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□ CASE REPORT □

A Case of Adult-onset Adrenoleukodystrophy with FrontalLobe Dysfunction: A Novel Point Mutation in the

ABCD1 Gene

Shinichiro Inoue 1, Seishi Terada 1, Tadashi Matsumoto 2, Hiroshi Ujike 1 and Yosuke Uchitomi 1

Abstract

We report the case of a 48-year-old man with adult-onset adrenoleukodystrophy (ALD) who developed de-

mentia with subacute onset. He was abulic, indifferent to his surroundings, and without insight with regards

to his own disease. An elevated plasma very long chain fatty acid level and a novel point mutation IVS3+2t>

g in the ABCD1 gene confirmed the diagnosis of ALD. Diffusion-weighted MRI revealed a high intensity

area in the white matter of the frontal lobes. Severe brain hypoperfusion in the frontal lobes was revealed.

We believe that this is a rare case of adult-onset adrenoleukodystrophy with predominant frontal lobe dys-

function.

Key words: adrenoleukodystrophy, diffusion-weighted MRI, frontal lobe dysfunction, MR spectroscopy, sin-

gle photon emission CT (SPECT)

(Intern Med 51: 1403-1406, 2012)(DOI: 10.2169/internalmedicine.51.6899)

Introduction

X-linked adrenoleukodystrophy (X-ALD) is a rare inher-

ited metabolic disease caused by an enzyme deficiency lead-

ing to accumulation of saturated very long chain fatty acid

(VLCFA). Its prevalence is currently estimated at 1:17,000

males in the USA (1), 1:20,000 males in France (2), and 1:

30,000 to 50,000 males in Japan (3). The disease phenotype

varies widely. The most frequent phenotypes are the infan-

tile cerebral form, which often has a fatal course during the

first decade of life due to the extensive demyelination of the

cerebral hemispheres, and adult adrenomyeloneuropathy,

which leads to slowly evolving spastic paraparesis (2-5).

The less frequently described forms include those observed

in heterozygous women, pure Addisonian forms, and adoles-

cent ALD and adrenomyeloneuropathy (AMN) with some

signs of cerebral involvement (5). Adult cerebral disease (X-

ALD presenting with adult-onset dementia) is the least fre-

quently observed phenotype, occurring in 2-3% of cases in

Western countries (5, 6). In Japan, the adult cerebral form is

reported to be more common (21.4%) (3). Neuroradiological

studies of adult-onset ALD have only rarely been re-

ported (7-9). Adult-onset ALD is often characterized by

psychotic-like features, ataxia, spasticity and extensive white

matter demyelination as revealed by MRI. In this report, the

clinical, neuropsychological, and neuroimaging findings of a

patient with genetically and biochemically confirmed X-

ALD who developed dementia with subacute onset in the

fifth decade of life are presented.

Case Report

The patient is a 48-year-old man with a negative family

history of hereditary diseases, and with normal psychologi-

cal development and education. He has two siblings, was

married at the age of 29, and has three children. There were

no particular findings in his history.

In May 2004, he became slightly irritable. In June, he

was confused and got on the wrong trains several times and

also went to work on a holiday by mistake. His family

pointed out his mistake to him, but he showed no concern

１Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan and ２Depart-

ment of Nursing, Nagasaki University School of Medicine, Japan

Received for publication November 8, 2011; Accepted for publication February 8, 2012

Correspondence to Dr. Seishi Terada, terada@cc.okayama-u.ac.jp

Intern Med 51: 1403-1406, 2012 DOI: 10.2169/internalmedicine.51.6899

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Figure　1.　1a: T2-weighted image reveals diffuse high signal intensity in the deep white matter. 1b: MR diffusion-weighted image reveals high signal intensity area in the white matter of the frontal lobes.

Figure　2.　1H-MR spectroscopy of the white matter of the frontal lobes reveals an extreme decrease of N-acetyl aspartate (NAA) and an increase of the choline (Cho)/creatinine (Cr) ra-tio.

and made similar mistakes repeatedly. His family worried

about his mental state, and in July, he came to our hospital.

Neurological evaluations revealed that his consciousness

was alert. His gait was slightly unstable, and tandem gait

was impossible. Examination of the cranial nerves revealed

only slightly nasal speech. Muscle power was normal, and

muscle atrophy was absent. Deep tendon reflexes were bilat-

erally increased, but without pathological reflexes. Ex-

trapyramidal symptoms and cerebellar signs were not found.

Sensation was normal. The Revised Hasegawa Dementia

Scale score was 19 (full score 30) (10). Orientation to time

and place was good (5/5, 2/2), delayed recall was somewhat

disturbed (2/6), and word fluency (fluency category, vegeta-

ble) was severely disturbed (0/5). He showed obvious per-

sonality change. He was abulic, indifferent to his surround-

ings, and without insight as to his own disease.

Plasma cortisol (21.7 μg/dL) was within normal limits,

but plasma ACTH (147.1 pg/mL; 9.0-52.0) was increased.

The plasma level of very long chain fatty acid was elevated:

C24:0/C22:0=1.725 (0.628-0.977), C25:0/C22:0=0.046

(0.012-0.023), C26:0/C22:0=0.024 (0.003-0.006). Anti-Hu

antibody was negative. Examinations of the cerebrospinal

fluid revealed an initial pressure of 120 mmH2O, watery and

clear appearance, cell count 2/mm3 (monocytes), total pro-

tein 45 mg/dL, sugar 60 mg/dL, IgG 2.8 mg/dL, IgG index

0.42, myelin basic protein 205 (<102), and a negative oligo-

clonal band.

Head MRI showed severe cerebral atrophy with diffuse

T2 high intensity areas in the cerebral white matter

(Fig. 1a). MR diffusion-weighted imaging revealed high in-

tensity areas only in the white matter of the frontal lobes

(Fig. 1b). There was severe brain hypoperfusion in the fron-

tal lobe of the cerebrum on single photon emission CT

(SPECT) with 99mTc-ECD (Fig. 2). 1H-MR spectroscopy

(MRS) of the white matter in the frontal lobes revealed an

extreme decrease of N-acetyl aspartate (NAA), and the NAA

peak could not be definitely identified (Fig. 3). An increase

in the choline (Cho)/creatinine (Cr) ratio was also found

(Fig. 3).

Molecular genetic studies

Genomic DNA was extracted from heparin-anticoagulated

peripheral blood samples from the patient with the written

informed consent of the patient and his family. All exons of

exon-intron boundaries of the ABCD1 gene were amplified

by polymerase chain reaction, and sequenced according to

the protocol of the ABI PRISM Dye Terminator Cycle Se-

quencing Ready Reaction Kit (Perkin-Elmer Applied Biosys-

tems, Santa Clara, CA, USA). A novel point mutation in the

ABCD1 gene (IVS3+2t>g) was found (Fig. 4a). No muta-

tions were detected in the other exons. Because this muta-

tion breaks a recognition site of the restriction enzyme KpnI

and creates an AvaII restriction site (Fig. 4b), restriction

fragment length polymorphism analysis using KpnI and

AvaII confirmed the mutation (Fig. 4c).

Discussion

Diagnosis

ALD is a rare, X-linked inherited metabolic disease that

is characterized by leukoencephalopathy, adrenal insuffi-

ciency, and hypogonadism. The genetic defect leads to de-

fective oxidization of very long chain fatty acids at the per-

oxisomal level and their consequent accumulation in nerve

tissue, the adrenal glands, other tissues, and plasma (5, 11).

X-ALD is a peroxisomal disorder with various clinical phe-

notypes, dependent on the age at presentation (5). Children

most often have rapidly progressive cerebral disease (infan-

tile ALD), whereas adults most often present with AMN.

These two phenotypes account for more than 75% of all X-

ALD cases (5). Adult-onset ALD is rare, and has a highly

variable but often rapidly worsening course (7-9). In the

present case, the period from the appearance of the initial

Intern Med 51: 1403-1406, 2012 DOI: 10.2169/internalmedicine.51.6899

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Figure　3.　Single photon emission CT (SPECT) with 99mTc-ECD shows hypoperfusion in the frontal lobes.

Figure　4.　4a: Sequence analysis in the border zone of exon 3 and intron 3 in the ABCD1 gene. A novel point mutation in the ABCD1 gene (IVS3+2t>g; 1224+2t>g) was detected. 4b: This mutation breaks a recognition site of the restriction en-zyme KpnI and creates an AvaII restriction site. 4c: Restric-tion fragment length polymorphism analysis of intron 3 of the ABCD1 gene using KpnI and AvaII restriction enzymes. KpnI digestion produced two bands in the control, whereas no di-gestion was observed in the patient. AvaII digestion produced two bands in the control because the PCR product has a com-mon AvaII recognition site. A longer band after AvaII diges-tion was cleaved into two in the patient’s analysis, resulting in three bands.

symptom (irritability) to the first consultation was only

about two months, and the progression of symptoms was

rapid (12). The elevated plasma level of very long chain

fatty acids was confirmed, and diffuse leukoencephalopathy

was obvious. A novel point mutation in the ABCD1 gene

(IVS3+2t>g) was found. The mutation produces a donor

splice variant and incorporation of 23 novel amino acids af-

ter the end of exon 3 with an early termination. Therefore,

he was diagnosed with X-ALD presenting with adult-onset

dementia.

Clinical symptoms

Kitchin et al. reviewed 109 cases of ALD, most of them

with onset before the age of 21, and found that the present-

ing symptom was exclusively psychiatric in 17%, while psy-

chiatric symptoms appeared during the course of the disease

in 56% (13). Typical ALD with an onset at 21 years or

older presented with some psychiatric problems in four of

six cases (67%) and with only psychiatric problems in one

of six cases (17%) (13). The most common psychiatric

manifestation was dementia, followed by learning difficul-

ties, behavioral changes, and schizophrenia-like symp-

toms (5, 13, 14). Luda and Barisone reported that the over-

all neuropsychological picture of patients with adult-onset

ALD was subcortical dementia, but that the alterations in

symbolic functions indicate the involvement of some cortical

areas, especially the frontal cortex (15). We suppose that the

present case with abulia and indifference also suffered from

frontal lobe dysfunction.

Neuroradiological findings

Neuroradiological findings of sixty boys with infantile

cerebral form of ALD revealed that predominantly frontal

and mixed locations of cerebral disease were 13% (8/60)

and 5% (3/60), respectively (16). Kumar et al. found three

cases of adult cerebral ALD among 54 adult male ALD

cases (most cases were adrenomyeloneuropathy) (17). Those

three cases showed parieto-occipital dominant white matter

lesions without frontal lobe lesions (17). Two cases of adult

cerebral ALD with frontal dominant lesion were re-

ported (7, 8). Loes et al. examined 206 boys and men with

cerebral ALD (18) and found the frontal dominant type in

15.5% (32/206) and combined but separate involvement type

of frontal and parieto-occipital white matter in only 2.5%

(5/206). Diffuse global white matter involvement was ob-

served only in 2.5% (5/206) and it was thought to represent

a late stage of the disease (18). The present case showed

diffuse white matter lesions from frontal to occipital lobes

on T2-weighted images at the initial evaluation. The diffuse

white matter involvement observed at the initial evaluation

in our case is thought to be a relatively rare pattern.

Diffusion-weighted brain MR imaging of patients with

adult onset ALD has not been reported. Ito et al. examined

11 boys with ALD and described three patterns of white

matter lesions on T2-weighted and isotropic diffusion-

weighted images: one was both isotropic diffusion and T2

high, the second was isotropic diffusion high and T2 not

very high, and the last was isotropic diffusion not very high

and T2 high lesions (9). They stated that isotropic diffusion

not very high and T2 high lesions were rare (9). Both iso-

tropic diffusion and T2 high lesions were reported to be

found in core areas, and isotropic diffusion high and T2 not

very high lesions spread in peripheral areas (9). Core areas

correspond to the third zone of Shaumburg and without any

Intern Med 51: 1403-1406, 2012 DOI: 10.2169/internalmedicine.51.6899

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evidence of an active process (19), whereas peripheral areas

correspond to the first and second zones of Shaumburg and

with active processes (19). Ito et al. made use of diffuson

tensor MRI. Therefore, their classification could not be di-

rectly applied to the present case. In our case, the T2 high

white matter lesion was diffuse from frontal to occipital

lobes, and the diffusion high lesion was only found in the

frontal lobe.

It has been reported that on MRS in ALD, a decrease in

NAA reflects neuronal damage or loss and that an increase

in Cho corresponds to active demyelination and glial prolif-

eration (20, 21). In recent reports, an obvious decrease of

NAA and increase of Cho were also reported in the cerebral

white matter of patients with ALD (infantile cerebral

form) (20-22). In the present case, proton MRS revealed an

obvious decrease of NAA and increase of Cho in the white

matter of the frontal lobe. These results suggest that axons

as well as myelin sheaths are involved in the pathological

process in ALD (20-22).

Brain hypoperfusion in cases with ALD have been re-

ported, but the pattern of hypoperfusion varies. In a boy

with ALD, markedly reduced blood flow in the occipital,

parietal, and temporal cortical gray matter was reported (23),

whereas in another report, extremely decreased values of ap-

proximately 28 and 10 mL/100 g/min in bilateral frontal

cortex and white matter, respectively, were recorded (24). In

the present case, obvious frontal hypoperfusion was present

on SPECT. In both diffusion tensor MR imaging and

SPECT, severe damage in the frontal lobe was suggested,

and the clinical symptoms of abulia or indifference suggest

frontal lobe dysfunction. It is suggested that the severe dam-

age in the frontal lobe shown by diffusion-weighted MR im-

aging and SPECT caused the frontal symptoms in this case.

Conclusion

We reported a case of adult-onset adrenoleukodystrophy

with predominant frontal lobe dysfunction. Diffusion-

weighted MR imaging and SPECT were useful to detect le-

sions in ALD.

The authors state that they have no Conflict of Interest (COI).

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