Table of Contents
- Etiology and Pathophysiology
- 1. Substrate Deficiency
- 2. Enzyme Deficiency
- A. Accumulation of Neurotoxic compounds
- B. Neurotransmitters and amino acid imbalance
- C. Brain Malformations
- 3. Vitamin / Co-factor deficiency
- A. Co-factors and Vitamins dependency
- B. Molecular transport abnormalities
- 4. ATP Depletion
- A. Reduced Energy Supply
- Clinical Approach
- Figure 1. Clinical approach to metabolic causes of epilepsy
- Further Reading
- Epilepsy is a chronic neurological disorder characterized by repeated aberrant electrical activity in the brain and recurrent spontaneous seizures.
- Major causes of epilepsy include:
- Genetic Disorders (e.g, Fragile X syndrome, Down syndrome, Angelman syndrome etc)
- Structural Aberrations (e.g, Tuberous sclerosis, Sturge-weber syndrome, atriovenous malformations, tumors etc)
- Metabolic Disturbances (e.g, GLUT-1 deficiency, MELAS syndrome etc)
- Immune Dysfunction (e.g, Rasmussen syndrome, anti-NMDA receptor encephalitis etc)
- Infectious Diseases (e.g, meningitis, toxoplasmosis, encephalitis etc)
- Unknown causes
- Metabolic reasons account for a minor part of epilepsy etiology, with more than 200 metabolic causes of epilepsy discovered thus far.
- They are often resistant to standard anti-epileptic therapy, but may respond differently depending on the cause.
- Dietary modification and supplementation, either alone or in conjunction with antiepileptic medicines, are used to treat the various kinds of metabolic epilepsy.
- Seizures are frequently accompanied by a range of other neurological, systemic, or metabolic symptoms. Presence of such symptoms lowers the threshold for investigating for metabolic etiology.
- A favourable long-term prognosis requires prompt diagnosis and management.
Metabolic abnormalities is the most prevalent cause of seizures in infancy and childhood
Etiology and Pathophysiology
A simple chemical reaction in the neurons is shown below:
Any change in the amounts of substrates, enzymes, cofactors, or ATP can result in reduced levels of neuronal function products. This is the foundation of metabolic causes of epilepsy.
Seizures in metabolic illnesses can have a complex etiology that involves one or more of the following mechanisms:
1. Substrate Deficiency
- A lack of a single substrate that creates several products required for appropriate neuronal function may result in impaired neuronal function and, eventually, seizures.
- One such example is Serine Deficiency.
Serine Deficiency d/t impaired Serine Biosynthesis → Impaired neuronal function → Seizures
2. Enzyme Deficiency
- Enzyme deficiency can lead to metabolic seizures by the following mechanisms:
A. Accumulation of Neurotoxic compounds
- Toxic substrates are broken down by enzymes into easily excretable compounds.
- Deficiency in such enzymes may result in hazardous chemical buildup in the CSF and brain, resulting in decreased neuronal function and seizures.
- Ammonia accumulation is one such example.
Ammonia accumulation → Increased glutamine synthesis → Swelling of astrocytes and brain edema → Seizures
- Examples of metabolic disorders in this category include Urea Cycle Disorders and Organic Acidemias.
B. Neurotransmitters and amino acid imbalance
- Neurotransmitters regulate the precise balance of inhibition and stimulation of neurons in the brain.
- A lack of enzymes, which results in a differential drop in neurotransmitter levels, can upset this balance.
- A hyperexcitable condition caused by an increase in excitatory neurotransmitters and/or a reduction in inhibitory neurotransmitters resulting in seizures.
- Glycine excess due to decreased hepatic glycine cleavage is one example in this case.
Glycine Excess → NMDA excitation in brain → Hyperexcitability → Seizures
- Example of metabolic disorders in this category include Epilepsy due to deficiency of GABA transaminase and defects of GABA metabolism.
C. Brain Malformations
- Enzyme deficiency may result in a buildup of substrates that must be broken down.
- The buildup of redundant contents in neurons can result in macroscopic brain abnormalities and disorganised neuronal activity in the brain.
Enzyme Deficiency → Substrates accumulation in brain → Neuronal Deformation and Brain Malformation → Uncoordinated neuronal activity → Seizures
- Example of metabolic disorder in this category include Zellweger syndrome.
3. Vitamin / Co-factor deficiency
A. Co-factors and Vitamins dependency
- Co-factors and vitamins are essential components of the body's chemical reactions.
- Neuronal metabolism is also largely reliant on the proper concentration of co-factors and vitamins required for numerous chemical processes.
- Any factor that reduces their concentration causes neurotransmitter imbalance and the accumulation of aberrant substrates, resulting in neuronal dysfunction and seizures.
- One such example is Pyridoxine Dependent Epilepsy.
Pyridoxal Phosphate Deficiency → Low Pyridoxine generation in neurons → Neurotransmitters Imbalance → Seizures
B. Molecular transport abnormalities
- Carrier proteins serve as a means of molecular transport in the body.
- Any factor impairing the transport of essential metabolic substrates, products or co-factors can lead to neuronal metabolic imbalances and cause seizures.
- One such example is the Menke Disease.
Impairment of copper transport → Dysfunction of several copper-dependent enzymes necessary for maintaining neuronal metabolism → Neuronal Impairment → Seizures
4. ATP Depletion
A. Reduced Energy Supply
- Glucose is the main energy source for the brain.
- Reduced energy states may arise due to: - Hypoglycemia - Impaired brain glucose transport - Impaired ATP generation in the mitochondria
- This state of hypoglycemia leads to seizures by neuronal function impairment.
Decreased ATP production → Neuronal Na/K-ATPase malfunction → unstable membrane potentials → Seizures
- Examples of metabolic disorders in this category include hypoglycemia, Glut-1 deficiency, respiratory chain deficiency, mitochondrial disorders.
A disturbed metabolic state (eg, high fever, hypocalcemia, hyponatremia) can cause acute symptomatic seizures by inducing a transient disruption of cortical neuronal function. These are a separate entity from metabolic seizures, transient and resolve once the trigger is removed.
Serine Deficiency Glycine Encephalopathy Maple Syrup Urine Disease Urea Cycle Disorders Organic Acidemia Sulfite Oxidase Deficiency Phenylketonuria
↓ serine and glycine in plasma and CSF ↑ Glycine in CSF and plasma Newborn screening; and ↑ Alloisoleucine and branched chain amino acids in serum, disturbing the normal isoleucine:leucine:valine ratio of 1:2:3 Newborn screening; ↑ plasma Ammonia levels ↑ 3-hydroxypropionic acid, methylcitric acid, and propionylglycine in propionic acidemia on urine organic acid analysis. ↑ methylmalonic and methylcitric acids in methylmalonic acidemia on urine organic acid analysis. ↑ S-sulfocysteine in plasma and urine Newborn screening (hyperphenylalaninemia), ↑ pterins in urine (atypical PKU)
Mutations in the PHGDH, PSAT1, and PSPH genes Mutations in the GLDC, AMT, and GCSH genes Mutations in the BCKDHA, BCKDHB, and DBT genes Mutation identification in the genes that encode the urea cycle enzymes: NAGS, OTC, CPS1, ASS1, ASL, and ARG1 For propionic acidemia: mutation identification in the PCCA or PCCB genes For methylmalonic acidemia: mutation identification in the MMUT gene Mutation identification in the SUOX gene that encodes sulfite oxidase enzyme Dihydropteridine reductase enzyme activity assessment in erythrocytes, fibroblasts and lymphocytes
Oral L-serine 200–600 mg/kg/day Sodium benzoate, NMDA receptor antagonists (seziure control) Branched-chain aminoacid restricted diet, adjunctive compounds Dietary protein restrictions; adjunctive compounds Dietary restrictions; adjunctive compounds to dispose of toxic metabolites or increase activity of deficient enzymes No specific therapy, low cysteine and methionine diet in some cases Phenylalanine restriction, BH4, L-Dopa, 5-hydroxytryptophan, and folinic acid supplementation
Mitochondrial diseases Glucose transporter type 1 deficiency Guanidinoacetate methyltransferase deficiency Fatty acid oxidation defects
Lactic acidemia, hypoglycemia, elevated TCA (tricarboxylic acid cycle) intermediates in urine organic acids, and elevated alanine in plasma amino acids. ↓ CSF glucose, ↓ CSF-to-blood glucose ratio (<0.46) ↑ guanidinoacetate in blood and urine Newborn Screening and acylcarnitine profile
Mutation identification in mtDNA or nDNA genes Mutation identification in the SLC2A1 gene Mutation identification in the GAMT gene DNA testing is confirmatory.
Adjunctive compounds Ketogenic diet Creatine monohydrate 350–500 mg/kg/day, dietary arginine restriction, ornithine supplementation
Pyridoxine-dependent epilepsy Pyridoxal phosphate-responsive epilepsy Early-onset vitamin B6-dependent epilepsy Cerebral folate deficiency Methylenetetrahydrofolate reductase deficiency Molybdenum cofactor deficiency Biotinidase deficiency Holocarboxylase synthetase deficiency Menke’s Disease
↑ 𝜶AASA levels in urine, plasma, and CSF, ↑ P6C in urine ↓ pyridoxal phosphate in CSF ↑ glycine and threonine in CSF and plasma ↑ 3-methoxytyrosine in CSF ↓ 5-hydroxyindolacetic acid and homovanillic acid in CSF. ↑ lactate, metabolic acidosis, ↑ glycine in plasma and CSF ↓ MTHF level in CSF with normal plasma folate levels ↑ total plasma homocysteine, ↓ methionine, ↓ CSF MTHF, ↓ blood folate level ↑ S-sulfocysteine in plasma and urine, ↑ total homocysteine and cystine in plasma ↓ serum uric acid level, ↑ urinary xanthine and hypoxanthine levels Metabolic acidosis, lactic acidosis, and hyperammonemia ↑ 3-methylcrotonylglycine, 3-hydroxyisovalerate, methylcitrate, propionylglycine, and hydroxypropionate in urine Metabolic acidosis, lactic acidosis, and hyperammonemia ↑ 3-methylcrotonylglycine, 3-hydroxyisovalerate, methylcitrate, propionylglycine, and hydroxypropionate in urine ↓ serum copper and cerulopasmin and ↑ urine homovanillic acid : vanillylmandelic acid.
Mutation identification in the ALDH7A1 gene Mutation identification in the PNPO gene Mutation identification in the PLPBP gene Mutation identification in the FOLR1 gene Mutation identification in the MTHFR gene Mutation identification in the MOCS1, MOCS2, or GPHN genes Mutation identification in the BTD gene Mutation identification in the HLCS gene Mutation identification in ATP7B gene
100 mg IV pyridoxine → oral 5–15 mg/kg/day in two divided doses Oral PLP 10 and 30 mg/kg/day Pyridoxine, pyridoxal phosphate, or a combination of both treatments Folinic acid supplementation, milk-free diet (debatable) Oral betaine supplementation IV cPMP for type A, No specific therapy for other types Oral biotin 5 to 10 mg/day Oral biotin Subcutaneous injections of copper histidine
Lesch-Nyhan syndrome Adenylosuccinate Iyase deficiency Dihydropyrimidine dehydrogenase deficiency Dihydropyrimidinase deficiency
↑ uric acid levels in urine and blood ↑ succinylaminoimidazole carboxamide riboside and succinyladenosine in urine, CSF, and plasma ↑ uracil and thiamine levels in urine, plasma and CSF ↑ dihydrouracil and dihydrothymine in urine Moderate elevations of uracil and thiamine in urine also seen.
Mutation identification in the HGPRT1 gene Mutation identification in the ADSL gene Mutation identification in the DPYD gene Mutation identification in the DPYS gene
Xanthine Oxidase inhibitors, symptomatic treatment No effective treatment Symptomatic treatment Symptomatic treatment
Zellweger spectrum disorder Gaucher disease type 2 and 3 Niemann-Pick type C Metachromatic leukodystrophy
↑ phytanic acid and VLCFA, ↓ plasmalogens Glucocerebroside deposits in liver, bones, kidneys, CNS, spleen Sphingomyelin accumulation in organs Sulfatide compounds accumulation in neural and nonneural tissue (kidneys and gallbladder)
Mutation identification in the PEX genes Mutation identification in the GBA gene Mutation identification in NPC1 or NPC2 genes Mutation identification in the ARSA gene
Dietary restrictions, adjunctive compounds No specific therapy Glycosphingolipid synthesis inhibitor No specific therapy
Congenital Disorders of Glycosylation
Mutation identification in the CAD gene
- First level investigations:
- complete blood count
- arterial blood gases and electrolytes
- blood glucose
- liver functions tests
- plasma ammonia
- serum uric acid
- thyroid functions tests
- Second level investigations:
- Newborns or infants with epilepsy and developmental delay
- Therapeutic trials with pyridoxine, pyridoxal 5 phospate or folinic acid;
- In patients with response to therapeutic trials:
- urinary vanillactic acid
- serum pipecolic acid
- SF pipecolic acid
- CSF alpha aminoadipic semialdehyde
- CF biogenic amine
- CF aminoacid;
- In patients without response to therapeutic trials:
- copper and ceruloplasmin in plasma
- CF aminoacids
- Patients with epilepsy and movement disorders
- Lactate, pyruvate, lactate/pyruvate ratio and guanidoacetate in blood
- Urinary creatine/creatinine ratio and pterins
- Lactate, pterins, biogenic amine and glycorrachia/glycemia ratio in CSF
- Patients with multiorgan involvement
- Lactate, pyruvate, lactate/pyruvate ratio, acylcarnitines, aminoacids, folic acids, homocysteine, sialotransferrin isoelectring focusing in plasma
- Ketones, organic acids, orotic acid, purine and pyrimidine in urine
- Third level investigations:
- Biopsy: skin (lysosomal storage disease) or muscle (mitochondrial diseases)
- Oriented molecular genetics investigations
Figure 1. Clinical approach to metabolic causes of epilepsy
It is vital to understand that the seizure itself may cause a rise in lactate levels; however, this increase is transitory, and lactate is swiftly eliminated when the seizure has ended. As a result, finding a sustained increase in lactate 1 or 2 hours after a seizure enhances the possibility of metabolic illnesses such as mitochondrial abnormalities and organic acidemias.
- Seizures that are refractory to conventional therapy, have involved more than one organ system, present with characteristic deformities and/or severity increasing with time, need a prompt metabolic workup.
- A correct diagnosis may not only impact therapy, but it may also allow for family counselling, which is an essential aim even if there are no direct therapeutic consequences.
- Once a diagnosis is reached, the possibility of a specific treatment is explored, which often improves epilepsy and also other symptoms.
- After initial stabilization of these patients, a comprehensive metabolic analysis as shown in the clinical approach section, is pursued.
- Pyridoxine and Pyridoxal Phosphate should be given as therapeutic trial to the patients.
- If seizures are refractory to anti-epileptic drugs, a trial of folinic acid is also recommended.
- Treatment with antiepileptic drugs often needs to be continued nevertheless.
- If no particular therapy is available, antiepileptic medication should be administered based on seizure phenotype and epilepsy syndrome.
- In the long-run, These errors of metabolism are treated with "sick–day" management, medical diets, cofactor/vitamin supplements, substrate inhibition, stem cell transplant, and gene therapy.
- Clinically and on EEG, therapeutic results range from full control to improvement or avoidance of epilepsy.
- Secondary outcomes include improved or stable psychomotor/cognitive development, behavioral/psychiatric disorders, seizures, and neurologic and systemic symptoms.
- Care must be taken in diagnosing the condition and once diagnosed, working up on the associated co-morbidities.
Valproic acid should NOT be used for seizure control in mitochondrial disorders and urea cycle disorders, and used with caution in many other inborn errors of metabolism.
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