Review
Occasional seizures, epilepsy, and inborn errors of metabolism Olivier Dulac, Barbara Plecko, Svetlana Gataullina, Nicole I Wolf
Seizures are a common paediatric problem, with inborn errors of metabolism being a rare underlying aetiology. The clinical presentation of inborn errors of metabolism is often associated with other neurological symptoms, such as hypotonia, movement disorders, and cognitive disturbances. However, the occurrence of epilepsy associated with inborn errors of metabolism represents a major challenge that needs to be identified quickly; for some cases, specific treatments are available, metabolic decompensation might be avoided, and accurate counselling can be given about recurrence risk. Some clinical presentations are more likely than others to point to an inborn error of metabolism as the cause of seizures. Knowledge of important findings at examination, and appropriate biochemical investigation of children with seizures of uncertain cause, can aid the diagnosis of an inborn error of metabolism and ascertain whether or not the seizures are amenable to specific metabolic treatment.
Introduction By contrast with the frequency of epilepsy in the general population, epilepsy due to inborn errors of metabolism (IEMs) is rare. Nevertheless, IEMs become an important differential diagnosis in children with therapy-resistant epileptic encephalopathy (panel 1). There are various circumstances in which IEMs can cause seizures: systemic illness with or without acute decompensation; neurometabolic disorders restricted to the brain; and seizures as an epiphenomenon of a metabolic, and most probably neurodegenerative, disorder. Seizures can be symptoms of and drastically change the course of many mitochondrial disorders.1 Among the various mechanisms of seizure generation in IEMs, the main causes are acute or chronic cerebral energy failure; acute or chronic toxic effects of accumulating metabolites; impaired neuronal function, including disturbance of neurotransmitter synthesis; associated brain malformations; and vitamin or cofactor dependency, including vitamin transporter defects (table 1).2 Seizures can result from acute metabolic decompensation—eg, hypoglycaemia or hyperammonaemia—which responds promptly to specific treatment, particularly in the neonatal period; they can also result from intermittent crises in previously healthy children and adolescents. Primary manifestation as status epilepticus can be a major challenge (eg, in pyridoxine-dependent epilepsy or thiamine transporter defect; panel 2). In these cases, urgent diagnostic workup is crucial because some of these disorders can be treated with cofactors or diets, which are most efficient if started early. The presentation as a particular epilepsy syndrome might already provide a diagnostic hint to identify the precise IEM. Imaging findings sometimes suggest a particular IEM, as is the case with molybdenum cofactor deficiency or Alpers’ disease, but more often will show non-specific changes (eg, hypoplastic corpus callosum, delayed myelination, or global brain atrophy), and normal brain structure and development do not exclude an IEM. Some IEMs, especially those presenting in the neonatal period, need specific therapeutic interventions (eg, vitamin supplementation) even before the diagnosis of an IEM has been established. Even in untreatable disorders, correct and early diagnosis provides information about www.thelancet.com/neurology Vol 13 July 2014
prognosis in addition to genetic background, and prevents unnecessary investigations. Because the biochemistry, epidemiology, and treatment of inherited metabolic diseases have been described elsewhere,3–5 we will not address these aspects in detail. Rather, the focus of this Review is to provide clinical clues and diagnostic strategies for the diagnosis of IEMs in epileptic encephalopathies, which will help to guide clinicians through the challenging complexity of seizures caused by IEMs by focusing on age at onset (table 2). Accordingly, we categorise IEMs according to seizure type, age of onset, and electroencephalogram (EEG) pattern. However, the occurrence of seizures within these criteria is not exclusively due to IEMs, and full symptombased differential diagnosis should be considered.
Lancet Neurol 2014; 13: 727–39 Paris Descartes University, Inserm U1129 (Prof O Dulac MD) and Inserm U1129 (S Gataullina MD), Paris, France; CEA, Gif-sur-Yvette, France (O Dulac); Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP–HP, Paris, France (O Dulac); Department of Child Neurology, University Children’s Hospital, University of Zurich, Switzerland (Prof B Plecko MD); Department of Child Neurology, VU University Medical Center, Amsterdam, Netherlands (N I Wolf MD); and Neuroscience Campus Amsterdam, Amsterdam, Netherlands (N I Wolf) Correspondence to: Prof Olivier Dulac, Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP–HP, 75015 Paris, France [email protected]
Panel 1: Summary Simple laboratory tests for IEMs include glucose, capillary blood gas analysis, lactate (plasma and CSF), ammonia, and CSF glucose (in glucose transporter-1 deficiency syndrome, the ratio of CSF glucose to blood glucose is less than 0·5). Megaloblastic anaemia can suggest a defect in folate or B12 metabolism. A diagnostic vitamin trial with pyridoxine, 30 mg/kg per day in 2 single dosages over 3 consecutive days is recommended in neonates with therapy-resistant seizures. If ineffective, pyridoxine should be replaced by pyridoxal 5ʹ-phosphate 30–50 mg/kg per day in four to six single dosages (unlicensed compound for oral use) at the discretion of the treating physician. Brain imaging is recommended but might show unspecific findings or could even be normal in many IEM cases. Polymicrogyria with neonatal hypotonia and focal motor seizures suggest a peroxisomal disorder. Non-ketotic hyperglycinaemia and antiquitin deficiency can show hypoplasia of the corpus callosum. Signal abnormalities in the striatum, thalamus, and multifocal cortical areas fit with thiamine transporter deficiency or mitochondrial disease. Hypomyelination occurs in defects of serine biosynthesis and folate receptor 1 deficiency. Proton magnetic resonance spectroscopy is useful for the diagnosis of the creatine deficiency syndromes; presence of a lactate peak suggests mitochondrial disorders but is not obligate (eg, as in Alpers’ disease). Ultrastructural analysis of a skin biopsy might be needed if a rare subtype of the neuronal ceroid lipofuscinoses is suspected. Light and electron microscopic examination of skeletal muscle or liver is used if a mitochondrial disorder is suspected, always together with biochemical analysis of the respiratory chain, preferably in fresh muscle. Nevertheless, biopsies of skin, liver, or muscle are not part of the routine diagnostic process. Preservation of DNA or fibroblasts should be considered in children with a degenerative course of unclear pathophysiology to enable testing of new genes in the future. IEMs=inborn errors of metabolism.
727
Review
Aetiology Energy deficiency
Hypoglycaemia, glucose transporter-1 deficiency, respiratory chain deficiency, pyruvate dehydrogenase deficiency, Krebs cycle defects, creatine deficiencies
Toxic effect
Aminoacidopathies, organic acidurias, urea cycle defects, molybdenum cofactor deficiency, sulphite oxidase deficiency
Impaired neuronal function
Storage disorders
Disturbance of neurotransmitter systems
Non-ketotic hyperglycinaemia, atypical phenylketonuria, GABA transaminase deficiency, succinic semialdehyde dehydrogenase deficiency
Associated brain malformations
Peroxisomal disorders (Zellweger syndrome), respiratory chain deficiency, pyruvate dehydrogenase deficiency, O-glycosylation defects (congenital muscular dystrophies)
Vitamin or cofactor dependency and vitamin transporter defects
Biotinidase deficiency, pyridoxine-dependent and pyridoxal 5ʹ-phosphatedependent epilepsy (folinic-acid-responsive seizures), thiamine transporter deficiency, Menkes’ disease, folate transporter defect (FOLR1), dihydrofolate reductase deficiency
Miscellaneous
Serine biosynthesis deficiency
Table 1: Epilepsies of metabolic origin according to their pathogenesis
Panel 2: Convulsive status epilepticus in the context of IEM In neonates, status epilepticus can be caused by systemic metabolic decompensation as hypoglycaemia or hyperammonaemia, IEMs as in pyridoxine-dependent epilepsy or pyridox(am)ine 5ʹ-phosphate oxidase deficiency, and peroxisomal disorders. Beyond the neonatal phase, focal clonic status epilepticus is often triggered by a febrile episode and can suggest Menkes’ disease, dihydropyrimidinase deficiency (unpublished data), and pyridoxine-dependent epilepsy. Convulsive status epilepticus is also a feature of 2-methyl3-hydroxybutyryl-CoA dehydrogenase deficiency. Clonic and myoclonic status epilepticus can be a late feature in late-infantile neuronal ceroid lipofucinosis. Alpers’ disease can present with refractory status epilepticus in previously healthy children aged 3–10 years and adolescents. In MELAS, status epilepticus can accompany stroke-like episodes, and is often subtle or “non-convulsive” with visual aura or impaired consciousness. It especially affects posterior and temporal regions. Myoclonic status epilepticus may complicate MERRF, other mitochondrial encephalopathies, and guanidinoacetate methyltransferase deficiency. Treatment of status epilepticus remains challenging. Pyridoxine and pyridoxal 5ʹ-phosphate dependent seizures usually respond to administration of these cofactors. Non-convulsive or myoclonic status epilepticus in guanidinoacetate methyltransferase deficiency drastically improves with creatine and ornithine supplementation. When specific therapy is not available, local guidelines and experience are followed with one exception—use of valproic acid is avoided if Alpers’ disease is suspected, to prevent hepatic failure. Possible treatment strategies are continuous midazolam, magnesium, clobazam, levetiracetam, topiramate, lamotrigine, and ketogenic diet. In refractory status epilepticus related to MELAS, intravenous administration of arginine or citrulline may be helpful. IEMs=inborn errors of metabolism. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MERRF=myoclonic epilepsy with ragged red fibres.
Occasional seizures Occasional seizures—seizures triggered by intermittent factors—can be the first manifestation of a systemic IEM that causes hyperammonaemia or hypoglycaemia. Such seizures can occur at any age, although neonates are at particular risk. In urea-cycle disorders, neurological signs mainly consist of altered consciousness in the neonatal period and can be combined with movement disorders and hallucinations in childhood, whereas seizures usually occur along with severe metabolic decompensation.6 728
Hypoglycaemia in the neonatal period, mostly resulting from hyperinsulinism or defects of fatty acid β oxidation and ketone-body metabolism, can trigger seizures or even status epilepticus when combined with cardiocirculatory failure or fever.7 MRI shows predominantly occipital subcortical white matter involvement, occasionally extending to the cortex. Status epilepticus with severe hypoglycaemia can be unilateral,8 and can be followed by severe sequelae including psychomotor delay and pharmacoresistant epilepsy.9,10 Recurrent occasional seizures are triggered by fever, and pharmacoresistant epilepsy can consist of infantile spasms or be focal (Gataullina S, unpublished). Basal ganglia or focal cortical areas are also affected, with the topography of these lesions mainly associated with the age at injury (figure 1).11 Fever can be a trigger in the manifestation of IEMs, because it can suggest late-onset pyridoxine-dependent epilepsy11 or enable decompensation of an IEM causing energy depletion, including defects of fatty acid oxidation, Menkes’ disease, and mitochondrial defects. Febrile seizures in this case are lengthy and often focal.
Epilepsy as an epiphenomenon IEMs affecting brain metabolism are likely to be complicated by epilepsy during the course of the disease, whichever structure is the most affected structure, including white matter and basal ganglia. However, in many IEMs, epileptic seizures are infrequent, nonspecific, or delayed events, occurring after the diagnosis has been established and other neurological signs or typical findings at neuroimaging can already be present. In this context, seizures might not give clues to the pathophysiology of epilepsy or to the metabolic disease itself, which is the case in various disorders including storage disorders and aminoacidopathies.
Epilepsy as the first and main expression: presentation according to age Neonatal period Early myoclonic epileptic encephalopathy starts during the very first weeks of life or even prenatally, consisting of 1–3 s volleys of myoclonic jerks corresponding to bursts of polyspikes on EEG, alternating with total inactivity of the body during EEG suppression. The pattern is therefore distinct from that of spasms in clusters occurring later in life. In addition to this suppression–burst pattern, EEG eventually records focal discharges.12,13 Consideration of a treatable IEM is mandatory, and diagnostic trials in addition to respective biochemical investigations should be done without delay. The main metabolic causes identified so far are non-ketotic hyperglycinaemia (figure 2),14 pyridoxine-dependent epilepsy15,16 (figure 2) due to mutations in ALDH7A1 that codes for antiquitine,17 pyridox(am)ine 5ʹ-phosphate oxidase deficiency due to mutations in PNPO,18 sulphite oxidase deficiency and molybdenum cofactor deficiency, congenital lack of glutamate transporter,19 and mitochondrial disorders.1 www.thelancet.com/neurology Vol 13 July 2014
Review
In most of these disorders, there is an excess of NMDA neurotransmission, in which glycine is a coneurotransmitter.20 High glycine concentration due to nonketotic hyperglycinaemia and high sulphite concentration due to deficiency of sulphite oxidase or molybdenum cofactor alter the kinetics of the two main subunits of the NMDA receptor (NR2A and NR2B) and increase the risk of pathological synchronisation of neuron firing leading to epilepsy.21 In pyridoxine-dependent epilepsy due to loss of ALDH7A and in pyridox(am)ine 5ʹ-phosphate oxidase deficiency, decreased activity of pyridoxal 5ʹ-phosphatedependent enzymes lead to an excess of glutamate, lack of GABA, changes in the synthesis of biogenic amines, and alterations in cerebral aminoacid metabolism. In very young rats, the electroclinical pattern of neonatal encephalopathy with suppression bursts can be reproduced by inhibition of glutamate transporters that normally reuptake glutamate from the synaptic cleft into astrocytes and neurones.22,23 Therefore, excessive activation of NMDA neurotransmission seems to be the common denominator of IEMs that produce neonatal encephalopathy with suppression bursts. The signs of non-ketotic hyperglycinaemia are hypotonia, apnoea and chronic hiccup, and erratic myoclonus that might be overlooked because of the severity of the hypotonia. In pyridoxine-dependent epilepsy, patients can show poor adaptation to extrauterine life that raises the suspicion of hypoxic–ischaemic encephalopathy (ie, meconium-stained amniotic fluid and early-onset seizures), but myoclonic jerks and convulsions occur within a few hours of birth, or even earlier, in conjunction with abnormal movements, including tremor, sleeplessness, and high-pitched cry.15 The identification of α-aminoadipic semialdehyde in urine and—less specific— elevation of pipecolic acid concentration in plasma, suggests the diagnosis of pyridoxine dependent epilepsy due to mutations in ALDH7A1, even if the patient is on pyridoxine.18,24,25 Pyridox(am)ine 5ʹ-phosphate oxidase deficiency lacks a specific biomarker, because changes in neurotransmitter metabolism and elevated excretion of vanillactate in urine are inconstant findings. In isolated sulphite oxidase deficiency and molybdenum cofactor deficiency, diffuse oedema followed by extensive necrosis of grey and white matter on brain MRI suggests the diagnosis.26 Molybdenum cofactor is endogenously synthesised and catalyses the action of sulphite oxidase, xanthin dehydrogenase, and aldehyde oxidase. As shown in isolated sulphite oxidase deficiency, the epilepsy phenotype is caused by accumulating sulphite due to impaired degradation of the sulphur-containing aminoacid cysteine. A low toxicity threshold for accumulating sulphite around the time of birth makes early diagnosis crucial. Increased sulphite levels also inhibit α-aminoadipic semialdehyde dehydrogenase, leading to accumulation of the enzyme and seizures partly responding to pyridoxine.27 The sulphite dipstick test is an easy bedside test of fresh urine, but can give false-negative results; therefore, www.thelancet.com/neurology Vol 13 July 2014
determination of urinary sulphocysteine remains the gold standard. Another IEM presenting with myoclonic jerks is holocarboxylase deficiency. This organoaciduria leads to impaired breakdown of aminoacids, pyruvate, and lipids, and in neonates is always accompanied by acute metabolic acidosis and encephalopathy. Less specific patterns of neonatal seizures can result from rarer IEMs, including other organic acidurias diagnosed by urinary chromatography and peroxisomal disorders such as Zellweger syndrome and neonatal adrenoleukodystrophy, which can be diagnosed by Aetiology Neonatal period
Hypoglycaemia, urea cycle defects, pyridoxine-dependent epilepsy (including folinic-acidresponsive seizures), pyridox(am)ine 5 -phosphate deficiency, non-ketotic hyperglycinaemia, holocarboxylase synthase deficiency, molybdenum cofactor deficiency, sulphite oxidase deficiency, organic acidurias, Zellweger syndrome, neonatal adrenoleukodystrophy, adenylosuccinate lyase deficiency, dihydrofolate reductase deficiency
Infancy
Sequelae of severe hypoglycaemia, glucose transporter-1 deficiency, creatine deficiency, biotinidase deficiency, aminoacidopathies, organic acidurias, congenital disorders of glycosylation, pyridoxine-dependent epilepsy, infantile neuronal ceroid lipofuscinosis (CLN1), folate and thiamine transporter deficiencies, peroxisomal disorders, Menkes’ disease
Toddlers
Late infantile neuronal ceroid lipofuscinosis (CLN2), mitochondrial disorders including Alpers’ disease, lysosomal storage disorders, thiamine transporter deficiency, folate transporter deficiency
School age Mitochondrial disorders, juvenile form of neuronal ceroid lipofuscinosis (CLN3), progressive myoclonic encephalopathies, lysosomal storage disorders, thiamine transporter deficiency, and adolescence Lafora’s disease, Gaucher’s disease, and Niemann-Pick type C disease Table 2: Epilepsies of metabolic origin according to most frequent age at onset
A
B
C
D
E
F
Figure 1: Severe hypoglycaemia and its sequelae Axial T2-weighted (A) and diffusion-weighted (B) images of a neonate with convulsions due to congenital hyperinsulinism, showing hyperintense signal of the posterior white matter and the splenium and ill-defined occipital and parietal cortex. These areas also show decreased diffusion. Axial T2-weighted image (C) showing basal ganglia damage following severe infantile hypoglycaemia at 9 months of age. Axial T2-weighted (D) and diffusion-weighted (E) images showing multifocal cortical oedema after severe hypoglycaemia and status epilepticus in a 14-month-old infant with congenital ACTH deficiency. An axial T2-weighted image (F) of an 18-year-old woman with recent manifestation of occipital lobe epilepsy. The occipital glioses are secondary to neonatal hypoglycaemia due to congenital hyperinsulinism. ACTH=adrenocorticotropic hormone.
729
Review
A
B
C
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 O2-O1 ECG THO_ EMG1 EMG2
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
20μV/mm 1 sec
30μV/mm 1 sec
D
E
F
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
FP2-C4 C4-O2 FP2-F8 F8-T6 T6-O2 FP1-C3 C3-O1 FP1-F7 F7-T5 T5-O1 PZ-O2 PZ-O1 EM1 EM2
FP2-C4
10μV/mm 1 sec
1 sec
C4-O2 F8-T6 T6-O2 FP1-C3 C3-O1 F7-T5 20μV/mm
G
H
I
FP2-C4
Fp1-F7 F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fz-Cz Cz-Pz Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 EKG
C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 ECG RESP 20μV/mm 1 sec
1 sec
15μV/mm
T5-O1
1 sec
FP2-C4 FP1-C3 C4-O2 C3-O1 F8-T6 F7-T5 F8-C4 C4-C3 C3-F7 T6-O2 O2-O1 O1-T5 ECG THO_ EMG1 EMG2 SLI
10μV/mm
20μV/mm
1 sec
1 sec
70μV
Figure 2: EEG in IEM according to aetiology (A) Interictal EEG in a 15-day-old baby with non-ketotic hyperglycinaemia, showing the characteristic suppression–bursts sequence (bursts of high-amplitude diffuse polyspikes separated by episodes of flat tracing). (B–D) EEG from a 3-month-old baby with pyridoxine-dependent epilepsy. (B) Epileptic spasms in clusters with high-amplitude slow complex and rhythmic waves. (C) High-amplitude rhythmic spike–waves predominate on the left hemisphere during a right clonic seizure. (D) After pyridoxine intravenous injection (100 mg), EEG shows flattening of the tracing. (E) Myoclonic status epilepticus in a 6-year-old girl with guanidinoacetate methyltransferase deficiency. Diffuse high-voltage spikes and spike–waves predominating on frontal or frontal-central areas; myoclonic jerks recorded on deltoid electromyography. (F) Atypical absence in an 11-year-old girl with glucose transporter-1 deficiency, with diffuse high-amplitude spike–waves. (G) Diffuse spikes, predominating on occipital areas triggered by slow photic stimulation in a 5-year-old girl with late-infantile neuronal ceroid lipofuscinosis. (H) 3-year-old girl with Alpers’ disease due to POLG1 mutations. Interictal EEG shows bilateral high-amplitude periodic sharp waves and spike–waves with left occipital predominance. (I) 16-year-old girl with MELAS and the classic mitochondrial 3243A→G mutation. EEG shows spike and spike–waves rhythmic discharges over the left posterior region, corresponding to the occipital area of hyperintense T2 signal. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
analysing very-long-chain fatty acids. Adenylosuccinate lyase deficiency28 produces encephalopathy with epilepsy, substantial psychomotor delay, and hypotonia followed (sometimes after years) by spasticity. The diagnosis of adenylosuccinate lyase deficiency is based on detection of succinyladenosine and succinylaminoimidazole carboxamide ribotide in the urine and CSF. MRI shows lack of or delayed myelination of cerebral white matter, with cerebellar atrophy.29 In dihydrofolate reductase deficiency, rapidly progressive microcephaly is combined with megaloblastic anaemia, pancytopenia, and convulsive seizures during early life.30
Infancy Complex febrile seizures that are focal, lengthy, and sometimes are followed by postictal paresis can be the 730
first expression of type II hyperprolinaemia,11 which results from δ-1-pyrroline-5-carboxylate dehydrogenase deficiency due to mutations in the mitochondrial ALDH4A1. δ-1-pyrroline-5-carboxylate forms a complex with and inactivates pyridoxal 5ʹ-phosphate, leading to secondary cerebral pyridoxal 5ʹ-phosphate deficiency. Pyridoxine supplementation prevents seizure recurrence, although many patients with type II hyperprolinaemia also respond to common anticonvulsants such as valproic acid and thus remain undiagnosed.31 Infantile spasms are the combination of spasms in clusters and hypsarrhythmia. Rarely, they are the expression of an IEM, although a whole range of disorders can be involved (table 3). Their occurrence after complex febrile seizures can be a diagnostic clue for some IEMs. www.thelancet.com/neurology Vol 13 July 2014
Review
Of the three IEMs that cause creatine deficiency, guanidinoacetate methyltransferase deficiency and X-linked creatine transporter deficiency can cause infantile spasms, whereas L-arginine:glycine amidinotransferase deficiency has a mild epilepsy phenotype with occasional febrile seizures.32 The hallmark of all three disorders is the absence of cerebral creatine, which can be readily visualised by proton magnetic resonance spectroscopy (figure 3). Febrile seizures can occur, and are often the first paroxysmal expression. Measurement of guanidinoacetate
Plasma
concentrations (high in guanidinoacetate methyltransferase deficiency, low to normal in L-arginine:glycine amidinotransferase deficiency, and normal in X-linked creatine transporter deficiency) and creatine (low in guanidinoacetate methyltransferase deficiency, low to normal in L-arginine:glycine amidinotransferase deficiency, and high in X-linked creatine transporter deficiency) in plasma and urine enables biochemical confirmation. In guanidinoacetate methyltransferase deficiency, virtually all untreated patients develop epilepsy
Urine
CSF
Others
Myoclonic encephalopathy with suppression bursts Pyridoxine-dependent epilepsy
Pipecolic acid
α-aminoadipic semialdehyde
Pipecolic acid, α-aminoadipic semialdehyde Low PLP in CSF
PNPO deficiency
··
Vanillactate
Neurotransmitters*
Low PLP in CSF
Non-ketotic hyperglycinaemia
Aminoacids
Aminoacids
Aminoacids
CSF:plasma glycine ratio
Biotinidase deficiency
Biotinidase activity
Organic acids
··
··
Phenylketonuria
Aminoacids
··
··
··
Atypical phenylketonuria
Aminoacids
··
Neurotransmitters, pterins
··
Serine deficiency
··
··
Aminoacids
··
Menkes’ disease
Copper, coeruloplasmin
··
··
··
GAMT deficiency
Guanidinoacetate
··
··
··
Zellweger syndrome
Very-long-chain fatty acids ··
··
··
Mitochondriopathies
Lactate
··
Lactate
··
PDH deficiency
Lactate
··
Lactate, pyruvate
··
Biotinidase deficiency
Biotinidase activity
Organic acids
··
··
Mitochondriopathies
Lactate
··
Lactate
··
Niemann-Pick type C
Oxysterols
··
··
Filipin staining in fibroblasts
Late-infantile NCL
··
··
··
Enzymatic and genetic analysis
MERRF
Lactate
··
Lactate
mtDNA testing
MELAS
Lactate
··
Lactate
mtDNA testing
Sialidosis
··
Sialic acid
··
Enzymatic testing
Gaucher’s disease
··
··
··
Enzymatic testing
Unverricht-Lundborg disease
··
··
··
Genetic testing
Lafora’s disease
··
··
··
Genetic testing, Lafora bodies
Infantile spasms
Myoclonic epilepsy
Progressive myoclonus epilepsies
Epilepsy with generalised tonic–clonic seizures GLUT1 deficiency
Glucose
··
Glucose
CSF:plasma glucose ratio
Mitochondriopathies
Lactate
··
Lactate
··
Juvenile NCL
··
··
··
Lymphocyte vacuoles, genetic testing
Epilepsy with multiple generalised seizure types GLUT1 deficiency
··
··
Glucose
CSF:plasma glucose ratio
Creatine deficiency
Guanidinoacetate (GAMT deficiency)
Creatine or creatinin (creatine transporter deficiency)
··
Low creatine in MRS
Atypical phenylketonuria
Aminoacids
··
Aminoacids, pterines
··
FOLR1 deficiency
··
··
Methyltetrahydrofolate
··
Dihydrofolate reductase deficiency
··
··
Methyltetrahydrofolate
Megaloblastic anaemia
··
··
··
Genetic testing
Epilepsia partialis continua Alpers’ disease
PNPO=pyridox(am)ine 5ʹ-phosphate oxidase. PLP=pyridoxal 5ʹ-phosphate. GAMT=guanidinoacetate N-methyltransferase. PDH=pyruvate dehyrogenase. NCL=neuronal ceroid lipofuscinosis. MERRF=myoclonic epilepsy with ragged red fibres. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MRS=magnetic resonance spectroscopy. FOLR1=folate receptor 1.
Table 3: Biomarkers of epilepsy and epilepsy syndromes due to inborn errors of metabolism
www.thelancet.com/neurology Vol 13 July 2014
731
Review
that starts in infancy with infantile spasms or tonic and tonic–clonic seizures (sometimes with severe cyanosis), which is refractory to treatment with antiepileptic medication. Non-convulsive status epilepticus and myoclonic and atonic seizures can occur in childhood (figure 2). Moderate to severe mental retardation is present in children and adults. Patients with X-linked creatine transporter deficiency usually come to attention because of developmental delay or intellectual disability before the occurrence of epilepsy and can subsequently develop several types of seizures.33 Unilateral clonic and often febrile status epilepticus in infancy can be the first manifestation of Menkes’ disease, occurring before the infantile spasms that are usually a major component in the disease course.34 This X-linked disorder is due to mutations in ATP7A, which encodes a transmembrane copper-transporting ATPase, interfering with energy production. Elevated lactate concentrations in plasma can lead to misdiagnosis of a mitochondrial disorder before the appearance of characteristic kinky hair. Phenylketonuria is easily overlooked in a child who has migrated from a country where neonatal screening is not established. The characteristic musty odour, discoloured hair, developmental delay, and delayed white matter maturation on MRI can be clues to phenylketonuria. Atypical phenylketonuria due to disturbed synthesis of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase and tyrosine hydroxylase, can in some patients not be picked up by high phenylalanine concentrations in newborn screening and warrants the additional analysis of pterins and biogenic amines in CSF. In atypical phenylketonuria (eg, dihydropteridin reductase deficiency) the clinical picture is dominated by a movement disorder, such as infantile parkinsonism or bradykinesia, hypotonia, and temperature dysregulation. Mitochondrial disorders can also cause infantile spasms. The most prevalent disease is Leigh syndrome, either due to the classic neuropathy, ataxia, and retinitis pigmentosa mutation in mitochondrial MT-ATP6 or secondary to mutations in nuclear genes or to pyruvate dehydrogenase complex deficiency.35,36 MRI findings include symmetrical basal ganglia lesions in Leigh syndrome, or corpus A
4
B
3
2
1
0
Figure 3: Guanidinoacetate methyltransferase deficiency Axial T1-weighted MRI without abnormalities showing the voxel in the occipital grey matter, in which proton magnetic resonance spectroscopy was done in a healthy child (A) and a 3-year-old girl with guanidinoacetate methyltransferase deficiency (B). The missing creatine peak should be higher than the choline peak. The large peak corresponds to N-acetylaspartylacetate.
732
callosum agenesis in pyruvate dehydrogenase complex deficiency and mitochondrial disorders.37 Skin, liver, or muscle biopsies for the investigation of oxidative phosphorylation can allocate the biochemical defect38,39 but, in the future, molecular analysis might become an easier and non-invasive way to diagnose mitochondrial disorders. An extremely floppy infant with infantile spasms could have a peroxisomal disorder. Additional clues including dysmorphic features (a high forehead and large anterior fontanelle), hepatomegaly, and peripheral neuropathy are often present. Focal seizures, originating in the areas of polymicrogyria, are usually present, and episodes of difficult-to-treat focal status epilepticus are common.2 The combination of developmental delay, epilepsy, and neonatal diabetes (DEND) is typical of DEND syndrome, caused by de-novo mutations in KCNJ11, which encodes the potassium channel Kir6.2. This syndrome is often mistaken for a metabolic disease because of the combination of early-onset diabetes, but it is not technically an IEM because the associated encephalopathy is a direct consequence of the channelopathy. Infantile spasms or tonic seizures are likely to be mediated by way of impaired potassium channel function; indeed, tolbutamide, a modulator of Kir6.2, has some effect on both diabetes and epilepsy.40,41 In most IEMs leading to infantile spasms, there is dysfunction or extensive lesions of the basal ganglia, often accompanied by cortical impairment. This finding led to basal ganglia being considered as the effectors of spasms.42 In the context of IEMs, response to treatment depends on the extent of brain dysfunction or lesions; infantile spasms mainly due to basal ganglia involvement (eg, dihydropteridine reductase deficiency43 or Leigh syndrome due to the mitochondrial MT-ATP6, 8993T→G/C mutation44 ) are more likely to be responsive to treatment than are those in which there is additional cortical dysfunction (eg, Menkes’ disease).34 The clinical course of mitochondrial disorders can vary from pharmacosensitive infantile spasms to intractable epilepsy leading to death.45 A few patients with serine synthesis deficiency, an autosomal recessive disease with congenital microcephaly and hypomyelination, have also been reported to exhibit infantile spasms.46 By contrast with myoclonic epilepsy that occurs in adolescence, myoclonic epilepsy that occurs in early infancy, even in parallel with psychomotor regression, usually does not suggest an IEM.47 The only reversible disorder (provided the diagnosis is done early and proper treatment is given) is biotinidase deficiency, which presents at 3 or 4 months of age with myoclonus after tachypnoea due to lactic acidosis, and is often preceded by alopecia and perioral dermatitis.48,49 Partial seizures in infancy can result from glucose transporter-1 deficiency.50 This deficiency manifests at the blood–brain barrier and is caused by dominant mutations in SLC2A1, which encodes the solute carrier family 2, facilitated glucose transporter member 1 protein. Most www.thelancet.com/neurology Vol 13 July 2014
Review
mutations of the SLC2A1 gene (>90%) occur de novo. More than 150 patients with glucose transporter-1 deficiency have been reported.51,52 Although seizures usually start in infancy with complex partial and convulsive seizures, the cause is often not recognised before global developmental delay and seizures triggered by fasting become apparent during childhood. About 50% of patients develop secondary microcephaly.51 Slow EEG activity on fasting might be a diagnostic clue. Virtually all patients in whom glucose transporter-1 deficiency was suspected had low CSF glucose concentrations (
Occasional seizures, epilepsy, and inborn errors of metabolism Olivier Dulac, Barbara Plecko, Svetlana Gataullina, Nicole I Wolf
Seizures are a common paediatric problem, with inborn errors of metabolism being a rare underlying aetiology. The clinical presentation of inborn errors of metabolism is often associated with other neurological symptoms, such as hypotonia, movement disorders, and cognitive disturbances. However, the occurrence of epilepsy associated with inborn errors of metabolism represents a major challenge that needs to be identified quickly; for some cases, specific treatments are available, metabolic decompensation might be avoided, and accurate counselling can be given about recurrence risk. Some clinical presentations are more likely than others to point to an inborn error of metabolism as the cause of seizures. Knowledge of important findings at examination, and appropriate biochemical investigation of children with seizures of uncertain cause, can aid the diagnosis of an inborn error of metabolism and ascertain whether or not the seizures are amenable to specific metabolic treatment.
Introduction By contrast with the frequency of epilepsy in the general population, epilepsy due to inborn errors of metabolism (IEMs) is rare. Nevertheless, IEMs become an important differential diagnosis in children with therapy-resistant epileptic encephalopathy (panel 1). There are various circumstances in which IEMs can cause seizures: systemic illness with or without acute decompensation; neurometabolic disorders restricted to the brain; and seizures as an epiphenomenon of a metabolic, and most probably neurodegenerative, disorder. Seizures can be symptoms of and drastically change the course of many mitochondrial disorders.1 Among the various mechanisms of seizure generation in IEMs, the main causes are acute or chronic cerebral energy failure; acute or chronic toxic effects of accumulating metabolites; impaired neuronal function, including disturbance of neurotransmitter synthesis; associated brain malformations; and vitamin or cofactor dependency, including vitamin transporter defects (table 1).2 Seizures can result from acute metabolic decompensation—eg, hypoglycaemia or hyperammonaemia—which responds promptly to specific treatment, particularly in the neonatal period; they can also result from intermittent crises in previously healthy children and adolescents. Primary manifestation as status epilepticus can be a major challenge (eg, in pyridoxine-dependent epilepsy or thiamine transporter defect; panel 2). In these cases, urgent diagnostic workup is crucial because some of these disorders can be treated with cofactors or diets, which are most efficient if started early. The presentation as a particular epilepsy syndrome might already provide a diagnostic hint to identify the precise IEM. Imaging findings sometimes suggest a particular IEM, as is the case with molybdenum cofactor deficiency or Alpers’ disease, but more often will show non-specific changes (eg, hypoplastic corpus callosum, delayed myelination, or global brain atrophy), and normal brain structure and development do not exclude an IEM. Some IEMs, especially those presenting in the neonatal period, need specific therapeutic interventions (eg, vitamin supplementation) even before the diagnosis of an IEM has been established. Even in untreatable disorders, correct and early diagnosis provides information about www.thelancet.com/neurology Vol 13 July 2014
prognosis in addition to genetic background, and prevents unnecessary investigations. Because the biochemistry, epidemiology, and treatment of inherited metabolic diseases have been described elsewhere,3–5 we will not address these aspects in detail. Rather, the focus of this Review is to provide clinical clues and diagnostic strategies for the diagnosis of IEMs in epileptic encephalopathies, which will help to guide clinicians through the challenging complexity of seizures caused by IEMs by focusing on age at onset (table 2). Accordingly, we categorise IEMs according to seizure type, age of onset, and electroencephalogram (EEG) pattern. However, the occurrence of seizures within these criteria is not exclusively due to IEMs, and full symptombased differential diagnosis should be considered.
Lancet Neurol 2014; 13: 727–39 Paris Descartes University, Inserm U1129 (Prof O Dulac MD) and Inserm U1129 (S Gataullina MD), Paris, France; CEA, Gif-sur-Yvette, France (O Dulac); Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP–HP, Paris, France (O Dulac); Department of Child Neurology, University Children’s Hospital, University of Zurich, Switzerland (Prof B Plecko MD); Department of Child Neurology, VU University Medical Center, Amsterdam, Netherlands (N I Wolf MD); and Neuroscience Campus Amsterdam, Amsterdam, Netherlands (N I Wolf) Correspondence to: Prof Olivier Dulac, Department of Paediatric Neurology, Hôpital Necker-Enfants Malades, AP–HP, 75015 Paris, France [email protected]
Panel 1: Summary Simple laboratory tests for IEMs include glucose, capillary blood gas analysis, lactate (plasma and CSF), ammonia, and CSF glucose (in glucose transporter-1 deficiency syndrome, the ratio of CSF glucose to blood glucose is less than 0·5). Megaloblastic anaemia can suggest a defect in folate or B12 metabolism. A diagnostic vitamin trial with pyridoxine, 30 mg/kg per day in 2 single dosages over 3 consecutive days is recommended in neonates with therapy-resistant seizures. If ineffective, pyridoxine should be replaced by pyridoxal 5ʹ-phosphate 30–50 mg/kg per day in four to six single dosages (unlicensed compound for oral use) at the discretion of the treating physician. Brain imaging is recommended but might show unspecific findings or could even be normal in many IEM cases. Polymicrogyria with neonatal hypotonia and focal motor seizures suggest a peroxisomal disorder. Non-ketotic hyperglycinaemia and antiquitin deficiency can show hypoplasia of the corpus callosum. Signal abnormalities in the striatum, thalamus, and multifocal cortical areas fit with thiamine transporter deficiency or mitochondrial disease. Hypomyelination occurs in defects of serine biosynthesis and folate receptor 1 deficiency. Proton magnetic resonance spectroscopy is useful for the diagnosis of the creatine deficiency syndromes; presence of a lactate peak suggests mitochondrial disorders but is not obligate (eg, as in Alpers’ disease). Ultrastructural analysis of a skin biopsy might be needed if a rare subtype of the neuronal ceroid lipofuscinoses is suspected. Light and electron microscopic examination of skeletal muscle or liver is used if a mitochondrial disorder is suspected, always together with biochemical analysis of the respiratory chain, preferably in fresh muscle. Nevertheless, biopsies of skin, liver, or muscle are not part of the routine diagnostic process. Preservation of DNA or fibroblasts should be considered in children with a degenerative course of unclear pathophysiology to enable testing of new genes in the future. IEMs=inborn errors of metabolism.
727
Review
Aetiology Energy deficiency
Hypoglycaemia, glucose transporter-1 deficiency, respiratory chain deficiency, pyruvate dehydrogenase deficiency, Krebs cycle defects, creatine deficiencies
Toxic effect
Aminoacidopathies, organic acidurias, urea cycle defects, molybdenum cofactor deficiency, sulphite oxidase deficiency
Impaired neuronal function
Storage disorders
Disturbance of neurotransmitter systems
Non-ketotic hyperglycinaemia, atypical phenylketonuria, GABA transaminase deficiency, succinic semialdehyde dehydrogenase deficiency
Associated brain malformations
Peroxisomal disorders (Zellweger syndrome), respiratory chain deficiency, pyruvate dehydrogenase deficiency, O-glycosylation defects (congenital muscular dystrophies)
Vitamin or cofactor dependency and vitamin transporter defects
Biotinidase deficiency, pyridoxine-dependent and pyridoxal 5ʹ-phosphatedependent epilepsy (folinic-acid-responsive seizures), thiamine transporter deficiency, Menkes’ disease, folate transporter defect (FOLR1), dihydrofolate reductase deficiency
Miscellaneous
Serine biosynthesis deficiency
Table 1: Epilepsies of metabolic origin according to their pathogenesis
Panel 2: Convulsive status epilepticus in the context of IEM In neonates, status epilepticus can be caused by systemic metabolic decompensation as hypoglycaemia or hyperammonaemia, IEMs as in pyridoxine-dependent epilepsy or pyridox(am)ine 5ʹ-phosphate oxidase deficiency, and peroxisomal disorders. Beyond the neonatal phase, focal clonic status epilepticus is often triggered by a febrile episode and can suggest Menkes’ disease, dihydropyrimidinase deficiency (unpublished data), and pyridoxine-dependent epilepsy. Convulsive status epilepticus is also a feature of 2-methyl3-hydroxybutyryl-CoA dehydrogenase deficiency. Clonic and myoclonic status epilepticus can be a late feature in late-infantile neuronal ceroid lipofucinosis. Alpers’ disease can present with refractory status epilepticus in previously healthy children aged 3–10 years and adolescents. In MELAS, status epilepticus can accompany stroke-like episodes, and is often subtle or “non-convulsive” with visual aura or impaired consciousness. It especially affects posterior and temporal regions. Myoclonic status epilepticus may complicate MERRF, other mitochondrial encephalopathies, and guanidinoacetate methyltransferase deficiency. Treatment of status epilepticus remains challenging. Pyridoxine and pyridoxal 5ʹ-phosphate dependent seizures usually respond to administration of these cofactors. Non-convulsive or myoclonic status epilepticus in guanidinoacetate methyltransferase deficiency drastically improves with creatine and ornithine supplementation. When specific therapy is not available, local guidelines and experience are followed with one exception—use of valproic acid is avoided if Alpers’ disease is suspected, to prevent hepatic failure. Possible treatment strategies are continuous midazolam, magnesium, clobazam, levetiracetam, topiramate, lamotrigine, and ketogenic diet. In refractory status epilepticus related to MELAS, intravenous administration of arginine or citrulline may be helpful. IEMs=inborn errors of metabolism. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MERRF=myoclonic epilepsy with ragged red fibres.
Occasional seizures Occasional seizures—seizures triggered by intermittent factors—can be the first manifestation of a systemic IEM that causes hyperammonaemia or hypoglycaemia. Such seizures can occur at any age, although neonates are at particular risk. In urea-cycle disorders, neurological signs mainly consist of altered consciousness in the neonatal period and can be combined with movement disorders and hallucinations in childhood, whereas seizures usually occur along with severe metabolic decompensation.6 728
Hypoglycaemia in the neonatal period, mostly resulting from hyperinsulinism or defects of fatty acid β oxidation and ketone-body metabolism, can trigger seizures or even status epilepticus when combined with cardiocirculatory failure or fever.7 MRI shows predominantly occipital subcortical white matter involvement, occasionally extending to the cortex. Status epilepticus with severe hypoglycaemia can be unilateral,8 and can be followed by severe sequelae including psychomotor delay and pharmacoresistant epilepsy.9,10 Recurrent occasional seizures are triggered by fever, and pharmacoresistant epilepsy can consist of infantile spasms or be focal (Gataullina S, unpublished). Basal ganglia or focal cortical areas are also affected, with the topography of these lesions mainly associated with the age at injury (figure 1).11 Fever can be a trigger in the manifestation of IEMs, because it can suggest late-onset pyridoxine-dependent epilepsy11 or enable decompensation of an IEM causing energy depletion, including defects of fatty acid oxidation, Menkes’ disease, and mitochondrial defects. Febrile seizures in this case are lengthy and often focal.
Epilepsy as an epiphenomenon IEMs affecting brain metabolism are likely to be complicated by epilepsy during the course of the disease, whichever structure is the most affected structure, including white matter and basal ganglia. However, in many IEMs, epileptic seizures are infrequent, nonspecific, or delayed events, occurring after the diagnosis has been established and other neurological signs or typical findings at neuroimaging can already be present. In this context, seizures might not give clues to the pathophysiology of epilepsy or to the metabolic disease itself, which is the case in various disorders including storage disorders and aminoacidopathies.
Epilepsy as the first and main expression: presentation according to age Neonatal period Early myoclonic epileptic encephalopathy starts during the very first weeks of life or even prenatally, consisting of 1–3 s volleys of myoclonic jerks corresponding to bursts of polyspikes on EEG, alternating with total inactivity of the body during EEG suppression. The pattern is therefore distinct from that of spasms in clusters occurring later in life. In addition to this suppression–burst pattern, EEG eventually records focal discharges.12,13 Consideration of a treatable IEM is mandatory, and diagnostic trials in addition to respective biochemical investigations should be done without delay. The main metabolic causes identified so far are non-ketotic hyperglycinaemia (figure 2),14 pyridoxine-dependent epilepsy15,16 (figure 2) due to mutations in ALDH7A1 that codes for antiquitine,17 pyridox(am)ine 5ʹ-phosphate oxidase deficiency due to mutations in PNPO,18 sulphite oxidase deficiency and molybdenum cofactor deficiency, congenital lack of glutamate transporter,19 and mitochondrial disorders.1 www.thelancet.com/neurology Vol 13 July 2014
Review
In most of these disorders, there is an excess of NMDA neurotransmission, in which glycine is a coneurotransmitter.20 High glycine concentration due to nonketotic hyperglycinaemia and high sulphite concentration due to deficiency of sulphite oxidase or molybdenum cofactor alter the kinetics of the two main subunits of the NMDA receptor (NR2A and NR2B) and increase the risk of pathological synchronisation of neuron firing leading to epilepsy.21 In pyridoxine-dependent epilepsy due to loss of ALDH7A and in pyridox(am)ine 5ʹ-phosphate oxidase deficiency, decreased activity of pyridoxal 5ʹ-phosphatedependent enzymes lead to an excess of glutamate, lack of GABA, changes in the synthesis of biogenic amines, and alterations in cerebral aminoacid metabolism. In very young rats, the electroclinical pattern of neonatal encephalopathy with suppression bursts can be reproduced by inhibition of glutamate transporters that normally reuptake glutamate from the synaptic cleft into astrocytes and neurones.22,23 Therefore, excessive activation of NMDA neurotransmission seems to be the common denominator of IEMs that produce neonatal encephalopathy with suppression bursts. The signs of non-ketotic hyperglycinaemia are hypotonia, apnoea and chronic hiccup, and erratic myoclonus that might be overlooked because of the severity of the hypotonia. In pyridoxine-dependent epilepsy, patients can show poor adaptation to extrauterine life that raises the suspicion of hypoxic–ischaemic encephalopathy (ie, meconium-stained amniotic fluid and early-onset seizures), but myoclonic jerks and convulsions occur within a few hours of birth, or even earlier, in conjunction with abnormal movements, including tremor, sleeplessness, and high-pitched cry.15 The identification of α-aminoadipic semialdehyde in urine and—less specific— elevation of pipecolic acid concentration in plasma, suggests the diagnosis of pyridoxine dependent epilepsy due to mutations in ALDH7A1, even if the patient is on pyridoxine.18,24,25 Pyridox(am)ine 5ʹ-phosphate oxidase deficiency lacks a specific biomarker, because changes in neurotransmitter metabolism and elevated excretion of vanillactate in urine are inconstant findings. In isolated sulphite oxidase deficiency and molybdenum cofactor deficiency, diffuse oedema followed by extensive necrosis of grey and white matter on brain MRI suggests the diagnosis.26 Molybdenum cofactor is endogenously synthesised and catalyses the action of sulphite oxidase, xanthin dehydrogenase, and aldehyde oxidase. As shown in isolated sulphite oxidase deficiency, the epilepsy phenotype is caused by accumulating sulphite due to impaired degradation of the sulphur-containing aminoacid cysteine. A low toxicity threshold for accumulating sulphite around the time of birth makes early diagnosis crucial. Increased sulphite levels also inhibit α-aminoadipic semialdehyde dehydrogenase, leading to accumulation of the enzyme and seizures partly responding to pyridoxine.27 The sulphite dipstick test is an easy bedside test of fresh urine, but can give false-negative results; therefore, www.thelancet.com/neurology Vol 13 July 2014
determination of urinary sulphocysteine remains the gold standard. Another IEM presenting with myoclonic jerks is holocarboxylase deficiency. This organoaciduria leads to impaired breakdown of aminoacids, pyruvate, and lipids, and in neonates is always accompanied by acute metabolic acidosis and encephalopathy. Less specific patterns of neonatal seizures can result from rarer IEMs, including other organic acidurias diagnosed by urinary chromatography and peroxisomal disorders such as Zellweger syndrome and neonatal adrenoleukodystrophy, which can be diagnosed by Aetiology Neonatal period
Hypoglycaemia, urea cycle defects, pyridoxine-dependent epilepsy (including folinic-acidresponsive seizures), pyridox(am)ine 5 -phosphate deficiency, non-ketotic hyperglycinaemia, holocarboxylase synthase deficiency, molybdenum cofactor deficiency, sulphite oxidase deficiency, organic acidurias, Zellweger syndrome, neonatal adrenoleukodystrophy, adenylosuccinate lyase deficiency, dihydrofolate reductase deficiency
Infancy
Sequelae of severe hypoglycaemia, glucose transporter-1 deficiency, creatine deficiency, biotinidase deficiency, aminoacidopathies, organic acidurias, congenital disorders of glycosylation, pyridoxine-dependent epilepsy, infantile neuronal ceroid lipofuscinosis (CLN1), folate and thiamine transporter deficiencies, peroxisomal disorders, Menkes’ disease
Toddlers
Late infantile neuronal ceroid lipofuscinosis (CLN2), mitochondrial disorders including Alpers’ disease, lysosomal storage disorders, thiamine transporter deficiency, folate transporter deficiency
School age Mitochondrial disorders, juvenile form of neuronal ceroid lipofuscinosis (CLN3), progressive myoclonic encephalopathies, lysosomal storage disorders, thiamine transporter deficiency, and adolescence Lafora’s disease, Gaucher’s disease, and Niemann-Pick type C disease Table 2: Epilepsies of metabolic origin according to most frequent age at onset
A
B
C
D
E
F
Figure 1: Severe hypoglycaemia and its sequelae Axial T2-weighted (A) and diffusion-weighted (B) images of a neonate with convulsions due to congenital hyperinsulinism, showing hyperintense signal of the posterior white matter and the splenium and ill-defined occipital and parietal cortex. These areas also show decreased diffusion. Axial T2-weighted image (C) showing basal ganglia damage following severe infantile hypoglycaemia at 9 months of age. Axial T2-weighted (D) and diffusion-weighted (E) images showing multifocal cortical oedema after severe hypoglycaemia and status epilepticus in a 14-month-old infant with congenital ACTH deficiency. An axial T2-weighted image (F) of an 18-year-old woman with recent manifestation of occipital lobe epilepsy. The occipital glioses are secondary to neonatal hypoglycaemia due to congenital hyperinsulinism. ACTH=adrenocorticotropic hormone.
729
Review
A
B
C
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 O2-O1 ECG THO_ EMG1 EMG2
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
20μV/mm 1 sec
30μV/mm 1 sec
D
E
F
FP2-C4 C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 T4-C4 C4-C3 C3-T3 ECG RESPI EMG1 EMG2
FP2-C4 C4-O2 FP2-F8 F8-T6 T6-O2 FP1-C3 C3-O1 FP1-F7 F7-T5 T5-O1 PZ-O2 PZ-O1 EM1 EM2
FP2-C4
10μV/mm 1 sec
1 sec
C4-O2 F8-T6 T6-O2 FP1-C3 C3-O1 F7-T5 20μV/mm
G
H
I
FP2-C4
Fp1-F7 F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fz-Cz Cz-Pz Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 EKG
C4-O2 FP2-T4 T4-O2 FP1-C3 C3-O1 FP1-T3 T3-O1 ECG RESP 20μV/mm 1 sec
1 sec
15μV/mm
T5-O1
1 sec
FP2-C4 FP1-C3 C4-O2 C3-O1 F8-T6 F7-T5 F8-C4 C4-C3 C3-F7 T6-O2 O2-O1 O1-T5 ECG THO_ EMG1 EMG2 SLI
10μV/mm
20μV/mm
1 sec
1 sec
70μV
Figure 2: EEG in IEM according to aetiology (A) Interictal EEG in a 15-day-old baby with non-ketotic hyperglycinaemia, showing the characteristic suppression–bursts sequence (bursts of high-amplitude diffuse polyspikes separated by episodes of flat tracing). (B–D) EEG from a 3-month-old baby with pyridoxine-dependent epilepsy. (B) Epileptic spasms in clusters with high-amplitude slow complex and rhythmic waves. (C) High-amplitude rhythmic spike–waves predominate on the left hemisphere during a right clonic seizure. (D) After pyridoxine intravenous injection (100 mg), EEG shows flattening of the tracing. (E) Myoclonic status epilepticus in a 6-year-old girl with guanidinoacetate methyltransferase deficiency. Diffuse high-voltage spikes and spike–waves predominating on frontal or frontal-central areas; myoclonic jerks recorded on deltoid electromyography. (F) Atypical absence in an 11-year-old girl with glucose transporter-1 deficiency, with diffuse high-amplitude spike–waves. (G) Diffuse spikes, predominating on occipital areas triggered by slow photic stimulation in a 5-year-old girl with late-infantile neuronal ceroid lipofuscinosis. (H) 3-year-old girl with Alpers’ disease due to POLG1 mutations. Interictal EEG shows bilateral high-amplitude periodic sharp waves and spike–waves with left occipital predominance. (I) 16-year-old girl with MELAS and the classic mitochondrial 3243A→G mutation. EEG shows spike and spike–waves rhythmic discharges over the left posterior region, corresponding to the occipital area of hyperintense T2 signal. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes.
analysing very-long-chain fatty acids. Adenylosuccinate lyase deficiency28 produces encephalopathy with epilepsy, substantial psychomotor delay, and hypotonia followed (sometimes after years) by spasticity. The diagnosis of adenylosuccinate lyase deficiency is based on detection of succinyladenosine and succinylaminoimidazole carboxamide ribotide in the urine and CSF. MRI shows lack of or delayed myelination of cerebral white matter, with cerebellar atrophy.29 In dihydrofolate reductase deficiency, rapidly progressive microcephaly is combined with megaloblastic anaemia, pancytopenia, and convulsive seizures during early life.30
Infancy Complex febrile seizures that are focal, lengthy, and sometimes are followed by postictal paresis can be the 730
first expression of type II hyperprolinaemia,11 which results from δ-1-pyrroline-5-carboxylate dehydrogenase deficiency due to mutations in the mitochondrial ALDH4A1. δ-1-pyrroline-5-carboxylate forms a complex with and inactivates pyridoxal 5ʹ-phosphate, leading to secondary cerebral pyridoxal 5ʹ-phosphate deficiency. Pyridoxine supplementation prevents seizure recurrence, although many patients with type II hyperprolinaemia also respond to common anticonvulsants such as valproic acid and thus remain undiagnosed.31 Infantile spasms are the combination of spasms in clusters and hypsarrhythmia. Rarely, they are the expression of an IEM, although a whole range of disorders can be involved (table 3). Their occurrence after complex febrile seizures can be a diagnostic clue for some IEMs. www.thelancet.com/neurology Vol 13 July 2014
Review
Of the three IEMs that cause creatine deficiency, guanidinoacetate methyltransferase deficiency and X-linked creatine transporter deficiency can cause infantile spasms, whereas L-arginine:glycine amidinotransferase deficiency has a mild epilepsy phenotype with occasional febrile seizures.32 The hallmark of all three disorders is the absence of cerebral creatine, which can be readily visualised by proton magnetic resonance spectroscopy (figure 3). Febrile seizures can occur, and are often the first paroxysmal expression. Measurement of guanidinoacetate
Plasma
concentrations (high in guanidinoacetate methyltransferase deficiency, low to normal in L-arginine:glycine amidinotransferase deficiency, and normal in X-linked creatine transporter deficiency) and creatine (low in guanidinoacetate methyltransferase deficiency, low to normal in L-arginine:glycine amidinotransferase deficiency, and high in X-linked creatine transporter deficiency) in plasma and urine enables biochemical confirmation. In guanidinoacetate methyltransferase deficiency, virtually all untreated patients develop epilepsy
Urine
CSF
Others
Myoclonic encephalopathy with suppression bursts Pyridoxine-dependent epilepsy
Pipecolic acid
α-aminoadipic semialdehyde
Pipecolic acid, α-aminoadipic semialdehyde Low PLP in CSF
PNPO deficiency
··
Vanillactate
Neurotransmitters*
Low PLP in CSF
Non-ketotic hyperglycinaemia
Aminoacids
Aminoacids
Aminoacids
CSF:plasma glycine ratio
Biotinidase deficiency
Biotinidase activity
Organic acids
··
··
Phenylketonuria
Aminoacids
··
··
··
Atypical phenylketonuria
Aminoacids
··
Neurotransmitters, pterins
··
Serine deficiency
··
··
Aminoacids
··
Menkes’ disease
Copper, coeruloplasmin
··
··
··
GAMT deficiency
Guanidinoacetate
··
··
··
Zellweger syndrome
Very-long-chain fatty acids ··
··
··
Mitochondriopathies
Lactate
··
Lactate
··
PDH deficiency
Lactate
··
Lactate, pyruvate
··
Biotinidase deficiency
Biotinidase activity
Organic acids
··
··
Mitochondriopathies
Lactate
··
Lactate
··
Niemann-Pick type C
Oxysterols
··
··
Filipin staining in fibroblasts
Late-infantile NCL
··
··
··
Enzymatic and genetic analysis
MERRF
Lactate
··
Lactate
mtDNA testing
MELAS
Lactate
··
Lactate
mtDNA testing
Sialidosis
··
Sialic acid
··
Enzymatic testing
Gaucher’s disease
··
··
··
Enzymatic testing
Unverricht-Lundborg disease
··
··
··
Genetic testing
Lafora’s disease
··
··
··
Genetic testing, Lafora bodies
Infantile spasms
Myoclonic epilepsy
Progressive myoclonus epilepsies
Epilepsy with generalised tonic–clonic seizures GLUT1 deficiency
Glucose
··
Glucose
CSF:plasma glucose ratio
Mitochondriopathies
Lactate
··
Lactate
··
Juvenile NCL
··
··
··
Lymphocyte vacuoles, genetic testing
Epilepsy with multiple generalised seizure types GLUT1 deficiency
··
··
Glucose
CSF:plasma glucose ratio
Creatine deficiency
Guanidinoacetate (GAMT deficiency)
Creatine or creatinin (creatine transporter deficiency)
··
Low creatine in MRS
Atypical phenylketonuria
Aminoacids
··
Aminoacids, pterines
··
FOLR1 deficiency
··
··
Methyltetrahydrofolate
··
Dihydrofolate reductase deficiency
··
··
Methyltetrahydrofolate
Megaloblastic anaemia
··
··
··
Genetic testing
Epilepsia partialis continua Alpers’ disease
PNPO=pyridox(am)ine 5ʹ-phosphate oxidase. PLP=pyridoxal 5ʹ-phosphate. GAMT=guanidinoacetate N-methyltransferase. PDH=pyruvate dehyrogenase. NCL=neuronal ceroid lipofuscinosis. MERRF=myoclonic epilepsy with ragged red fibres. MELAS=mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. MRS=magnetic resonance spectroscopy. FOLR1=folate receptor 1.
Table 3: Biomarkers of epilepsy and epilepsy syndromes due to inborn errors of metabolism
www.thelancet.com/neurology Vol 13 July 2014
731
Review
that starts in infancy with infantile spasms or tonic and tonic–clonic seizures (sometimes with severe cyanosis), which is refractory to treatment with antiepileptic medication. Non-convulsive status epilepticus and myoclonic and atonic seizures can occur in childhood (figure 2). Moderate to severe mental retardation is present in children and adults. Patients with X-linked creatine transporter deficiency usually come to attention because of developmental delay or intellectual disability before the occurrence of epilepsy and can subsequently develop several types of seizures.33 Unilateral clonic and often febrile status epilepticus in infancy can be the first manifestation of Menkes’ disease, occurring before the infantile spasms that are usually a major component in the disease course.34 This X-linked disorder is due to mutations in ATP7A, which encodes a transmembrane copper-transporting ATPase, interfering with energy production. Elevated lactate concentrations in plasma can lead to misdiagnosis of a mitochondrial disorder before the appearance of characteristic kinky hair. Phenylketonuria is easily overlooked in a child who has migrated from a country where neonatal screening is not established. The characteristic musty odour, discoloured hair, developmental delay, and delayed white matter maturation on MRI can be clues to phenylketonuria. Atypical phenylketonuria due to disturbed synthesis of tetrahydrobiopterin, the cofactor of phenylalanine hydroxylase and tyrosine hydroxylase, can in some patients not be picked up by high phenylalanine concentrations in newborn screening and warrants the additional analysis of pterins and biogenic amines in CSF. In atypical phenylketonuria (eg, dihydropteridin reductase deficiency) the clinical picture is dominated by a movement disorder, such as infantile parkinsonism or bradykinesia, hypotonia, and temperature dysregulation. Mitochondrial disorders can also cause infantile spasms. The most prevalent disease is Leigh syndrome, either due to the classic neuropathy, ataxia, and retinitis pigmentosa mutation in mitochondrial MT-ATP6 or secondary to mutations in nuclear genes or to pyruvate dehydrogenase complex deficiency.35,36 MRI findings include symmetrical basal ganglia lesions in Leigh syndrome, or corpus A
4
B
3
2
1
0
Figure 3: Guanidinoacetate methyltransferase deficiency Axial T1-weighted MRI without abnormalities showing the voxel in the occipital grey matter, in which proton magnetic resonance spectroscopy was done in a healthy child (A) and a 3-year-old girl with guanidinoacetate methyltransferase deficiency (B). The missing creatine peak should be higher than the choline peak. The large peak corresponds to N-acetylaspartylacetate.
732
callosum agenesis in pyruvate dehydrogenase complex deficiency and mitochondrial disorders.37 Skin, liver, or muscle biopsies for the investigation of oxidative phosphorylation can allocate the biochemical defect38,39 but, in the future, molecular analysis might become an easier and non-invasive way to diagnose mitochondrial disorders. An extremely floppy infant with infantile spasms could have a peroxisomal disorder. Additional clues including dysmorphic features (a high forehead and large anterior fontanelle), hepatomegaly, and peripheral neuropathy are often present. Focal seizures, originating in the areas of polymicrogyria, are usually present, and episodes of difficult-to-treat focal status epilepticus are common.2 The combination of developmental delay, epilepsy, and neonatal diabetes (DEND) is typical of DEND syndrome, caused by de-novo mutations in KCNJ11, which encodes the potassium channel Kir6.2. This syndrome is often mistaken for a metabolic disease because of the combination of early-onset diabetes, but it is not technically an IEM because the associated encephalopathy is a direct consequence of the channelopathy. Infantile spasms or tonic seizures are likely to be mediated by way of impaired potassium channel function; indeed, tolbutamide, a modulator of Kir6.2, has some effect on both diabetes and epilepsy.40,41 In most IEMs leading to infantile spasms, there is dysfunction or extensive lesions of the basal ganglia, often accompanied by cortical impairment. This finding led to basal ganglia being considered as the effectors of spasms.42 In the context of IEMs, response to treatment depends on the extent of brain dysfunction or lesions; infantile spasms mainly due to basal ganglia involvement (eg, dihydropteridine reductase deficiency43 or Leigh syndrome due to the mitochondrial MT-ATP6, 8993T→G/C mutation44 ) are more likely to be responsive to treatment than are those in which there is additional cortical dysfunction (eg, Menkes’ disease).34 The clinical course of mitochondrial disorders can vary from pharmacosensitive infantile spasms to intractable epilepsy leading to death.45 A few patients with serine synthesis deficiency, an autosomal recessive disease with congenital microcephaly and hypomyelination, have also been reported to exhibit infantile spasms.46 By contrast with myoclonic epilepsy that occurs in adolescence, myoclonic epilepsy that occurs in early infancy, even in parallel with psychomotor regression, usually does not suggest an IEM.47 The only reversible disorder (provided the diagnosis is done early and proper treatment is given) is biotinidase deficiency, which presents at 3 or 4 months of age with myoclonus after tachypnoea due to lactic acidosis, and is often preceded by alopecia and perioral dermatitis.48,49 Partial seizures in infancy can result from glucose transporter-1 deficiency.50 This deficiency manifests at the blood–brain barrier and is caused by dominant mutations in SLC2A1, which encodes the solute carrier family 2, facilitated glucose transporter member 1 protein. Most www.thelancet.com/neurology Vol 13 July 2014
Review
mutations of the SLC2A1 gene (>90%) occur de novo. More than 150 patients with glucose transporter-1 deficiency have been reported.51,52 Although seizures usually start in infancy with complex partial and convulsive seizures, the cause is often not recognised before global developmental delay and seizures triggered by fasting become apparent during childhood. About 50% of patients develop secondary microcephaly.51 Slow EEG activity on fasting might be a diagnostic clue. Virtually all patients in whom glucose transporter-1 deficiency was suspected had low CSF glucose concentrations (
