Peroxisomal disorders with infantile seizures

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.     

Molecular and clinical findings and diagnostic flowchart of peroxisomal diseases

Peroxisomal diseases are categorized into three large groups – peroxisome biogenesis disorders (PBD), single enzyme deficiencies (SED) and contiguous gene syndrome. Thirteen complementation groups and PEX genes responsible for all subgroups of PBD, plus 10 diseases and their responsible genes in SED have been identified. We have established a diagnostic system for peroxisomal diseases in Japan, and identified 45 Japanese patients with PBD, 12 patients with beta-oxidation enzyme deficiencies and more than 100 patients with adrenoleukodystrophy (ALD). It is important for effective therapy of the cerebral form of ALD to diagnose earlier after onset, and pre-symptomatic diagnosis should also be valuable. The division of diagnostic system into several specified centers of peroxisomal diseases in the whole world should be functional for overcoming these rare inherited neurometabolic diseases.     

Developmental and pathological expression of peroxisomal enzymes: their relationship of -bifunctional protein deficiency and Zellweger syndrome

We present the developmental changes of peroxisomal enzymes, catalase, -bifunctional protein ( -BF) and -bifunctional protein ( -BF), in the normal brains, and patients with -BF deficiency, a new peroxisomal disease. -BF immunoreactivity was observed in controls as early as 13 gestational weeks (GW) and increased with maturation. The adult pattern with fine granule staining of somata and dendrites became apparent in adolescence. -BF appeared at 20 GW in the cerebral cortex and Purkinje cells and positive glia appeared early in the white matter at 17 GW, and then increased with age. Catalase-positive neurons were identified in the same manner as -BF, -BF deficiency in both fetus and infant showed markedly diminished enzyme immunoreactivity. Patients demonstrate reduced -BF expression. Zellweger syndrome shows decreased expression for the three proteins. This study shows that the peroxisomal enzymes may be closely related to neuronal maturation and gliogenesis in human brain and to disturbance of neuronal migration as seen in Zellweger syndrome significant. -BF deficiency may exhibit a range of symptoms during the neonatal and early infantile periods some of which may be similar to Zellweger syndrome.     

Epilepsy in fragile X syndrome

The occurrence of seizures in patients with fragile X syndrome (Fra-X) is reported. Among the 30 patients, six had epilepsy that was particularly severe and two also showed atypical facial dysmorphism that was different from that seen in classical Fra-X. From the study performed in this series of Fra-X patients the authors arrived at the following conclusions. (1) The occurrence of seizures in Fra-X population is around 20%, as reported in the literature. (2) The EEG pattern of benign childhood epilepsy with central-temporal spikes (BCECTS) was found in only three patients (10%). (3) According to the pattern of seizures and EEGs, four groups may be recognizable, the less frequent being the uncommon group characterized by severe epilepsy unresponsive to treatment. (4) In this group atypical facial dysmorphism (although not similar in the two patients and different from the classical facial pattern of Fra-X) was found. The authors maintain that additional genetic factors might influence the clinical course and neurological aspects of Fra-X syndrome.     

The clinical spectrum of nodular heterotopias in children: report of 31 patients

Purpose: The phenotypic and etiologic spectrum in adults with nodular heterotopias (NHs) has been well characterized. However, there are no large pediatric case series. We, therefore, wanted to review the clinical features of NHs in our population. Methods: Hospital records of 31 patients with pathology or imaging‐confirmed NHs were reviewed. Two‐sided Fisher's exact t‐test was used to assess associations between distribution of NHs and specific clinical features. Key Findings: NHs were distributed as follows: 8 (26%) unilateral focal subependymal, 3 (10%) unilateral diffuse subependymal, 5 (16%) bilateral focal subependymal, 12 (39%) bilateral diffuse subependymal, and 3 (10%) isolated subcortical. The phenotypic spectrum in our population differs from that described in adults. Significant morbidity and mortality are associated with presentation in childhood. Twenty‐two of 31 patients (71%) died in the neonatal period or in childhood. Additional cerebral malformations were found in 80% and systemic malformations in 74%. The majority of patients had developmental delay, intellectual deficit, and intractable epilepsy. Patients with unilateral focal NHs were more likely to have ventriculomegaly (p = 0.027), and those with bilateral diffuse NHs more likely to have cerebellar abnormalities (p = 0.007). Isolated subcortical NHs were associated with multiple malformations (p = 0.049) and cardiac abnormalities (p = 0.027). Underlying etiology was heterogeneous and determined in only six cases (19%): del chr 1p36, del chr 15q11, pyruvate dehydrogenase deficiency, sialic acidosis type 1, Aicardi syndrome, and FLNA mutation. Significance: NHs are present in childhood as part of multiple cerebral and systemic malformations; developmental delay and refractory seizures are the rule rather than the exception. Milder forms go unrecognized until seizure onset in adulthood.     

Freeze lesion-induced focal cortical dysplasia predisposes to atypical hyperthermic seizures in the immature rat

Summary: Purpose: To determine the effects of focal cortical dysplasia on the behavioral and electrographic features of hyperthermia‐induced seizures (HSs) in rats. Methods: A right sensorimotor cortex freeze lesion was induced in postnatal day 1 (P1) rat pups, and HSs were provoked at P10 under continuous monitoring of core temperature; EEGs were recorded from the right amygdala during and after hyperthermia. Controls included both sham‐operated at P1 and naïve rats. Results: HSs began with jaw myoclonus, followed by hindlimb clonus and generalized convulsions (GCs), and terminated by a period of posthyperthermia depression. The threshold temperature and latency of jaw myoclonus were similar across the groups. However, both the threshold temperature and latency of GCs were significantly lower in lesioned pups than in controls (40.5 ± 0.5°C, n = 24, vs. 42.0 ± 0.2°C, n = 21; p < 0.001; 6.7 ± 0.6 min, n = 20, vs. 8.4 ± 0.6 min, n = 22; p < 0.05). In lesioned pups, the threshold and latencies for jaw myoclonus and hindlimb clonus were similar, whereas in controls, the progression from one to the other was marked by significant differences in both parameters. Posthyperthermia depression was longer in lesioned (13.3 ± 1.2 min, n = 21) than in control (8.0 ± 0.8 min, n = 20; p < 0.0001) pups. Ictal EEG activity was recorded during both behavioral seizures and posthyperthermia depression. Conclusions: An HS in rats with a localized freeze lesion results in lower threshold GC and prolonged ictal manifestations, thus supporting a pathophysiologic link between focal cortical dysplasia and atypical febrile seizures, conditions that have a high prevalence in children with mesial temporal lobe epilepsy.     

SPECT and MRI findings in a case of extensive neuronal migration disorder

We report a 20-year-old male with epilepsy, mild mental retardation, growth asymmetry, and MRI and SPECT features of unilateral subcortical ectopic cortex. The neurological examination showed mild growth asymmetry, hemiparesis and hemihypoesthesia and pyramidal signs on the left side. EEG showed focal abnormality in the right frontotemporal region. MRI revealed pachygyria and severe heterotopia associated with some abnormalities of ventricles and cerebellum on the right. Cortical responses were absent on stimulation of the left median and tibial nerves. Central motor conduction time from cortex to left upper extremity was prolonged in magnetic stimulation test. SPECT using 99 mTc-HMPAO revealed increased perfusion of the right subcortical region as compared with those of overlying cortical mantle and opposite hemisphere. To our knowledge, there has been no report documenting such a large and extensive subcortical ectopic cortex which appears as a mass distorting and shifting the middle structure in an adult, such as in our case.     

Clinical features and epileptogenesis of dysembryoplastic neuroepithelial tumor

Introduction Dysembryoplastic neuroepithelial tumor (DNT) frequently causes medically intractable epilepsy. Objective The aim of this study was to investigate the basic mechanism of epileptogenecity of the tumor. Materials and methods Clinicopathological data in 13 cases of DNT and immunohistochemical changes of ionotropic glutamate receptor subunits in the tumor and peritumoral epileptogenic cortex were studied. Conclusions Magnetic resonance imaging combined with electroencephalography (EEG), electrocorticography, and depth-electrode EEG was valuable to localize complicated epileptogenic zones of the patients with DNT. Neuropathological examinations of the peritumoral cerebral cortex presenting abnormal spikes showed different histopathological grades of neuronal migration disorder (NMD). The tumor cells in DNT disclosed increased immunopositivities of N-methyl-d-aspartate receptor 1 (NR1) and NR2A/B, and peritumoral epileptogenic NMD revealed increased immunopositivities of GluR2 and GluR3. The amplification of ionotropic glutamate receptor subunits in the tumor and peritumoral NMD may be the underlying cause of epileptic seizures in DNT patients.     

Developmental immunohistochemistry of the 22 kDa peroxisomal membrane protein in the human brain

We studied immunohistochemically the 22 kDa peroxisomal membrane protein (PMP 22). In the control brain, the immunopositive neurons for PMP 22 appeared 2–3 weeks earlier than those for peroxisomal enzymes. PMP 22-immunopositive glial cells appeared at 26–27 gestational weeks, increased with gestational age, and were rarely recognized after 1 year of age. In the patients with Zellweger syndrome, PMP 22-immunoreactivity was recognized in neurons, glias, liver and kidney cells.     

Epidemiologic Study of Epilepsy in Young Singaporean Men

PURPOSE: This survey of 20,542 Singaporean men born in 1974 studied the clinical features of young men diagnosed with epilepsy on preenlistment screening. METHODS: All male citizens in Singapore are medically screened at age 18 years before enlistment for compulsory military service. Patients suspected to have epilepsy are then referred to government hospitals for further management. We interviewed the patients and their parents and reviewed their hospital records. RESULTS: Eighty-nine patients with epilepsy were identified, indicating a lifetime prevalence of 4.9/1,000 males by age 18 years. The lifetime prevalence of epilepsy among Chinese, Malays, and Indians were 5.2, 2.8, and 6.4/1,000, respectively; these differences were not statistically significant. The mean age of seizure onset was 11.1 years. Generalized seizures (65.2%) were commoner than partial seizures (34.8%); common seizure types included generalized tonic-clonic seizures (52.8%), complex partial seizures with secondary generalization (24.7%), and myoclonic seizures (5.6%). Common epileptic syndromes included temporal lobe epilepsy (16.9%), juvenile myoclonic epilepsy (5.6%), and frontal lobe epilepsy (2.2%). Eighty-four (94.4%) patients sought medical treatment, and seven (7.9%) patients sought additional traditional treatment. Although 70 (78.7%) patients responded to medication, 14 (15.7%) patients remained refractory to treatment. CONCLUSIONS: The lifetime prevalence of epilepsy in young Singaporean men was 4.9/1,000. The majority (65.2%) had generalized seizures. Temporal lobe epilepsy was the commonest (16.9%) defined epilepsy syndrome. More patients with epilepsy (94.4%) sought medical treatment, although 15.7% remained refractory to medication.     

动态脑电图在癫痫与发作性疾病的诊断及鉴别诊断上的意义

目的　探讨动态脑电图(AEEG)对癫痫及发作性疾病的诊断及鉴别诊断的意义。方法　272例患者使用常规脑电图( EEG)与 AEEG 检查,并作比较。结果　272 例中 EEG 异常 105 例(38.60%),其中痫样放电 48 例( 17. 65%); AEEG 异常 174 例( 63. 97%),其中痫样放电 113 例(41.54%)。113例AEEG痫样放电中癫痫组87例,发作性疾病组 26 例,经χ2 检验均有非常显著差异(P <0.000 1)。结论　AEEG可提高痫样放电的检出率,在癫痫、发作性疾病的诊断、鉴别诊断上具有重要意义。     

神经元移行异常的大鼠脑皮层中NMDA的表达

目的 观察神经元移行异常(neurona1 migration disorders,NMDs)动物模型脑组织的病理变化以及N-甲基-D-天门冬氨酸受体(n-methyl-d-aspartate receptor,NMDA)的表达.方法 三组Sprague-Dawley孕鼠分别在孕15天,孕17天以及孕19天接受2.25Gy的X射线照射约5分钟,其后代成年后即为NMDs动物模型.观察指标为:存活率、脑组织的病理变化以及皮层中NMDA的表达.结果 胚胎期较早接受射线的大鼠,存活率低,大脑皮层结构紊乱严重,皮层NRl和NR2A的表达高.结论 在NMDs的大鼠脑皮层中,NRl和NR2A表达增加,且其表达增加的程度能反映NMDs的严重程度.NMDA的上调可能是NMDs患者致痫的主要病因.     

Fetal exposure to GABA-acting antiepileptic drugs generates hippocampal and cortical dysplasias

PURPOSE: The management of epilepsy during pregnancy entails a number of concerns. While seizures may affect adversely maternal and fetal outcome, antiepileptic drugs (AEDs) may increase the incidence of congenital abnormalities and possibly affect postnatal cognitive development in the offspring. Experimental animal studies can aid in assessing teratogenic features associated with individual AEDs and/or with seizures, and to identify the mechanisms involved. The purpose of this study was to investigate the consequences of prenatal exposure to (a) different AEDs and (b) maternal seizures on brain maturational processes in rats. METHODS: Pregnant rats received from embryonic days 14 to 19 intraperitoneal injections of carbamazepine (20 mg/kg/day), vigabatrin (200 mgkg/day), and valproate (100 mg/kg/day) at doses not widely different from those used clinically. Pups exposed to AEDs in utero were analyzed postnatally. Animals born to "kindled" pregnant animals that had experienced one generalized convulsive seizure per day during the same gestational period were analyzed in parallel. RESULTS: Prenatal exposure to vigabatrin and valproate, which act on GABA signaling, induced hippocampal and cortical dysplasias, which were likely to result from a neuronal migration defect and neuronal death. By contrast, offspring of rats exposed to carbamazepine (which at the dose used produced low plasma concentrations) or to generalized convulsive seizures showed no clear-cut evidence of dysplasias. CONCLUSIONS: We suggest that AEDs that increase the extracellular concentration of GABA might induce severe neuronal migration disorders. Drugs acting through other molecular targets would also perturb cortical maturation. The potential clinical relevance of these results should be a subject of future research.     

Epilepsy in Ehlers-Danlos syndrome

PURPOSE: Ehlers-Danlos syndrome (EDS) is a complex hereditary connective tissue disorder infrequently reported in association with epilepsy. Seven patients with ages ranging from 28 to 70 years with EDS and epilepsy are described. METHODS: Case review of clinical and diagnostic data. RESULTS: Two patients had occipital horn syndrome (EDS type IX) and partial seizures of probable supplementary motor area origin. Of these two, one had an area of frontal gliosis and was able to abate his seizures by hyperextending his neck; the other had a Dandy Walker malformation and also had pseudoseizures. The third patient of the series had complex partial seizures, pain asymbolia, and basilar artery hypoplasia. The fourth had ictal aphasia, left hemispheric hypotrophy, and distal right arm and left leg atrophy. The fifth patient had focal seizures, a venous parietal angioma, hyperekplexia, nocturnal head oscillations (jactatio capitis nocturna), monoclonal gammopathy-associated neuropathy, and Tourette syndrome. The sixth had affective illness, chronic fatigue, and complex partial seizures with autoscopic phenomena after intracranial bleed. The seventh patient had a previous stroke, peripheral neuropathy, and grand mal seizures. CONCLUSIONS: EDS may be accompanied by congenital or acquired central nervous system disorders and epilepsy. Additional neurologic conditions that are unrelated to EDS may be present.     

Depression and Mania in Patients with Epilepsy

Summary:  Depression has a major impact on quality of life in patients with epilepsy and is also the main risk factor for the increased suicide rate in epilepsy. The frequency of depressive disorders depends on the severity of epilepsy and the localization of the epileptogenic focus, with a prevalence of ≤50% in patients with intractable temporal lobe epilepsy. The diagnosis of depression in epilepsy may be difficult because symptoms of depression may be fluctuating, and some symptoms, such as memory complaints, may be misinterpreted as being a consequence of drug treatment or the epilepsy per se. Affective disorders in epilepsy may differ from those seen in patients without epilepsy. A possibility exists that patients with epilepsy will develop a specific interictal dysphoric syndrome related to limbic system dysfunction. Recent epidemiologic studies suggest a bidirectional relation between depression and epilepsy. Depression does not necessarily occur after the onset of epilepsy; the sequence may as well be the other way round, suggesting a common underlying mechanism for both disorders. Classic bipolar disorder type I is rarely seen in epilepsy, and manic episodes occur almost exclusively in the setting of postictal psychosis or after epilepsy surgery. This article explores the clinical manifestations of depressive and manic disorders in epilepsy and the differences from bipolar disorder.     

Atypical PEX16 peroxisome biogenesis disorder with mild biochemical disruptions and long survival

Background

Mutations in PEX16 cause peroxisome biogenesis disorder (PBD). Zellweger syndrome characterized by neurological dysfunction, dysmorphic features, liver disease and early death represents the severe end of this clinical spectrum. Here we discuss the diagnostic challenge of atypical PEX16 related PBD in 3 patients from highly inbred kindred and describe the role of specific metabolites analyses, fibroblasts studies, whole-exome sequencing (WES) and metabolomics profiling to establish the diagnosis.

Autistic Spectrum Disorder: Evaluating a Possible Contributing or Causal Role of Epilepsy

Summary:  The onset of epilepsy in brain systems involved in social communication and/or recognition of emotions can occasionally be the cause of autistic symptoms or may aggravate preexisting autistic symptoms. Knowing that cognitive and/or behavioral abnormalities can be the presenting and sometimes the only symptom of an epileptic disorder or can even be caused by paroxysmal EEG abnormalities without recognized seizures, the possibility that this may apply to autism has given rise to much debate. Epilepsy and/or epileptic EEG abnormalities are frequently associated with autistic disorders in children but this does not necessarily imply that they are the cause; great caution needs to be exercised before drawing any such conclusions. So far, there is no evidence that typical autism can be attributed to an epileptic disorder, even in those children with a history of regression after normal early development. Nevertheless, there are several early epilepsies (late infantile spasms, partial complex epilepsies, epilepsies with CSWS, early forms of Landau-Kleffner syndrome) and with different etiologies (tuberous sclerosis is an important model of these situations) in which a direct relationship between epilepsy and some features of autism may be suspected. In young children who primarily have language regression (and who may have autistic features) without evident cause, and in whom paroxysmal focal EEG abnormalities are also found, the possible direct role of epilepsy can only be evaluated in longitudinal studies.     

Epilepsy in patients with congenital cytomegalovirus infection

Patients with congenital cytomegalovirus (CMV) infection were at high risk for postnatal seizures, but little is known about epilepsy associated with congenital CMV infection. To define the features of epilepsy, we retrospectively reviewed the clinical, laboratory and neuroradiographic findings in 19 children (male 9) with congenital CMV infection. Seven (37%) patients had developed epilepsy (partial seizure 5 and epileptic spasms 2) at a mean age of 20 months (range 2–37 months). During the clinical course, West syndrome occurred in only three patients. The most common seizure type in our series was partial seizure. At the time of last follow-up (mean 96 months), seizures remained uncontrolled in six patients. Neonatal clinical manifestations (gestational age, gender distribution, birth asphyxia or symptoms at birth) were not predictive of the development of epilepsy. On the contrary, some neuroradiographic findings (ventricular dilatation and migration disorder) were significantly associated with the development of epilepsy.