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 oxidation 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 definition requires only two out of these three elements. Neonatal seizure: It is defined as seizures in neonates, it can be epileptic seizure or not.
Peroxisomes are organelles responsible for multiple metabolic pathways, mainly related to metabolism of lipids and peroxides. Lack of peroxisomes or dysfunction in any of their normal functions is the cellular basis for human peroxisomal disorders (PDs). PDs are clinically and genetically heterogeneous and can be classified mainly into three categories—peroxisome biogenesis disorders (PBDs), single peroxisomal enzyme deficiencies (SEDs) and contiguous gene syndrome (Table 1) [1]. The PBDs include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD) and rhizomelic chondrodysplasia punctata (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 peroxisomal matrix and membrane proteins. The second group includes disorders resulting from the deficiency of a single peroxisomal enzyme activity. About a dozen of such peroxisomal enzyme deficiencies have been identified [2].
⇑ 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:
[email protected] (J.-F. Lu).
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
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Table 1 Classification of peroxisomal disorders. Disorders of peroxisome biogenesis
Disorders of single peroxisomal enzyme
Contiguous gene syndrome
Zellweger spectrum Zellweger syndrome Neonatal adrenoleukodystrophy Infantile Refsum disease
X-linked adrenoleukodystrophy Acyl-CoA-oxidase deficiency D-bifunctional protein deficiency Thiolase deficiency 2-Methylacyl-CoA-racemase (AMACR) deficiency DHAP acyltransferase deficiency
CADDS
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 deletion 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 XALD, the most common PD, is estimated at between 1:20,000 and 1:50,000 [4]; the prevalence of PBDs is estimated to be 1:50,000 in US [5] and 1:500,000 in Japan [6]. The precise diagnosis of PDs requires a complex biochemical and genetic analyses. However, the life span of affected patients is usually limited. These conditions make it difficult to conduct satisfactory clinical investigations in peroxisomal disorders [7]. The epileptic seizures 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 congenital anomaly syndrome characterized by craniofacial abnormalities, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata [8,9]. Psychoneurologic symptoms are mainly manifested 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 demonstrate 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 developed 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 generalized tonic–clonic seizures [7]. The epileptogenic foci usually 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 clinically 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 craniofacial features are similar to that of ZS but are less pronounced. 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
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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 frequency 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 metaphyseal cupping, coronal clefts of the vertebral bodies, generalized epiphyseal stippling (chondrodysplasia punctata) and other evidence of disturbed ossification. Abnormalities of the central nervous system include cerebral and cerebellar atrophy, abnormalities of myelination and neuronal migration defects involving the midbrain [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. Seizure 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-oxidation of saturated very-long-chain fatty acids (VLCFAs). Onset of symptoms is usually at approx. 7.2 years
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(ranges 2.75–10 years) with changes in behavior, including emotional lability, withdrawal or hyperactive behavior [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 correspondence with the deteriorated demyelinating process [25]. 4.2. Defects of peroxisomal b-oxidation: Acyl-CoAoxidase deficiency, D-bifunctional protein deficiency (DBPD), peroxisomal thiolase deficiency, 2-methylacylCoA racemase deficiency Although there are defects in only a single peroxisomal 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 discriminate 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 psychomotor development, and neurological deterioration [27]. All the signs and symptoms are similar to that of NALD. About 90% of patients exhibit neonatal hypotonia 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 manifest Zellweger-like clinical phenotype including hypotonia, craniofacial dysmorphia and neonatal seizures [29,30]. Pathologic studies in DBPD revealed neuronal migration disorders similar to those in ZS [7,29,31]. Epileptic 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 profound hypotonia, intractable seizures since neonatal period 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-
Table 2 Comparisons of neurological manifestations of Zellweger spectrum disorders.
Epileptic seizure Neonatal seizure Seizure intractability Seizure pattern Neuronal migration disorder
ZS
NALD
IRD
+++ ++ + Partial motor +++
+++ + ++ Generalized seizure; epileptic spasms/infantile spasms +
+ + – +
–: Absent; +: mild or occasionally present; ++: moderate or frequently present; +++: severe or almost constantly present; ZS: Zellweger syndrome; NALD: neonatal adrenoleukodystrophy; IRD: infantile Refsum disease.
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Table 3 Comparisons of neurological manifestations in different defects of peroxisomal b-oxidation. Neurological symptom
Neonatal hypotonia Neonatal seizures Seizures after neonatal period Macrocephaly Retinopathy Hearing loss Peripheral neuropathy Neuronal migration defect Leukodystrophy
Childhood X-ALD
Racemase
+ + ± +
Acyl-CoA oxidase
D-BP
Peroxisomal thiolase deficiency
Biogenesis (ZSS)
CADDS
+ + +
+ + + +
+ +
+ + +
+
+
+ +
+ +
+
+ + +a + +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 comparison 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 variable degrees of severity. However, central nervous system is always affected and exhibits different clinical manifestations. Epileptic seizures are a common presentation in patients with PBDs and certain peroxisomal boxidation 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 diseases. Seizures of these patients may be difficult to control 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 biochemical abnormalities, such as aberrant fatty acid compositions 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-activated receptor-a (PPAR-a) agonist, has been shown to have anticonvulsive properties and may be related to the underlying mechanisms of the ketogenic diet regimen [40]. These findings may provide hope into future application of ketogenic diet in the treatment of intractable 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 paroxysmal 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 characteristics 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 assistance of manuscript preparation. This work was sup-
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