Metabolic medicine and neurology Flashcards
IEM and seizures intro
Though IEM are a relatively infrequent cause of epilepsy, epileptic seizures are a common feature in several IEM
An early age of presentation, co-morbid developmental delay/regression, and resistance to conventional antiepileptic drug therapy are common to many of these disorders
age-dependent presentation is presumably related to the sequential development of excitatory and inhibitory pathways in the neonatal brain: (GABA) functions initially as an excitatory neurotransmitter in the premature infant and a developmental switch changes its role to inhibition closer to term. This switch occurs as a result of the maturation of the cation-chloride cotransporter (KCC2). Subsequently, there is a surge of glutamatergic-related excitatory connections, which in turn lead to a developmental phase during which the immature brain favors excitability. The immaturity of inhibitory systems during early brain development and their dysregulation under metabolic dysfunction play a major role in neonates by lowering the seizure threshold and creating an epileptogenic milieu
IEM in neonatal period and early infancy
occurrence of seizures is most frequent in the neonatal period as compared to other age groups, given the unique vulnerability of the brain in terms of the excitation–inhibition imbalance. While common etiologies include birth asphyxia, hypoglycemia, hypocalcemia, intraventricular hemorrhage, and meningitis, IEM may present in the neonatal period with or without encephalopathy in the form of poor feeding and lethargy, accompanied by seizures. Excessive irritability, abnormal crying, abnormal sleep, and hiccups are typical clinical markers for the clinician to suspect an underlying IEM
clues to IEM: Parental consanguinity
Deterioration after a period of apparent normalcy
Family h/o neonatal deaths, neurological illnesses
Pregnancy–HELLP syndrome (FAOD), excessive fetal movements (intrauterine seizures)
Rapidly progressive encephalopathy
Severe metabolic acidosis
Hiccups
Unusual odors of urine, cerumen-rare
pyridoxine dependent epilepsy
early onset recurrent seizures that are resistant to conventional anti-epileptic drugs but responsive to pyridoxine
underlying molecular genetic defect was identified in 2006, to be causally linked to pathogenic mutations in ALDH7A1 gene resulting in the deficiency of α–aminoadipic semialdehyde dehydrogenase (antiquitin), which is involved in cerebral lysine metabolism, causing intermediary substrates of lysine metabolism to accumulate
usually presents very early, within hours or days of birth, with seizures that are refractory to conventional anti-epileptic (AED) therapy. In some patients, intrauterine seizures have been reported to occur, with onset at the end of the last trimester, with mothers perceiving excessive and jerky fetal movements. Infants may also develop emesis, abdominal distention, sleeplessness presenting as sepsis, or with features of hyperalertness, hyperacusis, irritability, paroxysmal facial grimacing, and abnormal eye movements
Multifocal and generalized myoclonic jerks, often intermixed with tonic seizures, and focal onset motor seizures are typical initially. If left undiagnosed and untreated, or in the case of non-response to pyridoxine, affected infants develop focal dyscognitive seizures, infantile spasms, and myoclonic seizures that are treatment-resistant. Late onset and other atypical presentations of PDE have also been described in one-third of patients. These include infants with a delayed presentation (usually with infantile spasms), infants whose seizures initially respond to conventional anti-epileptic drugs, but relapse later with refractory seizures, and patients whose seizures are not controlled by initial administration of pyridoxine but respond later to a second trial
Ictal and interictal EEGs in PDE pyridoxine-dependent epilepsy are variable and relatively non-specific, and may even be reported as normal; However, asynchronous bursts of high-voltage generalized epileptiform activity, multifocal discharges, slow-spike wave complexes, burst-suppression pattern, and hypsarrhythmia (in infants with West syndrome presentation) have also been described
Magnetic resonance imaging studies of the brain are variable, ranging from normal to the presence of white matter signal abnormalities, generalized cerebral atrophy, and hypoplasia or dysgenesis of corpus callosum
Diagnostic confirmation of PDE is done through demonstration of elevated levels of AASA in urine and ⁄ or plasma and cerebrospinal fluid; molecular diagnosis is confirmed with the identification of a pathogenic mutation in the ALDH7A1 gene
Treatment should be initiated in an intensive care setting with available ventilator support as these infants may develop apnea, profound hypotonia, and hypotension in response to the administration of pyridoxine; give iv pyridozine, delayed response is poss
Pyridoxine treatment has been associated with sensory peripheral neuropathy; thus, annual monitoring of nerve conduction is recommended where testing is possible - If there is any evidence of abnormality on neurophysiological testing or clinical symptoms of neuropathy, the dose of pyridoxine should be reduced to the lowest effective dose. Recently, the addition of a lysine-restricted diet has been shown to be potentially beneficial, as it reduces the levels of the neurotoxic AASA
most remain seizure free, however, some children may have breakthrough seizures during periods of intercurrent infection and fever. In such situations, doubling the regular dose of pyridoxine during the first few days of a febrile illness may be effective at preventing breakthrough seizures
PNPO def
Pyridox(am)ine 5′phosphate oxidase (PNPO) is essential for the synthesis of pyridoxal phosphate (PLP), which is the active form of vitamin B6. Deficiency of this enzyme has been described in a small number of infants worldwide who presented with seizures that were pyridoxine-resistant but PLP-responsive. Babies with PNPO deficiency are often premature, presenting with encephalopathy, seizures, lactic acidosis, and hypoglycemia
seizure semiology and EEG findings described are similar to those encountered in PDE. Maternal reports of in utero seizures are frequent. A burst-suppression pattern on EEG is frequently encountered in comparison to PDE. In contrast to PDE, breakthrough seizures while on PLP are frequently observed
PNPO deficiency lacks a specific biochemical marker in body fluids, but can be suspected on the basis of assays in blood and urine suggestive of l-aromatic acid decarboxylase deficiency (elevations in glycine, threonine, taurine, histidine, and low arginine) and treatment resistance to pyridoxine; definitive diagnosis can only be established by molecular genetic testing for mutations in the PNPO gene
folinic acid responsive seizures
first described in a group of newborns who had seizure onset in the first five days of life, along with irritability and white matter abnormalities on brain magnetic resonance imaging
antiquitin deficiency, with elevated urinary AASA and pathogenic mutations in the antiquitin gene
Folinic acid-responsive seizures and PDE due to antiquitin deficiency are currently considered genetically allelic disorders.
current recommendation is that, in a neonate with seizures who demonstrates an incomplete pyridoxine response, add-on treatment with folinic acid should be considered
Biotinidase and Holocarboxylase Synthetase Deficiency
Biotinidase deficiency is an autosomal recessively inherited neurocutaneous disorder with an impairment of the endogenous recycling of biotin
Epilepsy is frequent in untreated biotinidase deficiency, often starting after the first three or four months of life, as infantile spasms
Affected children present with hypotonia, seizures, eczematous skin rash, and alopecia. Some children may develop respiratory problems, such as hyperventilation, laryngeal stridor, and apnea. Conjunctivitis and candidiasis can be additional features. Later neurodevelopmental problems may occur in the form of ataxia, developmental delay, hearing loss, and vision problems such as optic atrophy
Biochemical abnormalities may include one or more of the following; ketosis, lactic acidosis, organic aciduria, and mild hyperammonemia. The seizures and skin manifestations respond promptly to small doses of biotin
neurodevelopmental sequelae such as developmental delay, optic atrophy, and hearing loss are usually irreversible
In holocarboxylase synthase deficiency, symptoms start during the neonatal period. Seizures are less frequent, occurring in 25–50% of all children; responds to treatment with biotin
Biotinidase and Holocarboxylase Synthetase Deficiency
Biotinidase deficiency is an autosomal recessively inherited neurocutaneous disorder with an impairment of the endogenous recycling of biotin
Epilepsy is frequent in untreated biotinidase deficiency, often starting after the first three or four months of life, as infantile spasms
Affected children present with hypotonia, seizures, eczematous skin rash, and alopecia. Some children may develop respiratory problems, such as hyperventilation, laryngeal stridor, and apnea. Conjunctivitis and candidiasis can be additional features. Later neurodevelopmental problems may occur in the form of ataxia, developmental delay, hearing loss, and vision problems such as optic atrophy
Biochemical abnormalities may include one or more of the following; ketosis, lactic acidosis, organic aciduria, and mild hyperammonemia. The seizures and skin manifestations respond promptly to small doses of biotin
neurodevelopmental sequelae such as developmental delay, optic atrophy, and hearing loss are usually irreversible
In holocarboxylase synthase deficiency, symptoms start during the neonatal period. Seizures are less frequent, occurring in 25–50% of all children; responds to treatment with biotin
Glucose Transporter Defect (GLUT1 Deficiency Syndrome)
gives impaired glucose transport into the brain
Infantile onset refractory seizures, developmental delay, acquired microcephaly, abnormalities of muscle tone (hypotonia or spasticity), and movement disorders such as choreoathetosis, ataxia, and dystonia
clinical spectrum of GLUT1 deficiency is understood to be broader and includes developmental delay, epilepsy, and familial and sporadic forms of paroxysmal exercise-induced dyskinesia
Varying degrees of cognitive impairment associated with dysarthria, dysfluency, and expressive language deficits are added features
usually appear normal at birth, and present with refractory focal motor seizures in early infancy. In addition, especially before meals or at times of fasting, patients may exhibit an episodic movement disorder with associated eye-rolling movements; 60% dev microcephalyBeyond infancy, generalized seizures are common. The EEG may be completely normal; recordings after an overnight fast can be used as an activation procedure to demonstrate the altered background activity or focal discharges
may also get myoclonic astatic epilepsy and early onset absence epilepsy
Clinical clues to GLUT1 deficiency include an increase in seizures before meals, cognitive impairment, or paroxysmal exercise-induced dyskinesia
diagnosis is suggested by the finding of low CSF glucose levels in the absence of other causes of hypoglycorrhachia such as infection; LP should be fasting
As many GLUT1 deficiency patients with normal CSF sugar levels have been described, molecular genetic testing for pathogenic mutations in the SLC2A1 gene may be considered the gold standard
ketogenic diet is an effective treatment for this condition as it provides alternative sources of energy; fat to non-fat ratio in the diet is usually 3:1 to 4:1
rugs that impair GLUT1 function, e.g., caffeine, phenobarbital, diazepam, chloral hydrate, and tricyclic antidepressants, are best avoided
serine biosynthesis disorders
Common clinical features of defects in serine biosynthesis include congenital or early acquired microcephaly, refractory seizures and global developmental delay in infancy, and progressive polyneuropathy in adults
Seizure types include; infantile spasms (in one-third), tonic–clonic seizures, tonic seizures, atonic seizures, gelastic seizures, and myoclonic seizures. Other clinical features variably present include cataracts, spastic quadriparesis, megaloblastic anemia, and irritability
brain MRI may show delayed myelination followed by cerebral atrophy
3 enzymes involved, low CSF serine levels are seen in all three disorders. Plasma serine levels may be low to borderline. The diagnosis can be confirmed by molecular genetic testing
supplement with serine and glycine
Molybdenum Cofactor and Isolated Sulfite Oxidase Deficiency
Both these disorders share similar clinical features characterized by the onset of intractable seizures, encephalopathy, and hypotonia in the neonatal period, often mimicking neonatal hypoxic ischemic encephalopathy. Subtle dysmorphic features such as elongated facies, small nose, and puffy cheeks may be present
Later, the affected infants develop epileptic seizures, developmental delay, and movement disorders. Clinical clues to this disorder in infancy include ophthalmological abnormalities such as lens subluxation, optic atrophy, or nystagmus
EEGs may show multifocal spike wave discharges or a burst suppression pattern. The MRI shows generalized brain edema in the early in the early stage, and a distinctive pattern of widespread restricted diffusion involving the cortical ribbon (at the depths of sulci), followed by development of cystic changes of the white matter and global brain atrophy
MRI pattern of multicystic encephalomalacia resembles that seen in perinatal hypoxic ischemic brain injury. Biochemical investigations confirm the low levels of uric acid and homocysteine in plasma and elevated Urinary S-sulfocysteine
In two-thirds of patients with molybdenum cofactor deficiency, a proximal defect in the pathway of molybdenum cofactor synthesis is responsible, leading to the failure of conversion of guanine triphosphate (GTP) to cyclic pyranopterin monophosphate - new treatment is available for these patients using purified intravenous cyclic pyranopterin monophosphate (cPMP)
menkes disease
X-linked recessive disorder of copper metabolism. Clinical clues to Menkes disease include hypotonia, seizures, cutis laxa, “kinky hair,” and hypothermia. The characteristic hair abnormality ‘pili torti’ on microscopic examination of hair is a diagnostic clue. Widespread cerebral and cerebellar degeneration, tortuosity of blood vessels can be demonstrated on neuroimaging (MRI, MRA), as well as bladder diverticulae, and skeletal abnormalities (presence of wormian bones on skull X-rays)
caused by mutations in the ATP7A gene, a ubiquitous copper transporter encoded on the X-chromosome and located in the trans-Golgi network, particularly active in the intestine, from which most of the dietary copper is absorbed.
results in impairment of Cu dependent enzymes
inc secondary elevations in plasma lactate are often noted due to cytochrome c oxidase impairment
disease is characterized by the appearance of seizures and developmental arrest and regression often around 6–8 weeks of age; 3 stages: irst stage (at 2–3 months of age) consists of focal seizures that evolve into status epilepticus. Typical EEG changes include focal epileptiform and ictal rhythms over posterior quadrants. Interictal abnormalities include polymorphic slow, spike and waves and multifocal epileptiform discharges. Three to eight months later, epileptic spasms occur with EEG changes consistent with hypsarrhythmia. Finally, a third late stage occurs (at 20–25 months of age) characterized by the development of multifocal seizures, tonic spasms, and myoclonus
suggested by low serum levels of copper and ceruloplasmin and the presence of neuroimaging abnormalities described above, and confirmed by molecular genetic testing for pathogenic mutations in the ATP7A gene
parenteral copper histidine has prolonged life expectancy if started early, but does not appear to significantly alter the neurological outcome. Copper supplementation may be more effective in cases where the causative mutation leads to a protein that retains some residual function
non-ketotic hyperglycinaemia
caused by deficiency of the glycine cleavage enzyme system and consequent accumulation of glycine in the brain. The classic form of nonketotic hyperglycinemia present in the newborn period with hypotonia, feeding difficulties, encephalopathy, seizures, and apneas
hiccups important clinical clue
EEG recordings show a burst suppression pattern which later evolves to hypsarrhythmia and multifocal epilepsy
MRI shows increased signal on diffusion weighted images in the areas that are myelinated at birth, most often in the posterior limb of the internal capsule; Hypoplasia or agenesis of the corpus callosum has also been reported. Magnetic resonance spectroscopy demonstrates a glycine peak in the proton MRS spectra
One-third of patients have a delayed presentation; in early to mid-infancy with seizures, hypotonia, and developmental delay
majority of patients have a poor outcome with severe global developmental delay and spasticity. They also develop progressive brain atrophy and multifocal seizures over time. The diagnosis is performed by measuring glycine concentrations in plasma and CSF. There is an increased ratio of CSF to plasma glycine
definitive diagnosis again is established by molecular genetic testing. Therapy with sodium benzoate and dextromethorphan (NMDA receptor antagonist) may be helpful in some milder forms of the disease, alongside AED and general supportive care - do not use valproate as further inhibs glycine metabolism
Uridine-Responsive Epileptic Encephalopathy
isorder of pyrimidine biosynthesis caused by CAD mutations
CAD encodes multifunctional enzyme involved in de novo pyrimidine biosynthesis. Pyrimidines can also be recycled from uridine
global developmental delay, epileptic encephalopathy, and anemia with anisopoikilocytosis; will die after neurodegen disease course, uridine supplementation stops seziures, improves neurological function, and resolves anaemia
Urea Cycle Defects, Organic Acidemias, and Aminoacidopathies
These disorders present either in the neonatal period with encephalopathy and seizures, or later episodes of encephalopathy, neurological worsening (ataxia, movement disorders, etc.) during periods of stress such as with intercurrent infections
Babies with urea cycle defects are normal at birth but soon develop lethargy, poor feeding, seizures, and tone abnormalities in the first 4–7 days of life. The EEG shows variable and nonspecific patterns of multifocal independent spike- and sharp-waves, repetitive paroxysmal discharges and low-voltage fast activity
Diagnosis is suspected by the presence of high ammonia levels in the absence of metabolic acidosis or ketosis and abnormal plasma concentrations of urea cycle intermediates and urine orotic acid. Diagnostic confirmation is by testing for the deficient enzyme activity and molecular genetic testing
In milder variants with partial deficiency of the enzyme, the affected children may have intermittent episodes of encephalopathy, ataxia, and/or seizures during periods of metabolic stress and concurrent infections
Organic acidemias such as methylmalonic aciduria, propionic aciduria, etc. may present either in the neonatal period or beyond the neonatal period with a presentation similar to urea cycle defects. The biochemical hallmark is the presence of significant metabolic acidosis with or without ketosis and hyperammonemia. Basal ganglia signal abnormalities may be seen on the MRI. The diagnosis is established by means of quantitative analysis of plasma amino acids and acylcarnitines, as well as urinary organic acids; Early diagnosis and specific treatment (special dietary formulae, cofactor supplementation) are essential to improve seizure management and prevent irreversible long-term sequelae.
classic variant of maple syrup urine disease also presents in the neonatal period with encephalopathy, tone abnormalities, and/or seizures, usually at the end of the first week of life. There is an absence of acidosis or hyperammonemia; the biochemical diagnostic clue is the presence of urine ketones. The MRI shows localized edema involving the myelinated parts of the brain such as the deep cerebellar white matter, the dorsal part of the brainstem, the cerebral peduncles, and the posterior limb of the internal capsule
Congenital Disorders of Glycosylation
multisystem disorders caused by genetic defects in glycoprotein, glycolipid, and glycan synthesis. Neurological features are common and include developmental delay, seizures, stroke-like episodes, hypotonia, ataxia, and peripheral neuropathy
clinical pointers to an underlying CDG include dysmorphic features such as unusual fat pads on the buttocks, inverted nipples, long fingers and toes, and craniofacial dysmorphic features
individuals developed recurrent and intractable epilepsy with heterogeneous seizure semiology including; tonic–clonic seizures, infantile spasms, and myoclonic seizures. The EEG abnormalities described in these patients included focal and multifocal epileptic discharges, slow background rhythms, generalized epileptic activity, and burst suppression pattern
symptomatic treatment
Peroxisomal Disorders
multisystem disorders and those associated with early onset seizures include Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum’s disease. The pathogenesis of seizures in these patients includes neuronal migration defects, biochemical abnormalities such as aberrant fatty acid composition of neuronal membranes, and dysregulation of GABAergic signaling
raniofacial abnormalities, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctate are features of peroxisomal disorders. Seizures occur in 70–90% of the patients and are difficult to control
Diagnosis is established by demonstration of elevated plasma VLCFA levels and relevant pathogenic mutation in one of the Peroxisomal Biogenetic Factor (PEX) genes. Treatment remains supportive
congenital disorders of autophagy
intracranial malformations, developmental delay, intellectual disability, epilepsy, movement disorders, and neurodegeneration
Diagnosis can only be established by timely recognition of the clinical phenotype and molecular genetic testing for mutations in the affected gene
clues to IEM epilepsy in young child-adolescent (older than infant)
Positive family history
Progressive myoclonic epilepsy phenotype
Epilepsy not fitting into a classical epilepsy syndrome
Associated intellectual disability/ cognitive decline
Presence of other neurological features: movement disorders, ataxia, spasticity
Presence of other system involvement: hepatosplenomegaly, retinitis pigmentosa
Seizures worsen with certain anti-epileptic drugs
Unexplained status epilepticus
Seizures occurring on fasting (GLUT1) or with high protein meals (urea cycle defects)
Unexplained slowing of the background activity on EEG
Paroxysmal responses during the photic intermittent stimulation at low frequencies on EEG
Disorders of Creatine Biosynthesis and Transport
Cerebral creatine deficiency states comprise two autosomal recessive disorders that affect creatine biosynthesis: arginine:glycine amidinotransferase (AGAT) deficiency and guanidinoacetate methyltransferase (GAMT) deficiency, and creatine transporter (SLC6A8) deficiency, an X-linked condition that affects creatine transport into brain and muscle
shared clinical features amongst these disorders include; developmental delay/intellectual disability, behavior problems, autistic features, speech delay, epilepsy, and movement disorders
Multiple seizure types have been described in these children including myoclonic, generalized tonic–clonic, focal onset with impaired awareness, head nodding, and drop attacks. Neurological findings include hypotonia in early stages, with dystonia in the later stage. EEG may show high amplitude slow background with multifocal spikes
MRI of the brain shows an abnormal hyperintense signal in the globi pallidi on T2 weighted sequences. A marked reduction of the creatine signal peak on proton magnetic resonance spectroscopy (MRS) is demonstrable. Urinary guanidinoacetate (GAA) levels are elevated. Intracellular accumulation of GAA in the brain is considered to be both neurotoxic and epileptogenic
Oral supplementation of creatine monohydrate (400 mg/day) is used to replenish deficient cerebral creatine levels. Therapeutic strategies to reduce GAA levels include high-dose l-ornithine supplementation to competitively inhibit AGAT activity, and dietary arginine restriction to induce substrate deprivation
Sodium benzoate may also be beneficial as it reduces the production of GAA via conjugation with glycine to form hippuric acid, which is subsequently excreted by the kidneys
Adenylosuccinate Lyase (ADSL) Deficiency
an autosomal recessive disorder of purine metabolism. Adenylosuccinate lyase deficiency type I is most common, and is characterized by severe psychomotor retardation, early onset seizures and microcephaly
Seizure semiology is variable including myoclonus, focal onset seizures with or without impaired awareness, epileptic spasms, and status epilepticus. Concurrent autistic features are frequently seen. MRI may show non-specific abnormalities such as cerebral atrophy and delayed myelination
emonstration of the abnormal purine metabolites in the urine and molecular genetic testing for pathogenic mutations in the ADSL gene can provide diagnostic and genetic confirmation. Therapeutic interventions that may be of value include d-ribose administration, which increases the provision of phosporibosylpyrophosphate (PRPP), which in turn increases de novo purine synthesis
Lysosomal Storage Disorders
include conditions such as neuronal ceroid lipofuscinosis (NCL), gangliosidosis (GM1, GM2), Niemann–Pick disease, Gaucher’s disease and sialidosis. The early features are of a child with cognitive decline and seizures, while motor regression occurs later.
Gangliosidosis, Niemann–Pick disease, Gaucher’s disease and sialidosis are characterized by the presence of hepatosplenomegaly in addition to seizures and cognitive decline. Coarse facies are noted in GM1 gangliosidosis. Biochemical assays of lysosomal acid hydrolases in plasma, white blood cell pellets, or cultured skin fibroblasts can establish diagnoses of many lysosomal storage diseases and the identification of pathogenic mutations by molecular genetic testing is advisable to provide genotype–phenotype correlation and counseling
mitochondrial disorders
Epilepsy is a frequent manifestation of mitochondrial diseases, with seizures reported to occur in 35–60% of individuals with biochemically confirmed mitochondrial disease
epilepsy syndromes they can get inc ohtahara, West syndrome, Lennox–Gastaut syndrome, Landau–Kleffner syndrome, generalized epilepsy, and focal epilepsy
seizures are often preceded by or associated with other symptoms such as developmental delay, failure to thrive, ataxia, vision impairment, deafness, and evidence of multiorgan involvement. The MRI may show symmetrical signal abnormalities in the basal ganglia and/or cerebellum, cerebral and/or cerebellar atrophy, and white matter signal abnormalities. MRS studies often demonstrate an elevated lactate peak in affected regions of the brain. Explosive onset of focal epilepsy or epilepsia partialis continua in early life should raise suspicion of Alpers syndrome, particularly in cases with coexisting or later onset liver dysfunction
molecular genetic testing
In recognizable phenotypes such as Alpers syndrome and MELAS, the diagnosis can be readily confirmed by mutation testing. In other suspected mitochondrial epilepsies, diagnosis requires testing of blood and CSF lactate (which may be variably elevated), MRI and MRS of the brain, muscle biopsy (histology may show ragged red fibers and cytochrome oxidase (COX) negative fibers) and analysis of the respiratory chain enzymes on the muscle biopsy
use of sodium valproate must be avoided in all patients with suspected mitochondrial epilepsies, as this carries the risk of inducing fatal hepatotoxicity
Some patients may benefit from supplementation of thiamine, riboflavin, l-carnitine or coenzyme Q10. Arginine may be beneficial in reducing the stroke-like episodes in patients with MELAS
Levetiracetam is the drug of choice for myoclonic seizures in MERRF syndrome and lamotrigine may have a neuroprotective effect; A ketogenic diet may be beneficial in patients with refractory epilepsy associated with respiratory chain defects
progressive myoclonic epilepsy
syndromes represent a distinctive electroclinical phenotype consisting of myoclonus, epileptic seizures (most often generalized tonic–clonic, but sometimes focal onset, and atypical absences), cognitive decline, cerebellar ataxia, and progressively worsening clinical course
Vision impairment may be associated in many cases. The EEG background is slow, and interictal generalized epileptiform discharges are often associated with a photoparoxysmal response
onset of PME may mimic that of Juvenile myoclonic epilepsy (JME). PME can be caused by IEM as well as genetic degenerative brain diseases such as Unverricht–Lundborg disease and juvenile Huntington’s chorea. Several inborn errors of metabolism can cause PME including ceroid lipofuscinosis, sialidosis type 1, Gaucher disease type III, mitochondrial cytopathies, and Lafora disease
Certain drugs may worsen seizures, such as phenytoin, carbamazepine, gabapentin, vigabatrin, tiagabine, and lamotrigine. Preferred drugs are benzodiazepines, valproate, levetiracetam, topiramate, zonisamide, and phenobarbital
adolescent epilepsey with intelectual disability
can be caused by late-onset presentations of disorders of creatine metabolism, mitochondrial disorders, GLUT-1 deficiency, urea cycle defects, organic acidemias, succinic semi-aldehyde dehydrogenase deficiency (SSADH), and lysosomal storage disorders such as juvenile Niemann–Pick disease Type C
Clues to an underlying IEM include episodes of encephalopathy (especially during periods of stress and intercurrent infections, vomiting, ataxia, movement disorders, multisystem involvement, laboratory evidence of liver disease, visceromegaly, and vision and hearing impairment
