1403 □ CASE REPORT □ A Case of Adult-onset Adrenoleukodystrophy with Frontal Lobe 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 1 Department of Neuropsychiatry, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan and 2 Depart- 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, [email protected]
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1403
□ CASE REPORT □
A Case of Adult-onset Adrenoleukodystrophy with FrontalLobe Dysfunction: A Novel Point Mutation in the
Intern Med 51: 1403-1406, 2012 DOI: 10.2169/internalmedicine.51.6899
1404
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:
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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