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Inborn errors of metabolism causing epilepsy

DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY Inborn errors of metabolism causing epilepsy SHAMIMA RAHMAN | EMMA J FOOTITT | SOPHIA VARADKAR | PETER T CLAYTON Clinical and Molecular Genetics and Neurosciences Units, University College London Institute of Child Health, London and Metabolic and Neurosciences Units, Great OrmondStreet Hospital for Children NHS Trust, London, UK.
Correspondence to Shamima Rahman at Clinical and Molecular Genetics Unit, University College London Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Seizures may be the first and the major presenting feature of an inborn error of metabolism (IEM), Accepted for publication 14th June 2012.
for example in a neonate with pyridoxine-dependent epilepsy. In other IEMs, seizures may be pre- Published online 24th September 2012.
ceded by other major symptoms: by a reduced level of consciousness in a child with an organicacidaemia or urea cycle defect; or by loss of skills, progressive weakness, ataxia, and upper motor signs in a child with a lysosomal storage disorder or peroxisomal leukodystrophy. This review concentrates on those IEMs for which specific treatment is available. The common metabolic causes of seizures vary according to the age at presentation. Features from the history, examination, imaging, and first line biochemical investigations can all provide clues to an inborn error. This review attempts to delineate these and to provide a guide to the specific tests that can be used to make the diagnosis of disorders with specific treatment.
PNPO Pyridox(am)ine 5¢-phosphate oxidaseSUOX Sulphite oxidase Inborn errors of metabolism (IEMs) are a relatively infrequent reported in more than 200 different IEMs, and seizures are a cause of epilepsy, but their recognition is of paramount impor- relatively common reason for referral to the metabolic paedi- tance because many of these conditions are treatable, particu- atrician or biochemical geneticist. Furthermore, although larly those presenting in the neonatal period and in early IEMs are rarely the cause of epilepsy, it is important to infancy. Many biochemical and genetic investigations are recognize and diagnose this group of disorders, since they requested by practising clinicians because of the imperative of may be treatable, and there are significant implications for not missing a treatable cause of the early onset epileptic encephalopathies. This review is timely because the genetic The classification of metabolic epilepsies is difficult.
basis of several treatable metabolic epilepsies has been estab- Seizures may be characterized by their semiology and electro- lished in recent years, and experimental treatments are being encephalographic (EEG) features, although epilepsies in IEMs developed and trialled in some conditions that were previously are associated with multiple, usually generalized, seizure types.
considered to be untreatable. These treatments include vita- The most recent International League Against Epilepsy Com- min supplementation, provision of alternative substrates (to mission on Classification and Terminology proposes ‘struc- bypass a block), and dietary manipulation.
tural ⁄ metabolic’ as an aetiology group for conditions or An epileptic seizure has been defined by the International diseases that have been demonstrated to be associated with a League Against Epilepsy and International Bureau for substantially increased risk of developing epilepsy, including Epilepsy as a ‘transient occurrence of signs and ⁄ or symptoms disorders of genetic origin.3 A more practical way of consider- due to abnormal excessive or synchronous neuronal activity ing the metabolic epilepsies is by age at presentation (Table I), in the brain’.1 The same groups defined epilepsy as ‘a disor- and in this review we consider those epilepsies that present in der of the brain characterized by an enduring predisposition the neonatal period and first 6 months of life; those that more to generate epileptic seizures and by the neurobiological, often present in late infancy and early childhood; and, finally, cognitive, psychological, and social consequences of this con- metabolic epilepsies presenting in later childhood and dition’. Although epilepsy is common, affecting at least 0.5% adolescence. There is, of course, considerable overlap between of the population,2 the precise prevalence of metabolic epi- these groups. We recently reviewed mitochondrial epilepsies lepsies is unknown, but they are likely to represent a small in a companion article in this journal,4 and so will not discuss minority of all causes of epilepsy. However, seizures are a them in great detail here, but will indicate which mitochon- frequent symptom in metabolic disease, having been drial epilepsies may present at particular ages.
ª The Authors. Developmental Medicine & Child Neurology ª 2012 Mac Keith Press The large number of IEMs associated with epilepsy may be • This paper provides a concise summary of the major inborn errors of metabolism explained by the plethora of different disease mechanisms that (IEMs) which may present with epilepsy, categorized by age at presentation.
may trigger seizures. In some patients electrolyte disturbance • An overview of key clinical, biochemical, and genetic diagnostic features to aid may lead to seizure generation, particularly in disorders associ- differential diagnosis is presented.
• Most importantly, this article emphasizes the treatable IEMs causing epilepsy ated with hyponatraemia, hypocalcaemia, or hypomagnesa- and provides information about appropriate medications, doses, and routes of emia. In other cases seizures may occur at times of acute metabolic decompensation due to hypoglycaemia (e.g. fat oxi-dation disorders, glycogen storage diseases, and disorders of should always suggest careful consideration of an IEM.
gluconeogenesis) or hyperammonaemia (e.g. urea cycle dis- Abnormal intrauterine movements (fluttering or hiccoughs) orders or organic acidaemias). Other pathogenic mechanisms can also be a pointer to a metabolic disorder.
associated with seizure generation include deficiency of a vita-min or cofactor (such as pyridoxal phosphate, 5-methyltetra- hydrofolate, biotin, or coenzyme Q10 [CoQ10]), cerebral energy deficiency (as in glucose transporter defects, disorders Pyridoxine-dependent epilepsy (PDE) due to antiquitin defi- of creatine biosynthesis or transport, and mitochondrial respi- ciency (a-amino adipic semialdehyde [a-AASA] dehydrogenase ratory chain deficiencies), chemical disruption of neurotrans- deficiency; OMIM 266100) is an inborn error of lysine catabo- mission (ion channel disorders and defects of neurotransmitter lism that results in a secondary deficiency of vitamin B6 due to synthesis or recycling), or physical disruption of neural net- adduct formation between D1-piperideine-6-carboxylate and works as a result of brain malformations or IEMs with cerebral pyridoxal 5¢-phosphate (PLP), the active form of vitamin B6 in accumulation of abnormal storage material. Finally, seizures humans.5,6 Patients with this disorder typically present in the may be triggered by direct neurotoxicity of accumulating first days of life with a severe seizure disorder that is resistant intermediates, as in untreated phenylketonuria.
to treatment with conventional anticonvulsant medicationsbut responsive to treatment with pyridoxine. Often the infant EPILEPTIC ENCEPHALOPATHY PRESENTING IN THE is in poor condition at delivery and the seizure disorder may be accompanied by multisystem symptomatology such as met- Seizures occur in 1 in 1000 live births, and the most common abolic acidosis, electrolyte disturbance, abdominal distension, cause is hypoxic–ischaemic encephalopathy. However, some and feed intolerance, resulting in misdiagnosis as hypoxic–is- newborn infants are in a poor condition at birth because they chaemic encephalopathy or sepsis.7 Frequent multifocal and have an underlying inborn error of metabolism so, if seizures generalized myoclonic jerks are observed in PDE, often inter- are persistent and difficult to treat with conventional mixed with tonic symptoms, abnormal eye movement, grimac- antiepileptic drugs (AEDs), the neonatologist should consider whether hypoxic–ischaemic encephalopathy is the primary Although in most instances PDE responds quickly and problem or whether there could be an underlying IEM. Clini- completely to pyridoxine, any child with a resistant epileptic cally, a semiology of infantile spasms or myoclonic seizures, encephalopathy should undergo an adequate treatment trial or, electrographically, hypsarrhythmia or burst suppression, of vitamin B6 (see recommended doses below) accompanied Table I: Classification of metabolic epilepsies according to age at presentation Lafora body and Unverricht–Lundborg disease Disorders of peroxisome biogenesis and b-oxidation Congenital disorders of glycosylationCathepsin D deficiency (congenital NCL) PDE, pyridoxine-dependent epilepsy; CoQ10, coenzyme Q10; PNPO, pyridox(am)ine 5¢-phosphate oxidase; MERRF, myoclonic epilepsy withragged-red fibres; MELAS, mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes; GLUT1, glucose transporter across the blood–brain barrier; POLG, gene encoding catalytic subunit of DNA polymerase gamma; MIRAS, mitochondrial recessive ataxia syndrome; SCAE,spinocerebellar ataxia with epilepsy; MEMSA, myoclonus, epilepsy, myopathy, sensory ataxia; NCL, neuronal ceroid lipofuscinosis.
Developmental Medicine & Child Neurology 2013, 55: 23–36 by EEG recording, as some patients do not show a dramatic Outcome in the first described cases was poor, with a high initial response, probably because of multiple contributing mortality in the first weeks of life. However, increased aware- pathologies. Treatment should initially be commenced in an ness of the disorder and prompt diagnosis has subsequently intensive care setting as these infants are vulnerable to revealed an expanded phenotype, with some children present- apnoea, profound hypotonia, and hypotension. Following a ing with a comparatively mild seizure disorder beyond the single 100mg dose of intravenous pyridoxine, seizures will neonatal period and some surviving into adulthood.
usually stop, and our practice is to follow this up with a Treatment is with PLP, which is currently available in an maintenance dose of 5 to 15mg ⁄ kg ⁄ day in two divided doses; oral formulation only; doses between 10 and 30mg ⁄ kg ⁄ day in however, higher doses (15–30mg ⁄ kg ⁄ d) have been recom- divided doses have been successful in controlling seizures. As mended by an international study group.9 Seizures, which with initiation of pyridoxine treatment, the first doses of PLP are of multiple types in children with PDE, will respond to should be given in an intensive care setting because of the risk both pyridoxine and PLP, although pyridoxine tends to be of respiratory and cardiovascular collapse. In the long term it used as the first-line treatment in the UK as there is more is recommended that children on PLP be monitored with liver experience of its use and it is available in both intravenous ultrasonography and liver function tests. This is based on the and oral formulations. Pyridoxine treatment has been associ- observation that PLP treatment has been associated with liver ated with peripheral neuropathy; thus, annual monitoring of damage in a single patient with PNPO deficiency (it has not nerve conduction is recommended in children who can coop- been firmly established that PLP, or the specific formulation erate. Clinicians should aim to reduce pyridoxine to the low- of PLP, was responsible for the patient’s liver damage). Prena- est effective dose if there is any evidence of abnormality on tal diagnosis of PNPO deficiency has been undertaken, and neurophysiological testing or clinical symptoms. Our experi- parents who had previously lost a child as a result of severe ence suggests that, to minimize the risk of neuropathy, in neonatal epileptic encephalopathy opted for termination most cases treatment with pyridoxine should not exceed a (unpublished observation); in theory, prenatal treatment total daily dose of 200mg in children.
would be an alternative but there are no data on the outcome Diagnostic confirmation of PDE is by measurement of ele- vated a-AASA in urine and ⁄ or plasma and cerebrospinal fluid(CSF). This can be done while the child is taking vitamin B6 and thus should not delay commencement of treatment. Other Folinic acid-responsive seizures were first described in a group investigations which may be suggestive of the diagnosis of neonates with onset of seizures (myoclonic or clonic) in the include plasma and CSF amino acids, CSF monoamine first 5 days of life, associated with irritability and white matter metabolites, and CSF PLP (Table II). PDE should also be abnormalities on brain magnetic resonance imaging (MRI).
considered in children who show an initial response to AEDs These infants also shared a characteristic unidentified ‘peak’ but subsequently become drug resistant, as they may represent on the CSF high-performance liquid chromatogram and all responded, to a variable degree, to folinic acid. Subsequently, In the long term, treated children with PDE remain seizure- other infants fulfilling these criteria have been identified whose free, although some have breakthrough fits during periods of seizures responded to pyridoxine and who have been diag- intercurrent infection and fever.7 In some children it has nosed with antiquitin deficiency, with elevated a-AASA and proved helpful to double the regular dose of pyridoxine during pathogenic mutations in the antiquitin gene. Thus, folinic the first few days of a febrile illness to prevent seizures. Mild acid-responsive seizures and PDE due to antiquitin deficiency to moderate learning difficulty is common, with speech and are now understood to be biochemically and genetically iden- language development being particularly impaired.
tical. The ‘peak’ on high-performance liquid chromatogramremains unidentified.9,11 Pyridox(am)ine 5 ¢-phosphate oxidase deficiencyPyridox(am)ine 5¢-phosphate oxidase (PNPO) is essential for Multiple carboxylase deficiency due to biotinidase or the synthesis of PLP.6 Deficiency of this enzyme (OMIM 610090) has been described in only a small number of families Both inherited disorders, biotinidase deficiency (OMIM worldwide and typically results in a severe neonatal seizure 253260) and holocarboxylase synthetase (HCS) deficiency disorder which responds to treatment with PLP. Often infants (253270), affect the vital coenzyme function of biotin. This with PNPO deficiency are born preterm and there may be a results in reduced activity of all four biotin-dependent carbox- family history of infertility and recurrent miscarriage. Seizures ylases (acetyl-CoA carboxylase, pyruvate carboxylase, propio- are similar to those seen in PDE, with prolonged episodes of nyl-CoA carboxylase, and 3-methylcrotonyl-CoA carboxylase) mixed multifocal myoclonic–tonic symptoms often associated and a clinical picture characterized by neurological disease with grimacing and abnormal eye movements.8 Alongside including seizures, often infantile spasms.12 Other typical clinical clues and an EEG burst suppression pattern, diagnosis symptoms include ataxia, hypotonia, encephalopathy, and skin of this disorder is suggested by secondary changes in plasma manifestations including alopecia and a generalized or perioral and CSF amino acids, together with reduced CSF PLP and eczematous rash. Age at presentation is extremely variable, as monoamine metabolites (Table II). The diagnosis may be is the pattern of symptoms; however, many patients present in confirmed by mutation analysis of the PNPO gene.10 the first months of life. Biochemical investigation in symptom- Table II: Investigation of metabolic epilepsies Fat oxidation disordersGlycogen storage diseasesDisorders of gluconeogenesis Disorders of calcium homeostasisRenal tubulopathyPDE Disorders of magnesium transportRenal tubulopathyPDE PDHc deficiencyMitochondrial respiratory chain defectsBiotinidase deficiencyLipoic acid synthetase deficiency Zellweger syndromeOther peroxisomal disorders Alpha methyl-acyl-CoA racemase deficiency Disorders of CoQ10 biosynthesis; secondary deficiency in some mitochondrial disorders Lysosomal storage disorders, including late Organic acidaemias, e.g. D and L-2-hydroxyglutaric acidurias, cobalamin C deficiency (form ofmethylmalonic aciduria); biotinidase ⁄ HCSdeficiencies Krebs cycle disorders; mitochondrial respiratory Developmental Medicine & Child Neurology 2013, 55: 23–36 Investigations in CSF (with paired blood sample) Mitochondrial respiratory chain disorderPDHc deficiency Dihydrofolate reductase deficiencyFolate receptor defectKearns–Sayre syndromeOther mitochondrial disordersMay be low in serine biosynthesis disorders and methylene tetrahydrofolate reductase deficiency PDE, pyridoxine-dependent epilepsy; PDHc, pyruvate dehydrogenase complex; mtDNA, mitochondrial DNA; NKH, non-ketotic hyperglycinaemia;PNPO, pyridox(am)ine 5¢-phosphate oxidase; VLCFA, very long-chain fatty acid; CoQ10, coenzyme Q10; NCL, neuronal ceroid lipofuscinosis; HCS,holocarboxylase synthetase; SUOX, sulphite oxidase; MoCoF, molybdenum cofactor; GAMT, guanidinoacetate methyl transferase; AGAT,arginine–glycine amidinotransferase; CSF, cerebrospinal fluid; GLUT1, glucose transporter across the blood–brain barrier; HVA, homovanillicacid; 5-HIAA 5-hydroxy indoleacetic acid.
atic patients usually shows lactic acidosis and a characteristic ring in the first 6 months of life. Semiology is often of cya- organic aciduria, although some patients do not have these notic attacks or of eye movement seizures which may be features present.13 Diagnosis is confirmed by measurement of mistaken for opsoclonus–myoclonus. The interictal EEG may serum enzyme activity in biotinidase deficiency and by muta- be normal. The ictal EEG may show focal slowing or tional analysis or lymphocyte or fibroblast carboxylase activity discharges, including 2.5 to 4 Hz spike and wave. A striking in HCS deficiency. Screening of newborn infants for biotini- difference between pre- and postprandial EEG may be seen, dase deficiency is performed in some countries.12 with a decrease in epileptic discharges following carbohydrate All patients with biotinidase deficiency and most with HCS intake. GLUT1 deficiency is now known to be a cause of deficiency respond excellently to oral biotin. Delay in treatment drug-resistant childhood absence epilepsy and of adult-onset will result in irreversible neurological disease; thus, a treatment absence epilepsy with a normal CSF glucose.
trial of 5 to 10mg oral biotin daily is justified in any child with A lumbar puncture, preferably while fasting, to demonstrate an unexplained neurological disorder including seizures, pend- hypoglycorrhacia is the first step in diagnosis. CSF glucose is ing confirmatory diagnostic investigations. This is particularly typically less than 2.5mmol ⁄ L, although values greater than true in unscreened populations such as in the UK.14 this have been reported. The ratio of CSF to plasma glucoseis particularly important, so a non-stressed (again, preferably, fasting) plasma glucose should be taken before the lumbar GLUT1 is a membrane transporter that facilitates glucose puncture. In the absence of central nervous system (CNS) transport across the blood–brain barrier. Defective GLUT1 infection, a CSF to blood ratio of less than 0.5 is diagnostic.
(OMIM 606777) results in cerebral deficiency of glucose, the CSF lactate is normal or low. The degree of hypoglycorrhacia vital source of energy for brain metabolism, and a low CSF and absolute ‘cut-off’ for a diagnosis of GLUT1 deficiency glucose concentration. The phenotype of this IEM is expand- remain a source of debate, and mild clinical phenotypes have ing with classical early onset seen before 2 years of age, later been reported with normoglycorrhacia and a normal CSF to onset between 2 and 10 years, and a non-classical form with blood glucose ratio; thus molecular genetic analysis of mental retardation* and movement disorder but no epi- the SLC2A1 gene is considered the standard criterion for lepsy.15,16 Familial transmission has been reported. In classical diagnosis.16 Approximately 80% of patients harbour patho- early-onset GLUT1 deficiency the neonatal period may be genic mutations. As GLUT1 is the predominant glucose normal and breastfeeding may be protective. Seizures are the transporter in red blood cells, reduced erythrocyte glucose main presenting symptom, with 79% of all first seizures occur- uptake may also be indicative of reduced glucose transportinto the CNS. However, this investigation is not routinelyavailable and may give false-negative results in mild cases.17 Epilepsy in GLUT1 deficiency is drug resistant and may be aggravated by fasting and by AEDs that inhibit GLUT1 Seizures are a major feature of the clinical presentations of (phenobarbitone, valproate, diazepam). GLUT1 deficiency is both 3-phosphoglycerate dehydrogenase deficiency (OMIM eminently treatable with the ketogenic diet, which should be 601815) and phosphoserine aminotransferase deficiency commenced at the earliest opportunity and continued until at (OMIM 610936).22,23 Microcephaly is present at birth or least adolescence, when the energy demands of the brain acquired in early infancy. Infants are hypertonic and show decrease. This high-fat, low-carbohydrate diet provides an severe developmental delay. The epilepsy is often character- alternative source of energy for the brain as ketone bodies, ized by infantile spasms and EEG hypsarrhythmia, and sub- which are produced in the liver and which can easily penetrate sequent evolution to a Lennox–Gastaut syndrome has been the blood–brain barrier. In the vast majority of patients the ke- reported.24 CSF amino acids should be analyzed after a 6- togenic diet is successful at controlling seizures, allowing with- hour fast and in affected individuals show a low concentra- drawal of AEDs.18 Seizures are controlled at lower blood levels tion of serine, often with a low glycine. Concentrations of of b-hydroxybutyrate than are needed to nourish the brain.
these amino acids may also be low in plasma. To controlseizures and improve the outcome, treatment with serine Organic acidurias, aminoacidopathies, and urea cycle (usually together with glycine) must be started soon after birth. The best outcome with 3-phosphoglycerate dehydro- In general, these disorders give rise to episodes of acute genase deficiency has been achieved when an affected infant encephalopathy in which seizures may occur as brain intoxica- was treated in utero.25 A more recent report described two tion progresses. There are usually associated features of siblings with a milder clinical phenotype of late childhood- systemic metabolic decompensation such as acidosis, ketonuria, onset absence epilepsy with typical EEG 3 Hz spike–wave and hyperammonaemia. Diagnosis is made on the basis of complexes, who had learning difficulties but normal head analysis of urine organic acids, blood spot acylcarnitine profile, and plasma and urine amino acids. A discussion of the treat-ment of these disorders is beyond the scope of this review, but Molybdenum cofactor and sulphite oxidase deficiencies many specific forms of treatment are available and if instituted Molybdenum is an essential cofactor for three enzymes in early will prevent death and severe neurological damage.
humans: xanthine dehydrogenase, sulphite oxidase, and alde-hyde oxidase. Patients with molybdenum cofactor (MoCoF) Disorders with novel ⁄ experimental therapies deficiency (OMIM 252150) are deficient in the activity of all Non-ketotic hyperglycinaemia (neonatal type) three enzymes; the clinical phenotype is characterized by a The typical neonatal form of non-ketotic hyperglycinaemia severe seizure disorder with onset in the first days of life, with (OMIM 605899) presents within the first days of life following dystonia and developmental delay, and the disease usually an apparently symptom-free period. A severe clinical picture results in death in early childhood.27 Equally, seizures may be evolves that is characterized by seizures, lethargy, encephalop- absent and the movement disorder mistaken for epilepsy, athy, profound hypotonia, and hiccoughs. Respiration AEDs being symptomatically useful for either. Burst suppres- becomes irregular, often progressing to apnoea necessitating sion may be seen on the EEG. The underlying disease process ventilation. EEG usually shows a burst suppression pattern is poorly understood; however, toxic accumulation of endo- which, in combination with the clinical features, is very sug- genous sulphite is the most likely pathogenic mechanism. A gestive of the diagnosis. Some patients have structural brain suspected diagnosis is confirmed by finding reduced plasma abnormalities on MRI, including dysgenesis of the corpus urate, the presence of sulphite or sulphocysteine in the urine, and a characteristic urinary purine profile in which uric acid is This devastating disorder is caused by a defective glycine replaced by xanthine.28 Hypohomocystinaemia has also been cleavage protein, which is a multienzyme complex that reported in some cases.29 Isolated sulphite oxidase (SUOX) degrades glycine in the CNS. If the diagnosis is suspected, deficiency (OMIM 272300) results in an identical clinical plasma and CSF amino acids should be measured and will phenotype to MoCoF deficiency and can be differentiated on reveal grossly elevated glycine, in particular an increased CSF the basis of biochemical investigations which, in contrast to to plasma ratio.20 It should be noted that sodium valproate MoCoF deficiency, show normal plasma urate and urinary therapy may also lead to increased glycine levels, although purine profile. Genetic confirmation is also possible. Elevated usually to a far lesser degree than is observed in non-ketotic urinary a-AASA characteristically associated with antiquitin deficiency, has also recently been described in both MoCoF Untreated, the neonatal form of non-ketotic hyperglycina- emia is associated with death in the first months of life.20 Up to two-thirds of patients with MoCoF deficiency have Therapy with sodium benzoate and dextromethorphan may a proximal defect in the pathway of molybdenum cofactor be helpful in some milder forms of the disease, alongside synthesis, resulting in the failure to convert GTP to cyclic AEDs and general supportive care.21 The epilepsy remains pyranopterin monophosphate. This disease type, ‘type A’, is drug resistant, infantile spasms may emerge, and the EEG potentially amenable to a new therapy and should be identi- evolves to hypsarrhythmia or multifocal discharges on a back- fied by mutation analysis of the MOCS1 gene.31 Treatment of ‘type A’ MoCoF using purified intravenous cyclic Developmental Medicine & Child Neurology 2013, 55: 23–36 pyranopterin monophosphate has shown early promise with a reduction in seizures and improved developmental pro- gress, as well as correction of biochemical abnormalities.32 Neonatal-onset epilepsy that is difficult to control with AEDs However, experience with this experimental treatment is can be a major presenting feature of disorders of peroxisome currently limited to only a few patients. This treatment is biogenesis (Zellweger syndrome; OMIM 214100) and dis- likely to be of benefit only when commenced early in life, orders of peroxisomal b-oxidation. An affected newborn infant before permanent neurological damage ensues; thus, prompt is hypotonic, and patients with Zellweger syndrome have char- diagnosis is of utmost importance, particularly in families acteristic dysmorphic features including large fontanelle, high who are known to harbour pathogenic mutations. Further- forehead, shallow supraorbital ridges, low-set posteriorly more, patients with MoCoF deficiency ‘type B’, who have a rotated ears, and small chin. The electroretinogram (ERG) is more distal defect in molybdenum cofactor synthesis (mo- frequently markedly reduced or absent. Skeletal radiology may lybdopterin synthase, encoded by MOCS2), will not benefit show punctate calcification of cartilage, small renal cysts may be apparent on ultrasound, and liver function tests may be Unfortunately, no definitive treatment is available for abnormal, sometimes with clinical jaundice. Plasma very long SUOX deficiency, which is managed primarily with supportive chain fatty acids are elevated. Areas of polymicrogyria are treatment for epilepsy and neurodisability. Attempts at treat- often frontal or opercular, resulting in a focal EEG and seizure ment with a diet restricted in sulphur-containing amino acids semiology, and there are often focal motor seizures.38 (methionine and cysteine) have been largely unsuccessful.33 Neonatal-onset seizures are a relatively unusual initial presen- Menkes disease (OMIM 309400) is an X-linked recessive dis- tation of mitochondrial disease. Neonatal mitochondrial epi- order of copper metabolism that characteristically presents leptic encephalopathies are usually devastating diseases, often with seizures and hypotonia in male infants during the first associated with multiorgan failure. In fact, involvement of few months of life. Patients with this neurodegenerative dis- multiple seemingly unrelated organs may alert the clinician to ease may also encounter clinical problems related to collagen the possibility of an underlying mitochondrial disorder. These abnormalities such as vascular tortuosity and bladder divertic- disorders are typically unresponsive to treatment, with the ulae, which may result in infection. Clinical clues to Menkes possible exception of CoQ10 deficiency (OMIM 607426).39,40 disease include skin laxity, hypothermia, and a particular facial Infants with RARS2 mutations (OMIM 611523), causing appearance with ‘sagging’ cheeks and frontal bossing. The defective mitochondrial protein synthesis,41 may present with characteristic hair abnormality ‘pili torti’, which is eventually profound lactic acidosis on the first day of life.42 The lactic present in all patients, may also be very helpful in making the acidosis may subsequently resolve, but the clinical course is severe, with intractable epilepsy and developmental stasis.
Copper is essential for the normal functioning of several This diagnosis should be suspected in any infant with ponto- copper-containing enzymes, many of which have their action cerebellar hypoplasia on MRI brain scan, particularly if there in the CNS. In Menkes disease, a defective ATP7A protein results in reduced copper efflux into the circulation from intes- Infants with mutations in SLC25A22 (OMIM 609304), tinal enterocytes and therefore reduced copper availability for which encodes the mitochondrial glutamate transporter, pres- dependent enzymatic processes. A reduced level of serum cop- ent in the neonatal period with intractable myoclonic seizures per and serum caeruloplasmin is very suggestive of the diagno- with burst suppression on the EEG and low amplitude visual sis and an abnormal ratio of urinary dopamine to evoked potentials.43 The ERG may also be abnormal. Serial noradrenaline (indicative of reduced activity of the copper MRI shows brain atrophy. Mitochondrial oxidation of gluta- dependent enzyme, dopamine b-hydroxylase) further supports mate is impaired but there is no readily available metabolite or this. Mutational analysis of the ATP7A gene is required for enzyme test to facilitate diagnosis of this disorder. Muscle biopsy is needed to diagnose other mitochondrial epilepsies The electroclinical syndrome has been characterized as presenting in the neonatal period, as discussed by Rahman early focal status precipitated by fever with ictal runs of slow and slow spike–wave posteriorly, evolution to infantile spasms Within the past 2 years, three disorders have been described with modified hypsarrhythmia later in the first year of life and that affect the synthesis of lipoic acid or its incorporation into then, in early childhood, multifocal seizures, tonic spasms, and mitochondrial enzymes (pyruvate dehydrogenase, a-ketogluta- myoclonus with multifocal high-amplitude discharges mixed rate dehydrogenase, and the glycine cleavage enzyme). One of these disorders, lipoic acid synthetase deficiency presented Untreated, Menkes disease is life-limiting, with patients sel- with neonatal seizures (which were unilateral, associated with dom surviving beyond 3 to 4 years. Therapy with subcutane- oral automatisms and initially controlled with phenobarbi- ous injections of copper histidine has prolonged life tone) and hypotonia, followed by progressive encephalopathy expectancy in some patients in whom it was started early (first and apnoea. Blood lactate and plasma glycine were elevated.
months of life), but it appears to have little impact on the Proteins which are normally lipoylated showed reduction in GAMT deficiency: cerebral energy deficiency (in common The dystroglycanopathies can present in the newborn period with arginine–glycine amidinotransferase and creatine trans- with congenital muscular dystrophy (weakness, hypotonia, and porter deficiencies) but also a direct neurotoxic effect of moderately elevated creatine kinase), seizures, and ocular guanidinoacetate, the accumulating metabolite in GAMT abnormalities. Imaging may show lissencephaly and other deficiency.50 Seizures occur in over 90% of patients with brain malformations. The diagnosis is usually made by muscle GAMT deficiency, and are typically of multiple types includ- ing myoclonic, generalized tonic–clonic, partial complex, headnodding, and drop attacks.51 Diagnosis may be achieved by demonstrating low cerebral creatine levels on magnetic reso- This disorder of purine metabolism (OMIM 608222) can nance spectroscopy; by measuring guanidinoacetate, creatine, present in the neonatal period with severe seizures and and creatinine levels in plasma and urine; and by molecular hypotonia. An affected infant may also show signs of intrauter- analysis of the three responsible genes (GAMT, GATM, and ine growth retardation and microcephaly. Diagnosis depends SLC6A8 for the GAMT, arginine–glycine amidinotransferase, on the identification of abnormal purine metabolites in the and transporter defects respectively). Treatment with oral creatine monohydrate is sufficient to restore cerebral creatinelevels, but dietary arginine restriction is additionally required in GAMT deficiency to reduce guanidinoacetate accumulation.
Cathepsin D deficiency (OMIM 610127) has been reported in Recent studies have indicated that ornithine supplementation, two families with congenital neuronal ceroid lipofuscinosis in addition to creatine supplementation and arginine restric- (NCL), presenting with microcephaly and intractable tion, improves clinical outcomes in GAMT deficiency.52 seizures,45 and in another child, who presented at schoolage.46 Affected infants with the congenital disorder presented with microcephaly from birth (with a history of deceleration Several disorders of folate metabolism and transport have been of head growth in the last trimester and abnormal fetal reported,53 often associated with megaloblastic anaemia movements suggestive of in utero seizures), and intractable and ⁄ or hyperhomocystinaemia. Recently, two defects of folate neonatal seizures leading to death by 10 days of age. Diagnosis metabolism have been shown to cause prominent seizures.
involves demonstration of abnormal storage material, assay of Mutations in the FOLR1 gene encoding the folate receptor a cathepsin D, and mutation analysis of the CTSD gene. Cur- (OMIM 613068), the major folate transporter across the rently there are no effective treatments for cathepsin D defi- blood–CSF barrier, have been reported in four families.54–56 ciency, or for any of the NCL disorders.
Patients presented with progressive ataxia and seizures (myo-clonic epilepsy and generalized tonic–clonic seizures) in the second year of life. Deficiency of dihydrofolate reductase 4-Aminobutyrate aminotransferase (GABA transaminase) defi- (OMIM 613839), the enzyme responsible for catalysing the ciency (OMIM 613163) is a rare cause of neonatal-onset sei- conversion of dihydrofolate to tetrahydrofolate, causes cere- zures and has been reported in three families to date.47–49 bral folate deficiency with generalized tonic–clonic and focal Consistent clinical features are intractable seizures, severe psy- seizures and megaloblastic anaemia or pancytopenia.57,58 Both chomotor retardation, hypotonia, hyperreflexia, and acceler- the folate receptor a and deficiencies of dihydrofolate ated linear growth. A spongy leukodystrophy was observed in reductase are associated with virtually undetectable levels of 5- two individuals in whom neuropathology was performed.
methyltetrahydrofolate in CSF, and clinical and biochemical Diagnosis can be made by demonstrating elevated levels of responsiveness to oral folinic acid supplementation. Cerebral GABA in the CSF or on proton magnetic resonance spectro- folate deficiency has also been linked to the presence of scopy of the brain; by enzyme assay in cultured lymphocytes; autoantibodies against the folate receptor in CSF, and may and by molecular analysis of the responsible gene ABAT.
occur as a secondary phenomenon in other IEMs including disorders of serine biosynthesis and mitochondrial disorders,particularly Kearns–Sayre syndrome caused by single mito- INFANCY AND EARLY CHILDHOODTreatable disorders Disorders of creatine biosynthesis and transport Disorders of CoQ10 biosynthesis represent the most treatable Three disorders of creatine metabolism have been described: mitochondrial disorders. Many present in infancy with a guanidinoacetate methyl transferase (GAMT) deficiency multisystem syndrome including epilepsy, frequently associ- (OMIM 612736) and arginine–glycine amidinotransferase ated with sensorineural hearing loss and a prominent steroid- deficiency (OMIM 612718), both of which are recessively resistant nephropathy. Other neurological features in these inherited, and the X-linked cerebral creatine transporter defect patients include nystagmus, ataxia, spasticity, and dystonia.
(OMIM 300352). All may be associated with epilepsy, but Mutations in five genes (COQ2, PDSS1, PDSS2, COQ9, and seizures are most prominent in GAMT deficiency. This is COQ6) have so far been reported to cause infantile onset of probably because two disease mechanisms are at play in CoQ10 deficiency.60 Treatment is with oral CoQ10 supple- Developmental Medicine & Child Neurology 2013, 55: 23–36 mentation; 10 to 30 mg ⁄ kg ⁄ day in three divided doses is usu- ized by elevated plasma proline and increased urinary excre- ally sufficient. The best outcome in this disorder was reported tion of proline, hydroxyproline, and glycine. It is the in a female who was diagnosed early because of an affected accumulation of pyrroline 5-carboxylate which adducts with older sibling, and in whom treatment was initiated at the first PLP that is thought to lead to vitamin B6 deficiency,66 a mechanism analogous to that of PLP with D1-piperideine-6-carboxylate in antiquitin deficiency (see above). Clinically, hyperprolinaemia type II is characterized by seizures that are Males with the X-linked form of pyruvate dehydrogenase usually precipitated by infection and fever. In at least one complex (PDHc) deficiency usually present with Leigh syn- reported case, seizures have shown a good response to pyri- drome (OMIM 308930), but females who are heterozygous for a severe mutation in the PDHA1 gene can present in thefirst 6 months of life with infantile spasms, an EEG showing hypsarrhythmia, and developmental regression (West syn- Seizures used to occur in infants with phenylketonuria drome), or just with severe myoclonic seizures (OMIM (OMIM 261600) before diagnosis by neonatal screening and 312170). MRI may show periventricular multicystic leukoen- early institution of a low-phenylalanine diet. In children from cephalopathy and agenesis of the corpus callosum. CSF lactate developing countries who have not been part of a comprehen- is often elevated, usually with an elevation of blood lactate, sive newborn screening programme, phenylketonuria should and fibroblast studies show reduced pyruvate dehydrogenase still be considered as a possible cause of seizures, particularly if complex activity. Some cases of pyruvate dehydrogenase complex deficiency respond well to treatment with thiamineand ⁄ or a ketogenic diet, and this response can include a There are some disorders that can be diagnosed by analysis ofurine organic acids and ⁄ or blood spot acylcarnitines in which seizures can occur without preceding signs of acute encepha- In males with X-linked adrenoleukodystrophy (OMIM lopathy and without evidence of acidosis, hyperammonaemia, 300100), other problems usually become evident before and so on. These include methylmalonic aciduria due to epilepsy: changes in behaviour, perceptive, and intellectual cobalamin defects (e.g. cobalamin C disorder; OMIM 277400) difficulties, expressive and motor difficulties, and visual distur- for which there are specific treatments, such as a high dose of bances. However, in one large series, 20 out of 485 individuals vitamin B12 and betaine, that may be able to help with seizure presented with seizures: focal seizures in six males and general- control; 4-hydroxybutyric aciduria (succinic semialdehyde ized in the remainder, with four having status epilepticus.63 A dehydrogenase deficiency; OMIM 271980), for which vigaba- careful history may identify symptoms attributable to adrenal trin may be beneficial; L-2-hydroxyglutaric aciduria (OMIM insufficiency such as weakness and tiredness, anorexia, vomit- 600721), for which treatment with riboflavin (with or without ing with diarrhoea or constipation, and crises with abdominal L-carnitine) has been shown to improve cognitive and motor pain, vomiting, and dehydration, and examination may reveal pigmentation of mucous membranes. The disorder is caused 236792) for which no successful treatment has been described; by mutations in the ABCD1 gene, which impair peroxisomal and 3-hydoxyisobutyryl-CoA hydrolase deficiency (OMIM b-oxidation, resulting in the accumulation of very long-chain 250620), which can be suspected on the basis of increased fatty acids in plasma. It has been suggested that presymptom- hydroxy-C4 carnitine in the blood spot and in which progres- atic patients may benefit from early intake of oleic and erucic sion of neurological disease has been arrested by treatment acids (combined in a 4:1 ratio in Lorenzo’s oil) in addition to with L-carnitine, dietary valine restriction, N-acetylcysteine, very long-chain fatty acid restriction,64 but this has not been and antioxidants (unpublished observation).
confirmed in other studies. Adrenal hormone replacement isnecessary in all patients with adrenal insufficiency. Haemato- poietic stem cell transplantation should be considered in males Infantile and late infantile neuronal ceroid lipofuscinosis who develop MRI abnormalities, since this treatment can NCLs are a group of autosomal recessive progressive neurode- arrest the cerebral demyelination.65 Haematopoietic stem cell generative disorders clinically characterized by the triad of epi- transplantation is not carried out routinely in all presymptom- lepsy, developmental regression ⁄ dementia, and pigmentary atic cases, since some affected individuals may never develop retinopathy. More than 10 genetic defects have been linked to progressive cerebral disease. Serial brain MRI is therefore the NCLs, most with characteristic ages at onset.50 All except extremely important in determining the need for and optimal infantile NCL (NCL type 1) are characterized by progressive timing of haematopoietic stem cell transplantation.
myoclonus. Neuronal ceroid lipofuscinosis type 1 presentswith developmental delay or arrest towards the end of the first year of life. Seizures are infrequent and myoclonus may be seen This disorder (OMIM 239510) results from a deficiency of as only isolated jerks. By contrast, in the late infantile form D1-pyrroline 5-carboxylate dehydrogenase and is character- (NCL type 2), myoclonus and tonic–clonic seizures are early and frequent with onset from 2 to 4 years. Neurophysiology Congenital disorders of protein N-glycosylation features can be very helpful in indicating the diagnoses in More than 13 disorders affecting N-glycosylation have been NCLs, including progressive loss of EEG activity and ERG in described, and the majority affect the CNS. They can present NCL type 1 and abnormal enlarged visual and somatosensory with failure to thrive and multisystem disease in early infancy; evoked potentials and posterior paroxysms triggered by photic hypotonia and seizures can be part of the clinical picture. Sei- zures can be a major presenting feature in an older infant.
Diagnosis rests on assay of enzyme activity (palmitoyl pro- They can be associated with hypotonia and ⁄ or ataxia, suggest- tein thioesterase and tripeptidyl thioesterase) in dried blood ing a diagnosis of cerebral palsy, but additional clinical fea- spots, followed by molecular analysis of the CLN1 and CLN2 tures can point the astute paediatrician to the correct genes. Rare cases are not caused by mutations in these two diagnosis; these include dysmorphic features such as unusual genes, and further investigation will necessitate electron fat pads on the buttocks, inverted nipples, long fingers and microscopic examination of skin or rectal biopsies to search toes, and craniofacial dysmorphic features. Diagnosis of most for characteristic inclusion bodies. If these are demonstrated, of the disorders of protein N-glycosylation can be made by sequence analysis of the CLN5, -6, -7, and -8 genes should be isoelectric focusing of serum transferrin. There is no specific form of treatment for the seizures associated with the disor-ders of N-glycosylation.
GangliosidosesInfants with infantile GM1 gangliosidosis (OMIM 230500) METABOLIC EPILEPSIES OF LATE CHILDHOOD AND are often hypotonic from birth and stop making develop- mental progress at 3 to 6 months of age. Examination will reveal coarsening of facial features, and usually hep- ato(spleno) megaly. Many have a cherry-red spot at the Very few metabolic epilepsies presenting in late childhood and macula, and radiology often shows dysostosis. Seizures are a adolescence are treatable; CoQ10 deficiency (OMIM 607426) major part of the progressive neurological dysfunction. GM2 is a notable exception.60 Late-onset CoQ10 deficiency syn- gangliosidosis (Tay–Sachs disease; OMIM 272800) presents dromes are frequently associated with epilepsy, particularly at 4 to 6 months with motor weakness, hypotonia, and a those caused by mutations in the ADCK3 (CABC1) gene.
typical startle response to sound (auditory myoclonus). Pro- Patients with ADCK3 mutations have a relatively homo- gressive loss of milestones, hypotonia, and visual inattentive- geneous phenotype, with cerebellar ataxia and seizures, and a ness follow. A cherry-red spot is almost always present.
favourable response to exogenous CoQ10 supplementa- Seizures and spasticity characterize the final phase of the ill- tion.72,73 Other patients with CoQ10 deficiency present with ness. Myoclonic seizures are common, and can be massive recurrent rhabdomyolysis and an encephalomyopathy includ- and multiple. Focal, generalized, and occasionally gelastic ing seizures,74 but the genetic basis of this variant of CoQ10 Alpers syndrome and other infantile-onset mitochondrial Alpers syndrome (progressive neuronal degeneration of chil- Progressive myoclonic epilepsies presenting in this age group dhood with liver disease; OMIM 203700) typically presents in include Unverricht–Lundborg disease (Baltic myoclonus; late infancy with intractable seizures, which may initially be OMIM 254800), Lafora body disease (OMIM 254780), and focal and subsequently generalize.70 Epilepsia partialis con- mitochondrial diseases such as MERRF (myoclonic epilepsy tinua and convulsive status epilepticus are common. A charac- with ragged-red fibres; OMIM 545000) syndrome, and disor- teristic and unusual EEG pattern of large-amplitude slow ders related to mutations in the DNA polymerase gamma.
activity with superimposed smaller multispike discharges may Unverricht–Lundborg disease is a Finnish heritage disorder be seen early on and then disappear as the disease progresses.
and occurs in approximately 1 in 20 000 of the Finnish popu- There may be an antecedent history of developmental delay lation. It has also been reported in other ethnic groups in and associated liver dysfunction. The disorder is caused by northern Europe and North America. Affected children are progressive depletion of the mtDNA, as a result of an underly- normal in early childhood, and usually present with clonic or ing recessively inherited defect of mtDNA replication, most tonic–clonic seizures followed by stimulus-sensitive, action- often because of defective DNA polymerase gamma function triggered myoclonus between the ages of 6 and 16 years. Asso- resulting from POLG mutations, although occasionally the ciated clinical problems include ataxia and mild learning diffi- responsible mutations may be in the PEO1 gene encoding the culties. The diagnosis is confirmed by finding mutations in the Twinkle DNA helicase.71 The course is usually rapidly pro- EPM1 gene encoding cystatin B.75 Severity and disease gressive; most affected infants die before the age of 3 years.
progression vary between and within families. The disease is Treatment is supportive. Other mitochondrial disorders pre- associated with severe disability but is not usually life-limiting.
senting with epilepsy in infancy, including maternally inher- Phenytoin is contraindicated in this condition since it may ited Leigh syndrome, have been discussed in detail in a recent Developmental Medicine & Child Neurology 2013, 55: 23–36 Lafora body disease presents in the same age group (6–18y) Type I sialidosis (neuraminidase deficiency; OMIM but is more rapidly progressive. Affected individuals are often 256550) often presents in the second or third decade with pro- bed bound and require almost constant rest, exhibit action- gressive visual handicap with impaired colour vision and ⁄ or triggered myoclonus, and develop severe dementia within 5 to night blindness; a cherry-red spot is typically present at the 10 years of disease onset. Visual seizures may be a feature.
macula. Severe myoclonic epilepsy follows in almost 50% of Convulsive status epilepticus often precipitates death. The cases, leading to the name ‘cherry-red spot myoclonus syn- diagnosis may be suspected by the identification of Lafora drome’. Seizures are often difficult to control.
bodies (polyglucosan inclusion bodies) in neurons in a Niemann–Pick type C (NPC; OMIM 257220) is a disor- full-thickness skin biopsy. Eighty per cent of affected individu- der of lysosomal cholesterol export with secondary accumu- als have mutations in the EPM2A gene encoding laforin, lation of sphingomyelin. Although the disease most often whereas approximately 20% have mutations in NHLRC1, presents in the first 2 years of life, late-onset forms present- encoding malin. No genetic defect is identified in a minority ing with epilepsy (partial, generalized tonic–clonic, and ato- nic seizures) are recognized. Hepatosplenomegaly andvertical supranuclear gaze palsy may provide clues to the underlying diagnosis, which may be tricky to establish.
Several mitochondrial disorders may present with seizures in Abnormal storage cells (sea-blue histiocytes) may be late childhood and adolescence.4 MERRF syndrome is usually observed in the bone marrow and filipin staining of cultured caused by a maternally inherited mtDNA mutation, most often the m.8344A>G mutation in the gene encoding the Approximately 95% of cases have mutations in the NPC1 transfer RNA for lysine. Recessive POLG mutations typically gene and 5% in NPC2. There is no curative treatment for cause Alpers syndrome (see above) or other infantile-onset Niemann–Pick type C but recently a glycosphingolipid syn- mtDNA depletion syndromes, but may also present in adoles- thesis (glucosylceramide synthase) inhibitor was approved for the treatment of this condition, based on evidence from a syndrome. Several acronyms have been coined for these late- randomized controlled trial that showed stabilization ⁄ slow- onset recessive POLG disorders associated with epilepsy, including MIRAS (mitochondrial recessive ataxia syndrome),SCAE (spinocerebellar ataxia with epilepsy; OMIM 607459), and MEMSA (myoclonus, epilepsy, myopathy, sensory ataxia), Alpha methyl-acyl-CoA racemase deficiency can produce a but these probably represent a disease continuum. Patients wide range of neurological problems with onset in childhood with MELAS (mitochondrial encephalomyopathy, lactic or adult life. These include developmental delay, epilepsy, acidosis, stroke-like episodes; OMIM 540000) syndrome typi- acute encephalopathy, tremor, pigmentary retinopathy, hemi- cally present towards the end of the first decade of life with a paresis, spastic paraparesis, peripheral neuropathy, depression, stroke-like episode which may be heralded by focal seizures, headache, and cognitive decline. One female presented at age migrainous headache, and vomiting. Eighty per cent of 13 with epilepsy and a postictal confusional state and had no patients with MELAS have the same genetic cause: the further symptoms for 5 years.77 Elevation of plasma pristanic m.3243A>G mutation in the gene encoding the transfer RNA The differential diagnosis of seizure disorders is extremely In juvenile NCL (Batten’s disease; OMIM 204200), retinopa- wide and includes ion channel disorders (e.g. SCN1A muta- thy is usually the presenting symptom, whilst epilepsy and tions), malformations of cortical development, neurocutane- dementia typically occur late in the disease course. The triad ous syndromes, chromosomal disorders, hypoxic–ischaemic of clinical features (retinopathy, epilepsy, and dementia), encephalopathy, congenital infection, sepsis, and tumours.
together with the presence of vacuolated lymphocytes in the However, certain features in the history and clinical examina- peripheral blood film, may suggest the diagnosis, which is con- tion may lead to suspicion of an underlying inborn error of firmed by mutation analysis of the CLN3 gene. Absence sei- metabolism. These include parental consanguinity, a similarly zures may be more frequent than tonic–clonic seizures.
affected sibling, and a history of in utero ‘hiccoughs’ or ‘flut- Myoclonus particularly affects the face.
tering’ movements, which might represent antenatal seizures.
In subacute ⁄ chronic neuronopathic Gaucher disease (Gau- Seizures occurring after fasting are suggestive of hypoglyca- cher type III; OMIM 231000) neurological symptoms with evidence of systemic disease (e.g. splenomegaly) typically The combination of particular facial features (large fonta- occur at a mean age of 10 years. One neurological phenotype nelle, high forehead, flat occiput, and shallow supraorbital is characterized by progressive myoclonic encephalopathy with ridges) with seizures may raise suspicion of a peroxisomal dis- seizures and dementia. In some cases this is preceded by supra- order, particularly Zellweger syndrome. A macular cherry-red nuclear gaze palsy, and there may be an extrapyramidal move- spot on fundoscopy, or vacuolated lymphocytes in the periph- ment disorder. As in juvenile NCL, facial myoclonus is a eral blood film, indicate a lysosomal storage disorder. In other patients there may be characteristic abnormalities of the skin Table III: Treatment of metabolic epilepsies Pyridoxine 100mg i.v. initial dose followed by 5–10mg ⁄ kg ⁄ d p.o., Pyridoxal 5¢-phosphate 10–30mg ⁄ kg ⁄ d p.o.
Disorders of creatine biosynthesis and transport Creatine 350–500mg ⁄ kg ⁄ d p.o. Arginine restriction in GAMT deficiency (15–25mg ⁄ kg ⁄ d; corresponds to 0.4–0.7 g ⁄ kg ⁄ d protein intake) L-Serine 200–600mg ⁄ kg ⁄ d p.o.; if seizures continue add glycine 200mg ⁄ kg ⁄ d p.o.
CoQ10 10–30mg ⁄ kg ⁄ d p.o. in children; 1200–3000mg ⁄ d in adults Copper injections (early diagnosed cases only) i.v., intravenous; p.o., per os; PNPO, pyridox(am)ine 5¢-phosphate oxidase; GLUT1, glucose transporter across the blood–brain barrier; GAMT,guanidinoacetate methyl transferase; CoQ10, coenzyme Q10; MOCS1, molybdenum cofactor synthesis gene 1.
and ⁄ or hair. For example, in Menkes syndrome defective suggestive but not diagnostic; for example, cystic degeneration keratinization of the hair leads to sparseness and a ‘kinky’ may be observed in SUOX and MoCoF deficiencies. Magnetic appearance caused by the formation of pili torti. Patients with resonance spectroscopy is essential for the diagnosis of the cre- Menkes syndrome also have typical facies and may have con- atine transporter disorder, since urinary levels of creatine nective tissue and bone abnormalities, as well as severe devel- metabolites may be normal in this condition.
opmental delay and epilepsy. Children with biotinidase The mainstay of diagnosis of IEMs is of course biochemical deficiency may present with an eczematous rash, particularly investigation. Metabolites may be assayed in blood, urine, or affecting the periorbital and perioral areas, together with alo- CSF (Table II). Where specific enzyme assays are available, pecia. They may also have optic atrophy and sensorineural these have been described in the appropriate sections above.
hearing loss, particularly if diagnosed late. Multisystem disease Genetic diagnosis is increasingly available for IEMs, and con- features may raise suspicion of a mitochondrial disorder.
stitutes the first line of investigation in rare instances where For example, the combination of steroid-resistant nephrotic there are no characteristic metabolites or diagnostic enzyme syndrome, sensorineural hearing loss, ataxia, and seizures is assay, such as mutation analysis of SLC25A22 for mitochon- drial glutamate transporter deficiency. Increased availability Although neither seizure type nor EEG appearance is specific and ease of genetic testing is leading to expansion of the for particular IEMs, an underlying metabolic disorder should epileptic phenotypes of many of the genetic and indeed the be considered in children with myoclonic seizures, intractable metabolic epilepsies, with GLUT1 and serine disorders being seizures resistant to multiple AEDs, epileptic encephalopathy, and those with a burst suppression EEG pattern. Burst suppres-sion is typically seen early in the disease course in several early- onset metabolic epilepsy syndromes, including non-ketotic hy- Specific treatments, where available, have been described in perglycinaemia, pyridoxine-dependent epilepsy, PNPO defi- the main text above, and are summarized in Table III.
ciency, defects of the mitochondrial glutamate transporterSLC25A22, and SUOX and MoCoF deficiencies, but is also a feature of many non-metabolic epilepsy syndromes. In Alpers IEMs are a relatively rare cause of epilepsy, but their recogni- syndrome there may initially be characteristic EEG changes tion and diagnosis is important because several disorders are (rhythmic high-amplitude delta waves with superimposed treatable, often with simple therapies such as vitamins. Prompt [poly]spikes over parieto-occipital regions), but later in the dis- treatment can affect long-term neurological outcome, there- ease course EEG abnormalities tend to generalize.70 fore diagnosis should not be delayed. Associated clinical, bio- Brain MRI usually reveals non-specific changes only. How- chemical, and imaging features may provide clues to the ever, in occasional cases, brain MRI may be diagnostic: for example, children with pontocerebellar hypoplasia visible onMRI that is associated with intractable seizures and develop- mental stasis may have RARS2 mutations, a disorder of mito- SR, EJF, and PTC are all supported by Great Ormond Street chondrial translation.42 In other conditions MRI may be Developmental Medicine & Child Neurology 2013, 55: 23–36 in Man (http://www.omim.org) for further information. OMIM num- It has not been possible to provide a detailed discussion of all the met- bers have been indicated throughout the text. Further information abolic epilepsies mentioned in this review, owing to space constraints; may also be found in The Online Metabolic and Molecular Bases of the reader is referred to the database Online Mendelian Inheritance Inherited Diseases (http://www.ommbid.com).
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