCALD) such as p rogressive co gnitive i m p a i rmen t and loss of me mory . However, the
early cognitive disturbance is rarely recognized by their families or at work in adult s [4] [6] [7]. In 18 cases,
progressive co gnitive decline is common as initial symptoms [3]-[10] [15]-[24]. Three cases reported psychiatric
symptoms as initial symp to ms [3] [15] [21]. These are a ggress i vit y a nd ab ul i a [3], halluci nat io ns a nd delusions
Y. Furuhashi, M. Ishikawa
725
Table 1. Summary of reviewed case studies.
Author Age of case Initial symptoms How to diagnosis
Carra-Dalliere et al. [3] 24 Psychiatric disturbances, spatial disorientati on, memory loss Family history, VLCFA,
M RI, ABCD 1 gene
Brownst one E. et al. [16] 50 Disorientation, petulance, p sychomotor agitation VLCF A , MRI
Inoue et al. [4] 48 Personality change, irritability VLCF A, MRI, ABCD 1 gene
Furuhashi Y. et al. [15] 21 Hallucination, delusion VLCF A , M RI, brain biopsy
Li et al. [5] 37 Progress ive gait un steadiness , impotenc e, incontinence family history, V LCFA, M RI,
ABCD 1 gene
Dohle C.I. et al. [6] 40 Progressive cognitive decline, seizure VLC FA, M RI, ABCD 1 gene,
brain biopsy
Saito T. et al. [7] 62 Dementia, spastic paraparesis V LCF A, MRI, ABCD 1 gene
Sutovsky S. et al. [8] 37 Progressive personality change VLC FA, M RI, ABCD 1 gene
Hitomi T. et al. [9] 20 Progressive hemiparesis, gai t disturbance V LCF A, MRI, ABCD 1 gene
La rner A.J. [10] 40 Beha vioral changes V LCF A , MRI, ABCD 1 gene
Luda E. et al. [17] 37 Mem o ry disturbance, personality chang es V LCF A, MRI
Sakakibara R. et al . [18] 34 Progressive spastic parapares is, genitourinary dysfunction V LCF A, MRI
Far r el l D.S. et al. [19] 30 Slurred speech, poor balance, headache, deteriorating vision family history, VLCFA, MRI,
ABCD 1 gene,
Tan E.K. et al. [20] 24 Addison’s disease, slurred speech, memory distur bance V LCF A , MRI
Gar s i d e S. et al. [21] 31 Tardive dyskinesia, psychosis VLCF A, MRI
Ochi K. et a l. [22] 24 Unstable gait, dysarthria, writing disturbance, finger tremor VLCF A, MRI
Leo R.J. [23] 42 Addison’s disease, irritable, impulsive V LCF A, MRI
Waragai M. et al.[24] 30 Progressive cerebellar ataxia, spast ic paraparesis V LCF A, MRI
MRI, Magnetic resonance imaging; VLCFA, Very long chain fatty acid s.
[15], and mania including impuls ivity, loudness, and perseveration [21]. So me stud ies reported that the pheno-
t yp i c presentation of AOCALD is mainly characterized by a gradual development of psyc hiatr ic symptoms mi-
micking schizop hrenia or psychosis [1] [2] [12]. H owev er , in 18 cases, there was a case that reported hallucina-
tions and delusions appeared as initial sympt oms [15]. Hallucinations and delusions were rare sympt om s as ini-
tial symptoms.
All ca ses were performed brain MRI and plasma VLCFA levels. Specific change s on brain Magnetic Reson-
ance Imaging (MRI) can have dia gnostic utility.
A study suggested that over a period of ten years, approximately 20% of patients with AMN developed addi-
tional cerebral demyelination [25]. In 18 cases, several cases revealed that patients with AMN d eveloped cere-
bral ALD [5] [7] [18] [22] [24]. As the s tudy [25] and these cases, patients with AMN can develop cerebral de-
myelination. It is important to follow the patients with AMN or Addison’s disease by re-examinations of MRI.
4. Diagnos is
The majority of adult-onset ALD patients is AMN. The incidence of AOCALD is less than 3% [13] [14].
AOCALD should be considered in the differential diagnosis of leukoencephalopathy in an adult even though
AOCALD is a rare disease. When ALD is suspected, the initial diagnostic step consists of analysis of VLCFA in
plasma. Most laboratories mea s u r e the absolute concentration of C26:0 as wel l as the C24:0/C22:0 and C26:0/
C22:0 ratios [13]. However, it is difficult to diagnose patients with AOCALD correctly when psych ia tric symp-
toms are initially isolated without more specific symptoms or a familial history [15]. Family history can be very
informative [3] [5] [19]. All 18 cases wer e performed brain MRI [3]-[10] [15]-[24]. MRI can have diagnostic
Y. Furuhashi, M. Ishikawa
726
utility, however, t here is considerable overlap among adult-onset leuko dystrophies. Thus, the p redictive value of
even mor e sophisticated MRI techniques is limited and there is still an essential need for bio logical markers that
can predict disease progress. Metabolic screening reveals increased VLCFA [3]-[10] [15]-[24]. The next step is
to confirm the diagnosis by performing ABCD1 mutation analysis [3] [4] [6]-[10] [12] [19].
In adult mal e s presenting with adrenocor tical insufficiency, X-linked ALD should be considered and deter-
mination of plas ma VLCFA levels should be performed [12]. Furt hermore, adult males presenting cognitive and
neurologic al sympto ms with white matter lesions on brain MRI should be considered for X-linked ALD and de-
termination of plasma VLCFA levels should be performed [12]. In adult men, t he mo s t common presenting
symptom of X-linked ALD is a chronic myelopathy [12]. Af te r ruling out a compressive myelopathy by MRI of
the sp inal co r d and other common causes of chr onic myelopathy, X-ALD sho uld be considered [12]. In adul t
males with confluent white matter changes, X-ALD should be considered, especially when there is increased
signal intensity on T2-weighed and FLAIR sequences in the parieto-occipital r egion and the splenium of the
corpus callosum [3]-[10] [12] [15]-[24] . Metabolic screening reveals increased VLCFA, the ne xt step is to con-
firm the diagnosis by performing ABCD1 mutation ana lysi s [3] [4] [6]-[10] [12] [19].
5. Treatment
Oral administration of Lorenzo’s oil normalizes or significantly lowers the levels of VLCFA in plasma [15].
However , the clinical efficacy of Lorenzo’s oil and the clinical indication s for use of Lorenzo’s oil are contro-
versial [12]. Approximately 70% of AMN patients develop pri ma ry adorenocortical insufficiency before the on-
set of neurological symptoms [25]. The treatment of adorenocortical insufficiency in X-linked ALD is no dif-
ferent from in patients with p r ima ry adrenal insufficiency. Glucocorticoid r eplacement therapy dose not inf lu-
ence the development or progression of neurological symptoms [25].
Treatment is mainly symptomatic . If cerebral ALD is advanced at the time of diagnosis, prognosis is poor [6]
[8] [10] [12] [15] [18] [23]. There is no proven treatment for AOCALD. There is currently no curative or pre-
ventive treatment for mos t of patients with AOCALD.
However , bone marrow transpla ntatio n (BMT) has been reported to have a long-term beneficial effect in
childhood onset ALD early in the clinical course [9]. Despite significant mortality risk, allo geneic haemato-
phietic cell transplantation (HCT) remains the only therapeutic intervention that can halt the pro gression of
cerebral demyelination in X-ALD, provided the proc edure is performed very early stage whe n affected boys or
men have no or mi nor s y mpt oms due to cerebral demyelinating disease [12].
Regular follow-up in AMN r ema in s important. So me studies reported that 20% of adult males with AMN
phenotypes will develop AOCALD later in life [12] [25]. It is important to study if an allogeneic HCT can be
successful. In additio n, the c hallenge of the future is to d iscover risk factors for the development of cerebral
ALD [12].
6. Conclusions
X-linked ALD is an intriguing disorder that is still incompletely understood and limited treatment options.
In addition, the incid ence of AOCALD is rare and AOCALD is some t im es diagnosed as other disease s. It is
important to recognize X-linked ALD because treatment is available in some cases suc h as HCT in early stage
of X-linked ALD. We realized that general practitioners should bear in mind the importance of performing neu-
rological and radiological examinations on psychiatric patients with chro nic illnesses in order to diagnose cor-
rectly. Increased awareness of this disorder will lead to accurate diagnosis, appropriate treatment selection, and
genetic counseling.
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