A Japanese Boy with H-ABC163
Tohoku J. Exp. Med., 2006, 209, 163-167
Received December 19, 2005; revision accepted for publication March 27, 2006.
Correspondence: Keisuke Wakusawa, Department of Pediatrics, Tohoku University School of Medicine, 1-1
Seiryomachi, Aoba-ku, Sendai 980-8574, Japan.
e-mail: k-wakusawa@nifty. com
Effective Treatment with Levodopa and Carbidopa for
Hypomyelination with Atrophy of the Basal Ganglia
KEISUKE WAKUSAWA, KAZUHIRO HAGINOYA, TARO KITAMURA, NORIKO TOGASHI,
MAMIKO ISHITOBI, HIROYUKI YOKOYAMA, SHUICHI HIGANO,1 AKIRA ONUMA,2
TAKAHIRO NARA3 and KAZUIE IINUMA
Department of Pediatrics, 1Department of Diagnostic Radiology,
Tohoku University School of Medicine, Sendai, Japan,
2Department of Pediatrics, Takutou Rehabilitation Center for Disabled
Children, Sendai, Japan, and
3Department of Rehabilitation, Miyagi Children’s Hospital, Sendai, Japan
WAKUSAWA, K., HAGINOYA, K., KITAMURA, T., TOGASHI, N., ISHITOBI, M., YOKOYAMA, H.,
HIGANO, S., ONUMA, A., NARA, T. and IINUMA, K. Effective Treatment with Levodopa and
Carbidopa for Hypomyelination with Atrophy of the Basal Ganglia and Cerebellum.
Tohoku J. Exp. Med., 2006, 209 (2), 163-167 ─ ─ Hypomyelination with atrophy of the
basal ganglia and cerebellum (H-ABC) is a rare leukoencephalopathy presenting in the in-
fantile period and characterized by diffuse cerebral hypomyelination, and atrophy of the
basal ganglia and cerebellum. As patients with H-ABC lack remarkable laboratory find-
ings, the diagnosis is based on brain magnetic resonance imaging findings alone. Only
eight cases have been reported in the literature, and thus the natural course and treatment
of this disease are not fully understood. We report a 35-month-old boy with H-ABC who
had hemidystonia, hypomyelination, and cerebellar ataxia. We diagnosed H-ABC after
considering a thorough differential diagnosis, excluding other diseases involving hemidys-
tonia, hypomyelination, and cerebellar ataxia. Furthermore, technetium-99m ethyl cyste-
inate dimmer-single-photon emission computerized tomography (Tc-ECD-SPECT) and
positron emission tomography with fluorodeoxyglucose 18F (FDG-PET) revealed
decreased blood flow and glucose metabolism in the bilateral lenticular nucleus, thalamus,
and cerebellum. A peroral levodopa preparation containing carbidopa (levodopa-carbidopa)
was effective at ameliorating and stopping the progression of the patient’s dystonia (final
effective doses: levodopa, 200 mg/day and carbidopa, 20 mg/day). This is the first case
report of a Japanese patient with H-ABC and treatment for this disease. Levodopa-
carbidopa may be an effective treatment for H-ABC. ──── H-ABC; levodopa-
carbidopa; hemidystonia; hypomyelination; cerebellar ataxia
© 2006 Tohoku University Medical Press
K. Wakusawa et al.164
In 2002, Van der Knaap (2002) first reported
patients who had hypomyelination with atrophy
of the basal ganglia and cerebellum (H-ABC).
H-ABC is an infantile-onset, progressive leukoen-
cephalopathy. As patients with H-ABC lack
remarkable laboratory findings, the diagnosis is
based on three brain magnetic resonance imaging
findings: diffuse cerebral hypomyelination, atro-
phy of the basal ganglia, and atrophy of the cere-
bellum. Only eight cases have been reported (van
der Knaap 2002; Mercimek-Mahmutoglu et al.
2005), and most of the details of this disease
remains unknown. More patients are needed to
establish this condition as a clinical disease entity.
Furthermore, there is no known treatment for this
condition, and there have been no reports of
Japanese patients with the same clinical and
radiological findings. Here, we report a Japanese
boy who appeared to have H-ABC and who was
effectively treated with levodopa-carbidopa.
A 35-month-old boy was born by normal
delivery after 40 weeks of gestation. His birth
weight was 3,032 g. He had no contributory fam-
ily history. Head control was achieved at 2.5
months of age; rolling, standing, and walking
alone were achieved at 4, 12, and 15 months,
respectively. However, because he could not walk
for more than a few steps until he was 18 months
old, he was referred to another hospital for evalu-
ation of delayed development. Brain magnetic
resonance imaging (MRI) revealed delayed
myelination. Dystonic posture of the right leg
had been evident upon walking since the age of 2
years. The gait disturbance gradually progressed,
and he could not walk alone at 34 months, when
his right arm also began to show a dystonic pos-
ture. He could barely use his right hand. He was
referred to our hospital for close evaluation of
right hemidystonia at 35 months of age.
At the first examination, he was 85 cm tall
(−2 S.D.) and weighed 12 kg (−1 S.D.); his head
circumference was 47 cm (within the normal
range). The right upper and lower extremities
showed rigidity and abnormally flexed posture
and were thought to have dystonia. His right
hand could not grasp anything. The deep tendon
reflexes were exaggerated in the right extremities,
and the Babinski reflex was positive on the right.
These clinical findings suggested that his right
extremities showed both pyramidal and extrapy-
ramidal signs. Muscle power and tonus and deep
tendon reflexes were normal on the left side. He
could not creep alternately; therefore, he moved
using his upper and lower limbs symmetrically
like a jumping frog. He had neither surface
anomalies nor a dysmorphic face. No abnormali-
ties of the sensory systems were observed. The
liver and spleen were not palpable. His mental
and motor development was delayed, and the
developmental quotient evaluated at age 2 was 53.
On brain MRI, the deep cerebral white mat-
ter, including the internal capsule and corpus cal-
losum, showed mildly elevated signal intensity on
T2-weighted images and low signal intensity on
T1-weighted images, compared with age-matched
controls (Figs. 1a and 1c). The pyramidal tracts
in the brain stem also showed mildly high signal
intensity on T2-weighted images and low signal
intensity on T1-weighted images. These findings
were consistent with hypomyelination. The puta-
men was very small bilaterally, and these regions
had high signal intensity on T2-weighted images.
In contrast, the globus pallidus and thalamus
appeared normal. The cerebellar vermis and
hemisphere were atrophic, whereas the pons
showed no atrophy.
Magnetic resonance spectroscopy (MRS)
demonstrated a decreased N-acetylaspartate/
creatinine (NAA/Cr) ratio in the basal ganglia and
thalamus (0.67; age-matched normal range:
1.33-1.65; Martin et al. 2001). There was no lac-
tate peak. These MRS findings might suggest the
decrease or poor development of neurons in the
basal ganglia. Magnetic resonance angiography
(MRA) was unremarkable. Technetium-99m eth-
yl cysteinate dimmer-single-photon emission
computerized tomography (Tc-ECD-SPECT)
revealed decreased cerebral blood flow (CBF) at
the basal ganglia, thalamus, and cerebellum (Figs.
2a and 2b). Positron emission tomography with
fluorodeoxyglucose 18F (FDG-PET) showed
decreased FDG uptake at the basal ganglia and
A Japanese Boy with H-ABC165
cerebellum (Figs. 2c and 2d).
evoked potentials of the median nerve, and flush
visual evoked potentials were normal. The brain
stem auditory evoked potentials showed an abnor-
mally prolonged interval of waves I to V (right:
5.04 milliseconds, left: 4.88 milliseconds; normal:
3.78-4.62 milliseconds), suggesting dysfunction
of the brain stem.
The following laboratory results were all
unremarkable: blood cell karyotype; blood gas
analysis; serum levels of uric acid, ammonia, cop-
per (Cu), ceruloplasmin, pyruvate, lactate, IgG,
IgA, IgM, CMV-IgM·IgG, HSV-IgM·IgG, and
rubella-IgM·IgG; anti-streptolysin O; antinuclear
antibody; anti-cardiolipin antibody; anti-double-
stranded DNA antibody; white blood cell
arylsulfatase A; the coagulation system, including
protein C, protein S, and anti-thrombin III; plasma
very-long-chain fatty acids (VLCFA); free biotin;
total biotin; biotinidase; neopterin; biopterin; the
neopterin/biopterin (N/B) ratio; transferrin iso-
electric focusing; acylcarnitine; and proteolipid
protein (PLP) gene analysis for Pelizaeus-
Merzbacher disease. The serum amino acid anal-
ysis showed an increased level of glycine (4.80
mg/dl; normal 1.23-2.83), although the glycine
level in the cerebrospinal fluid (CSF) was not
increased (0.03 mg/dl, normal). The CSF/serum
glycine ratio was 0.0062 (normal < 0.03; Hamash
1995). Urinary levels of organic acids analyzed
with gas chromatography-mass spectroscopy
(GC-MS), urinary electrolytes, creatinine, uric
acid, neopterin, biopterin, and the N/B ratio were
In the CSF, the cell count, glucose and pro-
tein levels, lactate, pyruvate, amino acids,
homovanillic acid (HVA), 5-hydroxyindole acetic
acid (5-HIAA), γ-aminobutyric acid, myelin-basic
protein, neopterin, biopterin, and N/B ratio were
Fig. 1. The Brain MR images on admission (at 35 months) and at 55 months.
T2-weighted (TR3600, TE95.9) axial MR images taken at 35 (a and b) and 55 (d and e) months and
T1-weighted (TR440, TE14.0) sagittal MR images taken at 35 (c) and 55 (f) months. The cerebral
white matter, including the internal capsule and corpus callosum (thin white arrows), had mildly
increased signal intensity on the T2-weighted images compared to the age-matched controls. The
putamen was very small bilaterally (black arrows), and this region had high signal intensity on
T2-weighted images. The cerebellar vermis and hemisphere were atrophic (thick white arrows).
K. Wakusawa et al. 166
unremarkable. The bone marrow (BM) and oph-
thalmologic examinations were unremarkable.
Given these findings, the patient was diag-
nosed with H-ABC. A peroral levodopa prepara-
tion containing carbidopa (levodopa-carbidopa),
vitamin B1, and biotin were all tried as treatments.
Soon after hospitalization, he began to have athe-
totic movement of the left fingers and ataxia of
the trunk. The drugs did not initially appear to be
effective (initial doses: levodopa; 1 mg/day and
carbidopa, 0.1 mg/day). However, because his
dystonic posture became worse when he did not
take levodopa-carbidopa, we decided to increase
the dose. His ability to stand and walk with sup-
port improved and equinovarus decreased on daily
doses of 200 mg levodopa, 20 mg carbidopa and
10 mg trihexyphenidyl HCl. He still could not
alternatively creep, and the ataxia of the trunk
At present, he is 5 years and 6 months old.
His hemidystonia has improved and he can use
his right hand and grasp objects, although his
right arm sometimes shows a dystonic or athetotic
posture. Mental retardation is still evident, but he
is able to use a few meaningful words. The
increased deep tendon reflexes of both legs with a
positive Babinski reflex, truncal ataxia, and loss
of alterative creeping persist. Repeat MRI taken
at 55 months of age showed no progression of
myelination compared with the previous study
(Figs. 1d and 1f).
The clinical and laboratory findings in our
patient were characterized as hemidystonia, hypo-
myelination, and cerebellar atrophy. FDG-PET
and Tc-ECD-SPECT studies showed that the basal
ganglia and cerebellum were severely impaired in
Fig. 2. ECD-SPECT (a, b) and FDG-PET studies (c, d) of Brain.
Slices including the basal ganglia (a, c) and cerebellar hemisphere (b, d). The CBF and FDG uptake
were decreased in the basal ganglia (thin black arrows), thalamus (thick black arrows), and cerebel-
lum (white arrows).
A Japanese Boy with H-ABC 167 Download full-text
this patient. There were no specific laboratory
findings. Our findings are likely to share the same
pathophysiological background as those in the
patients reported by van der Knaap (2002) and
Mercimek-Mahmutoglu et al. (2005).
Levodopa-carbidopa was partially effective
in our patient. However, MRI and laboratory
findings were not suggestive of a dopa-responsive
dystonia (Fukuyama and Kish 1999), such as
Segawa disease and tyrosine hydroxylase defi-
ciency, in our patient. We also excluded dopa
non-responsive dystonias, including glutaric acid-
uria type 1, biotinidase deficiency (Worthen et al.
1994), congenital disorder of glycoprotein syn-
drome, Wilson disease, Niemann-Pick disease
type C, ataxia-telangiectasia and glucose transport
protein 1 deficiency on the basis of laboratory and
clinical findings. Pontocerebellar hypoplasia type
II, neuronal intranuclear hyaline inclusion disease,
and Lesh–Nyhan syndrome were ruled out based
on the MRI findings.
Hypomyelinating encephalopathy was also
suspected in our case. However, peroxisomal dis-
orders, beta-oxygenation disorders, hyperglycin-
emia, Tay–Sachs disease, Cockayne syndrome,
and Pelizaeus-Merzbacher disease were excluded
on the basis of clinical and laboratory findings.
Vanishing white matter (van der Knaap et al.
1997) and van der Knaap disease (van der Knaap
et al. 1995) were also ruled out because of the
lack of typical MRI findings.
Some metabolic disorders causing dystonia
and cerebellar atrophy, such as glutaric aciduria
type 1 (al Aqeel et al. 1994), alpha-ketoglutaric
aciduria, 4-hydroxybutyric aciduria (Rahbeeni et
al. 1994), and 3-methylglutaconic aciduria were
excluded by the results of GC-MS.
After a thorough differential diagnosis as
outlined above, H-ABC was thought to be the
most likely disease. It is not known why our
patient initially exhibited hemidystonia despite
symmetric alteration of the basal ganglia, as seen
on MRI. However, because gradual progression
has been reported in severe H-ABC and because
his extrapyramidal symptoms appeared on the
other side after hospitalization, the impairment of
the right basal ganglia might have progressed fur-
ther than that of the left. Considering his brain
findings, his unilateral symptoms would likely
have become bilateral had he not received our
treatment. From this point of view, levodopa-
carbidopa may be effective for ameliorating the
dystonia in H-ABC.
We thank Drs. Junichi Takahashi (Department
of Pediatrics, Kameda Medical Center) and Marjo S.
van der Knaap (Child Neurology Free University
Medical Center) for providing thoughtful and kind
suggestions about our patient’s diagnosis.
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