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Contributors

Metabolic and degenerative disorders

Tiziana Granata*


Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

* Correspondence to: Tiziana Granata, MD, Department of Pediatric Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 1, 20133 Milano, Italy. Tel: + 39 02 23942702, Fax: + 39 02 23942181

E-mail address: granata@istituto-besta.it

Abstract

Epileptic seizures are frequent in metabolic and degenerative disorders, and may be the presenting or prominent symptoms in a proportion of patients. In a restricted number of diseases the characteristics of epilepsy and associated symptoms are specific enough to constitute a definite syndrome that guides the diagnostic workup: this is the case in progressive myoclonic epilepsies and, to a lesser extent, in neuronal ceroid lipofuscinosis and Alpers syndrome. In most cases, conversely, diagnostic suggestion comes from the recognition of selected – although nonspecific – electroclinical features properly integrated with clinical electrophysiological and imaging findings. In this chapter we summarize the more common electroclinical features that lead to suspicion of a progressive disease and discuss epilepsies with a well-defined syndromic picture. We will also summarize the metabolic diseases frequently associated with epilepsy, underscoring, when present, the peculiar epileptic characteristics. Finally, we will highlight the features of metabolic diseases amenable to specific treatment.

Introduction

At least 400 diseases are known to be due to an inborn error of metabolism, and this number increases almost every day thanks to the extraordinary progress of clinical and genetic research. Most inherited metabolic diseases affect the central nervous system and about 50 of them are consistently associated with seizures (Table 30.1), through varying pathogenetic mechanisms. Greatly simplified, the causes of epilepsy in metabolic disorders may be summarized as follows: (1) defects of energy metabolism, (2) imbalance of neurotransmitter systems with excess excitation or reduced inhibition, (3) direct toxic effects of nonproperly metabolized material, (4) impaired neuronal function owing to accumulation of storage products, and (5) metabolic interference with brain development resulting in cortical malformation, as in peroxisomal or in some of the mitochondrial disorders.

Table 30.1 Metabolic diseases associated with epilepsy according to the age at onset

Diseases amenable to specific treatment are shown in italics.

GABA, γ-aminobutyric acid; Glut1, glucose transporter type 1; GM2 (G, ganglioside; M2, the type of ganglioside).

Whatever the cause, epilepsy may be the first and prominent symptom of a metabolic disease and, particularly in pediatrics, can be the reason for medical referral. The diagnosis of epileptogenic metabolic diseases is often challenging, in particular when specific symptoms of the underlying disease are subtle or not (or not yet) fully expressed. Moreover, in infancy and early childhood, seizures, even if due to nonprogressive diseases, may manifest as an epileptic encephalopathy with neurological regression. It may be difficult to determine whether psychomotor regression in a given patient is due to epilepsy itself or to an underlying progressive disease.

This chapter cannot provide a comprehensive discussion of metabolic disorders affecting the nervous system. We will summarize the more common electroclinical features that lead to suspicion of a progressive disease, discuss epilepsies with a well-defined syndromic picture, i.e., the progressive myoclonic epilepsies. We will also summarize the metabolic diseases frequently associated with epilepsy, underscoring, when present, the peculiar epileptic characteristics. Finally, we will highlight the features of metabolic diseases amenable to specific treatment.

Epilepsy features in metabolic and degenerative disorders

With the exception of progressive myoclonic epilepsies (PMEs) that have clinical symptoms and electroencephalogram (EEG) patterns highly suggestive of specific diseases, the clinical presentation of epilepsy in progressive diseases is influenced more often by the age of the patient than the specific etiology. In some patients the epilepsy may be classified into one of the recognized syndromes (Table 30.2): in these cases the atypical features that are often present suggest a metabolic etiology. In many cases, the phenotype does not fit a specific epileptic syndrome. In these cases presence of a metabolic or degenerative disorder may be suggested by the type of seizures and pattern of recurrence, or EEG findings. Finally, in a proportion of cases, longitudinal evaluation of the course of epilepsy and changes in serial EEG recordings may help in diagnosis.

Table 30.2 Epileptic syndromes associated with progressive diseases*

GABA, γ-aminobutyric acid; Glut1, glucose transporter type 1; GM1, ; GM2, ; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome; MERRF, myoclonic epilepsy with ragged-red fibers.

* Note that in a high proportion of patients with metabolic degenerative disorders epilepsy manifests with clinical and electroencephalogram (EEG) characteristics that do not fit a specific epileptic syndrome; further, the above cited epileptic syndromes often show several clinical and EEG atypical features.

Neonatal seizures

These typically manifest with focal, often subtle, seizures or erratic myoclonus. When due to inborn errors of metabolism seizures usually appear as part of a clinical picture dominated by stupor or coma, severe brain edema, and an EEG pattern of burst–suppression or diffuse depression of brain activity. It must be underscored, however, that at times (including in disorders of vitamin B6 metabolism) seizures may be the one and only symptom.

Early epilepsy with burst–suppression

This is a frequent, rather nonspecific, electroclinical sign of metabolic disease with early onset. It presents with erratic, fragmentary, and massive myoclonus, associated with partial and, rarely, tonic seizures. The typical EEG consists of a periodic pattern of spikes, sharp, and slow waves lasting 1–3 seconds, alternating with periods of electric silence, invariable during both wakefulness and sleep (Fig. 30.1).

Fig. 30.1 Electroencephalogram recording in a 6-month-old patient with peroxisomal disease. The pattern of burst–suppression is present during wakefulness (A) and sleep (B). Myoclonic jerks (arrows) are visible on the electromyogram recording during sleep (B) and become more evident after arousal (C).

West syndrome

West syndrome (WS) is characterized by clusters of spasms and hypsarrhythmia on EEG, and may be observed at onset or during the course of a variety of metabolic diseases. However, WS often shows atypical features: epileptic spasms may be more prolonged (tonic spasms) and may be associated with focal, often subtle, seizures (that may also recur in clusters) or with other paroxysmal motor events, such as isolated or repetitive jerks, exaggerated startle responses, or sustained tonic phenomena (Fig. 30.2). The hypsarrhythmic pattern on the EEG tracing often shows a variant with prominent slow activity with few epileptic abnormalities, or a multifocal interictal epileptic pattern (Fig. 30.3).

Fig. 30.2 Electroencephalogram (EEG) recording in 2-year-old boy affected by Krabbe disease. (A) A cluster of tonic spasms is recorded soon after awakening, associated with diffuse high-voltage fast activity, more evident on the left hemisphere. (B) Magnified display of a spasm with EEG correlate.

Fig. 30.3 Electroencephalogram (EEG) recording in a patient aged 5 months, affected by mitochondrial encephalopathy due to multiple respiratory chain defects. The EEG was made at the time of occurrence of spasms in series intermingled with brief ictal eye deviation. (A) Brief eye versive seizure occurring during wakefulness. (B) Ictal EEG correlate and EOG magnified to show the short ictal run of fast activity, with a higher amplitude on the left. (C) Sleep recording showing a hypsarrhythmic EEG pattern with prominent polymorphic slow activity and rare sharp waves located in the posterior regions. EOG, electrooculogram; PNG, pneumogram.

Epilepsy with generalized seizures

Generalized seizures may include atypical absences, massive myoclonic seizures, and akinetic seizures; tonic seizures are rarely observed. The differential diagnosis from idiopathic generalized epilepsy rests on the unusual association of different types of seizure in an individual patient (e.g., the association of focal and generalized seizures, or the lack of tonic seizures during sleep in epilepsy resembling Lennox–Gastaut syndrome), on the frequent occurrence of stimulus-induced (light, noise) seizures, and on the EEG characteristics. EEG may show impaired background activity or sleep organization, unusual fast or rhythmic activity, association of focal and generalized epileptic abnormalities, and photic-induced epileptic discharges at low stimulus frequency (Figs 30.4–30.6).

Fig. 30.4 Electroencephalogram recording in a patient aged 8 months affected by peroxisomal disease in whom brief spontaneous myoclonic seizure occurred spontaneously (A) or following intermittent light stimulation (ILS) at low frequency (C). Nonepileptic startles, induced by unexpected stimuli, were also present (B). Sleep recording showed multifocal interictal epileptic discharges (D).

Fig. 30.5 Electroencephalogram (EEG) recording in a patient aged 7 years affected by a mitochondrial encephalopathy due to a defect in complex IV of the respiratory chain. The interictal EEG shows multifocal epileptic discharge abnormalities (A and B). Intermittent light stimulation induces massive myoclonia associated with a diffuse discharge of irregular spikes and waves (C, arrow), followed by periodic sharp waves higher on the posterior regions. Subtle myoclonic jerks are recorded from distal muscles.

Fig. 30.6 Electroencephalogram recording in a patient aged 5 years affected by late infantile lipofuscinosis. (A) Recording of an atypical absence, associated with a diffuse discharge of irregular spikes and waves. (B) Low-frequency intermittent light stimulation (ILS) elicits a discharge of irregular spikes and waves more evident on the posterior regions. (C) Continuous irregular spikes and waves during sleep.

Epilepsy with focal seizures

Focal seizures are the most frequent epileptic manifestation in patients with metabolic disorders and may appear at any age. Although generally considered scarcely specific, focal epilepsy may show some peculiarities that may hint at the diagnosis of a progressive disease. These include varying seizure patterns in an individual patient, their association with generalized seizures, particularly myoclonic or with generalized EEG epileptic discharges (Fig. 30.7), their clustering or recurrence as in status epilepticus, and their shifting course during either single or successive epileptic events. As far as the ictal semiology, motor seizures (including epilepsia partialis continua; see below) are most frequently observed, in line with the striking epileptogenic susceptibility of the motor cortex. Another type of seizure frequently observed arises from posterior areas. EEG characteristics include the impairment of background activity with progressive slowing or voltage decrease, posterior prominence of epileptic abnormalities, and presence of unusual rhythmic or fast activity. Furthermore, a peculiar pattern that may be observed is the association of focal ictal or interictal discharges with a pathological photic response (Fig. 30.7).

Fig. 30.7 Electroencephalogram (EEG) recording in a patient aged 17 years affected by a mitochondrial encephalopathy with lactic acidosis and stroke (MELAS). Interictal EEG shows diffuse paroxysmal discharges of sharp waves at rest and induced by photic stimulation (PS) (AC). The interictal diffuse paroxysmal discharges are interrupted by the occurrence of a partial motor seizure of the left upper limb associated with contralateral centroparietal signal attenuation (arrow) and recruiting slow activity (D).

Epilepsia partialis continua

Epilepsia partialis continua (EPC) is characterized by almost continuous, focal, rhythmic muscle jerks that are present during wakefulness and sleep, and persist for hours to days or, rarely, years. Although most frequently associated with fixed epileptogenic lesions (ischemia, cortical dysplasia, vascular malformation) and with Rasmussen syndrome, it may also be related, particularly in children, to a progressive disease. EPC has been described as a frequent and prominent feature in Alpers disease (either in the form due to polymerase gamma 1 (POLG1) mutations or in the similar phenotype associated with Twinkle mutations) as well as in the mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS), and mitochondriopathies due to respiratory chain defects (Fig. 30.8).

Fig. 30.8 Electroencephalogram recording in a patient aged 4 years affected by mitochondrial encephalopathy due to defect of complex I of the respiratory chain. (A) Recurring myoclonic jerks (epilepsia partialis continua (EPC)) on the left arm are associated with periodic slow activity on the central region of both hemispheres, with higher amplitude on the right. Note that sporadic myoclonic jerks are also evident on the right distal muscles (arrow a). (B) While EPC persists on the left arm, a motor seizure occurs on the right arm starting from the deltoid muscle (arrow b) and involving the distal muscles (arrow c).

Progressive myoclonic epilepsies

Progressive myoclonic epilepsies (PMEs) refers to a group of rare syndromes, clinically characterized by the association of generalized tonic–clonic and myoclonic seizures (at times associated with absence and focal seizures) with ataxia, action myoclonus, and dementia. The syndrome is due to a large number of different genetic diseases causing neurodegeneration. Most PMEs are autosomal recessive disorders and, with the exception of Lafora body disease (and of the more rare ataxia PME), result from abnormal lysosomal storage (Ramachandran et al., 2009). PMEs may also be due to mutations of mitochondrial genes that, when familial, are transmitted through the maternal line (as is the case of myoclonic epilepsy with ragged-red fibers (MERRF)) (Rosing et al., 1985; Shoffner et al., 1990), or may be inherited as autosomal dominant disorders, as is dentatorubral–pallidoluysian atrophy (DRPLA) or familial adult myoclonic epilepsy (Naito and Oyanagi, 1982; Uyama et al., 2005).

Action myoclonus, typically fragmentary, multifocal, and facilitated by posture, action, and external stimuli, persistent and difficult to treat, is the hallmark of all the PMEs (Fig. 30.9). The severity of cerebellar signs, mental deterioration, and seizures, by contrast, varies in different syndromes.

Fig. 30.9 Electroencephalogram (EEG) recordings in patients with progressive myoclonic epilepsy. (A and B) EEG recorded in a patient with Unverricht–Lundborg disease showing a fairly normal EEG activity and action myoclonus. Intermittent light stimulation (ILS) elicits myoclonic jerks on facial muscle, which appear on the EEG as artifacts. (C and D) EEG recorded from a patient with Lafora body disease showing posterior spikes and waves and diffuse polyspike paroxysms associated with spontaneous positive–negative myoclonus. Intermittent light stimulation facilitates the diffuse epileptic paroxysms that manifest as sustained discharge of polyspikes. Note that in (C) and (D) action myoclonus irregularly superimposes mild tonic contraction.

Lafora body disease

Onset, usually between 7 and 18 years, usually is marked by tonic–clonic seizures or myoclonus, often associated with focal visual seizures or nonepileptic hallucinations. In some cases epilepsy onset may be preceded by headaches, learning difficulties, or behavioral changes. Symptoms progressively worsen: seizures and hallucination become intractable, myoclonus is nearly continuous, mental deterioration progresses to profound dementia, the patient develops spastic tetraparesis, and death occurs 2–10 years after the onset. The EEG recordings at onset demonstrate spike and wave discharges increased by intermittent light simulation (ILS), but not enhanced by sleep. While disease progresses, background activity and sleep organization rapidly deteriorate and multifocal, particularly posterior, epileptic abnormalities appear (Fig. 30.9C, D).

Lafora body disease is caused by mutations in genes encoding the interacting proteins laforin (EPM2A gene) or malin (EPM2B gene), whose defect leads to accumulation of Lafora bodies (dense aggregates of abnormally branched glycogen molecules termed polyglucosans) in brain, muscle, liver, heart, and sweat glands (Aguado et al., 2010; Rao et al., 2010). The diagnosis rests on the association of generalized and focal occipital seizures, erratic myoclonus and rapid deterioration of EEG activity; it may be confirmed by the examination of eccrine sweat gland ducts by axillary skin biopsy and by the molecular analysis of EPM2A and EPM2B genes.

Unverricht–Lundborg disease

The onset of Unverricht–Lundborg disease (ULD) is between 6 and 13 years, usually with generalized convulsions (that are usually controlled by drugs), followed by myoclonus, typically more frequent at awakening, and mild ataxia. The severity of the myoclonus increases and represents the most incapacitating symptom in the first years of the disease (Fig. 30.9A, B). Later, the form stabilizes, with mild or no cognitive decline. However, mood lability is frequently observed. On EEG the abnormalities consist of 3–5 Hz spike–wave or multispike–wave discharges that are markedly enhanced by ILS, with well-preserved background activity. ULD is due to a single mutation of the gene encoding the protease inhibitor cystatin B (CSTB); the increased activity of protease and resulting increased apoptosis is the putative pathogenetic substrate. The diagnosis of ULD, once suspected on electroclinical grounds, may be confirmed by the molecular analysis of cystatin B gene (Joensuu et al., 2008).

Action myoclonus–renal failure syndrome

Action myoclonus–renal failure syndrome is an autosomal recessive disease associated with mutations in the gene coding for the lysosomal protein SCARB2. It is a rare form of PME without dementia in which the distinguishing feature is the occurrence of renal failure (due to focal glomerulosclerosis), which may precede or follow the onset of neurological symptoms. The onset of neurological symptoms is at about 19–20 years; the clinical phenotype at onset is similar to that observed in ULD, but the course of the disease is more severe and symptoms relentlessly progress, with death usually occurring by age 35 years (Badhwar et al., 2004). Mutations of SCARB2 have been recently demonstrated also in patients with a phenotype resembling ULD in the early course of the disease, not associated with renal failure (Rubboli et al., 2011). This observation expands the phenotypic range associated with SCARB2 and suggests that screening of this gene should be considered in PME patients without dementia, even in the absence of renal impairment (Dibbens et al, 2009).

Myoclonic epilepsy with ragged-red fibers

Myoclonic epilepsy with ragged-red fibers (MERRF) is a multisystem disorder in which the cardinal symptoms of PME are associated with typical myopathy with ragged-red fibers seen on muscle biopsy, indicating dysfunction of the mitochondrial respiratory chain. The multisystem involvement is also shown, particularly in advanced stages, by the presence of symptoms such as deafness, peripheral neuropathy, short stature, optic nerve atrophy, and, more rarely, cardiomyopathy, pigmentary retinopathy, ophthalmoparesis, pes cavus, and multiple lipomatosis. Symptoms can begin in childhood as well as in adulthood, and, in familial cases, there may be a wide variability of age at presentation and of clinical expression. EEG shows slow background activity, diffuse atypical generalized spike and wave discharges, at times associated with focal epileptic activity. MERRF is a mitochondrial disease that is due in about 80% of cases to a A > G mutation at nucleotide 8344 (Shoffner et al., 1990).

Sialidosis

These autosomal recessive diseases are associated with a deficit of the lysosomal enzyme α-N-acetyl-neuramin-idase. In these diseases, a characteristic cherry red spot feature is seen in the ocular fundus examination. Sialidosis type I (cherry red spot myoclonus syndrome) is the mildest form: clinically the main symptom is severe action myoclonus that appears during adolescence and is associated with gradual visual loss, ataxia, and generalized seizures, but not dementia. Sialidosis type II has an earlier onset and a more severe phenotype: myoclonus and cherry red spot are associated with dysmorphisms, bony deformities, early developmental delay, and hearing loss. The most consistent EEG finding in sialidosis is the presence of low-voltage fast activity, and 10–20 Hz vertex spiking associated with massive myoclonus. The diagnosis may be suspected clinically when the typical cherry red spot is detected, and confirmed by elevated urinary excretion of sialic acid, and by levels of α-N-acetyl-neuraminidase in leukocytes or cultured fibroblasts.

Gaucher disease type III

This may develop in late childhood to adulthood with a PME phenotype, associated with supranuclear oculomotor palsy and splenomegaly. The key diagnostic features are pancytopenia, increased serum acid phosphatase, moderate splenomegaly, and reduced glucocerebrosidase activity in lymphocytes.

Rarer causes of progressive myoclonic epilepsies

These include familial autosomal dominant myoclonic epilepsy, DRPLA, as well as the phenotypic PME presentation of a wide number of degenerative disorders such as neuronal ceroid–lipofuscinosis, GM2 gangliosidosis, neuroaxonal dystrophy, and Alzheimer disease.

Diagnostic workup and differential diagnosis

At the beginning of the disease, clinical and EEG features of PMEs may be similar to those observed in idiopathic generalized epilepsy (IGE); at this stage neurophysiological evaluation, including EEG with polymyography, is probably the most useful tool in differential diagnosis. The detection of segmental myoclonus is, in fact, the key symptom that differentiates PME from IGE. Furthermore, a specific EEG feature that strongly suggests PME is the increase in polyspike and wave discharges following ILS. Additional neurophysiological techniques that aid diagnosis are: (1) jerk-locked back averaging, which demonstrates the cortical origin of myoclonus, (2) somatosensory-evoked potentials that are usually increased in amplitude, (3) the long-loop reflex (C-reflex) that can appear at rest in patients with cortical myoclonus and shows an abnormally large amplitude during motor activation (Shibasaki, 2006; Canafoglia et al., 2010). Once the diagnosis of PME is established, the differential diagnosis among the different forms rests on clinical (including neurological and systemic symptoms) and EEG criteria, as well as on the pattern of inheritance. Epilepsy characteristics may also be helpful: focal visual seizures suggest Lafora disease; prominent myoclonus suggests ULD, MERRF or sialidosis. Longitudinal EEG evaluations show preserved background activity and rare epileptic discharges in ULD and type I sialidosis, whereas severe disruption of signal organization and highly expressed diffuse paroxysmal activity, often mixed with occipital spikes, occur early in Lafora disease. An important clue is mental deterioration that is constant and severe in Lafora disease, and typically mild or absent in ULD, sialidosis type I, Gaucher type III, and action myoclonus–renal failure syndrome.

Metabolic diseases more frequently associated with epilepsy

Mitochondrial diseases

The mitochondrial diseases are the most frequent causes of seizures due to a neurometabolic disorder.

Mitochondria are double-membrane nuclear organelles whose main function is to produce energy through oxidative phosphorylation (OXPHOS) of carbohydrates, fats, and amino acids; they are also involved in the synthesis of important metabolic precursors, contribute to intracellular calcium homeostasis, and participate in apoptotic pathways. The definition of mitochondrial disease is restricted to syndromes resulting from OXPHOS deficiency. The OXPHOS process takes place in the internal membrane of mitochondria, through a sequential series of reactions of reduction and oxidation, which form cellular respiration and are carried out by the four enzymatic complexes of the mitochondrial respiratory chain (complex I, complex II, complex III, and complex IV or cytochrome c oxidase). In this reaction, electrons liberated by the controlled degradation of nutrients are ultimately combined with molecular oxygen to produce water. The energy liberated during these reactions is utilized by complex V, or ATP synthetase, to produce the compound adenosine triphosphate (ATP), the fundamental fuel for cellular metabolism. Disorders of mitochondrial activity primarily affect tissue with the highest energy demand, including the brain, the skeletal muscles, and the heart (hence the term encephalomyopathies or encephalocardiomyopathies); however, given that mitochondria are present in all tissues, any organ may be affected. Mitochondrial diseases are more frequent in the first two decades of life, because of the greater need for energy during development and growth, but adult-onset syndromes are also well known.

To understand the pathogenesis, clinical presentation, and mode of inheritance of mitochondrial diseases a summary of peculiar genetic characteristics is required (Zeviani and Carelli, 2007; Spinazzola and Zeviani, 2009).

Mitochondria are unique mammalian organelles that possess their own genetic material, called mitochondrial DNA (mtDNA). The respiratory chain is composed of proteins encoded by the two different genetic systems: the nuclear genome, which is inherited from both parents, and the mitochondrial genome, which is derived exclusively from the oocyte and therefore inherited exclusively from the mother. mtDNA is a small, circular minichromosome containing only 37 genes that encode protein subunits of the OXPHOS complexes, as well as transfer and ribosomal RNA molecules that are essential for the in situ synthesis of mtDNA-encoded protein subunits. A peculiarity of mtDNA genetics is heteroplasmy: each mitochondrion contains 2–10 copies of mtDNA. Since each cell contains multiple mitochondria, there are thousands of mtDNA molecules in each cell. Alterations of mtDNA may hit all the mtDNA molecules (homoplasmy), but more frequently deleterious mtDNA mutations strike only a fraction of the mitochondrial genomes of an individual, leading to the coexistence in cells and tissues of two mtDNA populations, one normal and one mutated (heteroplasmy). Heteroplasmy explains the variability in clinical symptoms in patients harboring an identical mutation: an individual with a large proportion of the mutant DNA will be more severely affected than one with a low percentage of the same mutation. Other factors that influence the expression of a mtDNA mutation are the distribution of a given mutation in different tissues, and the threshold effect: cells with high metabolic activity may be severely affected by a relatively low level of mtDNA mutations. Given the complexity of metabolic pathways and peculiar genetics, mitochondrial disorders may be classified according to the underlying biochemical defect or according to the site (nuclear or mtDNA) of the mutation. From a biochemical point of view, abnormal mitochondrial metabolism may be due to: (1) defects in transport and degradation of fatty acids, (2) defects of pyruvate metabolism due either to a defect of pyruvate carboxylase in the first reaction of gluconeogenesis or to a defect of the pyruvate dehydrogenase complex in the last step of glycolysis pathway, (3) Krebs cycle defects, including deficiency of fumarase and α-ketoglutarase dehydrogenase, (4) defect of oxidation–phosphorylation coupling, and (5) respiratory chain defects (either for defects of a single complex or combined defects of different chain components).

Diagnosis of mitochondrial diseases is often difficult, given the variable clinical manifestations. Suspicion of mitochondrial disorder is usually raised by the association of different symptoms, involving several organs. The main neurological symptoms include delay or regression in psychomotor development, epileptic seizures, myoclonic, movement disorders, complicated migraine, stroke-like episodes, ophthalmoplegia, myopathy, and peripheral neuropathy, hearing loss, and vision loss (due to retinitis pigmentosa or optic atrophy). Involvement of other organs may be shown by cardiomyopathy or cardiac conduction abnormalities, diabetes mellitus, hepatopathy, and gastrointestinal and renal involvement. Failure to thrive with poor growth or short stature are very frequent symptoms. Neuroradiological evaluation based on brain magnetic resonance imaging (MRI) and/or mass spectrometry is often helpful to confirm the diagnosis and may suggest specific mitochondrial disorders (Saneto et al., 2008). Preliminary laboratory screening must include complete blood count, glucose, electrolytes, ammonia level, tests of liver and kidney function, quantification of lactate, pyruvate and alanine (in blood and, even better, in cerebrospinal fluid (CSF)), carnitine (including free carnitine and esterified carnitine), amino acids, and urinary organic acids. Electrocardiography, echocardiography, electromyography (EMG), and electroneuronography provide information on muscle, nerve, and heart involvement. The neurophysiological study must include EEG and evoked potentials. A second step in diagnostic workup is the direct study of muscle tissue. Histological and histochemical examination may detect ragged-red fibers, typical of many mitochondrial myopathies, or abnormal distribution of oxidative enzymes succinate dehydrogenase (SDH) and cyclooxygenase (COX). It must be noted, however, that the histological abnormalities are often not specific or sensitive: similar abnormalities may be observed in non mitochondrial myopathies, and, conversely, not detected in a number of mitochondrial diseases mostly in children. Biochemical measurement of specific activities of the respiratory chain complexes, pyruvate dehydrogenase complex (PDHC), and fatty acid β-oxidation enzymes and coenzyme Q content must be eventually carried out. Molecular analysis of mitochondrial or nuclear DNA, aimed at the detection of the causative mutated gene, is essential to provide genetic counseling and prenatal diagnosis.

The number of mitochondrial diseases is enormous and their description is beyond the scope of this chapter. We will describe the mitochondrial diseases that most often include epilepsy among the presenting or prominent symptoms (Veggiotti et al., 1995; Canafoglia et al., 2001; Kang et al., 2007; Engelsen et al., 2008; Khurana et al., 2008; Lee et al., 2008; Riquet et al., 2008; Wolf et al., 2009a; El Sabbagh et al., 2010; Seo et al., 2010). There are few common characteristics of epilepsy in mitochondrial diseases. Epilepsy is often the presenting symptom or the symptom leading to medical consultation. With the exception of MERRF, in which myoclonus and generalized seizures are prominent, true generalized epilepsy is extremely rare (Canafoglia et al., 2001; Finsterer et al., 2001). Most patients, both adults and children, manifest focal seizures, particularly of simple motor type, that may recur as prolonged clusters or even epilepsia partialis continua (Figs 30.7 and 30.8) (Veggiotti et al., 1995; Elia et al.1996; Riquet et al., 2008). Beside the motor area, the posterior cortical areas seem to be particularly involved in epileptogenesis, as demonstrated by the frequent occurrence of visual seizures and prominence of posterior interictal EEG discharges and photoparoxysmal responses. In infants, epilepsy may present with early epilepsy with burst–suppression (Molinari, 2010; Seo et al., 2010) or with infantile spasms (Canafoglia et al., 2001; El Sabbagh et al., 2010).

Mitochondrial encephalopathies with epilepsy associated with mtdna mutations (maternal inheritance)

Epilepsy is a cardinal symptom in MERRF, and in MELAS, and seldom reported in Kearn–Sayre syndrome and in the neurogenic muscle weakness–ataxia–retinitis pigmentosa syndrome (NARP).

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome

This syndrome, most commonly caused by an A>G transition mutation at position 3243 of the mitochondrial genome, usually manifests in childhood or young adulthood. The most common presenting symptoms are seizures, recurrent headaches, anorexia, and recurrent vomiting. Other common symptoms include myoclonus, ataxia, exercise intolerance, muscle weakness, episodic coma, short stature, hearing loss, peripheral neuropathy, diabetes, and mental decline. Other systemic symptoms may be associated, including cardiomyopathy, ophthalmoplegia, pigmentary retinopathy or optic atrophy, hirsutism, gastrointestinal dysmobility, and nephropathy.

Seizures are extremely common, often marking the onset of the disease, favored by fever and associated with stroke-like episodes (Hirano and Pavlakis, 1994; Canafoglia et al., 2001; Sproule and Kaufmann, 2008). The stroke-like episodes mainly involve occipital cortex and subjacent white matter; at MRI examination lesions are often transient and do not conform to the territories supplied by major cerebral arteries. Lesions can be detected as increased signal on routine T2-weighted MRI and, contrasting with what is seen in typical strokes, they show normal or increased signal on apparent diffusion coefficient studies, suggesting vasogenic edema (Saneto et al., 2008). Generalized and focal seizures can be associated in an individual patient. Focal seizures are mainly of motor type, although visual, auditory, and complex partial may also be observed. Status epilepticus and epilepsia partialis continua may herald or complicate the epileptic syndrome (Montagna et al., 1988; Veggiotti et al., 1995). EEG commonly shows background slowing, and epileptic discharges, mostly in the posterior areas, that may be increased by photic stimulation (Tulinius and Hagne, 1991; Fujimoto et al., 1999; Canafoglia et al., 2001) (Fig 30.7).

The biochemical marker of the disease is elevation of lactate and pyruvate levels in blood and CSF at rest or after moderate physical activity, although in rare cases these metabolites are in the normal range. Muscle biopsy may show COX-positive ragged-red fibers, and dosage of chain respiratory enzymes may detect multiple partial defects. The definite diagnosis is reached by the molecular test demonstrating mutations in the mitochondrial tRNA leucine gene (MTTL1).

Neurogenic muscle weakness–ataxia–retinitis pigmentosa syndrome

Neurogenic muscle weakness–ataxia–retinitis pigmentosa (NARP) syndrome is characterized by neurogenic muscle weakness, ataxia, and retinitis pigmentosa and is associated with the mutation T8993G in the gene encoding subunit 6 of mitochondrial ATPase (complex V of the respiratory chain). Symptoms usually appear in adulthood and, although rarely, may include seizures or even progressive myoclonic epilepsy (Keränen and Kuusisto, 2006; Jung et al., 2007). When the same T8993G mutation is present in a high dosage of the mitochondrial genomes, it leads to a severe, early onset, maternally inherited Leigh syndrome (MILS) that may include in its symptoms severe epilepsy with infantile spasms or focal seizures (Canafoglia et al., 2001; Desguerre et al., 2003).

Kearn–Sayre syndrome

This is due to a macrodeletion of mtDNA and is a sporadic disorder that affects preferentially cerebral white matter, diencephalon, and subtentorial structures. This anatomical localization can probably explain the low epileptogenicity of this disease. However, occasional seizures may occur as the result of electrolyte imbalance secondary to hypoparathyroidism.

Myoclonic epilepsy with ragged-red fibers

MERRF presents primarily as a progressive myoclonic epilepsy and has been discussed above.

Mitochondrial encephalopathies with epilepsy associated with nuclear DNA mutations (mendelian inheritance)

Three syndromes inherited by mendelian inheritance include seizures as prominent symptoms. Furthermore, epilepsy may be the main symptom in a considerable number of patients affected by a defect of mitochondrial metabolism, whose clinical picture does not fit a specific syndrome.

Alpers syndrome (Alpers–Huttenlocher syndrome, Alpers hepatopathic poliodystrophy)

Alpers syndrome, first described in 1931, is a severe progressive encephalopathy with onset in infancy or childhood (onset in adulthood has been seldom reported). Recently the syndrome has been associated with deficiency in mtDNA polymerase gamma (POLG) catalytic activity (Naviaux et al., 1999; Naviaux and Nguyen, 2004; Isohanni et al., 2011). It is characterized by epilepsy, myoclonus, acquired microcephaly, cortical blindness, and spastic tetraparesis, and is associated with hepatic failure that may be precipitated by valproate therapy. The pathological correlate described by Huttenlocher in 1975 is spongy degeneration of gray matter with severe loss of neurons and astrogliosis, and liver steatosis or cirrhosis. The course of epilepsy has been described in patients before and after the identification of the molecular defect: epilepsy may mark the onset of the disease but often it is preceded by developmental delay, failure to thrive, and ataxia. Epilepsy may manifest with simple and complex partial seizures, or with generalized convulsive seizures. It is invariably drug resistant and almost invariably complicated by epilepsia partialis continua or recurrent status epilepticus that may be the cause of death (Harding, 1990; Engelsen et al., 2008; Wolf et al., 2009a). Occipital seizures with positive (illusional or delusional) or negative symptoms, nystagmus, or oculoclonus appear to be particularly frequent and are often the first ictal symptoms. Consistent EEG abnormalities are very slow activity, of high amplitude, and rhythmic high-amplitude delta waves with superimposed spikes or polyspikes that involve the occipital leads early on (Engelsen et al., 2008; Wolf et al., 2009a). MRI that is normal at the onset of disease shows progressive impairment of gray matter with cortical atrophy and signal abnormalities within the occipital regions, deep cerebellar nuclei, thalamus, and basal ganglia (Tzoulis et al., 2006).

A clinical phenotype resembling those associated with recessive POLG1 mutations has also been described recently in patients carrying recessive mutations of C10orf2, a gene encoding for the mtDNA helicase Twinkle, which works in close connection with POLG1 (Hakonen et al, 2007). A similar clinical phenotype has been described in patients affected by different mitochondrial disorders including defects of pyruvate dehydrogenase and cytochrome c oxidase (Prick et al., 1981, 1982; Uusimaa et al., 2003).

Leigh syndrome (subacute necrotizing encephalomyelopathy)

This is the most common disease due to abnormalities in nuclear genes related to mitochondrial OXPHOS. The causes of Leigh syndrome are biochemically and genetically heterogeneous. Leigh syndrome has been associated with defects of pyruvate carboxylase, PDHC, and mitochondrial respiratory chain complexes I, IV or both. Leigh syndrome may also be due to the NARP-related T8993G mutation when it is present in a high percentage of the mitochondrial genomes. The inheritance pattern, consequently, may be autosomal recessive or maternally inherited (MILS), depending on the causative gene. The disease was originally described by Denis Leigh (1951), in a 6.5-month-old infant presenting with developmental regression that progressed quickly to death 6 weeks later. The pathology of the specimens in the original paper demonstrated multiple symmetric foci of spongy degeneration with microvascular proliferation in the brainstem tegmentum, thalami, cerebellum, posterior columns of the spinal cord, and optic nerves. The clinical presentation shows heterogeneous onset age and rate of progression, and is most frequent in infancy with progressive psychomotor delay after an initial normal development. Onset may also be acute during a febrile illness or follow a seizure. In addition to developmental regression, failure to thrive, feeding problems, generalized hypotonia, recurrent vomiting, abnormalities in breathing rate, poor coordination of eye movements, progressive vision loss due to optic neuropathy or pigmentary retinopathy, hearing loss, and ataxia are typical manifestations. Respiratory dysfunction is often prominent and frequently causes death. Epilepsy is particularly frequent in infants with MILS and in Leigh syndrome due to PDHC deficiency, with spasms and focal seizures, but myoclonic and generalized seizures are rare (Canafoglia et al., 2001). In older infants or young children, Leigh syndrome may begin with ataxia, dystonia, or intellectual decline. Adult-onset Leigh syndrome is extremely rare, although there has been a recently reported case in an adult who presented with progressive myoclonic epilepsy (Dermaut et al., 2010). The diagnosis of Leigh syndrome is supported by the finding of an increased level of lactate in blood and CSF and by the typical MRI changes. MRI demonstrates progressive signal abnormalities, most frequently in the lentiform and caudate nuclei, often associated with changes in the thalamus, substantia nigra, inferior olivary nuclei, periaqueductal gray matter, and brainstem tegmentum. The MRI high T2 signal reflects the spongiform changes and vacuolation in the deep gray structures. In some cases, white matter may be involved in the form of gliosis and cystic degeneration. Finally, in some cases, global atrophy may be observed (Saneto et al., 2008).

Coenzyme Q10 deficiency

Coenzyme Q10 (CoQ10) is a small lipophilic molecule located in the inner mitochondrial membrane that transfers reducing equivalents from complexes I and II to complex III. Deficiency of CoQ10, detectable in skeletal muscle, results from defects of biosynthesis and has been associated with four major phenotypes: cerebellar ataxia and atrophy, predominantly myopathic form (characterized by recurrent myoglobinuria, ragged-red fibers, and encephalopathy with seizures, ataxia, or mild mental retardation), infantile encephalomyopathy with nephropathy, and a pure myopathic form. Epilepsy has been reported in all the forms with the exception of the pure myopathic. Symptoms of the CoQ10 deficiency (including partial and generalized seizures) dramatically respond to CoQ10 supplementation; therefore, although rare, the possibility of this disease must be kept in mind for an appropriate pharmacological therapy (Rötig et al., 2007).

Lysosomal diseases

Lysosomes are subcellular organelles responsible for the physiological turnover of cell constituents containing catabolic enzymes. The defect of lysosomal enzymatic activity leads to the accumulation of macromolecules that in turn cause cellular dysfunction. More than 40 lysosomal storage diseases are described that are generally classified by the accumulated substrate. In this section we will focus on the lysosomal diseases that may manifest with epilepsy as a prominent symptom.

Sialidosis and Gaucher disease present as progressive myoclonic epilepsy and have been discussed above.

Neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinosis (NCL) comprises a group of inherited, neurodegenerative, lysosomal storage disorders that share characteristic neuropathology consisting of neuronal and extracerebral autofluorescent pigment accumulations that may be observed in a variety of cell types including eccrine secretory cells. On ultramicroscopic examination pigment accumulations take three different forms, one of which dominates in each NCL: granular osmophilic deposits (GRODs), curvilinear profile, and fingerprints bodies (Fig. 30.10). At present, eight forms of NCL are described based on genetic background, pathological findings, and clinical presentation. In all NCLs epilepsy is invariably present; other consistent symptoms include progressive mental decline, ataxia, spasticity and movement disorders, and visual loss. The prominence and severity of epilepsy and associated symptoms vary in the different NCLs (Nardocci et al., 1995; Binelli et al., 2000; D’Incerti, 2000; Veneselli et al., 2000; Jalanko and Braulke, 2009; Kohlschütter and Schulz, 2009).

Fig. 30.10 Ultrastructural features in skin biopsies of neuronal ceroid lipofuscinosis patients. (A) Granular osmophilic deposit (GROD) accumulation in the cytoplasm of an eccrine sweat gland, composed of granular osmophilic dense material intermingled with lipid droplets (arrows). These deposits are typical ultrastructural findings of NCL1; rarely, they can also be observed in NCL2,NCL4,NCL8, and NCL10. (B) Membrane-bound accumulation of little C-shaped electron-dense structures (curvilinear profiles (CLPs)) in a smooth muscle cell of a piloerector muscle. CLPs are the hallmark of NCL2, but they have been described in NCL3, NCL4, NCL5, NCL6, NCL7, NCL8, and NCL9 patients. (C) Membrane-bound accumulation of fingerprint profiles (FPPs) in the cytoplasm of an eccrine sweat gland. These deposits are composed of electron-dense lamellae with electron-lucent spaces, often organized in honeycomb/lattice-like structure (arrows). FPPs can be detected alone, in particular in NCL3 (except in muscle cells) and NCL4. In other NCLs they are often associated with CLPs and sometimes with GRODs. (D) Finger print (bold arrows) and CLP (thin arrow) accumulation in the cytoplasm of an eccrine sweat gland. These mixed deposits are typical of NCL6, but they have been observed also in some NCL4, NCL5, and NCL7 patient biopsies.

Courtesy of Dr. Michela Morbin, Neurological Institute C. Besta, Milan, Italy.

NCL1 (early infantile neuronal ceroid lipofuscinosis)

Onset is between 8 and 18 months with irritability, rapid psychomotor deterioration, deceleration of head growth, and visual loss followed by myoclonus and seizures. Early neurophysiological findings are the disappearance of EEG occipital response to eye opening and flattening of the electroretinogram (ERG) and visual-evoked potentials. Longitudinal EEG evolution is classically defined as vanishing EEG to underscore the progressive impoverishment of brain electrical activity. It is worth noting that, in addition to the classic early infancy onset, rare cases of later onset, including in adulthood, have been described. CLN1 (ceroid-lipofuscinosis neuronal 1) encodes a lysosomal enzyme (palmitoyl protein thioesterase (PPT1)) that removes palmitate from proteins; the enzymatic defect leads to accumulation of palmitate that appears as GRODs.

NCL2 (late infantile neuronal ceroid lipofuscinosis)

Onset is between 2 and 4 years and is marked by generalized seizures: myoclonic, tonic–clonic, atonic, and atypical absences that may be associated with – or preceded by – subtle gait and language disturbances. In a few months, cognitive function deteriorates, vision is lost, and spasticity and ataxia develop. The EEG shows background slowing and generalized epileptic discharges, associated with posterior spikes or polyspike–waves induced by low-frequency photostimulation (Fig. 30.6). ERG progressively attenuates, whereas in the first stages visual and somatosensory-evoked potentials are abnormally broad. Neuropathology shows curvilinear bodies. CLN2 encodes the lysosomal enzyme tripeptidyl peptidase (TPP1). NCL5, NCL6, NCL7, and NCL8 may be considered as variants of late infantile NCL2 showing a later age at onset, different timing in symptom appearance and severity, and a different and more heterogeneous pathological pattern.

NCL3 (juvenile neuronal ceroid lipofuscinosis)

This presents between 4 and 10 years with visual failure (that may be the only symptom for years) due to optic atrophy, followed by behavior disturbances, mental decline, and parkinsonism; seizures, mostly convulsive, rarely are a major problem. The main neurophysiological changes are flattening of ERG and attenuation of visual-evoked potentials. EEG shows background slowing and generalized epileptic discharges enhanced during sleep but not by photic stimulation. Ultrastructurally, NCL3 patients show a fingerprint profile.

NCL4 (adult form, Kufs disease)

This is a rare disease that may present as a progressive myoclonic epilepsy in adulthood, with extrapyramidal signs or ataxia and dementia. Visual function is preserved and the fundus oculi is normal. The EEG shows marked photosensitivity, and ERG is normal. Recently, mutations in CLN6 gene, known to be associated with one variant, late infantile NCL, have been found in six pedigrees with recessive Kufs disease (Arsov et al., 2011).

NCL10 (congenital neuronal ceroid lipofuscinosis)

The congenital form is due to mutations of the CTSD gene (CLN10) that encodes the proteolytic enzyme cathepsin D. The disease is evident at or before birth and is characterized by severe encephalopathy with status epilepticus, brain atrophy, and early death. However, disease onset may be later, in which case the disease course is protracted, and includes progressive motor decline, loss of speech, and retinal atrophy.

Diagnosis of NCL is suggested by the association of seizures (often of myoclonic type), dementia, and visual loss. Important clues for diagnosis come from EEG, ERG, visual-evoked potential, and somatosensory-evoked potential studies, as specified above. MRI studies show progressive cortical atrophy that may be associated with thalamic and white matter signal abnormalities and cerebellar atrophy. Once suspected, the diagnosis is confirmed by ultramicroscopic study of peripheral tissue that demonstrates typical inclusions. Other diagnostic markers are the enzymatic assays of the lysosomal enzymes PPT1, TPP1, and cathepsin D, encoded by CLN1, CLN2, and CLN10, respectively. Finally, molecular screening may be done for CLN2, CLN3, CLN5, CLN6, CLN8, and CLN10 genes.

Sphingolipidoses

The sphingolipidoses are lysosomal diseases due to absent or deficient degradation of sphingolipids, which are essential components of CNS membranes. Epileptic seizures are common and striking features in the GM1 and GM2 gangliosidosis, in Krabbe disease and, to a lesser extent, in metachromatic leukodystrophy (Blom, 1967; Eggers et al., 1977; Balslev et al., 1997; Bostantjopoulou et al., 2000; Wang et al., 2001).

Gangliosidosis

GM1 gangliosidosis is caused by β-galactosidase deficiency. Three clinical subtypes of GM1 gangliosidosis are recognized, classified by age of onset. Epilepsy, associated with ataxia and dementia, is frequent only in type 2, which manifests between ages 1 and 3 years.

GM2 gangliosidosis includes Tay–Sachs disease, caused by a deficiency of hexosaminidase A, and Sandhoff disease, caused by a deficiency of hexosaminidase A and B. Clinically, Tay–Sachs disease is characterized by developmental regression, blindness, cherry red spot at fundoscopic examination, and epilepsy with focal seizures or atypical absences. A distinctive associated paroxysmal symptom is the exaggerated startle response, often with myoclonic jerks. The EEG shows multifocal paroxysms with prominent central spikes (Nalini and Christopher, 2004).

Another disorder with accumulation of gangliosides is Niemann–Pick type C. Unlike types A and B, which are due to a defect of sphingomyelinase, Niemann–Pick type C is caused by a defect in intracellular cholesterol traffic. Neurological manifestations include progressive ataxia, supranuclear vertical palsy, progressive extrapyramidal syndrome, and seizures. Epilepsy manifests with complex partial, or with apparently generalized, tonic–clonic seizures. Cataplexy attacks, often precipitated by upward gaze or by sudden laughter, although not constant, are highly suggestive of the disease. Abnormally high and diffuse background α activity, enhanced by intermittent photic stimulation, has been reported as well as the presence of rhythmic cortical myoclonus (Canafoglia et al., 2006).

Krabbe disease

This is due to a defect of β-galatocerebrosidase. In the most frequent infantile form, the disease manifests within the first year of life, with developmental regression, increased irritability, and progressive spasticity. Epilepsy may manifest with infantile spasms that are frequently associated with myoclonic jerks, tonic fits, and startle myoclonus. The EEG may show hypsarrhythmia but, more frequently, is characterized by bilateral delta activity and asynchronous spike and polyspike discharges (Husain et al., 2004). In a minority of patients, symptoms begin late, between 15 months and 10 years, usually presenting with spastic paralyses, cerebellar ataxia, visual failure, and peripheral neuropathy. In these cases with late presentation, epilepsy is rare, usually appearing months to years after symptom onset, although sporadic cases presenting with myoclonic seizures have been reported (Morse and Rosman, 2006).

Metachromatic leukodystrophy

Metachromatic leukodystrophy results from a deficiency of arysulfatase A and manifests with four distinct phenotypes that vary according to the age at onset. In spite of the fact that this disorder affects primarily the white matter, epilepsy is rather common as a late symptom. Seizures are usually of focal type, and appear in about one-quarter of patients with the late infantile form and in about half of those affected with the juvenile-onset form. EEG findings include diffuse high-voltage slowing and occasional burst of spikes. Focal interictal epileptic discharges predominate in the late infantile form (Wang et al., 2001).

Mucopolysaccharidosis

The mucopolysaccharidoses (MPS) are caused by a deficiency of enzymes involved in the degradation of glycosaminoglycans; they are all characterized by multisystem involvement, organ enlargement, abnormal facial features, and dysostosis. MPS types IIIa, b, c, and d, also named Sanfilippo disease, present with predominant neurological symptoms at the age of 2–6 years in the form of behavioral problems, followed by mental decline. Seizures are present in about half of the patients; they may be the symptom of onset and are usually easily treatable (Ruijter et al., 2008; Valstar et al., 2010).

Peroxisomal disorders

Peroxisomes are cellular organelles associated with plasmalogen and bile acid biosynthesis, oxidation of very long chain and dicarboxylic fatty acids, and degradation of phytanic acid and pipecolic acid through catalysis of hydrogen peroxide. There are at least 20 peroxisomal diseases, and the number is still increasing. Diagnosis of almost all the peroxisomal disorders relies on the finding of high levels of very long chain fatty acids in blood. The most frequent peroxisomal disorder is X-linked adrenoleukodystrophy. In the childhood form of the disease, symptoms start between the ages of 4 and 10 years and include neurological regression, ataxia, spasticity, cortical blindness, cognitive decline, and Addison disease. Partial motor seizures, sometimes secondary generalized, are the most frequently observed. EEG shows progressive impoverishment of background activity with high-voltage polymorphic delta activity (Mamoli et al., 1979).

Generalized defects of peroxisomal functions present with more severe and early encephalopathies, among which Zellweger syndrome is the most common and best defined. This syndrome is characterized by hypotonia, hyporeflexia, kidney and liver dysfunction, blindness, and distinctive dysmorphic features. The almost constant presence of cortical malformations, consisting of diffuse or localized polymicrogyria, mostly in frontal or opercular areas, contributes to the high epileptogenicity of this disease. Epilepsy is almost invariably present, usually beginning in the neonatal period or early infancy. Seizure types include focal, myoclonic, and atypical spasms. EEG may be characterized by burst–suppression, or multifocal epileptic discharges predominantly in the frontal motor cortex, or, more rarely, hypsarrhythmia (Takahashi et al., 1997).

Organic acidurias

The organic acidurias (OAs) are biochemical disorders of intermediary metabolism that affect various biochemical pathways of amino acids, fatty acids, ketogenesis, ketolysis, pyruvate, carbohydrates, and the Krebs cycle. The disorders of organic acid metabolism therefore comprise a large number of diseases, a minority of which involve the central nervous system. However, epilepsy is a frequent symptom of OAs with neonatal or infantile onset. The most frequent OAs during the neonatal period are: isovaleric aciduria, propionic acidemia, methylmalonic acidemia, and maple syrup urine disease. Neonatal seizures (most often focal, or with tonic posture) are usually part of a more heterogeneous array of symptoms but in some instances may be the presenting one. EEG may show dysmature features, diffuse delta activity or a burst–suppression pattern. In older infants methylmalonic acidemia has been reported in association with West syndrome (Campeau et al., 2010). Seizures, including infantile spasms, have been described in 3-methylcrotonyl-CoA carboxylase deficiency, in 3-methylglutaconic aciduria, and in 3-methylglutaric aciduria (al Aqeel et al., 1994; Koling et al., 2000; Dirik et al., 2008; Wortmann et al., 2010). Epileptic seizures or even status epilepticus can be among the presenting symptoms, even in adolescents and adults in organic acidurias with a slow course, such as L-2-hydroxyglutaric aciduria (L-2-HGA) (Adeva-Bartolomè et al., 2009; Steenweg et al., 2010). The diagnosis of L-2-HGA may be suggested by the typical distribution of signal abnormalities in subcortical white matter demonstrated by MRI (D’Incerti et al., 1998). Finally, seizures are often the first clinical sign of glutaric aciduria type 1, particularly during a febrile illness, indicating the acceleration of the clinical course of the disease (McClelland et al., 2009).

Aminoacidurias

There are numerous inborn errors of amino acid metabolism that can be associated with epileptic seizures. The most common are due to errors of phenylalanine and tyrosine metabolism and nonketotic hyperglycinemia.

Phenylketonuria is caused by phenylalanine hydroxylase deficiency. Generalized seizures occur in one-quarter of patients, associated with EEG focal or generalized slowing or epileptic discharges. Hyperphenylaninemia may also be due to disorders of tetrahydrobiopterin (BH4) homeostasis. The defect can present with recurrent status epilepticus or hypsarrhythmia. Inborn errors of tyrosine metabolism may cause neonatal seizures or infantile spasms. EEG shows generalized voltage attenuation with single spike and polyspike discharges in the parieto-occipital areas.

Nonketotic hyperglycinemia is due to the defect of one of the four enzymes that cleave the amino acid glycine. It classically presents in the newborn period after a symptom-free interval of several days. Clinical symptoms are lethargy, poor feeding, apneic spells, altered muscular tone, and intermittent ophthalmoparesis. Erratic myoclonus is an early symptom, and may be associated with spasms or tonic seizures and with the EEG pattern of burst–suppression (Hoover-Fong et al., 2004; Rossi et al., 2009).

Urea cycle disorders

The urea cycle involves a series of biochemical steps in which nitrogen from protein metabolism is converted to urea. Deficiency of one of the enzymes involved in this process causes disorders collectively known as urea cycle disorders (Gropman et al., 2007). The biochemical hallmark of these disorders is hyperammonemia. In most cases, the symptoms appear within the first days of life, with lethargy, vomiting, hypothermia, and hyperventilation. Seizures are frequent during the early stages of hyperammonemia, before hyperammonemic coma develops. This stage can be associated with EEG low-voltage, asymmetric theta–delta activity or with an EEG pattern of burst–suppression. By contrast, once the metabolic disease is properly treated, epilepsy is rare. The treatment aims at reducing plasma ammonia concentration; it includes medications and/or supplements (to provide alternative pathways for ammonia removal) and restriction of protein intake to limit ammonia production.

Urea cycle disorders may also manifest in childhood and adolescence (or, rarely, in adulthood), when the enzymatic deficiency is mild. The most common urea cycle disorder is the X-linked ornithine transcarbamylase deficiency (OTC), which may manifest in female carriers, especially during metabolic stress, with acute focal neurological deficits and confusion mimicking complex partial status epilepticus (Bogdanovic et al., 2000).

Miscellaneous disorders

Menkes disease

This X-linked, recessive disorder, also known as kinky hair disease, is a neurodegenerative disease due to impaired copper transport, resulting in copper deficiency. As copper is a cofactor in many enzymatic reactions (including mitochondrial cytochrome c oxidase, superoxide dismutase, dopamine β-hydroxylase and tyrosinase), the main features of the disease are mitochondrial chain respiratory dysfunction, alteration in the molecular bridges of collagen that cause hair abnormalities (pili torti, alopecia), and vascular irregularity with elongated and fragile vessels. The first symptoms begin in the neonatal period, or in early infancy (Kaler et al., 2008). Epilepsy is almost invariably present and may manifest as infantile spasms, at times preceded and followed by focal or myoclonic seizures (Sfaello et al., 2000; Bahi-Buisson et al., 2006). The diagnosis is based on the finding of low serum copper and ceruloplasmin. Early copper therapy may reduce seizure frequency (Prasad et al., 2011).

Canavan disease

Canavan disease, also known as spongy degeneration of the brain, is an autosomal recessive neurodegenerative disease caused by mutations of the gene encoding the enzyme aspartoacylase (Matalon et al., 1988). The enzymatic deficiency leads to the accumulation of N-acetylaspartic acid (NAA) in brain and increased concentration of N-acetylaspartic acid in the CSF, plasma, and urine. In the infantile, most common, form, developmental delay, hypotonia, head lag, and progressive macrocephaly appear by the age of 3–6 months, followed by spasticity and cortical blindness; seizures usually develop in the second year of life. MRI reveals symmetrical, progressive white matter degeneration that progresses with age; magnetic resonance spectroscopy shows accumulation of NAA. The diagnosis, suggested by the triad hypotonia, head lag, and macrocephaly and by the neuroimaging findings, is established by gas chromatography for measurement of NAA in urine, plasma and CSF, and further confirmed by the DNA mutation analysis.

Congenital disorders of glycosylation

Congenital disorders of glycosylation (CDG) are a group of disorders characterized by multisystem involvement and prominent neurological symptoms (Jaeken and Carchon, 2004). More than 12 glycosylation-related enzyme deficiencies are known with a large variety of phenotypes. They show variable association of dysmorphic features, hypotonia, ataxia, nystagmus, myopia, progressive retinal degeneration, developmental delay, pericardial effusion, esotropia, retinitis pigmentosa, and strabismus. Epilepsy is a prominent symptom in CDG type Ic (Grünewald and Matthijs, 2000), whereas it is seldom observed in CDG type Ia during acute, stroke like episodes. CDG may be diagnosed by transferrin isoelectrofocusing; antithrombin III activity and thyroglobulin levels may be low, these all being glycoprotein targets of the primary defect of glycosylation.

Molybdenum cofactor deficiency

This is a rare condition, but consistently associated with seizures (Slot et al., 1993; Topcu et al., 2001). Molybdenum is a trace element that acts as an essential cofactor for reactions of four different enzymes: sulfite oxidase, mitochondrial amidoxime reducing component, xanthine dehydrogenase, and aldehyde oxidase (Reiss and Hahnewald, 2011). Deficiency of molybdenum cofactor causes a progressive encephalopathy with recurrent and refractory seizures, mainly of focal, tonic, or myoclonic type, appearing in the neonate period. The EEG may be characterized by multifocal paroxysms or by a burst–suppression pattern. MRI shows cystic degeneration of white matter and severe atrophy. An easy diagnostic screening test is the sulfite level in freshly collected urine.

Acute porphyrias

Porphyrias are a group of genetic disorders caused by mutations in enzymes of the heme biosynthesis pathway. The clinical manifestations of the acute intermittent form of porphyria include recurrent attacks of acute abdominal pain with gastrointestinal symptoms; the attacks may be associated with neurological symptoms including polyneuropathy, transient sensory–motor symptoms and cognitive or behavioral abnormalities, and, in about 15% of patients, seizures (Solinas and Vajda, 2008). Rarely, seizures may be the inaugural symptom of the disease (Winkler et al., 2005).

Management of epilepsy is difficult, as many anticonvulsants (including barbiturates, phenytoin, valproate, carbamazepine, lamotrigine, and topiramate) may worsen seizures and the associated symptoms.

Metabolic disease amenable to specific treatment

Glucose transporter type 1 deficiency syndrome

The protein glucose transporter type 1 (GLUT1), encoded by the gene SLC2A1, is selectively expressed in brain endothelial cells, astroglia, and erythrocytes. It is the major glucose transporter in the mammalian blood–brain barrier and allows glucose entrance into the brain. Mutations or, more rarely, deletions of the gene SLC2A1 are responsible for a rare and treatable neurological disease: the GLUT1 deficiency syndrome which was first described in infants with early onset epilepsy (De Vivo et al., 1991; Seidner et al., 1998). This classical phenotype is characterized by the onset of seizures in the first year of life, acquired microcephaly, and mental retardation. Various forms of seizures have been described: generalized tonic–clonic, tonic, myoclonic, astatic, atypical absences, and focal fits. Other paroxysmal events may occur, including apneic spells, intermittent ataxia, confusion, lethargy, sleep disturbances, and recurrent headache (Wang et al., 2005). In recent years, patients with nonclassical phenotypes have been increasingly reported; these include early onset absences, (Roulet-Perez et al., 2008; Suls et al., 2009; Anand et al., 2011; Byrne et al., 2011), and myoclonic epilepsies (Gaspard et al., 2011; Mullen et al., 2011). Mutations of SLC2A1 have been detected also in patients with movement disorders, in particular exercise-induced dyskinesia, or intermittent ataxia not associated with seizures (Wang et al., 2005; Zorzi et al., 2008; Schneider et al., 2009; Pons et al., 2010). In all cases the symptoms are worsened by fasting. The biochemical