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Peroxisomal disorders with infantile seizures

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Brain & Development 33 (2011) 777–782

www.elsevier.com/locate/braindev

Review article

Peroxisomal disorders with infantile seizures

Jao-Shwann Liang a, Jyh-Feng Lu b,⇑
a
Department of Pediatrics and Medical Research, Far Eastern Memorial Hospital, Taipei, Taiwan
b
School of Medicine, Fu Jen Catholic University, Taipei, Taiwan

Received 14 January 2011; received in revised form 11 February 2011; accepted 12 February 2011

Abstract

Peroxisomes are organelles responsible for multiple metabolic pathways including the biosynthesis of plasmalogens and the oxi-
dation of branched-chain as well as very-long-chain fatty acids (VLCFAs). Peroxisomal disorders (PDs) are heterogeneous groups
of diseases and affect many organs with varying degrees of involvement. Even pathogenetically distinct PDs share some common
symptoms. However, several PDs have uniquely characteristic clinical findings. The durations of survival in PDs are also variable.
Infants with PDs are usually presented with developmental delay, visual and hearing impairment. Generalized hypotonia is present
in severe cases. Epileptic seizures are also a common characteristic of patients with certain PDs. Nonetheless, the classification and
evolution of epilepsy in PDs have not been elucidated in detail. Here, we review the relevant literatures and provide an overview of
PDs with particular emphasis on the characteristics of seizures in infants.
Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Keywords: Peroxisomal disorders; Infantile seizures; Epilepsy

1. Definition of terms 2. Introduction

Epileptic spasms: Epileptic seizures characterized by
brief axial contraction, in flexion, extension or mixed,
symmetric or asymmetric, lasting from a fraction of a
second to 1–2 s. This type of epileptic seizures can be
associated with or without particular EEG pattern,
hypsarrhythmia.
Infantile spasms: Epileptic spasms in clusters with
hypsarrhythmia that start in the first year of life.
West syndrome: It is the triad of infantile spasms, a
pathognomonic EEG pattern (called hypsarrhythmia),
and mental retardation – although the international def-
inition requires only two out of these three elements.
Neonatal seizure: It is defined as seizures in neonates,
it can be epileptic seizure or not.
⇑ Corresponding author. Address: School of Medicine, Fu Jen
Catholic University, 510 Chungcheng Rd., Hsinchuang, Taipei County
24205, Taiwan. Tel.: +886 2 29053464; fax: +886 229052096.
E-mail address: 049696@mail.fju.edu.tw (J.-F. Lu).
Peroxisomes are organelles responsible for multiple
metabolic pathways, mainly related to metabolism of
lipids and peroxides. Lack of peroxisomes or dysfunc-
tion in any of their normal functions is the cellular basis
for human peroxisomal disorders (PDs). PDs are clini-
cally and genetically heterogeneous and can be classified
mainly into three categories—peroxisome biogenesis
disorders (PBDs), single peroxisomal enzyme deficien-
cies (SEDs) and contiguous gene syndrome (Table 1)
[1]. The PBDs include Zellweger syndrome (ZS), neona-
tal adrenoleukodystrophy (NALD), infantile Refsum
disease (IRD) and rhizomelic chondrodysplasia puncta-
ta (RCDP) type I. They are all caused by defects in PEX
genes, which encode peroxins, proteins necessary for
peroxisome biogenesis and the import of the peroxi-
somal matrix and membrane proteins. The second group
includes disorders resulting from the deficiency of a sin-
gle peroxisomal enzyme activity. About a dozen of such
peroxisomal enzyme deficiencies have been identified [2].

0387-7604/$ - see front matter Ó 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.braindev.2011.02.004
 Author's personal copy

778 J.-S. Liang, J.-F. Lu / Brain & Development 33 (2011) 777–782

Table 1
Classification of peroxisomal disorders.
Disorders of peroxisome biogenesis Disorders of single peroxisomal enzyme Contiguous gene syndrome
Zellweger spectrum X-linked adrenoleukodystrophy CADDS
Zellweger syndrome Acyl-CoA-oxidase deficiency
Neonatal adrenoleukodystrophy D-bifunctional protein deficiency
Infantile Refsum disease Thiolase deficiency
2-Methylacyl-CoA-racemase (AMACR) deficiency
DHAP acyltransferase deficiency
Rhizomelic chondrodysplacia punctata Alkyl DHAP synthase deficiency
Refsum disease secondary to PEX7 mutation Hyperoxaluria type I
Unclassified/atypical PBD Adult Refsum’s disease
Acatalasemia
Mulibrey nanism
Other defects in peroxisomal b-oxidation
PBD: peroxisome biogenesis disorder; CoA:coenzyme A; DHAP: dihydroxyacetone phosphate; CADDS:contiguous ABCD1 DXS1357E deletion
syndrome.

Even though the peroxisomes are morphologically intact
and functioning in patients with SEDs, the clinical and
neurological manifestations could be as severe as PBDs.
In addition, a novel group of patients with phenotype
resembling ZS was reported due to a contiguous dele-
tion spanning the 50 ends of the ABCD1 gene, which is
defective in X-linked adrenoleukodystrophy (X-ALD),
and DXS1357E in Xq28 (CADDS) [1,3].
The incidence of PDs is relatively low and is variable
among populations. For example, the prevalence of X-
ALD, the most common PD, is estimated at between
1:20,000 and 1:50,000 [4]; the prevalence of PBDs is esti-
mated to be 1:50,000 in US [5] and 1:500,000 in Japan
[6]. The precise diagnosis of PDs requires a complex bio-
chemical and genetic analyses. However, the life span of
affected patients is usually limited. These conditions
make it difficult to conduct satisfactory clinical investi-
gations in peroxisomal disorders [7]. The epileptic sei-
zures are common in patients with PDs, but the
classification and evolution of epilepsy in PDs have
not been elucidated in details. In this article, we review
the literatures with emphasis on the seizure pattern
and neurological aspects of specific peroxisomal diseases
in infants.
3. Clinical and neurological manifestations
3.1. Peroxisome biogenesis disorders (PBDs)
3.1.1. Zellweger syndrome spectrum (ZSS) disorders
3.1.1.1. Zellweger syndrome (ZS). ZS is a multiple con-
genital anomaly syndrome characterized by craniofacial
abnormalities, eye abnormalities, neuronal migration
defects, hepatomegaly, and chondrodysplasia punctata
[8,9]. Psychoneurologic symptoms are mainly mani-
fested at birth or in the neonatal period. Death usually
occurs within the first year of life due to the failure of
developmental progress, although a few patients could
survive beyond that and reach some developmental
milestones [10]. The brain abnormalities in ZS demon-
strate a unique neuronal migration defect. There are
areas of cortical dysplasia, polymicrogyria, Purkinje cell
heterotopia, and abnormalities of the olivary nucleus
[11]. Based on Heymans’ survey of 114 patients with
ZS reported in the literature, 56 out of 61 (92%) patients
with available information developed epileptic seizures
[5]. In Takahashi’s series, about 70% of patients devel-
oped epileptic seizures in neonatal period. The pattern
started as partial motor seizure in the arms or legs or
facial muscles which almost never culminates to general-
ized tonic–clonic seizures [7]. The epileptogenic foci usu-
ally correlated to the neuronal migration defects in
patients with ZS, however, some epileptogenic foci
could also occur in other regions [7,12].
3.1.1.2. Neonatal adrenoleukodystrophy (NALD) and
infantile Refsum disease (IRD). Although NALD and
IRD appear to be symptomatically distinct from ZS,
they are continuous spectrum of disease severity clini-
cally and pathologically; ZS is at the most severe end
of the spectrum, whereas IRD represents the mildest
syndromic phenotype [13]. Survival of mildly affected
patients into adulthood had been reported. The milder
presentation and longer life span among patients of
these disorders result in more varied initial presentations
and progress histories. The boundaries between children
diagnosed as NALD or IRD are often blurred, so it
seems more appropriate to consider these disorders as
a continuum of peroxisome deficiency [14]. The majority
of the affected children exhibit hypotonia but attain
some degree of psychomotor development. The cranio-
facial features are similar to that of ZS but are less pro-
nounced. On the contrary, the development of
sensorineural hearing loss and retinitis pigmentosa in
these patients are more common and apparent than in
ZS. Neuronal migration defects are not consistently
 Author's personal copy
J.-S. Liang, J.-F. Lu / Brain & Development 33 (2011) 777–782
present in patients with NALD; they were only observed
in 20% of the patients [15–18]. Moreover, there was no
significant correlation between seizures and neuronal
migration defects in these patients [7,17]. Seizures may
either be present in the neonatal period or manifest later.
The epileptic seizures in patients with NALD are always
generalized, with tonic, clonic and myoclonic varieties.
Both epileptic spasms and infantile spasms have been
reported [19–21]. In comparison with ZS, the seizure fre-
quency and intractability are more severe in NALD. In
IRD, epileptic seizures and neonatal seizure had also
been observed [18]. The comparison of neurological
manifestations in Zellweger spectrum disorders is listed
in Table 2.
3.1.1.3. Rhizomelic chondrodysplasia punctata (RCDP).
The main clinical features of RCDP include shortening
of the proximal long bones (rhizomelia) with metaphy-
seal cupping, coronal clefts of the vertebral bodies, gen-
eralized epiphyseal stippling (chondrodysplasia
punctata) and other evidence of disturbed ossification.
Abnormalities of the central nervous system include
cerebral and cerebellar atrophy, abnormalities of myeli-
nation and neuronal migration defects involving the mid-
brain [22]. Most RCDP children have manifested
profound growth and psychomotor retardation. Seizures
are common. In White’s study, 84% of individuals who
lived beyond 2 months of age developed seizures [23].
The average age of seizure onset was 0.4 ± 2.2 years. Sei-
zure types included absence, myoclonic, tonic, and tonic–
clonic. Different seizure types could evolve in the same
patient with age. However, the EEG often showed
non-specific generalized changes [23].
The lifespan is broad with some children dying in the
first year and others surviving into young adulthood.
The degree of plasmalogen deficiency correlates directly
with phenotypic severity [24].
4. Single enzyme deficiency
4.1. X-linked adrenoleukodystrophy (X-ALD)
X-ALD is the most common PD with impaired b-oxi-
dation of saturated very-long-chain fatty acids (VLC-
FAs). Onset of symptoms is usually at approx. 7.2 years
Table 2
Comparisons of neurological manifestations of Zellweger spectrum disorders.
ZS
Epileptic seizure +++
Neonatal seizure ++
Seizure intractability + ++
Seizure pattern Partial motor
Neuronal migration disorder +++
–: Absent; +: mild or occasionally present; ++: moderate or frequently present; +++: severe or almost constantly present; ZS: Zellweger syndrome;
NALD: neonatal adrenoleukodystrophy; IRD: infantile Refsum disease.
779
(ranges 2.75–10 years) with changes in behavior, includ-
ing emotional lability, withdrawal or hyperactive behav-
ior [19]. Focal or generalized seizures occur in the late
stage of the disease. The EEGs may be normal or exhibit
slowing of the background activity with a maximum in
the posterior regions corresponding to the localization
of the white matter lesions in the early stage. Slow wave
would become progressively widespread, sometimes
accompanied with paroxysmal discharges, in correspon-
dence with the deteriorated demyelinating process [25].
4.2. Defects of peroxisomal b-oxidation: Acyl-CoA-
oxidase deficiency, D-bifunctional protein deficiency
(DBPD), peroxisomal thiolase deficiency, 2-methylacyl-
CoA racemase deficiency
Although there are defects in only a single peroxi-
somal enzymatic process, these disorders can be as
severe as those in which peroxisomal activities are nearly
or completely absent. The clinical presentations of the
first three disorders resemble that of the ZSS. Moreover,
the marked clinical similarities make it impossible to dis-
criminate between the PBDs and certain single enzyme
deficiencies on clinical grounds [26]. Acyl-CoA-oxidase
deficiency was first described in 1988 in siblings with
neonatal hypotonia, seizures, severely delayed psycho-
motor development, and neurological deterioration
[27]. All the signs and symptoms are similar to that of
NALD. About 90% of patients exhibit neonatal hypoto-
nia and early-onset seizures [26,28]. The D-bifunctional
protein is involved in the b-oxidation of all fatty acids
metabolized in peroxisomes. Patients with DBPD man-
ifest Zellweger-like clinical phenotype including hypoto-
nia, craniofacial dysmorphia and neonatal seizures
[29,30]. Pathologic studies in DBPD revealed neuronal
migration disorders similar to those in ZS [7,29,31]. Epi-
leptic seizures usually develop in early infancy and are
intractable. Epileptic spasms or infantile spasms had
been reported [7,32]. Peroxisomal thiolase deficiency
had only been described in a single patient with pro-
found hypotonia, intractable seizures since neonatal per-
iod and subtle dysmorphic features [33,34]. In contrast
to all other patients with defects involving peroxisomal
b-oxidation, those with 2-methylacyl-CoA racemase
deficiency do not present seizure early in life, but epi-
NALD IRD
+++ +
+ +
–
Generalized seizure; epileptic spasms/infantile spasms
+ +
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780 J.-S. Liang, J.-F. Lu / Brain & Development 33 (2011) 777–782

Table 3
Comparisons of neurological manifestations in different defects of peroxisomal b-oxidation.
Neurological symptom Childhood Racemase Acyl-CoA D-BP Peroxisomal Biogenesis (ZSS) CADDS
X-ALD oxidase thiolase
deficiency
Neonatal hypotonia + + + + +
Neonatal seizures + + + +
Seizures after neonatal period + + + + +
Macrocephaly +
Retinopathy + + +
Hearing loss + +
Peripheral neuropathy ± + +a
Neuronal migration defect + + +
Leukodystrophy + + + +b Delayed myelination
X-ALD, X-linked adrenoleukodystrophy; D-BP:D-bifunctional protein deficiency; ZSS, Zellweger syndrome spectrum; CADDS, contiguous
ABCD1 DXS1357E deletion syndrome.
A plus sign (+) denotes presence; a minus sign () denotes absence ; a plus/minus sign (±) denotes that the clinical symptom may or may not be
present.
a
Seen in IRD.
b
Seen in NALD.

lepsy and neuropathy developed later on [19]. A com-
parison of the clinical consequences of specific defects
involving peroxisomal b-oxidation is shown in Table 3.
5. Contiguous ABCD1 DXS1357E deletion syndrome
(CADDS)
CADDS is a new contiguous-gene deletion syndrome
with novel phenotype resembling ZS [1,3]. These male
patients manifested profound neonatal hypotonia, failure
to thrive, cholestatic liver disease, accumulation of
VLCFA and short life span (<1 year). Two out of three
patients with CADDS have early-onset seizures at
2 months of age.
6. Conclusion
PDs include heterogeneous disease groups, with var-
iable degrees of severity. However, central nervous sys-
tem is always affected and exhibits different clinical
manifestations. Epileptic seizures are a common presen-
tation in patients with PBDs and certain peroxisomal b-
oxidation defects [7,14,19,25,35]. Seizures can also occur
in neonatal period or infancy. There was correlation
between earlier onset of seizures and the severity of dis-
eases. Seizures of these patients may be difficult to con-
trol despite the use of multiple anticonvulsants due to
the heterogeneous pathogenetic mechanisms involving
in PDs. Not only disordered cytoarchitecture of the
cerebral cortex resulted from neuronal migration defects
or demyelination can cause seizures, but other biochem-
ical abnormalities, such as aberrant fatty acid composi-
tions in neuronal membranes [36] or misregulation of
GABAergic signaling [37], would also contribute to
the pathogenesis of seizures in patients with PDs. The
ketogenic diet has been used as a treatment in case of
intractable childhood epilepsy, and reported to have
greater than 50% reduction in seizure frequency among
40–50% of children under the ketogenic diet [38,39].
Recently, fenofibrate, a peroxisome proliferator-acti-
vated receptor-a (PPAR-a) agonist, has been shown to
have anticonvulsive properties and may be related to
the underlying mechanisms of the ketogenic diet regi-
men [40]. These findings may provide hope into future
application of ketogenic diet in the treatment of intrac-
table seizures in certain patients with PDs. Although
EEG changes are usually non-specific in PDs, multifocal
spikes in the early stage and evolutionary diffuse slow
background activity, sometimes together with paroxys-
mal discharges in the late stage, are common features
observed among patients with PDs. In addition, EEG
in patients with certain PDs did show notable findings.
For example, epileptic spasms or infantile spasms with
hypsarrythmia have been observed in patients with
NALD and DBPD. Moreover, seizures of NALD and
DBPD are intractable.
Due to the lack of large series of studies, the epileptic
characteristics among different groups of PDs could not
be efficaciously evaluated. Based on currently available
literatures, though it seems that there were no easily
observable differences in the electroclinical characteris-
tics among patients with epilepsy classified into different
genetic complementation groups of PBDs, some specific
epileptic syndrome does exist in certain PDs. For
instance, West syndrome had been observed in the
NALD and DBPD [20,21]. However, the characteristics
of epileptic seizures in patients with different PDs should
be further clarified in the future.
Acknowledgments
We would like to thank Mr. Kevin Liu for the assis-
tance of manuscript preparation. This work was sup-
 Author's personal copy
J.-S. Liang, J.-F. Lu / Brain & Development 33 (2011) 777–782
ported in part by grants of Far Eastern Memorial Hos-
pital (FEMH-99-C-034), Taiwan.
This paper was presented in the Joint Meeting of
Infantile Seizure Society (13th Annual Meeting) and
Taiwan Child Neurology Society (14th Annual Meet-
ing), International Symposium on Epilepsy in Neuro-
metabolic Diseases, Taipei, Taiwan, March 26–28, 2010.
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