Metabolic and Monogenic Causes of Seizures in Neonates and Young Infants

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YMGME-05018; No. of pages: 17; 4C: Molecular Genetics and Metabolism xxx (2011) xxx–xxx

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Molecular Genetics and Metabolism

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Minireview Metabolic and monogenic causes of seizures in neonates and young infants

Johan L.K. Van Hove ⁎, Naomi J. Lohr 1

Department of Pediatrics, University of Colorado, Clinical Genetics, Mail Stop 8400, Education 2 South, L28-4122, 13121 E. 17th Avenue, P.O. Box 6508, Aurora, CO 80045, USA article info abstract

Article history: Seizures in neonates or young infants present a frequent diagnostic challenge. After exclusion of acquired Received 13 March 2011 causes, disturbances of the internal homeostasis and brain malformations, the physician must evaluate for Received in revised form 20 April 2011 inborn errors of metabolism and for other non-malformative genetic disorders as the cause of seizures. The Accepted 20 April 2011 metabolic causes can be categorized into disorders of neurotransmitter metabolism, disorders of energy Available online xxxx production, and synthetic or catabolic disorders associated with brain malformation, dysfunction and degeneration. Other genetic conditions involve channelopathies, and disorders resulting in abnormal growth, Keywords: Seizures differentiation and formation of neuronal populations. These conditions are important given their potential Metabolic diseases for treatment and the risk for recurrence in the family. In this paper, we will succinctly review the metabolic Neurotransmitters and genetic non-malformative causes of seizures in neonates and infants less than 6 months of age. We will then provide differential diagnostic clues and a practical paradigm for their evaluation. © 2011 Elsevier Inc. All rights reserved.

Contents

1. Introduction ...... 0 2. Disorders of neurotransmitter metabolism ...... 0 2.1. Nonketotic hyperglycinemia ...... 0 2.2. Pyridoxal-5′-phosphate responsive encephalopathy ...... 0 2.3. Pyridoxine-dependent epilepsy ...... 0 2.4. Folinic acid responsive seizures ...... 0 2.5. Mitochondrial glutamate transporter ...... 0 2.6. Aromatic amino acid decarboxylase deficiency (AADC) ...... 0 2.7. D-2-hydroxyglutaric aciduria ...... 0 2.8. GABA disorders: 4-hydroxybutyric aciduria or succinic semialdehyde dehydrogenase deficiency and GABA transaminase deficiency . . . 0 3. Disorders of energy metabolism ...... 0 3.1. Glucose transporter deficiency ...... 0 3.2. Pyruvate dehydrogenase deficiency (PDH) and pyruvate carboxylase deficiency (PCD) ...... 0 3.3. Biotinidase deficiency ...... 0 3.4. Respiratory chain disorders ...... 0 3.5. Menkes disease ...... 0 3.6. Fumarase deficiency ...... 0 3.7. Sulfite oxidase deficiency ...... 0 3.8. Purine disorders: adenylosuccinate lyase deficiencyandAICA-ribosiduria...... 0 3.9. Creatine synthesis and transporter defects ...... 0 4. Biosynthetic defects: brain malformation and dysfunction ...... 0 4.1. Peroxisomal disorders ...... 0 4.2. Congenital disorders of glycosylation (CDG) ...... 0 4.3. Glycolipid synthesis: GM3 synthase deficiency ...... 0 4.4. Cholesterol synthesis: Smith–Lemli–Opitz syndrome ...... 0 4.5. Deficiency syndromes of the amino acids serine and glutamine ...... 0 4.6. Methylation disorders: homocysteine and folate disorders ...... 0

⁎ Corresponding author. Fax: +1 720 777 7322. E-mail address: [email protected] (J.L.K. Van Hove). 1 Fax: +1 720 777 7322.

4.7. Neuronal ceroid lipofuscinosis ...... 0 4.8. Lysosomal disorders ...... 0 5. Monogenic causes of neonatal and early infantile seizures ...... 0 5.1. ARX gene ...... 0 5.2. CDKL5 gene ...... 0 5.3. STXBP1 gene ...... 0 5.4. MECP2 gene ...... 0 5.5. PNKP gene ...... 0 5.6. Rare seizure genes ...... 0 5.7. Channelopathies ...... 0 5.8. eIF2B genes ...... 0 6. Clinical conclusions ...... 0 Acknowledgments ...... 0 References ...... 0

1. Introduction 2. Disorders of neurotransmitter metabolism

Seizures are a common neurologic symptom in neonates and 2.1. Nonketotic hyperglycinemia young infants. They can portend a poor prognosis, particularly when they are associated with an epileptic encephalopathy. The electroen- Nonketotic hyperglycinemia is caused by deficient glycine cleavage cephalogram patterns of burst suppression and hypsarrhythmia tend enzyme activity and characterized by elevated glycine in body fluids. to be associated with a particularly poor prognosis. There are many Patients with classic nonketotic hyperglycinemia present as neonates in causes for seizures in neonates and young infants. These can include the first days of life with hypotonia, feeding difficulties, lethargy environmental factors such as hypoxic-ischemic injury, traumatic progressing to coma, seizures, and apnea requiring ventilation in 70% brain injury, or congenital infections, malformations such as holo- of cases [4–7]. They often have a burst suppression pattern on electro- prosencephaly or cortical migration abnormalities, and genetic factors encephalogram (EEG), which over time evolves into hypsarrhythmia, such as trisomies or chromosomal deletion syndromes. Up to 10% of and later multifocal epilepsy. On magnetic resonance imaging (MRI), infants with severe seizure disorders have microdeletions. Other most neonatally presenting patients have increased signal on diffusion- genetic causes of early seizures include channelopathies, neurotrans- weighted images in the areas that are myelinated at birth, most often in mitter receptor mutations and developmental problems such as the posterior limb of the internal capsule and sometimes in the long mutations in the ARX gene. Metabolic disorders make up a special tracts in the brain stem. Some patients have hypoplasia or agenesis of the category of causes of neonatal and early infantile seizures. They are corpus callosum, hydrocephalus with posterior fossa abnormalities, or particularly important because many conditions are treatable, and all simplification of gyri. One third of patients present in early to mid of them have a risk for recurrence in the same family. In this article, infancy with seizures, hypotonia, and developmental delay. Long term, we will review inherited metabolic diseases that present predomi- the majority of patients have a very poor outcome. These patients make nantly with seizures in neonates and young infants. We will review no developmental progress, and have signs of spasticity at less than the conditions and present a paradigm for their evaluation. 6 months of age. They develop progressive brain atrophy and multifocal General disturbances of internal homeostasis that affect the seizures. However, a subset of patients (1/6 of patients presenting functioning of the cell will cause seizures. This includes a lack of neonatally and 1/2 of patients presenting in infancy) have a better oxygen as in hypoxic-ischemic injury, electrolyte abnormalities such outcome [4–7]. These patients make developmental progress, but as hypocalcemia, hypoglycemia, hyperammonemia, and severe remain moderately to severely mentally retarded (IQ 20–60); they can metabolic disturbances such as organic acidurias and maple syrup learn to sit and grasp, and develop choreatic movements. Their seizure urine disease. In such cases, the decreased consciousness and the disorder is milder and is often easily treated with a single anticonvulsant. abnormal neurological and clinical picture dominate the clinical The glycine cleavage enzyme system consists of 4 subunits named presentation rather than the seizures. Broad screening of electrolytes, P, T, H, and L. Diagnosis of nonketotic hyperglycinemia is made by glucose, ammonia, plasma or serum amino acids and urine organic finding elevated glycine in serum and cerebrospinal fluid (CSF) with acids should be obtained immediately, particularly if accompanied by an increased ratio of CSF:plasma glycine (N0.06 with normal ≤0.02) decreased consciousness. [8]. The diagnosis can be confirmed by enzyme activity assay in a liver Specific metabolic causes of epilepsy in neonates and early infancy biopsy or by mutation analysis. Mutations have been found in the AMT can be categorized in three groups: gene encoding the T-protein in 25% of patients and in the GLDC gene encoding the P-protein in 75% of patients [7,9]. Up to 20% of mutations 1. disturbances in neurotransmission associated with an epileptic in the GLDC gene are exonic deletions [10]. The condition is usually encephalopathy, treated with benzoate to reduce the glycine levels, and with NMDA 2. disorders of energy production such as the use of glucose, pyruvate, receptor blockers such as dextromethorphan. Early myoclonic the Krebs cycle, and the respiratory chain, seizures respond to benzodiazepines, but seizure control becomes 3. disorders associated with brain malformation, dysfunction, and more difficult in severely affected patients during the first year of life, degeneration on a metabolic basis. often requiring multiple anticonvulsants by 1 year of age.

Monogenic causes of epilepsy can include syndromic forms of brain 2.2. Pyridoxal-5′-phosphate responsive encephalopathy malformation or can involve genes that have a speciﬁc predisposition for seizures without major brain malformations. Genes responsible for Pyridoxal-5′-phosphate is the active cofactor form of vitamin B6 and brain cortical malformation as causes of seizures have been reviewed is used in many enzymatic reactions including such brain processes as elsewhere [1–3]. Here we will review the latter. These genes are the synthesis of GABA as well as in the glycine cleavage enzyme. involved in channelopathies or the abnormal growth, differentiation, Pyridoxine and pyridoxamine are phosphorylated to pyridox(am)ine- and formation of neuronal populations. phosphate and are then oxidized to pyridoxal-phosphate by pyridox

(am)ine phosphate oxidase [11].Deficiency of this oxidase results in 2.5. Mitochondrial glutamate transporter deficiency of the active cofactor pyridoxal-5′-phosphate. Many patients have been born prematurely often with low Apgar scores [12,13].They Patients with this condition have a deficiency in the mitochondrial develop neonatal seizures and an epileptic encephalopathy with H+/glutamate transporter encoded by the SLC25A22 gene [27,28]. myoclonic and severe tonic–clonic seizures. The EEG shows a burst Patients present with neonatal intractable myoclonic seizures and suppression pattern. Diagnosis is suggested by finding in CSF elevated develop brain atrophy. They have a burst suppression pattern on EEG. levels of threonine and glycine and low levels of monoamine The visual evoked potentials are of low amplitude although the metabolites. The decline in normal values in CSF threonine from electroretinogram (ERG) is normal in some, abnormal in others. 45–120 μMinthefirst week to 20–45 μM by 6 months of age should be Diagnosis is made by decreased mitochondrial oxidation of glutamate taken into account. A more direct and reliable indicator is a low level of and by mutation analysis. There is no specific treatment. This pyridoxal-5′-phosphate in CSF [14]. The diagnosis is confirmed by condition was identified in 2 of 30 patients screened with early sequencing the PNPO gene [15]. Treatment with pyridoxal-5′-phosphate seizures [28]. Absence of clinically available testing and of a specific (30 mg/kg/day) can result in a good outcome if treatment is initiated biomarker makes this condition hard to diagnose. early [13]. These patients do not respond to pyridoxine, and this condition is different from pyridoxine-dependent epilepsy, which is 2.6. Aromatic amino acid decarboxylase deficiency (AADC) described below. Aromatic amino acid decarboxylase catalyzes the conversion of 2.3. Pyridoxine-dependent epilepsy dopa to dopamine and of 5-hydroxytryptophan to serotonin. Its deficiency results in severely reduced dopamine and serotonin, and The vast majority of patients with pyridoxine-dependent epilepsy low concentrations of their CSF metabolites homovanillic acid (HVA) have a deficiency in α-amino adipic semialdehyde dehydrogenase [16]. and 5-hydroxyindoleacetic acid (5-HIAA) [29]. CSF dopa levels are Alpha-aminoadipic semialdehyde is derived from the catabolism of increased and vannillactic acid is present in urine. These patients lysine through pipecolic acid and is in equilibrium with Δ1-piperideine- present in the first months with motor symptoms of axial hypotonia, 6-carboxylate (6-PC), which reacts with pyridoxal-5′-phosphate. These hypokinesia, athethosis, dystonia, and limb rigidity [29,30]. They have patients have elevated α-aminoadipic semialdehyde and 6-PC in urine ocular symptoms of oculogyric crises and convergence spasms, which and serum and a secondary elevation of pipecolic acid in serum. They can resemble seizures. They have autonomic symptoms of ptosis, present with seizures in the neonatal period or early infancy [17–20]. nasal congestion, hypothermia, sweating, temperature instability, and They are often encephalopathic with irritability and temperature blood pressure lability. They often have abnormal sleep, feeding instability. As neonates, they usually have a burst suppression pattern difficulties, and gastroesophageal reflux. Patients with AADC defi- on EEG. Later they have hypsarrhythmia and often develop multifocal ciency do not have seizures but the oculogyric crises with autonomic seizures. Most patients have developmental delay and some have white instability are often misdiagnosed as seizures. Patients who were matter abnormalities. Diagnosis is made by treatment with intravenous reported with a biochemical picture of AADC and who had neonatal pyridoxine 100 mg under EEG monitoring, followed with oral pyridox- seizures were later shown to have a deficiency in pyridox(am)ine ine 30 mg/kg/day for at least 3 days. The response to intravenous phosphate oxidase, since pyridoxal-5′-phosphate is a cofactor of this pyridoxine alone lacks sensitivity and specificity [21].Amoredirect enzyme [31]. The outcome of AADC deficiency tends to be poor with diagnosis is by demonstration of α-aminoadipic semialdehyde or 6-PC marked impairment in motor and speech. Diagnosis is made by in urine or serum and confirmation by sequencing analysis of the monoamine metabolite analysis in CSF and by measurement of the ALDH7A1 gene [16,22]. Treatment is with oral pyridoxine 15 to enzyme activity in serum, with confirmation by mutation analysis of 30 mg/kg/day, and monitoring for neuropathy in those patients treated the AADC gene. These children are treated with dopamine agonists, at high doses. Most patients have seizure control, but still have some monoamine oxidase inhibitors, and with trihexyphenidyl. developmental delay. A few rare patients have been reported who present with West 2.7. D-2-hydroxyglutaric aciduria syndrome with hypsarrhythmia whose seizures respond to pyridoxine. These patients do not have α-aminoadipic semialdehyde dehydrogenase D-2-hydroxyglutaric acid is made from bacterial gut metabolism, deficiency and represent a separate disorder, the cause of which is from catabolism of hydroxylysine, from 5-aminolevulinic acid in the currently not yet known [19,23]. The outcome in these patients seems to porphyrin synthesis via 2-ketoglutarate semialdehyde and S-2-hydro- be favorable with treatment. This treatable condition warrants a three xyglutarylglutathione, and from GABA via its conversion to succinic day trial with pyridoxine in all patients with West syndrome regardless semialdehyde through the hydroxy acid:oxoacid transhydrogenase of biochemical findings. (Hot) enzyme [32]. D-2-hydroxyglutaric acid is removed by the enzyme D-2-hydroxyglutarate dehydrogenase to 2-ketoglutarate [33].Deficien- 2.4. Folinic acid responsive seizures cy of this enzyme causes an autosomal recessive condition where severely affected patients present with neonatal or early infantile, Patients were described who presented with an abnormal peak on severe epilepsy [34]. They have hypotonia, visual failure, and severe HPLC analysis of CSF for monoamine metabolites [24].Thepatients developmental delay. Some patients have cardiomyopathy, facial presented with myoclonic seizures evolving into multifocal seizures dysmorphisms, and episodic vomiting. On MRI they have delayed since birth or early infancy. On EEG they had burst suppression or brain maturation of the white matter, of gyration, and particularly of hypsarrhythmia evolving into multifocal epilepsy. They have been operculation. They often had subependymal cysts and dilated ventricles described as responding to folinic acid 3 to 5 mg/kg/day, although the [35,36]. Three patients have been described with spondylenchondro- outcome of these patients has been poor. Some of these patients have dysplasia [37,38]. Patients with a milder form of the disorder who responded to pyridoxine [24,25]. Recent studies have shown that all present with hypotonia, developmental delay, and even asymptomatic patients diagnosed based on the abnormal peak detectable during patients have been described. There does not seem to be a genotype– monoamine metabolite analysis had elevated α-aminoadipic semialde- phenotype correlation, since twins with the same genetic make-up can hyde and mutations in the ALDH7A1 gene, thus making the condition have divergent phenotypes [39]. Diagnosis is made by finding 2- identical to pyridoxine-dependent epilepsy [26]. These patients should hydroxyglutarate on urine organic acids and separation of this into the be treated with pyridoxine. D- and L-form. GABA is sometimes elevated in CSF. The diagnosis can be

Please cite this article as: J.L.K. Van Hove, N.J. Lohr, Metabolic and monogenic causes of seizures in neonates and young infants, Mol. Genet. Metab. (2011), doi:10.1016/j.ymgme.2011.04.020 4 J.L.K. Van Hove, N.J. Lohr / Molecular Genetics and Metabolism xxx (2011) xxx–xxx confirmed by molecular analysis of the D2HGD gene [33]. There is no genetic defects reside in the E1α-subunit which is located on the specific treatment. X-chromosome [51]. Boys with this defect tend to have a mild mutation with residual enzyme activity. They present with Leigh 2.8. GABA disorders: 4-hydroxybutyric aciduria or succinic semialdehyde disease, lactic acidosis, ataxia, and often agenesis of the corpus dehydrogenase deficiency and GABA transaminase deficiency callosum [52,53]. Girls tend to have severe mutations, but have a mixed clinical picture due to the effects of lyonization. They present Patients with succinic semialdehyde dehydrogenase deficiency with dysmorphisms, microcephaly, moderate to severe mental accumulate succinic semialdehyde derived from GABA transamination, retardation, and spastic quadriplegia. They often have periventricular which is converted into 4-hydrobybutyric acid and excreted in urine. multicystic leukoencephalopathy and agenesis of the corpus callosum. These patients present with motor delay, ataxia, language delay, In these girls, seizures are common. They present in the first 6 months hypotonia, and mental delay, each present in more than 70% of patients of life, often as West syndrome with infantile spasms or with severe [40,41]. Seizures are present in 48% of patients and EEG abnormalities myoclonic seizures [52,53]. Pyruvate dehydrogenase will show an were noted in 26% of patients. Seizures often start in infancy. Less elevated lactate and an elevated pyruvate with a normal ratio if the frequent symptoms include absent reflexes or hyperkinesis or excessive lactate is greater than 2.5 mmol/L [54]. In contrast, pyruvate sleepiness. Whereas 26% of patients have problems in the neonatal carboxylase deficiency will show an increased lactate with elevated period, an equal number have normal early development. The diagnosis lactate:pyruvate ratio. Diagnosis can be made by enzyme assay either is suspected on finding 4-hydoxybutyric acid on urine organic acids in lymphocytes or in fibroblasts (more accurate), and confirmed by analysis, and confirmation can be done by enzyme assay or molecular molecular sequencing [52]. Pyruvate dehydrogenase deficiency is analysis of the ALDH5A1 gene. Treatment is symptomatic [42]. treated by providing the brain an alternative fuel, specifically ketones GABA transaminase deficiency is a rare disorder described in two through a ketogenic diet, which can sometimes result in surprising families [43,44]. The phenotype involves psychomotor retardation, improvements in functionality [55], including improvements of infantile seizures, hypotonia, hyperreflexia, and accelerated growth. seizures [53]. A few patients respond to pharmacologic treatment MRI showed diffusion restriction in the internal and external capsule with thiamine [56]. Pyruvate carboxylase deficiency presents with and subcortical white matter areas. There is elevation of GABA, beta- marked lactic acidosis. Patients develop a leucoencephalopathy with alanine, and homocarnosine, most notable in the CSF [43]. Elevated seizures. Pyruvate carboxylase deficiency can be treated with GABA can be recognized on magnetic resonance spectroscopy [44]. anaplerotic support such as triheptanoin oil or aspartate and citrate The diagnosis can be confirmed by enzyme assay or mutation analysis [57,58]. of the ABAT gene [43]. 3.3. Biotinidase deficiency 3. Disorders of energy metabolism In biotinidase deficiency, biotin is not recycled from biocytin to 3.1. Glucose transporter deficiency biotin. This leads to a deficiency of the biotin cofactor with subsequent deficient enzyme activities of the carboxylases: pyruvate carboxylase, Glucose is the main fuel of the brain. It is transported across the propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and blood–brain-barrier and into astrocytes by the glucose transporter the acetyl-CoA carboxylases. The clinical presentation is in infancy on (GLUT1, also called SLC2A1). Patients are haploinsufficient due to a average starting around 7 weeks of age. Patients present with seizures, mutation in the GLUT1 gene and have a partial deficiency of the often grand mal or myoclonic. They have hypotonia, lethargy, and transporter function [45]. Most (76%) patients present in the first ataxia. They develop a skin rash which is often eczematoid, alopecia, 6 months of life [46–50]. They have a variety of seizures including and keratoconjunctivitis [59]. Untreated, they develop psychomotor complex seizures, generalized seizures, and myoclonic seizures. Early retardation, hearing loss, and can develop irreversible optic atrophy. absence seizures have also been reported. The seizures, which are Some patients have initially presented with severe infantile seizures often therapy resistant, sometimes improve with feeding and worsen such as Ohtahara syndrome [60]. The biochemical presentation mimics with barbiturates, such as phenobarbital, which partially inhibits this holocarboxylase synthase deficiency. Clinical diagnosis is suspected transporter. The EEG often shows a 2.5 to 4 Hz spike wave pattern. from elevated lactate and from metabolites of the carboxylases on Other symptoms include ataxia which is sometimes intermittent, urine organic acids such as elevated 3-hydroxyisovaleric acid, 3- language delay, developmental delay, spasticity, choreoathetosis, and methylcrotonylglycine, lactic acid, methylcitric acid, 3-hydroxypro- dystonia. They can develop microcephaly. Hypometabolism in the pionate, or from an abnormal plasma acylcarnitine profile (elevated thalami and temporal lobes has been demonstrated on PET scanning. C3- and hydroxy-C5-acylcarnitines). It is confirmed by assaying the Untreated patients have substantial developmental delay. The biotinidase enzyme activity in serum in which patients with severe diagnosis is suspected by the finding of hypoglycorachiab45 mg/dl deficiency have less than 10% residual activity [61], and by mutation in CSF, and a CSF:plasma glucose ratiob0.4 (normal 0.6), in the analysis [62]. Most patients are currently detected presymptomati- absence of other causes of hypoglycorachia. The diagnosis can be cally by newborn screening, preventing a clinical presentation with confirmed by mutation analysis of the GLUT1 gene or by an uptake seizures. Treatment with biotin 10 mg/day results in good outcome. assay of labeled 3-O-methylglucose into red blood cells. Treatment This utterly treatable condition should not be missed as an etiology of consists of feeding the brain with an alternative fuel, specifically infantile seizures and physicians should not rely solely on the results of ketones, using a ketogenic diet. The aim is to keep the serum ketones newborn screening, which does not replace diagnostic testing. above 3 mM. Inhibitors of the GLUT1 transporter such as barbiturates and caffeine should be avoided. Seizure control is improved with 3.4. Respiratory chain disorders treatment, but residual developmental delays often persist. Respiratory chain disorders have many phenotypes. The lethal 3.2. Pyruvate dehydrogenase deficiency (PDH) and pyruvate carboxylase infantile phenotype presents with a severe neurological picture. This deficiency (PCD) often includes severe and progressive brain damage which includes seizures. These patients nearly always have elevated lactate in serum The pyruvate dehydrogenase complex catalyzes the conversion of or CSF. Enzymatic defects in each of the complexes have been pyruvate to acetyl-coenzyme A. It is composed of multiple subunits, described with this presentation. Mutations can exist in mitochon- and defects in each of them have been described. The most frequent drial DNA or in nuclear DNA in genes encoding for components of the

Please cite this article as: J.L.K. Van Hove, N.J. Lohr, Metabolic and monogenic causes of seizures in neonates and young infants, Mol. Genet. Metab. (2011), doi:10.1016/j.ymgme.2011.04.020 J.L.K. Van Hove, N.J. Lohr / Molecular Genetics and Metabolism xxx (2011) xxx–xxx 5 respiratory chain, for the assembly of these components, or for the [75,76]. On EEG, 10/11 patients had epileptiform features. There is maintenance and expression of mitochondrial DNA. visual impairment, optic atrophy, dysmorphic features including Leigh disease is a condition in which damage occurs in the basal frontal bossing, hypertelorism, and a depressed nasal bridge. On brain ganglia, brain stem, and dentate nuclei of the cerebellum. Patients MRI imaging, there is an open sylvian operculum, enlarged ventricles, often present with progressive motor dysfunction including dystonia, and in several patients, polymicrogyria, decreased white matter ataxia, bulbar symptoms, and Parkinsonism. There are many genetic volume, small brain stem, and agenesis of the corpus callosum. The causes of Leigh disease in infancy and include the mitochondrial outcome is severe mental retardation and children often die in the tRNALeu(UUR) gene with the mt.A3243G mutation, the assembly first years of life. The diagnosis is suspected by findings on urine proteins of complex IV such as the SURF1 protein, nuclear coding organic acids analysis of high fumarate, and to a lesser extent, genes of complex I, but also the mt.T8993G mutation in complex V. In elevation of succinate and α-ketoglutarate. The diagnosis is confirmed most cases of Leigh disease, seizures are a late symptom, except in the by enzyme assay in fibroblasts or leukocytes and by mutation analysis. mt.T8993G mutation, where seizures can be an early and presenting Treatment is symptomatic. symptom [63]. Alpers disease is a combination of a progressive poliodystrophy and a 3.7. Sulfite oxidase deficiency hepatopathy [64,65]. Seizures are usually the first symptom and worsen progressively [66]. They may have been preceded by developmental Sulfite oxidase with its cofactor molybdopterin performs the last step delay, failure to thrive, and vomiting. There is neurological regression, in the metabolism of sulfur-containing amino acids by oxidizing sulfite and often lesions in the occipital and temporal lobes. Liver disease is derived from cysteine to sulfate. When sulfite oxidase is deficient, sulfite often initially insidious and biochemically subtle, until sudden hepatic builds up along with the other toxic metabolites, such as S-sulfocysteine failure develops, often following treatment with valproate. There is and thiosulfate. The clinical presentation of sulfite oxidase or molybdop- fibrosis and steatosis on liver biopsy. The brain exhibits neuronal loss, terin cofactor deficiency includes neonatal or early infantile presentation spongiosis, and astrocytosis, particularly in the striate cortex with a of refractory convulsions, severe psychomotor retardation, failure to predilection for the calcarine cortex. There is occasionally hypoglycemia thrive, hypo- or hypertonia, lens dislocation, and early death [77].Lactate [66] or elevated 3-methylglutaconic acid in blood or urine [67].Onbrain is elevated in 50% of cases, and homocysteine reduced to below normal imaging there is cortical atrophy mostly in the posterior and occipital [78]. Brain MRI imaging often shows initial edema followed by cystic lobes. The EEG shows polyspikes, high amplitude slow activity degeneration. Early seizures with burst suppression pattern, sometimes predominantly posterior, or epilepsia partialis continua [68].Lactate mimicking hypoxic ischemic injury with restricted diffusion in the cortex levels in serum and CSF are often normal, but CSF protein is usually and subcortical white matter, is common [79,81,82].Moremildlyaffected elevated. The respiratory chain enzymes are often normal in muscle, but patients have involvement of the globus pallidus [83].Sulfite oxidase can deficient in liver, and always normal in fibroblasts. A depletion of mtDNA occur as isolated sulfite oxidase deficiency or can be due to a deficiency in is often present in liver. Common genetic causes are mutations in the cofactor molybdopterin with an associated deficiency in xanthine mitochondrial DNA polymerase-γ encoded by the POLG1 gene, resulting oxidase [84].Diagnosisofsulfite oxidase deficiency is made by finding in deficient polymerase γ activity with depletion of mtDNA [64,69]. increased S-sulfocysteine in urine or plasma. Isolated sulfite oxidase defi ciency is diagnosed by molecular analysis of the SUOX gene. Defects in 3.5. Menkes disease the synthesis of molybdopterin are diagnosed additionally by elevated xanthine and severely reduced uric acid (usuallyb1 mg/dl); verification In Menkes disease, copper is not effectively exported from cells, is made by molecular analysis of MOCS1 (type A), MOCS2 and MOCS3 resulting in poor incorporation into copper containing enzymes such as (type B), and Gephyrin GPHN (type C) genes [85].Treatmentincludes cytochrome c oxidase, dopamine β-hydroxylase, and lysyl-oxidase. This dietary limitation of sulfur-containing amino acids cysteine and X-linked condition presents in baby boys with seizures, hypotonia, methionine for mildly affected cases, but is ineffective for severely failure to thrive, and progressive spasticity with loss of milestones. On affected patients. For patients with type A and a defect in the MOCS1 gene, brain imaging there is brain atrophy and delayed myelination, with a treatment with intravenous cyclic pyranopterin monophosphate (cPMP) lactate peak on MRS, and tortuous vessels on MR angiography. improves metabolic control and symptoms [86]. Connective tissue symptoms include skin laxity, cephalhematoma, wormian bones, hernias, pectus excavatum, hair loss with pili torti, and 3.8. Purine disorders: adenylosuccinate lyase deficiency and AICA-ribosiduria bladder diverticula. Lactic acid can be present. Most patients die in early childhood. Therapy resistant seizures often start at age 2 to 3 months The de novo synthesis of purines from ribose-5-phosphate begins with and involve focal clonic status epilepticus or intractable infantile spasms the formation of phosphoribosyl pyrophosphate (PRPP). PRPP is then [70–72]. Diagnosis is often suspected with the finding of low serum converted in ten steps to inosine monophosphate (IMP). The eighth step copper (b11 μM) and low ceruloplasmin (b210 mg/L). An improved in the biosynthesis converts 5-phosphoribosyl-5-aminoimidazole-4-(N- biochemical marker is the analysis of serum catecholamines with an succino)carboxamide (SAICAR) to 5’-phosphoribosyl-5-aminoimidazole- increased ratio of dihydroxyphenylalanine:dihydroxyphenylglycol 4-carboxamide (AICAR) by the enzyme adenylosuccinate lyase. In its reflecting the poor activity of dopamine β-hydroxylase [72,73],and absence, SAICAR accumulates. The next step converts AICAR to 5′- confirmation of diagnosis is performed by sequencing the ATP7A gene phosphoribosyl-5-formamidoimidazole-4-carboxamide by the enzyme [71]. Treatment with parenteral copper histidine has been successful phosphoribosylaminoimidazole-carboxamide formyl transferase (AICAR following very early treatment, particularly in mildly affected patients transformylase), and in its absence AICAR accumulates. Inosine is including improved control of seizures [72–] 74 . converted to adenosine by the formation of adenylosuccinate, followed by the release of succinate by adenylosuccinate lyase. Thus, adenylosucci- 3.6. Fumarase deficiency nate lyase deficiency has an increase in both SAICAR and adenylosuccinate, whereas AICAR transformylase deficiency accumulates AICAR and to The fumarase enzyme converts fumarate to malate. Both the a lesser extent SAICAR. cytosolic enzyme and the mitochondrial Krebs cycle enzyme are Deficiency of adenylosuccinate lyase results in three types of encoded by the same FH gene. The clinical presentation is in infancy clinical presentations depending on the severity. Patients with Group I with a static neurological picture including severe hypotonia, (classic) present with severe psychomotor retardation, seizures, profound mental retardation (IQb25), and seizures of various types autistic features, and muscle wasting. Patients with Group II (mild) with a generalized convulsive status being present in 44% of patients have severe hypotonia and mild developmental delays. Patients with

Group III (neonatal) present with intrauterine growth retardation, including seizures, hypotonia, and polymicrogyria in the perisylvian lack of fetal heart rate variability, microcephaly, fetal and neonatal fissure, dysmorphic features including a broad forehead with a broad hypokinesia, early severe seizures (myoclonic, burst suppression), anterior fontanel, cholestasis, liver fibrosis, chondrodysplasia punc- severe hypotonia, and early death [87,88]. tata, and adrenal dysfunction [103]. The severity ranges from the most Deficiency of AICAR transformylase results in an accumulation of severe form of Zellweger syndrome, to the least severe form of AICA riboside and presents with clinical symptoms in the neonatal infantile Refsum disease. Seizures are present in 92% of Zellweger period of dysmorphic features, seizures, blindness, and developmental patients [104]. Diagnosis is made by finding elevated very long chain delays [89]. The Bratton–Marshall test (urine succinylpurines) provides fatty acids with an elevated C26:C22 ratio being the most sensitive an inexpensive screening test for these uncommon conditions [90] with indicator [105]. If elevated, one should measure other metabolites the metabolites confirmed by HPLC or tandem mass spectrometry [91]. which include abnormal bile acids, decreased plasmalogens, and Confirmation of adenylosuccinate lyase deficiency is made through increased phytanic acid in older patients. Abnormalities in all these molecular analysis the ADSL gene. Confirmation of AICA ribosiduria is metabolites indicate the diagnosis of a peroxisomal biogenesis made by molecular analysis of the gene ATIC. disorder. Confirmation is made with molecular analysis of the PEX SAICAR has an effect on glucose utilization, and patients with genes. The most common causes of peroxisomal biogenesis disorders adenylosuccinate lyase deficiency have decreased brain uptake of are mutations in the PEX1 gene. Testing for other PEX genes is also glucose on PET scan [92,93]. Severity of the condition seems to available. In rare patients with D-bifunctional protein deficiency, correlate with the ratio of succinyladenosine/SAICAR [88]. Experi- which typically presents with seizures in the first month of life, very mental treatments with ribose and with S-adenosylmethionine have long chain fatty acids are normal, but MRI findings such as not shown much improvement thus far [94]. polymicrogyria or white matter disease can guide one to the need for more biochemical testing such as C26:0 β-oxidation in fibroblasts 3.9. Creatine synthesis and transporter defects [106].

Creatine is important in brain and skeletal muscles as it provides a source for conversion into phosphocreatine, which is involved in 4.2. Congenital disorders of glycosylation (CDG) energy transmission. Creatine synthesis and transporter defects result in decreased creatine in the brain. Two enzymes, arginine glycine After translation, many proteins are modified by the addition of amidinotransferase (AGAT) and guanidinoacetate methyltransferase sugar moieties to an asparagine in N-linked glycosylation or to a serine (GAMT) are involved in synthesis of creatine, and a transporter or threonine in O-linked glycosylation [107,108]. N-linked glycosylation (CRT1) is involved in creatine transport from the blood into the brain. is a multistep process and involves first the synthesis of a polyglycan Patients with severe deficiency of GAMT activity present in infancy chain on dolichol, followed by transfer of the glycan onto the nascent with severe to intractable seizures, severe mental retardation, protein in the endoplasmatic reticulum, and subsequent modification of expressive speech delay, hypotonia, and symptoms of autism. They this glycan on its protein in the Golgi apparatus. CDG syndromes are can also develop extrapyramidal symptoms and brain imaging may classified as CDG Type I which includes all enzymatic defects in the show globus pallidus lesions [95,96]. Patients with a mild deficiency in synthesis in the cytosol and endoplasmic reticulum, or as CDG Type II GAMT activity present with mild seizures, mental retardation, and which includes enzymatic or processing defects of glycan modification particularly expressive speech delay. Patients with AGAT deficiency in the Golgi apparatus. Combined defects also involve a deficiency of present with mild febrile seizures, developmental delay, and language O-linked glycosylation in addition to N-linked glycosylation. So far, delay [97]. Patients with a defect in CRT1 present with moderate more than 25 different enzymes have been identified whose disruption seizures, mental retardation, severe language delay, autistic symptoms, results in a clinical phenotype. This is, not surprisingly, a diverse group of and behavioral problems [98]. disorders that can present clinically in many different ways. Common The diagnosis is made by assaying creatine and guanidinoacetate in clinical phenotypes include some or all of the following symptoms: mild urine and plasma [99,100]. Creatine in the brain will be low on magnetic to severe seizures, developmental delay, hypotonia, ataxia, and resonance spectroscopy in all cases. Urine and plasma creatine levels dysmorphic features (including microcephaly, inverted nipples and will be low in GAMT deficiency and high in CRT1 deficiency with an persistent fat pads or lipodystrophy). Other organ systems that can be elevated creatine:creatinine ratio. Urine and plasma guanidinoacetate involved include gastrointestinal with hepatic fibrosis, protein-losing will be elevated in GAMT deficiency, decreased in AGAT deficiency and enteropathy, hypoglycemia, failure to thrive as well as hematologic with low or normal in CRT1 deficiency. The diagnosis can be confirmed with coagulopathy, thrombocytopenia, and anemia. Diagnosis is made by enzymatic assays or by molecular analysis of the GAMT and AGAT genes, analyzing the glycosylation of a prototypic N-glycosylated protein and in CRT1 deficiency by creatine uptake assay in fibroblasts or more transferrin such as by isoelectric focusing or by mass spectrometry, commonly by molecular analysis of the gene SLC6A8. Treatment of AGAT which will identify most CDG syndromes but not all. Urine oligosac- and GAMT deficiency includes creatine supplementation, and in GAMT charides may identify an additional disorder. Diagnosis is confirmed by deficiency dietary arginine restriction with ornithine supplementation genetic sequencing of the enzyme directly involved in that particular [101,102]. There is currently no effective treatment for CRT1 defects. step. Only symptomatic treatment is available. Some disorders have severe seizures dominating the clinical picture. 4. Biosynthetic defects: brain malformation and dysfunction They also have severe mental retardation and hypotonia. These include the disorders ALG3-CDG (CDG-Id), DPM1-CDG (CDG-Ie), ALG2-CDG 4.1. Peroxisomal disorders (CDG-Ii), DPAGT1-CDG (CDG-Ij), ALG1-CDG (CDG-Ik), RFT1-CDG (CDG- 1n), ALG11-CDG (CDG-1p), DK-CDG (CDG-1m), and GCS1-CDG (CDG- Peroxisomes are important cellular organelles for the beta- IIb). Additional symptoms for these are coloboma for ALG3-CDG (CDG-Id), oxidation of very long chain fatty acids, branched chain fatty acids, liver dysfunction for ALG1-CDG (CDG-Ik) and GCS1-CDG (CDG-IIb), and bile acids, for alpha-oxidation of 2-methylbranched chain fatty corpus callosum hypoplasia for ALG3-CDG (CDG-Id), nephrotic syndrome acids, and for the synthesis of ether lipids. Disorders of peroxisomes in ALG1-CDG (CDG-Ik), infantile spasms in DPAGT1-CDG (CDG-Ij), occur when the peroxisomes are not formed correctly (biogenesis sensorineural hearing loss in ALG11-CDG (CDG-1p), and dry, ichtyosiform disorder) or when an enzyme used in the peroxisomes is deficient. and parchment-like skin in DK-CDG (CDG-1m). Each of these disorders Patients with peroxisomal biogenesis disorders or single enzyme can be identified by analysis of the transferrin glycan forms, except for deficiencies can present neonatally with multi-system involvement GCS1-CDG (CDG-IIb) which is identified by the excretion of a

Please cite this article as: J.L.K. Van Hove, N.J. Lohr, Metabolic and monogenic causes of seizures in neonates and young infants, Mol. Genet. Metab. (2011), doi:10.1016/j.ymgme.2011.04.020 J.L.K. Van Hove, N.J. Lohr / Molecular Genetics and Metabolism xxx (2011) xxx–xxx 7 tetrasaccharide in urine identified on urine oligosaccharide analysis CoA reductase inhibitor simvastatin. Both have improved the biochem- [109–124]. ical profile, but clinical effect on developmental progress was not Other disorders have mild seizures with a static neurological picture. demonstrated [140,141], and not enough data is available on the impact These include the disorders PMM2-CDG (CDG-Ia), MPDU1-CDG of either treatment on seizures. (CDG-If), ALG9-CDG (CDG-Il), and MGAT2-CDG (CDG-IIa). Additional symptoms include dysmorphism in the severe form of PMM2-CDG 4.5. Deficiency syndromes of the amino acids serine and glutamine (CDG-Ia) and MGAT2-CDG (CDG-IIa), ichtyosiform skin in MPDU1-CDG (CDG-If), decreased immunoglobulins in ALG12-CDG (CDG-Ig), peri- Serine is an amino acid involved in the synthesis of important cardial effusions in PMM2-CDG (CDG-Ia) and ALG9-CDG (CDG-Il), brain components such as glycine, cysteine, sphingomyelins, and cerebellar hypoplasia in PMM2-CDG (CDG-Ia), very low cholesterol in cerebrosides. Serine is synthesized from glucose by conversion of the ALG6-CDG (CDG-Ic), and nephrotic syndrome in PMM2-CDG (CDG-Ia) glycolytic intermediate 3-phosphoglycerate to 3-phosphopyruvate by [125–130]. 3-phosphoglycerate dehydrogenase, followed by formation of 3- The combined defects of N-linked and O-linked glycosylation are phosphoserine by 3-phosphoserine aminotransferase, and finally due to trafficking defects in the Golgi apparatus. The propensity for serine is formed by 3-phoshoserine phosphatase [142].Deficiency in seizures varies. COG7-CDG (IIe) and ATP6V0A2-CDG disorders have either 3-phosphoglycerate dehydrogenase or 3-phosphoserine ami- encephalopathy with some seizures, failure to thrive, hyperthermia, notransferase presents with severe psychomotor retardation, con- and cutis laxa. COG8-CDG patients have episodes of encephalopathy genital microcephaly, and with white matter hypointensity in 3- often with seizures, and a cerebellar syndrome, whereas COG1-CDG phosphoglycerate dehydrogenase. Seizures may begin anywhere from patients did not have seizures [131,132]. 2 months to 14 months. Initially patients can be diagnosed with West syndrome with hypsarrhythmia on EEG [143], but the seizures 4.3. Glycolipid synthesis: GM3 synthase deficiency develop into multiple different types as patients grow older. Other clinical features include spastic tetraparesis, adducted thumbs, and GM3 synthase catalyzes the initial step in the formation of GM3 hyperexcitability. Occasionally, cataracts, nystagmus, hypogonadism, ganglioside from lactosylceramide. Gangliosides are important in the and megaloblastic anemia have been reported. Brain MRI shows cell membrane, the myelin, and are involved in cell-signaling in the absent myelination with cortical and subcortical atrophy. CSF amino central nervous system. Absence of GM3 synthase activity was acids show decreased CSF serine (b15 μM, normal 42–86) and glycine described in infants presenting from 3 weeks to 2 months with poor (1–4 μM, normal 6–21 μM in neonates). Sometimes, decreased CSF 5- tone, feeding difficulties, and failure to thrive [133].Inthefirst year of methylfolate may also be seen. Fasting plasma amino acids will also life, an affected child will develop difficult to control tonic-clonic show a decreased plasma serine, but postprandial plasma amino acids seizures, myoclonus, and an EEG showing multifocal epileptiform may be normal. The diagnosis is confirmed by finding decreased discharges. With the onset of seizures, there can be profound enzyme activity in fibroblasts, and mutations in the respective genes developmental stagnation or regression, choreoathetoid movements, [144]. Treatment with serine (400–500 mg/kg/day) in 4 to 6 doses per reduced deep tendon reflexes, and visual deterioration. Brain MRI can be day and glycine (200–300 mg/kg/day) results in clinical improvement normal or show diffuse atrophy. Patients can be screened for this after 1 to 2 weeks, including major improvement of seizures in all disorder by analysis of ganglioside composition showing increased patients [145]. If identified prenatally, treatment of the mother during lactosylceramide and absent gangliosides of the series GM1-GM2-GM3, pregnancy is indicated [146]. with increased neutral glycosphingolipids Gb3 and G4. The disorder is Glutamine synthetase is a key enzyme in the glutamine–glutamate autosomal recessive and molecular analysis of the gene SIAT9 confirms cycle between astrocytes and neurons. Deficiency of glutamine the diagnosis. No specific treatment is available. A clinical screening synthetase was described in two neonates with immature brain assay of gangliosides should be developed for easy recognition of this with hyperintense white matter, microcephaly and attenuated gyri, group of conditions. and neonatal mortality [147]. There were multifocal generalized seizures. Other symptoms in one patient were erythema of the skin 4.4. Cholesterol synthesis: Smith–Lemli–Opitz syndrome and enteropathy, ascites, and renal failure. Glutamine levels were very low in serum and CSF, but glutamate was normal. A more mildly Smith–Lemli–Opitz Syndrome is caused by a deficiency in 7- affected patient presented in early infancy with encephalopathy, dehydrocholesterol reductase which catalyzes the final step in the seizures, and white matter atrophy, and is still alive at age 3 years biosynthesis of cholesterol, and is biochemically characterized by [148]. increased 7,8-dehydrocholesterol [134]. The clinical presentation is variable and can involve multiple organ systems. Neurologically, these 4.6. Methylation disorders: homocysteine and folate disorders patients can present with seizures, developmental delay, autistic symptoms and behavioral problems [135]. The most severely affected Homocysteine is a component of the metabolic pathway of the patients have brain malformations, present in 37% of biochemically sulfur-containing amino acid methionine. There are several disorders in confirmed patients [135], and these patients can have neonatal onset this pathway that can cause seizures including cystathionine β-synthase seizures [136] or infantile spasms [135] . They usually have dysmorphic deficient homocystinuria, methylene-tetrahydrofolate reductase defi- features including anteverted nares, ptosis, cleft palate, microcephaly, ciency, and cobalamin deficiency (specifically Cobalamin C and and low-set ears. Other organ systems involved can include cardiac, sometimes Cobalamin D, E, or G). Half of the patients with these renal, genital, pulmonary, and gastrointestinal. Acral limb abnormalities conditions present in the neonatal period, frequently with seizures are common. Up to 99% of patients have 2–3 toe syndactyly, which [149]. provides an easy recognizable clinical diagnostic sign. Rare patients Classic homocystinuria is caused by the absent cystathionine β without 2–3 toe syndactyly have been reported, but their neurological synthase enzyme activity. This defect results in multi organ system involvement is mild and would not include early onset seizures [137]. involvement including developmental delay and seizures. Seizures Diagnosis is made by assaying for elevated 7,8-dehydrocholesterol and occur in 50% of affected individuals, although rarely in infancy (1/55) mutation analysis of the DHCR7 gene. The inheritance is autosomal [80]. Diagnosis is made by finding elevated homocysteine, elevated recessive. Severity correlates with the ratio of 7,8-dehydrocholesterol to methionine, decreased cystathionine, and low levels of cysteine. cholesterol [138] and with mutations [139]. Treatment has included Treatment includes oral pyridoxine, folic acid, betaine supplementation, dietary supplementation of cholesterol and treatment with the HMG- and a low methionine diet with cysteine supplementation.

Methylene-tetrahydrofolate reductase catalyzes the reduction of 4.8. Lysosomal disorders 5,10-methylene-tetrahydrofolate to 5-methyltetrahydrofolate which then donates a carbon group in the methylation of homocysteine to Many lysosomal enzymes are involved in the degradation of brain methionine. Deficiency of methylene-tetrahydrofolate reductase can molecules such as sphingolipids. Missing or malfunctioning lysosomal result in seizures in infancy as well as a progressive encephalopathy, enzymes result in the accumulation of specific sphingolipids which developmental delay, microcephaly, and apnea [149,150]. Brain imaging results in interference with other cell functions. Many classic neuronal can show hydrocephalus, progressive atrophy, and microgyria. The lysosomal disorders with an infantile presentation exhibit excessive diagnosis is made with elevated homocysteine and low methionine and startle and some developmental slow down in the first 6 months of confirmed by enzyme assay performed on skin fibroblasts. Treatment life, but seizures develop only after 6 months of age. This includes may include betaine and folic acid supplementation, vitamin B12, and disorders such as Tay-Sachs disease, GM1 gangliosidosis, Niemann- sometimes supplementation with methionine. Early recognition and Pick disease type A, early onset metachromatic leukodystrophy, treatment with betaine may prevent severe brain disease [151,152]. multiple sulfatidase deficiency, Gaucher disease type II, mannosidosis, Dihydrofolate reductase deficiency due to mutations in the DHFR and fucosidosis. gene was described in patients with megaloblastic anemia and Krabbe disease results from deficiency of galatosylceramidase cerebral folate deficiency. These patients developed therapy resistant which breaks down galactosylceramide, which is a major component seizures in the first weeks of life. Some patients had cerebral and of myelin [157]. A toxic metabolite called galactosylsphingosine cerebellar atrophy, some patients had calcifications in basal ganglia induces apoptosis of cells. Infantile Krabbe disease presents in the and subcortical white matter, and one patient had abnormal white first 6 months of life with clinical symptoms of irritability, stiffness, matter mostly subcortical [153]. Development was normal until arrest in motor and intellectual development, and episodes of 3 months of age, but became severely delayed thereafter. The seizures temperature elevation. Some patients present with seizures in the and the anemia responded to treatment with folinic acid. Levels of first 6 months. Peripheral neuropathy with hypotonia and hyporeflexia plasma homocysteine, methylmalonic acid, folate, and vitamin B12 develops. CSF studies reveal increased protein. A brain MRI will show are normal, but 5-methyltetrahydrofolate and tetrahydrobiopterin in increased signal intensity of the white matter on T2 and FLAIR CSF are reduced. sequences with decreased signal intensity in the thalami. There can Cobalamin (vitamin B12) is a cofactor for multiple enzymes in the be high signal on diffusion weighted images and loss of diffusional body. Cobalamin C defect refers to an early step in cobalamin anisotropy. Diagnosis is made by assaying galactocerebrosidase enzyme processing. This affects formation of methylcobalamin which is a activity in leukocytes or fibroblasts, and genetic testing of the GALC necessary cofactor for methionine synthase to convert homocysteine gene. Treatment is primarily symptomatic. Hematopoietic stem cell to methionine. It also affects the formation of adenosylcobalamin transplantation has a poor outcome in symptomatic individuals. which is a cofactor in the conversion of methylmalonyl-CoA to However if performed presymptomatically in newborns following succinyl-CoA. The cobalamin C defect is the most frequent inborn diagnosis prenatally or neonatally, it has shown some stabilization of error of cobalamin metabolism. Patients present in infancy with the cerebral disease, but continued progression of the peripheral developmental delay and some infants have seizures. They can also neuropathy [158]. have nystagmus, microcephaly, lethargy, and feeding difficulties. Imaging may show hydrocephalus or brain atrophy. Laboratory studies will show elevated plasma homocysteine and cystathionine, 5. Monogenic causes of neonatal and early infantile seizures low or normal plasma methionine and elevated methylmalonic acid fi levels. Confirmation of the diagnosis is made by molecular testing of Other monogenic genetic causes of seizures in the rst 6 months of the MMACHC gene or by complementation studies of functional life without apparent brain malformations are: defects in cellular metabolism. Cobalamin D and Cobalamin G defects – can mimic these clinical symptoms as well. Treatment includes ARX: in boys with West syndrome – parenteral hydroxocobalamin (0.1 to 0.3 mg/kg/day parenterally CDKL5: in girls with West syndrome, also less frequently in boys – depending on patient response) and oral betaine (250 mg/kg/day), STXBP1 – and diet. Clinical response with improvement in biochemistry and MECP2 in males and PNKP with congenital brain disease – functionality is common, but certain symptoms, particularly retinop- Rare causes: MAGI2, alpha-II spectrin, phospholipase C beta-1 fi athy, persist in cobalamin C disorder. de ciency – Microdeletions/duplications in 10% of resistant seizures – Channelopathies: potassium and sodium channelopathies and 4.7. Neuronal ceroid lipofuscinosis related genes – eIF2B-related disorders The congenital form of neuronal ceroid lipofuscinosis (CLN10) is caused by a deficiency of cathepsin D, which is a lysosomal aspartic protease involved in the regulation of apoptosis [154]. This is the most 5.1. ARX gene severe form of neuronal ceroid lipofuscinosis and patients may present with prenatal and neonatal status epilepticus, severe ARX mutations are seen in boys with West syndrome. They are also congenital microcephaly, spasticity, respiratory distress, and apnea observed in boys with neonatal or very early infantile epileptic [154,155]. These patients may die in the first few days or weeks of life. encephalopathy with burst suppression pattern. Seizures are often Examination of the brains at autopsy shows a small brain with severe therapy resistant and progressive brain atrophy follows. Abnormal neuronal and white matter loss. Histopathology of neurons shows genitalia such as a small penis can sometimes be an indicator. A granular osmiophilic deposits (GROD) in a whirling, laminated common mutation is the expansion of the polyalanine tract from 16 to pattern. Diagnosis can be made by skin biopsy and identifying 27 alanines due to a duplication [159]. A variety of other mutations GROD bodies in nonmyelinated Schwann cells [156]. This is an including truncating mutations have also been reported with this autosomal recessive disorder and molecular analysis shows mutations phenotype. ARX mutations also cause X-linked mental retardation, in the CTSD gene. There is no treatment for this disorder. Other Proust syndrome, Partington syndrome, X-linked myoclonic epilepsy neuronal ceroid lipofuscinosis disorders, including the infantile with spasticity and intellectual disability, and X-linked lissencephaly variant, exhibit symptoms after 6 months of age. with abnormal genitalia.

5.2. CDKL5 gene 5.6. Rare seizure genes

CDKL5 is another gene located on the X-chromosome which was Rarely described causes of West syndrome include MAGI2, alpha-II first identified in two girls with X-linked West syndrome [160] and spectrin, and phospholipase C beta-1 deficiency. Some patients with later in girls and boys with atypical early Rett syndrome [161]. Girls Williams–Beuren syndrome and larger deletions exhibit infantile spasms with mutations in the CDKL5 gene present with hypotonia and early and hypsarrhythmia. Fine mapping of the deletions identified hemi- seizures with onset between 1 and 15 weeks, often therapy resistant zygosity of the MAGI2 gene as responsible for the epileptic phenotype. [162,163]. Some develop infantile spasms. They develop microcephaly Additional symptoms include delayed development and hypotonia. The with deceleration of head growth, stereotypies and hand apraxia at MAGI2 gene is involved in the synaptic scaffold of synapses. later age, and some have hyperventilation episodes. CDKL5 mutations In-frame deletions in the alpha-II spectrin gene were identified in 2 or deletions account for approximately 10% of girls with early patients with West syndrome and severe hypomyelination including seizures, and 28% of girls with early onset seizures and infantile thin, shortened corpus callosum and atrophy of the cerebellum, spasms [163]. Early epilepsy with normal interictal EEG and severe resulting in severe spastic quadriplegia, no developmental progress, hypotonia, often later developing into infantile spasms are key clinical and visual inattention [172]. This gene is involved in maintaining features [162]. MRI can show mild cortical and cerebellar atrophy and voltage gated channels in position. abnormal high signal in the posterior white matter and dentate nuclei. A boy is described with focal seizures at 10 weeks developing into Rare boys with early infantile seizures, severe mental retardation and West syndrome at age 6 months, who was found to have a deletion in spasticity, and mutations in CDKL5 have also been reported [164]. the phospholipase C beta 1 gene, which is associated with hippocampal acetylcholine receptor signaling [173]. Mutations in this gene were excluded in 12 other patients with infantile spasms. 5.3. STXBP1 gene Microdeletions or duplications in a variety of locations were identified by array CGH in up to 10% of patients with syndromic Patients with heterozygous missense mutations or deletion in the epilepsy including infantile spasms [174]. syntaxin binding protein 1 (STXBP1) gene exhibited early onset epileptic syndromes (seizures between 3 days and 4.5 months) such 5.7. Channelopathies as early infantile epileptic encephalopathy with burst suppression fi pattern as Ohtahara syndrome, West syndrome, and less speci c Benign familial neonatal seizures are an autosomal dominant epileptic syndromes [165,166]. Males and females are both affected syndrome caused by mutations in the voltage-gated potassium accounting for 5.6% of patients with early onset epileptic encepha- channel genes, KCNQ2 or, more rarely, KCNQ3 [175,176]. Seizures lopathies. Epileptic spasms were preceded by other seizure types start in the first week of life as brief, generalized or focal, tonic–clonic often partial epilepsy [167]. Some also had myoclonic seizures seizures sometimes with apnea, with a normal physical exam and compatible with early myoclonic encephalopathy. All patients normal EEG, but a few patients may have focal discharges. The develop severe mental retardation, and most have ataxia and often seizures respond to phenobarbital. The neurodevelopmental outcome are wheelchair bound. Vigabatrin is the most effective antiepileptic is normal, and seizures disappear after 2 to 15 weeks with medication. The STXBP1 protein regulates synaptic vesicle release by normalization of the EEG in 24 months. Up to 16% of patients later binding syntaxin 1A and the SNARE complex. develop epilepsy. Rare patients have therapy resistant seizures with cognitive delays and myokymia. Both point mutations and deletions 5.4. MECP2 gene have been noted. Voltage-gated channels repolarize neuronal mem- branes after activation of excitatory neurotransmitter ion channels, Males with MECP2 gene mutations or deletions present with and neurons with reduced function of KCNQ2 would remain longer congenital encephalopathy often with respiratory insufficiency and depolarized and activated. Benign neonatal-infantile seizures with apnea as well as seizures [168,169].Iftheinfantsurvives,heshows onset around 3 months are related to mutations in the sodium hypotonia, deceleration of head growth, movement disorders and lack channel SCN2A [177]. of cognitive development. The family history can have female relatives Mutations in the sodium channel SCN1A cause a number of clinical with a diagnosis of Rett syndrome with typical clinical features. phenotypes including severe myoclonic epilepsy of infancy. Patients Diagnosis is made through sequencing of MECP2 or analysis for with severe myoclonic epilepsy of infancy develop generalized deletions using multiplex ligation-dependent probe amplification seizures, often associated with fever, around 6 months of age. They (MLPA) or array comparative genomic hybridization (aCGH). Treat- often present with hemiclonic or febrile status epilepticus. The – ment is symptomatic with antiepileptic medications and supportive subsequent seizures develop into generalized tonic clonic, myoclon- care. Diagnosis of this in a male infant may also have important ic, absence, and simple and complex partial seizures. They later have reproductive implications for females in the family. Epilepsy is common developmental stagnation, moderate developmental delay, and in girls with Rett syndrome due to mutations in MECP2, but occurs after ataxia. They are caused by de novo mutations in the sodium channel 7 months of age and on average at age 3 years [170]. gene SCN1A. Missense mutations account for 70% of patients and copy number variations for about 3% of patients, with truncating mutations and more dissimilar missense mutations more likely associated with 5.5. PNKP gene this phenotype [178,179]. Rare patients have mutations in SCN1B, SCN2A, or the voltage-gated GABA receptor gene, GABRG2 [177,180]. PNKP gene mutations have been documented in six families with Vaccine-related epileptic encephalopathies have been later attributed individuals who presented with infantile-onset intractable seizures, to SCN1A mutations [181]. severe microcephaly, developmental delay, and variable behavioral problems [171]. Brain magnetic resonance imaging shows preserved 5.8. eIF2B genes brain structure, and no other neurologic problems are reported. This gene has been implicated in the repair of single and double-stranded Mutations in the eIF2B-subunits cause vanishing white matter DNA breaks. The inheritance is autosomal recessive affecting both boys syndrome. The protein complex eIF2B is composed of five subunits and girls. Treatment is symptomatic with antiepileptic medications and encoded by five genes (EIF2B1–EIF2B5) and interacts with initiation supportive care. factors of mRNA translation. This condition is characterized with

Fig. 1. Differential diagnosis of brain MRI ﬁndings in young infants with seizures.

Fig. 2. Select brain MRI images of young infants with seizures. Legend: Restricted diffusion of the long tract in the brain stem (A) and posterior crux of the internal capsule (B) in a newborn patient with nonketotic hyperglycinemia. Multiple periventricular cysts and brain atrophy are noted in a girl with pyruvate dehydrogenase deﬁciency (C). Increased signal is noted on T2 weighted images in the striatum of a patient with a mitochondrial DNA mutation mt.8993GNA (D). In a young infant with Menkes disease, diffusion restriction is noted in the striatum on both diffusion weighted images (E) and ADC mapping (F). Perisylvian polymicrogyri are noted on the coronal section of this neonate with Zellweger syndrome (G). Hydrocephalus due to aqueduct stenosis developed in this infant with methylene-tetrahydrofolate reductase deﬁciency (H).

Fig. 2 (continued).

Biotinidase enzyme activity Pyridoxal-5′-phosphate Uric acid Monoamine metabolites (Homovanillic acid, 5-hydroxyindolea- Total homocysteine cetic acid and 3-O-methyldopa) Very long chain fatty acids Methyltetrahydrofolate 7-dehydrocholesterol A skin biopsy must be considered, particularly if there is Pipecolic acid and alpha-amino adipic semialdehyde microcephaly and brain atrophy, looking for storage products Creatine and guanidinoacetate speciﬁcally for congenital ceroid neuronal lipofuscinosis (CLN10). CDG testing such as glycosylation analysis of transferrin The following treatment trials should be initiated, particularly in Urine analysis should include: neonatal epileptic encephalopathy, but also for infantile seizures:

Succinylpurines Pyridoxine 100 mg intravenous, then 30 mg/kg/day enterally Creatine and guanidinoacetate divided in 3 doses for 3 days Urine organic acids looking for fumarate, 4-hydroxybutyrate and Pyridoxal-5′phosphate 30 mg/kg/day divided in 3 doses for 3 days 2-hydroxyglutarate A therapeutic trial with folinic acid is no longer indicated. Alpha-aminoadipic semialdehyde or 6-PC Sulfocysteine and xanthine Finally, genetic testing should be considered since several genes have a substantial diagnostic yield. The clinical utility of testing for Cerebrospinal fluid should be analyzed in all neonates and infants genes such as ARX, CDKL5, and STXBP1 is considered high due to the with a severe seizure disorder for: ability to provide a firm diagnosis to avoid complex further etiologic Always cell count and protein (at least to ensure adequate testing, and for its genetic counseling implications [191]. All children quality, since any admixture of blood or serum causes false should have testing for STXBP1 and an array CGH, and in addition for boys: ARX, MECP2, and for girls: CDKL5. The place of SLC25A22 is yet interpretation of many metabolic tests; protein is elevated in unclear as the high yield in one study still requires confirmation. POLG1 and in Krabbe disease) The presentations of these disorders are often dramatic, and Glucose in CSF and in blood (obtained immediately before the despite extensive investigations causes are only found in a small spinal tap) portion of cases. The new genetic causes have increased the diagnostic Amino acids: glycine, serine, threonine and glutamine (with yield, yet only about 20% of cases are etiologically solved in those plasma amino acids at a similar time) children where perinatal injury, malformations, and infections have Lactate and pyruvate been excluded. The therapeutic yield of these investigations is limited.

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Please cite this article as: J.L.K. Van Hove, N.J. Lohr, Metabolic and monogenic causes of seizures in neonates and young infants, Mol. Genet. Metab. (2011), doi:10.1016/j.ymgme.2011.04.020