Table of Contents
Epilepsy Research and Treatment
Volume 2013, Article ID 124934, 20 pages
Review Article

Metabolic Causes of Epileptic Encephalopathy

Department of Neurology, Children’s National Medical Center, 111 Michigan Avnue, Washington, DC 20010, USA

Received 22 February 2013; Accepted 16 April 2013

Academic Editor: Giangennaro Coppola

Copyright © 2013 Joe Yuezhou Yu and Phillip L. Pearl. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Epileptic encephalopathy can be induced by inborn metabolic defects that may be rare individually but in aggregate represent a substantial clinical portion of child neurology. These may present with various epilepsy phenotypes including refractory neonatal seizures, early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and generalized epilepsies which in particular include myoclonic seizures. There are varying degrees of treatability, but the outcome if untreated can often be catastrophic. The importance of early recognition cannot be overemphasized. This paper provides an overview of inborn metabolic errors associated with persistent brain disturbances due to highly active clinical or electrographic ictal activity. Selected diseases are organized by the defective molecule or mechanism and categorized as small molecule disorders (involving amino and organic acids, fatty acids, neurotransmitters, urea cycle, vitamers and cofactors, and mitochondria) and large molecule disorders (including lysosomal storage disorders, peroxisomal disorders, glycosylation disorders, and leukodystrophies). Details including key clinical features, salient electrophysiological and neuroradiological findings, biochemical findings, and treatment options are summarized for prominent disorders in each category.

1. Introduction

Inherited metabolic epilepsies are disorders that, while individually rare, are in aggregate a substantial clinical portion of child neurology, as well as a complex field of knowledge for physicians, investigators, and students to tackle. A subset of these disorders can lead to the development of epileptic encephalopathy, that is, a brain disturbance due to highly active clinical or electrographic ictal activity. The epileptologist may view these from the viewpoint of syndromic phenotypes such as early myoclonic encephalopathy, early infantile epileptic encephalopathy, infantile spasms, and myoclonic epilepsies. They have various degrees of treatability at present, with some requiring prompt diagnosis and intervention to avoid otherwise catastrophic outcomes. Careful consideration of metabolic disorders in patients presenting with epileptic encephalopathy is therefore warranted, and to this end, we hope a review may be helpful.

This paper provides an overview of inborn metabolic errors associated with epileptic encephalopathy, summarizing key clinical features and underlying biochemistry, salient electrophysiological and neuroradiological findings, and primary treatment options where appropriate. Examples of specific disorders are discussed, with full listings of the multiple enzyme defects and diseases in particular categories presented in tables. The range of inherited metabolic disorders has been organized by the category of molecules or the biochemical process involved: for example, small molecule disorders include dysfunction involving amino, organic, or fatty acids, neurotransmitters, the urea cycle, vitamers and cofactors, and disorders of the mitochondria. Large molecule diseases cover defects in glycosylation, lysosomal and peroxisomal function, and leukodystrophies.

2. Small Molecule Disorders

2.1. Amino and Organic Acid Disorders

Amino acidopathies and organic acidemias, resulting from disorders in amino or fatty acid catabolism, present with seizures and cognitive, behavioral, or motor disturbances resulting from the accumulation of toxic intermediaries, or possible structural damage [1]. Some may induce an epileptic encephalopathy. Seizure types and EEG findings vary, though myoclonic epilepsies predominate, and diffuse background slowing is a common EEG finding. More typical EEG findings in metabolic encephalopathies are burst suppression, hypsarrhythmia, and generalized spike-wave discharges. Table 1 lists the protean disorders along with the enzyme defect and metabolites detected on diagnostic studies.

Table 1: Amino acidemias and organic acidopathies.

2.1.1. Methylmalonic Acidemia and Cobalamin Deficiencies

The finding of elevated methylmalonic acid can be caused by a number of distinct disorders including defects in the vitamin B12-related enzymes cobalamin A, B, C, or D and methylmalonyl CoA mutase (MUT). Early myoclonic encephalopathy, as well as other epilepsies and epileptic encephalopathies, has been associated with this finding. The most common methylmalonic acidemia involving cobalamin is cobalamin C deficiency (Figure 1); individuals may present in infancy or early childhood with seizures and progressive encephalopathy. Patients presenting with status epilepticus have also been reported. Treatment with hydroxycobalamin is effective, including prenatal supplementation in affected families but may not reverse existing neurological injury in delayed diagnoses [3].

Figure 1: Cobalamin transport and metabolism. Hydroxycobalamin (OH-Cbl) enters the cell bound to transcobalamin (TC), a binding protein. The hydroxycobalamin-transcobalamin complex is broken down inside the lysosome, and the enzyme cobalamin C (CblC) removes the hydroxyl group to generate free cobalamin (Cbl), which is synthesized via additional steps into methyl- and adenosyl-cobalamin.
2.1.2. Propionic Acidemia

Propionic acidemia (PA) is caused by defects in the enzyme propionyl CoA carboxylase and commonly presents with lethargy, vomiting, metabolic acidemia, and sometimes hyperammonemia [4]. A severe presentation of this disease in infancy with infantile spasms and hypsarrhythmia is reported [5]; myoclonic and generalized seizures are common in early childhood and infancy and typically evolve into mild generalized and absence seizures later in life [6].

2.1.3. Ethylmalonic Acidemia

Ethylmalonic encephalopathy is usually lethal in infancy or early childhood and has a severe presentation including seizures, brain structural malformations, neurodevelopmental regression, pyramidal and extrapyramidal symptoms, chronic diarrhea, and dermatological findings including petechiae and acrocyanosis. MRI has shown frontotemporal atrophy, enlargement of the subarachnoid spaces, and basal ganglia T2-weighted hyperintensities [7]. EEGs may worsen over time, with multifocal spike and slow waves and background disorganization [8].

2.1.4. 3-Hydroxy-3-Methylglutaric Acidemia

When untreated, dysfunction of the enzyme 3-hydroxy-3-methylglutaryl CoA lyase (which cleaves 3-hydroxy-3-methylglutaryl CoA into acetyl CoA and acetoacetate) leads to metabolic acidosis with absent ketone production, lactic acidemia, hypoglycemia hepatomegaly, and lethargy, possibly progressing to coma and death. Seizures are linked in most cases to lactic acidemia or hypoglycemia and are associated with multifocal spike-wave discharges on EEG [8]. Some presentations show particular association with white matter lesions, dysmyelination, and cerebral atrophy on neuroimaging [9, 10].

2.1.5. Glutaric Acidemia

Dysfunction of the enzyme glutaryl CoA dehydrogenase prevents the metabolism of tryptophan, hydroxylysine, and lysine, resulting in increased urine glutaric acid metabolites. This is a cerebral organic acidopathy, with predominantly neurological symptoms featuring macrocephaly, increased subarachnoid spaces, and progressive dystonia and athetosis with striatal injury [11]. Seizures can be a presenting sign and are seen during acute encephalopathic events [12, 13]. EEGs show background slowing with generalized spike-and-wave and mixed multifocal discharges [8, 14]. Therapy using a low-protein diet (especially low lysine and tryptophan), carnitine supplementation, and aggressive emergency management can significantly improve the outcomes. The antiepileptic valproate should be avoided, however, because it is believed to affect acetyl CoA/CoA ratios and may exacerbate metabolic imbalance [13].

2.1.6. 3-Methylglutaconic Acidurias

Five subtypes of 3-methylglutaconic aciduria (MGA) have been categorized (Table 1); all are cerebral organic acidopathies resulting from defects in the leucine catabolic pathway. Neurological and developmental symptoms are central in all five types although seizures are prominent mainly in Type I. Patients with Type I MGA present with leukoencephalopathy and epileptic encephalopathy with psychosis and depression, in addition to ataxia, optic atrophy, and sensorineural hearing loss. These are often accompanied by systemic issues including cardiomyopathy, liver and exocrine pancreatic dysfunction, and bone marrow failure [15]. EEGs show diffuse slowing and white matter lesions can be seen on MRI, usually in a supratentorial location [8, 15, 16].

2.1.7. Canavan Disease

Canavan disease is primarily a disease of demyelination. It is thought to be caused by brain acetate deficiency resulting from a defect of N-acetylaspartic acid (NAA) catabolism [17]. Accumulation of NAA, a compound thought to be responsible for maintaining cerebral fluid balance, can lead to cerebral edema and neurological injury. Presentation of Canavan disease includes progressive epileptic encephalopathy with developmental delay, macrocephaly, leukodystrophy, and optic atrophy [18, 19]. Seizures often begin in the second year of life, and treatment is primarily supportive, including antiepileptic medications.

2.1.8. D- and L-2-Hydroxyglutaric Aciduria

D-2-Hydroxyglutaric aciduria results from the loss of enzyme function in either D-2-hydroglutaric dehydrogenase or hydroxyacid-oxoacid transhydrogenase, which metabolizes GHB (gamma-hydroxybutyrate). Though presentations vary, severe cases manifest in the neonatorum with encephalopathy, intractable epilepsy, and cardiomyopathy. Seizures are present in almost all cases, and MRI findings have included signal alterations in the basal ganglia and diencephalon, as well as agenesis of the corpus callosum.

The enantiomer, L-2-Hydroxyglutaric aciduria, is a disorder of alpha ketoglutarate synthesis. It presents with neurodevelopmental delay, generalized seizures, and progressive ataxia. Multifocal spike-waves and burst suppression can be seen on EEGs [20, 21], and characteristic MRI findings include cerebellar atrophy, subcortical white matter loss, and symmetric T2-weighted hyperintensities in the cerebellar dentate nuclei, globus pallidi, and thalami.

2.1.9. Fumaric Aciduria

Seizures are a prominent feature in fumaric aciduria, due to a defect in the conversion of fumarate to malate. The disorder can present prenatally with polyhydramnios and cerebral ventriculomegaly and manifests in infancy and early childhood with epilepsy, serious neurodevelopmental delay, macrocephaly, opisthotonus, and vision loss. Status epilepticus is well reported. Diffuse polymicrogyria, decreased white matter, large ventricles, and open opercula are seen on neuroimaging [22].

2.1.10. Maple Syrup Urine Disease and Dihydrolipoamide Dehydrogenase Deficiency

Dysfunction of the enzyme branched-chain 2-keto dehydrogenase (BCKD) in maple syrup urine disease (MSUD) prevents normal degradation of the branched-chain amino acids leucine, isoleucine, and valine, leading to toxic accumulation of metabolites. Neurological symptoms present in infancy and include cerebral edema, seizures, lethargy, vomiting, and “bicycling” movements [23]. Seizures are related to the cerebral edema and hyperlycinemia, and these symptoms can progress to coma and death. The EEG may show a characteristic comb-like rhythm (Figure 2). Treatment focuses on removing leucine from blood with dialysis or by reversing catabolism through feeding.

Figure 2: EEG of 4-day-old infant with MSUD shows comb-like rhythm over the right central (C4) area. (sensitivity 7 mcv/mm, HFF 70 Hz, time constant 0.5 sec, 8 sec epoch). Pearl [2].

Dihydrolipoamide dehydrogenase deficiency, sometimes referred to as MSUD Type III, is due to a defect in a subunit of BCKD, as well as 3 other essential enzymes. The disorder leads to metabolic acidosis and neurological injury, and patients can present with hypoglycemia, absent ketones, elevated liver transaminases, and seizures [24]. The disorder is often fatal at an early age, representing multienzyme failure.

2.2. Disorders of GABA Metabolism

Seizures are an important problem in disorders of the synthesis or degradation of gamma-aminobutyric acid (GABA), the brain’s primary inhibitory neurotransmitter. The most common of these is succinic semialdehyde dehydrogenase (SSADH) deficiency, though GABA-transaminase deficiency—while extremely rare—features a more severe, progressive epileptic encephalopathy. Both are inherited metabolic disorders affecting GABA degradation.

2.2.1. Succinic Semialdehyde Dehydrogenase Deficiency (4-Hydroxybutyric Aciduria)

Deficiency of the enzyme succinic semialdehyde dehydrogenase (SSADH) results in increased systemic and CSF levels of GABA and its catabolite, 4-hydroxybutyric acid (GHB). Patients present with neurodevelopmental delay, expressive language impairment, hypotonia, hyporeflexia, ataxia, and behavioral disorders that commonly include obsessive compulsive and attention deficit hyperactivity disorders. Over 50% of individuals with SSADH deficiency will develop seizures, most commonly tonic-clonic and atypical absence seizures [25]. Recurring status epilepticus and sudden unexpected death in epilepsy patients (SUDEP) have been reported, the latter associated with escalating seizure frequency and severity [26]. MRIs show increased T2-weighted signals in the globus pallidus, cerebellar dentate nucleus and subthalamic nucleus, and variably cerebral and cerebellar atrophy [27]. EEGs typically show generalized spike-wave activity although some may have partial features and variable hemispheric lateralization (Figure 3). Treatment is currently limited to antiepileptic and behavioral medications. While valproate is generally avoided due to its ability to inhibit any residual enzymatic activity, its use has been associated with improvement in some patients with challenging epilepsy including epileptic encephalopathy.

Figure 3: (a) EEG of 3-year-old female with SSADH deficiency. Note diffuse spike-wave paroxysm with lead-in over right hemisphere. (b) Same recording as top, showing left-sided spike-wave paroxysm. Pearl [2].
2.3. Fatty Acid Oxidation Disorders

Severe seizures can be a presenting sign of defects in fatty acid beta-oxidation, a biochemical process that produces alternatives source of acetyl-CoA and ketone bodies for energy. Fatty acid oxidation (FAO) disorders (Table 2) are a large category of diseases that particularly endanger the CNS and other organ systems that have high energy demands. Metabolic decompensation can be triggered by physiological stressors such as fasting, fever, or physical exertion, and symptoms can appear at any age. Acute crises resemble Reye syndrome, with cardiomyopathy and arrhythmia, as well as rhabdomyolysis and hypoketotic hypoglycemia [28, 29].

Table 2: Fatty acid oxidation disorders and biochemical characteristics.

Blood and urine laboratory tests are informative towards a diagnosis, particularly if done while the patient is symptomatic. Treatment is dependent on clinical presentation and include avoidance of fasting with frequent low-fat and carbohydrate-rich intake for nonsymptomatic patients and moderation of physical stress in combination with medium-chain triglyceride (MCT) supplementation for patients symptomatic with myopathy. Patients in metabolic crisis require close management in an inpatient setting, with immediate reversal of the catabolism [30, 31].

2.4. Mitochondrial Diseases

Epilepsy is a common secondary feature of mitochondrial disease, and disorders in this category (Table 3) have been associated with severe epileptic encephalopathy. Seizures can be a logical consequence of mitochondrial dysfunction: deficient energy generation disrupts the active maintenance of neuronal membrane potential, and seizure-induced cellular hyperactivity adds further oxidative stress to already deficient ATP generation. Up to 60% of patients with mitochondrial disease develop seizures, and many of these can be refractory to treatment [32]. Myoclonic epilepsies are the most commonly reported, but almost all seizure types have been seen, and individual patients can often show multiple types.

Table 3: Mitochondrial disorders and epilepsy.

2.4.1. POLG1 Disease

Mutations in the gene POLG1, which facilitates mitochondrial DNA replication, have been linked to a range of disease phenotypes, the most prominent being Alpers’ disease [33] (Figure 4). Alpers-Huttenlocher disease is a rapidly progressive encephalopathy, causing intractable epilepsy and diffuse neuronal degeneration. Partial complex and myoclonic seizures are most common, although the disorder can evolve to include multiple seizure types [34]. The use of valproate is contraindicated; it has been associated with liver failure in patients with POLG1 mutations, as well as epilepsia partialis continua.

Figure 4: 7-year-old boy diagnosed with Alpers’ syndrome presented with encephalopathy, tonic-clonic seizures and myoclonic seizures. EEG shows high amplitude anterior poorly formed 2-3 Hertz sharp and slow activity. Pearl [2].

A syndrome of myoclonic epilepsy myopathy sensory ataxia (MEMSA) has also been seen in patients with mutations in POLG1. Seizures, usually focal and often refractory, begin in young adulthood, though other symptoms including sensory neuropathy and cerebellar ataxia may occur in adolescence. Over time, individuals develop cognitive decline and myopathy [35].

2.4.2. Myoclonic Epilepsy with Ragged Red Fibers (MERRF)

Myoclonic epilepsy with ragged red fibers (referring to the appearance of affected muscle cells) is a progressive epilepsy syndrome associated with prominent myoclonus, cognitive decline, optic atrophy, hearing loss, and myopathy [36]. It is associated with mtDNA mutations, and symptoms usually become noticeable in adolescence or young adulthood [37]. EEG findings include focal discharges, atypical spike- or sharp- and slow-wave discharges, and suppression of this activity during sleep [38].

2.4.3. Leigh Syndrome

Leigh syndrome, also known as subacute necrotizing encephalomyopathy, can be seen in disorders involving mitochondrial DNA (as well as nonmitochondrial disorders). Individuals present with neurologic regression with worsening hypotonia, spasticity, and brainstem failure as the disease progresses. Neuroimaging may show bilateral, symmetric lesions in the basal ganglia, thalami, midbrain, and brainstem as well as cortical and cerebellar atrophy [39]. Focal and generalized epilepsy are associated with this phenotype, and epilepsia partialis continua, as well as infantile spasms and hypsarrhythmia, has been described [40].

2.5. Cerebral Folate Deficiency

Cerebral folate deficiency can be a common end result of diverse metabolic and genetic conditions (Table 4). A suspected pathology in primary CFD involves impaired transport of folate across the choroid plexus into the central nervous system. This may be due to one of multiple causes, including loss of function mutations in the folate FR1 receptor, blocking autoantibodies to the folate receptor, or disrupted uptake due to valproic acid. Secondary folate deficiency can also be seen in inborn metabolic diseases, such as Rett syndrome, 3-phosphoglycerate dehydrogenase deficiency (a congenital serine biosynthesis disorder), and mitochondrial disorders such as Kearns-Sayre or Alpers disease [4144].

Table 4: Cerebral folate deficiencies.

Primary cerebral folate deficiency (CFD) is characterized by normal blood but low CSF levels of 5-methylhydrofolate (5-MTHF), the physiologically active form of folate. The common phenotype includes epilepsy, along with neurodevelopmental delay (or regression) and dyskinesias. Individuals with blocking autoantibodies to folate receptors present in early childhood with intractable generalized tonic-clonic seizures. In some cases, treatment with high doses of folinic acid (as opposed to folic acid, which has poor blood-brain barrier entry) has been reported to ameliorate seizures and improve neurological function [45].

2.6. Serine Synthesis Defects

Lserine, a nonessential amino acid, is synthesized from 3-phosphoglycerate by the sequential activity of three enzymes, each with associated disorders (Table 5). The majority of patients with serine deficiencies are affected by an abnormality in the first step, 3-phosphoglycerate dehydrogenase. The clinical phenotype, which includes congenital microcephaly and psychomotor retardation with refractory seizures and hypsarrhythmia, is nonspecific, likely leading practitioners to suspect in utero processes such as TORCH (Toxoplasmosis, Syphilis, Rubella, Cytomegalovirus, Herpes simplex, HIV) or static perinatal difficulties. MRI findings in infantile onset patients have revealed cortical and subcortical atrophy, as well as delayed myelination [46]. Juvenile onset has also been reported, with presentation at school age with absence seizures and moderate developmental delay [47]. Supplementation with oral serine and glycine has been reported to significantly improve seizures, spasticity, behavior, and feeding, as well as white matter volume and myelination [48, 49].

Table 5: Serine synthesis defects.

2.7. DEND Syndrome (Developmental Delay, Epilepsy, and Neonatal Diabetes)

A syndrome that combines the problems of developmental delay, epilepsy, and neonatal diabetes is an epileptic channelopathy associated with mutations in potassium channel and sulfonylurea receptor genes [50]. These mutations permanently “lock in” the KATP channel in an open state, leading to insufficient insulin release and severe hyperglycemia within the first six months of life [5153]. Clinical manifestations include neurodevelopmental delay, dysmorphic features, hypotonia, and seizures starting as early as the neonatorum. Infantile spasms with hypsarrhythmia, as well as severe tonic-clonic and myoclonic epilepsies, are reported. Neonatal hyperglycemia in DEND can be managed with insulin or sulfonylureas, but the latter is capable of bypassing the defective regulation of KATP channels and may have better efficacy for the neurological phenotype [50, 54, 55].

2.8. Hyperinsulinism-Hyperammonemia (HI-HA)

HI-HA is a syndrome of congenital hyperinsulinism and hyperammonemia that has been related to activating mutations affecting GDH (glutamate dehydrogenase), a participant in the insulin secretion pathway. These defects cause GDH to become insensitive to inhibition, resulting in excess ammonia production and insulin release and neurological sequelae from hypoglycemic insults and hyperammonemia [56]. The clinical constellation of generalized epilepsy, learning disorders, and behavior problems, in the context of hypoglycemia (both postprandial and fasting) and persistent hyperammonemia, is characteristic.

Hypoglycemic seizures may be the first apparent indication. However, some patients have been observed to experience paroxysms, accompanied by generalized electroencephalographic features, without hypoglycemic episodes. This suggests that epilepsy in HI-HA may not be due solely to low CNS glucose availability [5759]. HI-HA is manageable with a combination of dietary protein restriction, glucagon, antiepileptic medications, and diazoxide, a KATP channel agonist that inhibits insulin release [60].

2.9. Glucose Transporter 1 Deficiency

Glucose transporter type I (Glut-1) facilitates the passage of glucose across the blood-brain barrier, and its dysfunction in the developing brain leads to the development of a metabolic encephalopathy. CSF shows hypoglycorrhachia associated with normal plasma glucose and low-to-normal CSF lactate, measured in a fasting state. A wide array of phenotypes has been associated with this disorder, but 90% of affected children develop epilepsy (of various types, including absence, focal, generalized myoclonic, clonic, tonic, and nonconvulsive status epilepticus) [61]. Microcephaly, ataxia, and psychomotor delay may be present [62], but patients may also suffer from epilepsy without any accompanying motor or cognitive deficiencies. Haploinsufficiency (of the SLC2A1 gene) is correlated with the severity of symptoms [63]. EEG findings vary and may be normal, but usually include either focal or generalized slowing or attenuation, or spike-and-wave discharges (generalized, focal, or multifocal). Neuroimaging results may demonstrate diffuse atrophy.

Glucose transporter I deficiency has emerged as the leading metabolic indication for the ketogenic diet, a dietary therapy that replaces glucose with ketone bodies as the primary biochemical energy source. Response is rapid, even in the case of formerly refractory seizures, and treatment should be maintained long term. Additionally, there are certain compounds known to inhibit Glut-1, including phenobarbital, diazepam, methylxanthines (theophylline, caffeine), and alcohol, which should be avoided [64].

2.10. Pyridoxine, Folinic Acid, and Pyridoxal-5′-Phosphate Dependent Epilepsies

There are various epileptic encephalopathies related to vitamin B6 metabolism (Table 6), and pyridoxine-dependent epilepsy (PDE) is the prototype, resulting from a loss of the biologically active pyridoxal-5′-phosphate (PLP) due to a dysfunction of the protein antiquitin (ALDH7A1) [65]. PDE normally presents within the first hours following birth with serial refractory seizures responsive to pyridoxine administration. Improvement is significant and usually rapidly appreciable on EEG [66]. Variants of the disorder that respond to folinic acid instead of, or in addition to, pyridoxine have also been described, as well as atypical cases with long asymptomatic periods or presenting later in infancy (i.e., weeks or months following birth) [67, 68].

Table 6: Pyridoxine and pyridoxal-5′-phosphate-dependent Epilepsies.

PNPO, or pyridox(am)ine phosphate oxidase, deficiency is a distinct disorder involving refractory seizures responsive not to pyridoxine but to its biologically active form, pyridoxal-5′-phosphate (PLP) [69, 70]. This disorder is due to a defect in the enzyme PNPO, which synthesizes PLP from precursors pyridoxine-P and pyridoxamine-P [71]. Patients may present prenatally with fetal seizures and premature birth and if untreated can progress to status epilepticus and death. Laboratory and genetic testings are available to confirm these diagnoses (Table 6); trials of systemic pyridoxine administration require close cardiorespiratory monitoring.

2.11. Urea Cycle Disorders

The urea cycle (Figure 6), the metabolic mechanism for nitrogen detoxification and removal, is facilitated by six enzymes and a mitochondrial transporter and carrier, each being susceptible to dysfunction (Table 7). In the event of an enzyme or transport defect, the resulting hyperammonemia can lead to overwhelming encephalopathy, often accompanied by seizures and hypotonia that may be exacerbated by metabolic stresses such as fever or infection [72]. EEG monitoring should be initiated early in the course of acute treatment, as seizure activity is thought to be related to hyperammonemic crises or structural damage, and subclinical electrographic seizures are reported. Males with OTC deficiency typically present in the neonatorum and with high mortality, whereas female heterozygotes can vary in the severity and timing of presentation depending on hepatic lyonization [72].

Table 7: Urea cycle defects and biochemical characteristics.

The goals of therapy during metabolic crisis are removal of ammonia through hemodialysis, nitrogen scavenging with agents including sodium benzoate and sodium phenylacetate [73], and reversal of catabolism. Immediate antiepileptic therapy is indicated for optimizing treatment; valproate, however, may interfere with the urea cycle and precipitate metabolic crises [74]. Maintenance therapy of urea cycle defects hinges on the restriction of protein intake while providing sufficient essential amino acids. Orthotopic liver transplant may be curative, but cannot reverse existing neurologic injury.

2.12. Creatine Biosynthesis and Transport Deficiencies

Half of the body’s daily requirement of creatine is synthesized from arginine and glycine by the enzymes AGAT (arginine:glycine amidinotransferase) and GAMT (guanidino acetate methyl transferase). A specific creatine transporter, CT1, encoded by an X-linked gene, facilitates the uptake into tissues. Patients with deficiencies in creatine synthesis or transport present with early developmental delay, seizures, neurologic regression, intellectual disability, autistic behavior, hypotonia, and movement disorders. Females with heterozygous mutations of the creatine transporter gene may be symptomatic with more moderate intellectual disability, learning and behavior problems, and epilepsy [75].

Approximately half of individuals with GAMT deficiency, and most males with creatine transporter deficiency, develop epilepsy [76]. Patients with GAMT deficiency have abnormal MRI signals of the globus pallidus and background slowing and generalized spike-and-wave discharges on EEG. Individuals with creatine transporter deficiency present with generalized and partial epilepsy, with EEG usually reported as showing generalized polyspike or multifocal epileptiform discharges [77, 78].

Laboratory identification using urine creatine metabolites (Table 8) is necessary to distinguish the three disorders [79]. In the case of creatine synthesis disorders, treatment with oral creatine supplementation can improve seizures and neurological function, and arginine restriction and ornithine supplementation are utilized in GAMT deficiency. Creatine transport disorders, however, are not significantly amenable to therapy other than with traditional antiepileptic medications.

Table 8: Creatine synthesis defects.

2.13. Glycine Encephalopathy

Glycine encephalopathy is an inherited disorder of glycine degradation resulting from defects in the mitochondrial glycine cleavage system (GCS). The excitatory effects of glycine on the cortex and forebrain, mediated by N-methyl-D-aspartate(NMDA) receptors, lead to excess intracellular calcium accumulation and subsequent neuronal injury with intractable seizures [80]. Based on age at presentation and clinical outcomes, different categories of glycine encephalopathy (GE) can be distinguished. The majority of patients present with a severe neonatal-onset form, with primarily myoclonic and intractable seizures, hypotonia, apnea, and coma [81]. Outcomes are generally poor, particularly in the presence of brain malformations such as corpus callosum hypoplasia. There are attenuated forms, lacking congenital malformations, with a better outcome.

Laboratory analyses reveal elevated plasma and CSF glycine, as well as an increased CSF to plasma glycine ratio. EEG findings include multifocal epileptiform activity, hypsarrhythmia, and burst-suppression patterns (Figure 5) [82]. Treatment with benzoate and a low-protein diet may reduce glycine levels in plasma, and combined antiepileptic treatment is necessary for most individuals.

Figure 5: EEG of term infant with glycine encephalopathy shows burst-suppression pattern. Pearl [2].
Figure 6: The urea cycle. The urea cycle is a pathway of cytosolic and mitochondrial proteins involved in the conversion of ammonia (NH4) to urea for excretion via the kidneys. The enzymes in the pathway are as follows: carbamoylphosphate synthetase (CPS1), ornithine transcarbamylase (OTC); argininosuccinic acid synthase (ASS); argininosuccinic acid lyase (ASL); arginase I (ARG); nitric oxide synthase (NOS). Pearl [2].
2.14. Sulfide Oxidase Deficiency/Molybdenum Cofactor Deficiency

Sulfite oxidase deficiency due to molybdenum cofactor deficiency (MOCOD) and isolated sulfite oxidase deficiency (ISOD) are inherited disorders of the metabolism of sulfated amino acids [83]. They typically present in the first days of life with poor feeding following an uneventful pregnancy and delivery. Seizures, primarily myoclonic or tonic-clonic, begin in the first few weeks of life; they can be refractory to therapy and may develop into status epilepticus [84]. Signs of encephalopathy with opisthotonus, apnea, prolonged crying, and provoked erratic eye movements or myoclonias can be seen, and up to 75% of patients will have slight dysmorphia including widely spaced eyes, small nose, puffy cheeks, and elongated face [85].

EEG findings include burst suppression patterns and multifocal spike-wave discharges [86], and neuroimaging results are usually profoundly abnormal, including diffuse cerebral edema evolving into cystic lesions and brain atrophy within weeks [87]. Low total plasma homocysteinemia is associated with both ISOD and MOCOD, and hypouricemia due to secondary xanthine dehydrogenase deficiency can be indicative of MOCOD. Therapy has historically been symptomatic, with combination or monoantiepileptics.

2.15. Homocysteinemias

Disorders involving homocysteine metabolism, specifically methionine and cystathionine synthesis, are characterized by elevated urine and serum homocysteine in the context of neurological symptoms. The spectrum of neurological dysfunction in homocysteine metabolism disorders is wide, including epilepsy, encephalopathy, peripheral neuropathy, ataxia, microcephaly, and psychiatric disorders. Cystathionine beta-synthetase (CBS) deficiency is the most common of the homocysteinemias, with severe defects involving multiple systems due to the essentiality of homocysteine and methionine to normal biochemical function. Focal seizures, stroke, neurodevelopmental delay, and cognitive deficiency, as well as psychosis are common neurological findings. Marfan-like skeletal symptoms, connective tissue abnormalities in the optic lens, and vasculopathies causing thrombosis and multiorgan infarcts may also be present. Treatment and biochemical findings in CBS, as well as other homocysteine disorders are summarized in Table 9.

Table 9: Biochemical characteristics and treatment of homocysteine metabolism disorders.

Autosomal recessively inherited deficiency of methylene tetrahydrofolate reductase (MTHFR) may present in early infancy with severe epileptic encephalopathy [88]. The presentation with hypotonia, lethargy, feeding difficulties, and recurrent apnea may progress from seizures to coma and death. Infantile spasms may also be the presenting feature, with evolution to multiple seizure types including the Lennox-Gastaut syndrome. Status epilepticus, both clinical and subclinical, has been reported. Progressive microcephaly and global encephalopathy may ensue as seizures continue, but there is evidence for reversibility with treatment comprised principally of the methyl donor betaine [89].

2.16. Purine and Pyrimidine Defects

Disorders of purine and pyrimidine metabolism may present with epileptic encephalopathies (Table 10), including adenylosuccinase (adenylosuccinate lyase) deficiency which has a broad phenotypic spectrum including neonatal seizures [90]. Lesch-Nyhan disease, or X-linked hypoxanthine-guanine phosphoribosyltransferase deficiency, may result in epileptic seizures, but these can be difficult to distinguish from the extrapyramidal manifestations, specifically dystonic spasms, tremor, and myoclonus. Generalized tonic-clonic seizures are the most commonly reported epilepsy type in the literature [91, 92]. Treatment with allopurinol is essential for hyperuricemia and may provide some antiepileptic effect. Antiepileptic drug choices must weigh the possibility of exacerbating underlying behavioral irritability with levetiracetam and others. Topiramate and zonisamide are avoided due to the risk of nephrolithiasis.

Table 10: Purine and pyrimidine metabolism disorders involving epilepsy.

3. Large Molecule Disorders

3.1. Disorders of Glycosylation

Disorders of protein glycosylation, due to defects in the synthesis of N- and O-linked glycoproteins, are characterized by multiple organ system dysfunction, developmental delay, hypotonia, and epilepsy. Certain of these disorders are associated with severe encephalopathy, particularly those involving alpha-dystroglycan, a protein component of the extracellular matrix, essential to muscle integrity. These are known as dystroglycanopathies.

3.1.1. Walker-Warburg Syndrome

Walker-Warburg syndrome (WWS) is a severe dystroglycanopathy which can present at birth or prenatally with hydrocephalus and encephaloceles on imaging. Seizures and significant structural abnormalities (e.g. cerebellar atrophy, hypoplasia of the corpus callosum), migrational defects (type II lissencephaly), hypomyelination, and ophthalmologic defects are seen. Life expectancy is less than three years [93, 94].

3.1.2. Fukuyama Congenital Muscular Dystrophy

Fukuyama congenital muscular dystrophy (FCMD) classically presents in the neonatorum or even prenatally (poor fetal movement) with frequent seizures and severe brain abnormalities (migration defects, cobblestone lissencephaly, delayed myelination, hypoplasia of the pons, cerebellar cysts). By the age of 3, most patients develop epilepsy. Muscular degeneration and cardiac involvement are progressive [95, 96].

3.2. Lysosomal Storage Disorders

Lysosomal storage disorders (LSD) are a major category of diseases that involve defects in lysosomal enzyme function, lysosomal biogenesis, activation, trafficking, or membrane transporters. Over two-thirds of LSDs are neurodegenerative and some are associated with epileptic encephalopathy. Table 11 lists lysosomal storage disorders by subgroup, and prominent examples are covered below.

Table 11: Lysosomal storage disorders.
3.2.1. Neuronal Ceroid Lipofuscinoses (NCLs)

Neuronal ceroid lipofuscinoses are genetically heterogeneous neurodegenerative disorders associated with defects in transmembrane proteins and are characterized by the accumulation of autofluorescent lipopigments in lysosomes. The symptoms include cognitive decline, seizures, vision loss, and motor impairment, though age of onset and clinical course vary [97]. The development of epilepsy can indicate a more severe clinical course, though myoclonic seizures should be distinguished from myoclonus, which is also a frequent and sometimes progressive feature of this disorder [98]. Generalized cerebral and cerebellar atrophy can be seen on neuroimaging [99].

3.2.2. Sphingolipidosis and Gaucher Disease

Defects in the degradation of sphingolipids, an essential component of myelin sheaths and neuronal tissue, lead to progressive neurodegeneration, epilepsy, peripheral neuropathy, extrapyramidal symptoms, and characteristic “cherry-red spots.” Subtypes (II and III) of Gaucher Disease, which result from a deficiency in glucocerebrosidase, can cause devastating and rapid neurological deterioration. Neuroimaging is usually normal in patients with Gaucher Disease, but EEG can show several abnormalities including polyspikes with occipital predominance sensitive to photostimulation, diffuse slowing with high-voltage sharp waves during sleep, and multifocal spike-and-wave paroxysms [100, 101].

3.2.3. Gangliosidosis and Tay-Sachs Disease

Tay-Sachs disease is an example of defects involving the degradation of gangliosides, which are vital signaling, transport, and regulatory proteins in the lysosomal membrane. Seizures typically begin within the first year of life and worsen in frequency and severity. They are difficult to control with antiepileptics and can acutely and rapidly progress; in these cases, EEG and clinical deterioration can follow until death [102].

3.3. Peroxisomal Diseases

As a participant in cellular detoxification, lipid metabolism, as well as myelin, neuronal function, migration, and brain development [103], peroxisomes are essential for neuronal health. Nearly all peroxisomal disorders (Table 12) are known to impair neurological function, though peroxisomes are present in almost all eukaryotic cells, and consequently its associated diseases will also manifest in multiple organ systems. Seizures occur particularly in the neonatal period and may be a result of cortical migration defects. Symptomatic treatment using anticonvulsants is the predominant therapy [104, 105].

Table 12: Peroxisomal disorders.
3.3.1. Rhizomelic Chondrodysplasia Punctata

Rhizomelic chondrodysplasia punctata is a peroxisomal biogenesis disorder characterized by white matter abnormalities including inflammatory demyelination and noninflammatory dysmyelination, as well as cerebellar degeneration and loss of Purkinje cells, leading to profound intellectual deficiency. Almost all patients develop seizures, with nonspecific EEG findings. Neurological defects and degeneration are severe, and most individuals do not survive the first two years of life [106].

3.4. Leukodystrophies

Genetic leukoencephalopathies, or inherited white matter disorders, are diseases that primarily affect myelinated structures in the brain and peripheral nervous system. The majority of leukodystrophies primarily feature motor dysfunction rather than encephalopathy, particularly early on in the development of the disease. Epilepsy, however, can be a prominent symptom in certain classic leukodystrophies (Table 13) such as Alexander’s disease. This is associated with defects in the GFAPgene encoding astrocyte intermediate filaments. Early onset forms of Alexander’s disease (Type I) frequently feature seizures, particularly associated with fever, that are difficult to control. The clinical course of type I Alexander’s disease is normally progressive neurodegeneration involving megalencephaly, psychomotor retardation, and spastic paraplegia [107].

Table 13: Leukodystrophies including epilepsy as a manifestation.

4. Conclusion

Epileptic encephalopathies represent a challenging area of pediatric neurology and epilepsy and have a broad differential diagnosis [108]. There are protean inborn errors of metabolism which may lead to epileptic encephalopathies. They have various degrees of treatability at present, with some requiring prompt diagnosis and intervention to avoid otherwise catastrophic outcomes. The epileptologist may view these from the viewpoint of syndromic phenotypes. In general, early myoclonic encephalopathy and myoclonic seizures represent a classic epilepsy syndrome and seizure type, respectively, associated with inborn errors of metabolism. Yet, the phenotypic spectrum of epilepsy caused by hereditary metabolic disorders is wide and includes refractory neonatal seizures, early infantile epileptic encephalopathy (syndrome of Ohtahara), infantile spasms, and progressive myoclonic epilepsies, as well as syndrome variations such as early onset absence epilepsy in glucose transporter deficiency. A careful approach to metabolic disorders is helpful to consider the various diseases that may present and develop into an epileptic encephalopathy.

The small molecule disorders include amino and organic acidopathies such as maple syrup urine disease, homocysteinemia, multiple organic acid disorders, and cobalamin deficiencies. Dietary intervention is key in preventing encephalopathy in maple syrup urine disease and glutaric aciduria, and hydroxycobalamin has a therapeutic role starting in prenatal intervention in cobalamin C deficiency. Neurotransmitter and fatty acid oxidation disorders may result in epileptic encephalopathies, and mitochondrial disorders present with a range of epilepsy phenotypes, including intractable epilepsy and epilepsia partialis continua in polymerase gamma mutations. Cerebral folate deficiency appears to result from a variety of causes but primary deficiency, associated with mutations of the folate receptor or blocking antibodies, has a phenotype of intractable generalized tonic-clonic seizures in infancy which may respond to folinic acid. Disorders of serine synthesis may respond to pre- and postnatal supplementation with serine and glycine. There are several potassium channelopathies involving the pancreas and brain, presenting either with neonatal diabetes or hypoglycemia, specifically (developmental delay, epilepsy, and neonatal diabetes) DEND and (hyperinsulinism-hyperammonemia) HI-HA with specific therapeutic implications. Glucose transporter deficiency appears to be the prototype of transport defects causing epilepsy and having specific therapy, in this case being the ketogenic diet to supply an alternative brain fuel to glucose, and the disorders related to the pyridoxine vitamers, specifically pyridoxine and pyridoxal-5-phosphate, require prompt identification and therapy to avert a catastrophic outcome. Autosomal recessively inherited deficiency of MTHFR may be reversible with use of betaine, whereas other small molecule defects causing epileptic encephalopathy, for example, glycine encephalopathy and sulfite oxidase deficiency, have no specific therapy at this time.

Large molecule disorders involve a complex constellation of disorders of glycosylation, lysosomal storage diseases, and peroxisomal disorders. Those including severe epilepsy include Walker-Warburg syndrome, Fukuyama congenital muscular dystrophy, gangliosidoses such as Tay-Sachs and Sandhoff diseases, and the neuronal ceroid lipofuscinoses. While epilepsy represents significant gray matter involvement in neurological disease, seizures can be a prominent aspect of leukodystrophies such as Alexander’s disease. The epileptologist should consider these hereditary disorders in the investigation of patients with epileptic encephalopathies, leading to specific diagnostic steps and, in some cases, potential therapeutic maneuvers to address the metabolic defect.


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