Report

Mutations in the Gene Encoding Peroxisomal Sterol Carrier Protein X
(SCPx) Cause Leukencephalopathy with Dystonia and Motor Neuropathy
S. Ferdinandusse,1 P. Kostopoulos,2 S. Denis,1 H. Rusch,1 H. Overmars,1 U. Dillmann,2
W. Reith,3 D. Haas,4 R. J. A. Wanders,1 M. Duran,1 and M. Marziniak2
1

Laboratory Genetic Metabolic Diseases, Academic Medical Center at the University of Amsterdam, Amsterdam; Departments of 2Neurology
and 3Neuroradiology, Saarland University, Homburg/Saar, Germany; and 4Center for Metabolic Diseases, University Children’s Hospital,
Heidelberg, Germany

In this report, we describe the first known patient with a deficiency of sterol carrier protein X (SCPx), a peroxisomal
enzyme with thiolase activity, which is required for the breakdown of branched-chain fatty acids. The patient
presented with torticollis and dystonic head tremor as well as slight cerebellar signs with intention tremor, nystagmus,
hyposmia, and azoospermia. Magnetic resonance imaging showed leukencephalopathy and involvement of the
thalamus and pons. Metabolite analyses of plasma revealed an accumulation of the branched-chain fatty acid
pristanic acid, and abnormal bile alcohol glucuronides were excreted in urine. In cultured skin fibroblasts, the
thiolytic activity of SCPx was deficient, and no SCPx protein could be detected by western blotting. Mutation
analysis revealed a homozygous 1-nucleotide insertion, 545_546insA, leading to a frameshift and premature stop
codon (I184fsX7).
To date, several peroxisomal fatty-acid oxidation defects
due to deficiency of a single enzyme and/or protein in
the peroxisome have been identified, including X-linked
adrenoleukodystrophy (MIM 300100), Refsum disease (MIM 266500), and a-methylacyl-CoA racemase
(AMACR) deficiency (MIM 604489). Peroxisomes play
an important role in the breakdown of very-long-chain
fatty acids (VLCFAs), polyunsaturated fatty acids, and
branched-chain fatty acids, like phytanic and pristanic
acid, but also have a role in the formation of primary
C24-bile acids by b-oxidation of the bile-acid intermediates di- and trihydroxycholestanoic acids (DHCA and
THCA).1 Peroxisomes in mammals contain two sets of
b-oxidation enzymes, which differ in substrate specificity1 (fig. 1). Straight-chain acyl-CoA oxidase (SCOX) is
responsible for the initial oxidation of VLCFAs, whereas
branched-chain acyl-CoA oxidase (BCOX) oxidizes the
branched-chain acyl-CoAs pristanoyl-CoA, DHC-CoA,
and THC-CoA. The enoyl-CoA esters of both straightand branched-chain fatty acids are then hydrated and
subsequently dehydrogenated by the same enzyme: Dbifunctional protein (DBP). The second multifunctional
protein in the peroxisome, L-bifunctional protein, is involved in the degradation of long-chain dicarboxylic ac-

ids, but these acids are also handled by DBP.2 The last
step of the b-oxidation process, thiolytic cleavage, is performed by sterol carrier protein X (SCPx) in the case of
branched-chain substrates, whereas straight-chain substrates are most likely handled by both SCPx and the
classic 3-ketoacyl-CoA thiolase.1 In addition to the boxidation enzymes, AMACR is required for b-oxidation
of branched-chain substrates. Since the peroxisomal boxidation system is stereospecific and only accepts S isomers as substrate—and pristanic acid naturally occurs
as a mixture of two different diastereomers—(2R)-pristanic acid must first be converted to its S isomer before
it can be degraded via b-oxidation (fig. 1). AMACR is
responsible for this conversion and also converts (25R)DHCA and (25R)-THCA, formed exclusively from cholesterol, into their respective S isomers. Consequently,
patients with a deficiency of AMACR accumulate pristanic acid, DHCA, and THCA.
In addition to patients with an isolated deficiency of
SCOX (MIM 264470) or DBP (MIM 261515),1 a patient with a tentative peroxisomal 3-ketoacyl-CoA thiolase deficiency has been described, but reinvestigation of
this patient revealed the true defect to be at the level
of DBP.3 All patients with a peroxisomal fatty-acid ox-

Received January 11, 2006; accepted for publication March 7, 2006; electronically published March 29, 2006.
Address for correspondence and reprints: Dr. S. Ferdinandusse, Academic Medical Center, Laboratory Genetic Metabolic Diseases, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. E-mail: s.ferdinandusse@amc.uva.nl
Am. J. Hum. Genet. 2006;78:1046–1052. 䉷 2006 by The American Society of Human Genetics. All rights reserved. 0002-9297/2006/7806-0014$15.00

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Figure 1

Schematic representation of the fatty-acid b-oxidation machinery in human peroxisomes catalyzing the oxidation of VLCFACoAs and branched-chain fatty acyl-CoAs (pristanoyl-CoA and THC-CoA). Because BCOX can handle only S isomers, (2R)-pristanoyl-CoA
and (25R)-THC-CoA first have to be converted to their S isomers by AMACR. Subsequently, the branched-chain fatty acyl-CoAs are oxidized
by BCOX, DBP, and SCPx, whereas oxidation of VLCFA-CoAs involves SCOX, DBP, and both 3-ketoacyl-CoA thiolase and SCPx. “VLCFACoA n-2” represents VLCFA-CoA shortened by two carbon atoms after one b-oxidation cycle.

idation defect present with neurological symptoms. In
most of the disorders, the neurological symptoms are
present from birth or childhood, but, in the majority of
patients with Refsum disease and AMACR deficiency,
these symptoms develop only after adolescence.
The patient we describe here, a 45-year-old white man,
was admitted to the hospital with a 28-year history of
dystonic head tremor and spasmodic torticollis. The patient reported that he had noticed a stutter for the first
time when he was a 7-year-old boy. At age 17 years, he
observed a spasmodic torticollis to the left side, with a
dystonic head tremor in stressful situations. At age 29
years, he consulted a urologist for a fertility checkup,
and hypergonadotrophic hypogonadism and azoospermia were diagnosed. The 44-year-old brother of the patient was fertile and did not have any neurological symptoms, whereas the 41-year-old brother was reported to
have similar neurological complaints as the patient. According to his mother, he is infertile and stutters; however, he declined to undergo neurological examination
or further diagnostic tests.
During the past several years, the dystonic symptoms
in the patient had worsened, and, when he was age 44
years, additional clinical and laboratory investigations
were performed. Cranial magnetic resonance imaging
(MRI) showed bilateral hyperintense signals in the thalamus, butterfly-like lesions in the pons, and lesions in
the occipital region, without gadolinium enhancement
(fig. 2). Neurological examination revealed hyposmia,
pathological saccadic eye movements, and a slight hypoacusis, but it was otherwise a normal cranial nerve
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examination. There were brisk deep-tendon reflexes of
the upper extremities but diminished reflexes of the
lower extremities, plantar sole responses, no pareses,
normal superficial sensation (pin-prick, light touch, and
temperature), and a reduced vibration sense of 4/8 at
the lateral malleoli. There were signs of slight cerebellar
ataxia with a left-sided intention tremor, balance and
gait impairment, and a slight left-sided rebound phenomenon. Ophthalmologic investigation revealed no
abnormalities.
A complete blood count, coagulation analysis, and
serum electrolytes and liver enzyme levels were normal.
Serum cholesterol was slightly elevated at 5.7 mmol/liter.
Copper and ceruloplasmin levels in serum and urine
were within the normal range. A lumbar puncture
yielded clear, colorless cerebrospinal fluid (CSF) at normal pressure. The CSF contained 1 cell/ml, and the protein, lactate, and glucose concentrations were normal.
Because of the absence of pleiocytosis and the negative
results for oligoclonal bands, borrelia serology, and virological examination of CSF, an inflammatory central
nervous process was considered to be very unlikely.
Nerve conduction studies of the lower extremities
showed a predominantly motor and slight sensory neuropathy, with conduction blocks in the tibial nerves, reduced motor action potentials in the left peroneal nerve,
and a reduced amplitude of the left sural nerve (table
1). Nerve conduction velocities of the right median nerve
displayed a reduced conduction velocity, normal F-wave
latencies, and normal motor action potentials. The motor-evoked potentials of the abductor digiti minimi mus-

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Figure 2

A, Axial T2-weighted MRI showing bilateral pons lesions. B, Axial T2-weighted MRI showing bilateral intense signals in
the thalamus. C, Coronal T1-weighted MRI showing bilateral involvement of the pons and thalamus.

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cle were prolonged and revealed double-sided lesions of
the pyramidal tract to the upper extremity. After cortical
stimulation, motor-evoked potentials of the tibial anterior muscle were abolished, also suggesting bilateral pyramidal lesions to the legs. The sensory-evoked potentials showed bilateral lesions of the posterior funiculus
of the spinal cord. The bilateral latencies of peak V of
the acoustic-evoked potentials and the interpeak latency
between peaks I and V and between peaks III and V
were prolonged, corresponding to a bilateral pontine
lesion (table 2). The blink reflex, with a reproducible
prolonged R2c latency after left stimulation, was compatible with a medullary lesion. Nystagmography showed
a spontaneous nystagmus to the left side, which could
be suppressed by fixation; square wave jerks and slowed
saccades could be detected, indicating vestibulo-cerebellar lesions. Extracranial and transcranial Doppler
sonography showed normal results.
Because of a clinical suspicion of AMACR deficiency,
the plasma levels of the branched-chain fatty acids pristanic acid and phytanic acid were measured. The level
of pristanic acid was markedly increased (39.8 mmol/
liter; control range 0–3.1 mmol/liter), and the level of
phytanic acid was slightly increased (10.1 mmol/liter;
control range 0–9 mmol/liter), whereas the level of the
straight-chain fatty acid C26:0 was just above the highest value of the normal range (table 3). Traces of the
bile acid intermediates DHCA and THCA were detectable in both plasma and urine. Subsequent investigations
in cultured skin fibroblasts of the patient revealed a
strongly reduced b-oxidation activity with pristanic acid
as substrate (131 pmol/h/mg; control range 691–2,178
pmol/h/mg), normal C26:0 b-oxidation activity (1,048
pmol/h/mg; control range 1,025–2,994 pmol/h/mg), and
normal C26:0 level (0.31 mmol/g; control range 0.18–
0.38 mmol/g). The biochemical abnormalities were indicative of AMACR deficiency, but, surprisingly, direct
measurement of AMACR activity in fibroblasts showed
no abnormalities. Because of the reduced pristanic acid
b-oxidation activity, we measured the activity of all the
other enzymes involved in the peroxisomal breakdown
of branched-chain fatty acids. BCOX activity was normal, and DBP activity was even increased, but the activity of SCPx, measured as described elsewhere,4 was
completely deficient in fibroblasts of the patient.
SCPx is a 58-kDa protein that consists of an aminoterminal thiolase domain and a carboxy-terminal sterol
carrier protein 2 (SCP2) domain.5,6 After import into
peroxisomes, the domains are cleaved, giving rise to a
46-kDa thiolase and a 13-kDa SCP2.4,7 Immunoblot
analysis with an antibody against SCPx revealed the absence of both the full-length 58-kDa SCPx and the 46kDa thiolase domain of SCPx in fibroblasts of the patient
(fig. 3A). Because SCP2 also has its own promoter,5
immunoblot analysis with an antibody against SCP2

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Table 1
Electrophysiological Findings in the SCPx-Deficient Patient
A. Nerve Conduction Studies
PATIENT

Tibial nerve right
Tibial nerve left
Peroneal nerve right
Peroneal nerve left
Median nerve right
Sural nerve right
Sural nerve left

NORMAL RANGE

Amplitude

NCV
(m/s)

F-Wave
(ms)

Amplitude

NCV
(m/s)

F-Wave
(ms)

9.6/3.9a mV
6.0/2.4amV
2.9/2.9amV
2.2/1.3amV
7 mV
4 mV
2.4 mV

44
45
46
44
43
42
44

56.5
60.7
ND
ND
25
NA
NA

12.6 mV
12.6 mV
12.7 mV
12.7 mV
15 mV
14 mV
14 mV

140
140
140
140
150
141
141

!51
!51

!26

NA
NA

B. Sensory-Evoked Potentials
PATIENT

Tibial nerve right
Tibial nerve left
Median nerve right
Median nerve left

NORMAL RANGE

P40
(ms)

ERB
(ms)

N20
(ms)

P40
(ms)

ERB
(ms)

N20
(ms)

NPR
NPR
NA
NA

NA
NA
11
11

NA
NA
24.6
24

!45.7
!45.7

NA
NA
!12.1
!12.1

NA
NA
!22
!22

NA
NA

C. Motor-Evoked Potentials
PATIENT

NORMAL RANGE

Cortical
(ms)

IF
(ms)

F-Wave
(ms)

Cortical
(ms)

IF
(ms)

F-Wave
(ms)

NPR
NPR
23.1
23.4

19
18.5
15.3
14.4

60
62
27.2
28

!33.6
!33.6
!22.2
!22.2

!17.5
!17.5
!15.4
!15.4

!51
!51
!29
!29

TA muscle right
TA muscle left
ADM muscle right
ADM muscle left
D. Blink Reflex

PATIENT

Right
Left

NORMAL RANGE

R1

R2

R2c

R1

R2

R2c

11.5
11.0

35.6
38.1

37.1
42.8

!12.2
!12.2

!39.1
!39.1

!40.1
!40.1

NOTE.—ADM p abductor digiti minimi; IF p intervertebral foramen; NA p not applicable; NCV p nerve conduction velocities; ND p not done; NPR p no potential
recordable; TA p tibial anterior.
a
Shown as distal stimulation/proximal stimulation.

showed the normal presence of the 13-kDa SCP2. The
classic peroxisomal 3-ketoacyl-CoA thiolase was also
normally present in fibroblasts of the patient, as shown
by immunoblot analysis. To confirm the SCPx deficiency
Table 2
Acoustic-Evoked Potentials in the SCPx-Deficient Patient

ACOUSTIC-EVOKED
POTENTIALS
Right
Left
Normal range

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LATENCY
(ms)

INTERPEAK LATENCY
(ms)

I

III

V

I-III

III-V

I-V

1.45
1.46
!1.86

4.05
4.12
!4.16

6.70
6.65
!6.23

2.61
2.66
!2.72

2.64
2.52
!2.31

5.25
5.19
!4.67

at the molecular level, we amplified the SCPx cDNA in
three overlapping fragments, followed by sequencing,
and found a homozygous 1-nt insertion (of an adenine)
at position 545 (545_546insA) (fig. 3B) leading to a
frameshift and premature stop codon (I184fsX7). Homozygosity was confirmed at the genomic level, and the
patient’s mother was heterozygous at the genomic level.
No biochemical abnormalities were found in plasma or
urine from the patient’s mother.
Because of the elevated pristanic acid levels, the patient began a phytanic acid–restricted diet. After 9 mo
of the diet, the phytanic acid levels in plasma were within
the normal range and the pristanic acid levels had decreased to 6.2 mmol/liter. Another analysis, performed

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Table 3
Biochemical Data on Plasma and Fibroblasts from the Patient
and Control Subjects
SAMPLE AND
BIOCHEMICAL MEASURE
Plasma (mmol/liter):
Phytanic acid
Pristanic acid
DHCA
THCA
C26:0
Fibroblasts:
C26:0a
C26:0 b-oxidationb
Pristanic acid b-oxidationb
Phytanic acid a-oxidationb
AMACR activityc
SCOX activityc
BCOX activityc
DBP-hydratase activityc
DBP-dehydrogenase
activityc
SCPx activityc

CONTROL SUBJECTS
PATIENT Mean Ⳳ SD

Range

10.1
39.8
.1
.1
1.34

2.8 Ⳳ 2.1
.3 Ⳳ .4
.003 Ⳳ .014
.007 Ⳳ .019
.77 Ⳳ .19

.31
1,048
131
46
167
293
211
433

.29 Ⳳ .06
.18–.38
1,552 Ⳳ 399 1,025–2,994
1,450 Ⳳ 393 691–2,178
62 Ⳳ 23
32–173
99 Ⳳ 28
45–149
90 Ⳳ 28
49–151
178 Ⳳ 79
87–340
278 Ⳳ 88
121–600

217
NDd

93 Ⳳ 53
86 Ⳳ 28

knockout mice contain increased levels of 3a,7a,12atrihydroxy-27-nor-5b-cholestane-24-one, which is
an alternative metabolite of the substrate of SCPx,
3a,7a,12a-trihydroxy-24-keto-cholestanoyl-CoA, and
is formed by decarboxylation.14 Interestingly, tandem
mass spectrometric analysis of urine from our patient
consistently showed large peaks, with m/z 611 and 627,

0–9
0–3.1
0–.13
0–.09
.46–1.31

25–261
49–139

a

mmol/g.
pmol/h/mg.
c
pmol/min/mg.
d
Not detectable.
b

after 14 mo of the diet, showed that the pristanic acid
levels had stabilized at a marginally elevated level (8.1
mmol/liter). The levels of C26:0 were completely normal
on both occasions (0.54 and 0.68 mmol/liter, respectively). Since the beginning of the diet, no progression
of symptoms has been observed. A follow-up cranial
MRI showed no increase of the leukoencephalopathy.
Mice with a targeted disruption of the gene encoding
SCPx develop ataxia, reduced muscle tone, and peripheral neuropathy (uncoordinated movements, unsteady
gait, and trembling) when fed a phytol-enriched diet8
and thus closely resemble their human counterpart.
The present patient also shows striking similarities to
AMACR-deficient patients, both at the clinical and at
the biochemical level. The most prominent clinical symptom of AMACR deficiency is adult-onset sensory motor
neuropathy,9–11 which was also present in our patient.
Similar to a recently described AMACR-deficient patient, our patient showed high signals in the thalamus
and pons on MRI. These gray and white matter abnormalities are present not only in SCPx and AMACR deficiencies but also in DBP deficiency.12 Remarkably, the
SCPx-deficient patient does not have retinitis pigmentosa, which is frequently observed in AMACR deficiency
and Refsum disease.9–11,13
Just like AMACR-deficient patients, our patient accumulated pristanic acid. However, only trace amounts
of the bile acid intermediates DHCA and THCA were
detectable in plasma and urine. Bile and serum of SCPx
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Figure 3

A–C, Immunoblot analysis of fibroblasts from two
control subjects, the SCPx-deficient patient, two patients with Zellweger syndrome, and one patient with RCDP type 1. A, Antibody was
used against SCPx. The arrowheads indicate the 58-kDa full-length
protein and the 46-kDa thiolase domain of SCPx. B, Antibody was
used against SCP2 (13 kDa). C, Antibody was used against peroxisomal 3-ketoacyl-CoA thiolase. The arrowheads indicate the 44-kDa
precursor form and the 41-kDa mature form of 3-ketoacyl-CoA thiolase. D, Automated sequence analysis revealed a homozygous insertion
of an adenine (545_546insA) at both the cDNA and the genomic level,
leading to a frameshift and premature stop codon (I184fsX7).

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Figure 4

Negative-ion electrospray tandem mass spectrometric analysis of urine bile acids and bile alcohols from the SCPx-deficient
patient (A), a patient with CTX (B), and a control subject (C). Abnormal glucuronic acid conjugates of bile alcohols were detected in urine
from the SCPx-deficient patient and the patient with CTX. We postulated the identity of the metabolites as follows: m/z 597, 27-nor-5bcholestanetetrol glucuronide; m/z 611, pentahydroxy-27-nor-5b-cholestane-24-one or 5b-cholestanetetrol glucuronides; m/z 613, 27-nor-5bcholestanepentol glucuronide; m/z 627, hexahydroxy-27-nor-5b-cholestane-24-one or 5b-cholestanepentol glucuronides; m/z 629, 27-nor-5bcholestanehexol glucuronide; and m/z 643, heptahydroxy-27-nor-5b-cholestane-24-one or 5b-cholestanehexol glucuronides.

which most likely correspond to pentahydroxy-27-nor5b-cholestane-24-one and hexahydroxy-27-nor-5bcholestane-24-one glucuronides, respectively (fig. 4).
In addition, compounds with m/z 613 and 629 were
abundantly present, which most likely correspond to 27nor-5b-cholestanepentol and 27-nor-5b-cholestanehexol
glucuronides, respectively (fig. 4). This may be considered indirect evidence of the inability to metabolize
3a,7a,12a-trihydroxy-24-keto-cholestanoyl-CoA and is
in full agreement with the findings in SCPx knockout
mice.14 Furthermore, the presence of large amounts of
bile alcohols in the patient’s urine suggests that the block
in bile acid biosynthesis at the level of SCPx may initiate
an alternative pathway for bile acid biosynthesis not
requiring a peroxisomal b-oxidation step—that is, the
microsomal 25-hydroxylase pathway.15 Metabolites of
this pathway, bile alcohols, are also found in patients
with cerebrotendinous xanthomatosis (CTX [MIM
213700])16 (fig. 4), who have a deficiency of the mitochondrial 27-hydroxylase, which is a step upstream of
SCPx in bile acid biosynthesis. In plasma of the SCPxwww.ajhg.org

deficient patient, 3a,7a,12a-trihydroxy-27-nor-5b-cholestane-24-one could not be detected, most likely because
this compound is not ionized efficiently and therefore
cannot be detected using our tandem mass spectrometric
method.
In vitro studies have shown that both SCPx and the
classic 3-ketoacyl-CoA thiolase can handle VLCFAs as
substrates.1 Patients with rhizomelic chondrodysplasia
punctata (RCDP) type 1 (MIM 215100) lack 3-ketoacylCoA thiolase in their peroxisomes because of a defect
in PEX7, the gene encoding the peroxisome-targeting
signal 2 receptor.17,18 Although 3-ketoacyl-CoA thiolase
is mistargeted in RCDP type 1, no abnormality in
VLCFA b-oxidation has been observed in patients,19,20
which suggests that SCPx can take over its function for
the straight-chain fatty acyl-CoAs. The fact that our
SCPx-deficient patient had normal levels of VLCFAs suggests that the classic 3-ketoacyl-CoA thiolase also can
maintain normal VLCFA b-oxidation activity in the absence of SCPx.
In conclusion, we have identified the first known pa-

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tient with SCPx deficiency. This patient presented with
dystonia, a predominant motor neuropathy, advanced
leukoencephalopathy with cerebellar signs, and involvement of the pyramidal tract and the posterior columns.
Our findings imply that the group of single peroxisomal
b-oxidation enzyme deficiencies extends to AMACR,
SCOX, DBP, and SCPx deficiencies. The elucidation of
the true defect in this case has increased our knowledge
of the peroxisomal b-oxidation system and its substrates
and of the clinical consequences of metabolic derangements associated with defects in the peroxisomal b-oxidation system.

Acknowledgments
We thank A. E. van Lint and C. W. T. van Roermund, for
technical assistance, and P. G. Barth and M. Engelen, for helpful discussion. This work was supported by the Netherlands
Organisation for Scientific Research (NWO grant 916.46.109)
and by the FP6 European Union Project “Peroxisome” (LSHGCT-2004-512018).

Web Resources
The URL for data presented herein is as follows:
Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm
.nih.gov/Omim/ (for X-linked adrenoleukodystrophy; Refsum
disease; AMACR, SCOX, and DBP deficiencies; CTX; and RCDP
type 1)

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The American Journal of Human Genetics

Volume 78

June 2006

www.ajhg.org