Approach to Epileptic Encephalopathies

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Algorithm for approach to investigations in Epileptic Encephalopathies - Click here

If EEG or MRI results are available click here to consider typical situations

Differential Diagnosis

  1. Epileptic Encephalopathies presenting with seizures as prominent /unique symptom
  2. Epileptic encephalopathies presenting with seizures associated in a syndromic phenotype associated with Suggestive somatic characteristics (i.e. dysmorphic features and/or alterations of head circumference)
  3. Epileptic encephalopathies presenting with Seizures associated with Movement disorders
  4. Epileptic encephalopathies presenting with seizures associated in a syndromic phenotype associated with acute multiorgan involvement

Rationale for the various investigations


Molecular Genetics

Epileptic encephalopathies presenting with seizures as prominent/unique symptomback-to-top-icon - Differential Diagnosis

Vitamin or enzymatic cofactor dependency

  • Pyridoxine dependent epilepsy
  • Folinic acid responsive epilepsy
  • Pyridoxal-5′-phosphate responsive epilepsy


  • Dravet and Dravet-like syndrome

Unknown/multiple etiology

  • Ohtahara syndrome (EIEE)
  • Early myoclonic encaphalopathy (EME)

Single enzyme or protein dysfunction

  • Syntaxin binding Protein 1 (STXBP1) deficiency
  • Glutamate mitochondrial transporters deficiencies (SLC25A22 and SLC25A18)
  • Phospholipase C beta-1 deficiency
  • MAGI2 related epileptic encephalopathy
  • Protocadherin 19 related epileptic encephalopathy

Disorders of amino acids metabolism

  • Hyperprolinemia type II

Neurotransmitters disorders

  • GABA transaminase deficiency

Epileptic encephalopathies presenting with seizures associated in a syndromic phenotype associated with Suggestive somatic characteristics (i.e. dysmorphic features and/or alterations of head circumference)back-to-top-icon- Differential Diagnosis


  • 1p36 monosomy
  • Wolf-Hirschhorn syndrome
  • 18q- syndrome
  • Angelman syndrome
  • Ring chromosome 20 syndrome
  • Down syndrome

Single enzyme or protein dysfunction

  • Cyclin-dependent kinase-like 5 (CDKL5) deficiency
  • Rett Syndrome (MeCP2, CDKL5 or FOXG1-related)

Cerebral malformations associated disorders

  • Focal cortical dysplasia (TSC1 and TSC2)
  • Polymicrogyria (SRPX2, KIAA1279, GPR56, PAX6, TBR2, COL18A1,
  • RAB3GAP1, 22q11., FLN1A, ARFGEF2, LRP)
  • Subcortical band heterotopia (DCX, LIS1, trisomy 9p)
  • Periventricular nodular heterotopia (unbalanced translocation,t[1; 6][p12; p12.2)]
  • Lissencephaly (LIS1, DCX, microdeletion in 17p including LIS1 and
  • YwaE, ARX, TUBA1A, RELN)
  • Schizencephaly (EMX2 involved in sporadic cases)
  • Early infantile epileptic encephalopathy type I (ARX-related EIEE1)
  • Miller-Dieker syndrome
  • Smith-Lemli–Opitz syndrome

Disorders of amino acids metabolism

  • Phenylketonuria and hyperphenylalaninemias

Vitamin or enzymatic cofactor dependency

  • Sulfite oxidase deficiency
  • Molybdenum cofactor deficiency
  • Menkes disease

Purine and pyrimidine metabolism disorders

  • Adenilosuccinate lyase deficiency
  • Dihydropyriminidase and Dihydropyrimidine dehydrogenase deficiency


 Epileptic encephalopathies presenting with Seizures associatd with Movement disordersback-to-top-icon - Differential Diagnosis

  • Energetic failure
    • GLUT1 deficiency syndrome
    • Creatine deficiency syndromes (AGAT, GAMT and X-linked creatine transporter deficiency)
  • Cerebral malformations associated disorders
    • EIEE1 (ARX-related epileptic encephalopathy)
  • Neurotransmitters disorders
    • 4-hydroxybutyric aciduria (SSADH)

 Epileptic encephalopathies presenting with seizures associated in a syndromic phenotype associated with acute multiorgan involvementback-to-top-icon - Differential Diagnosis

  • Acute multiorgan involvement
    • Endogenous toxicity
      • Urea cycle disorders
      • Organic acidurias
      • Congenital disorders of glycosilation
      • Glutathione synthetase deficiency
      • Mitochondrial disorders (SUCLA2, SUCLG1)
    • Vitamin or enzymatic cofactor dependency
      • Biotin metabolism disorders
    • Neurotransmitters disorders
      • Congenital glutamine deficiency
    • Channellopathy
      • Developmental delay, Epilepsy and Neonatal Diabetes (DEND syndrome)
    • Single enzyme or protein dysfunction
      • Hyperinsulinism/Hyperammoniemia (HI/HA)
  • Chronic multiorgan involvement
    • Energetic failure
      • Mitochondrial disorders (Leigh syndrome, multiple deletion syndrome or Alpers disease, pyruvate dehydrogenase deficiency)
    • Storage disorders
      • Lysosomal disorder (Krabbe disease)
      • Peroxisomal disorder (neonatal adrenoleukodystrophy, Zellweger syndrome, infantile Refsum disease, punctuate rhyzomelic chondrodysplasia)
      • Niemann-Pick disease type A and C
      • Neuronal ceroid lipofuscinosis
    • Single enzyme or protein dysfunction
      • MAGI2 deletion syndrome
    • Disorders of amino acids metabolism
      • Serine byosynthesis disorders
    • Unknown
      • Nesidioblastosis

Rationale for the various investigationsback-to-top-icon



Urine Vanillactic acid : Urine Vanillactic acid (VLA) is increased in pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency and Aromatic L-amino acid decarboxylase deficiency.

Cerebrospinal Fluid

CSF Pipecolic acid and Alphaamino adipic acid : Elevated quantities of Plasma alpha-aminoadipic semialdehyde (AASA) and its cyclic Shiff base, piperideine-6-carboxylate (P6C) are diagnostic for Pyridoxine-Dependent Seizures. Pipecolic acid may also be moderately elevated.
CSF Semialdehyde homovanillic acid
CSF 5 hydroxy indoleacetic acid
CSF 3methoxy thyroxine
CSF Aminoacids

Biochemical markers for Pyridoxine-dependent epilepsy and pyridox(am)ine phosphate oxygenase deficiency are, decreased concentrations of homovanillic acid and 5-hydroxyindoleacetic acid (stable breakdown products of dopamine and serotonin), and increased concentrations of 3-methoxytyrosine, glycine and threonine in cerebrospinal fluid.

Common Aminoacidopathies and Associated Amino Acid Elevationsback-to-top-icon


Common AminoacidopathiesElevated Amino Acids
Primary Aminoacidopathies  
Arginase deficiency Arginine, glutamine
Arginosuccinase deficiency Argininosuccinate, glutamine
Citrullinemia Citrulline, glutamine
Cystinuria Cystine, arginine (urine only)
Homocystinuria Homocystine
Maple syrup urine disease (MSUD) Valine, alloisoleucine
Phenylketonuria (PKU) Phenylalanine
Tyrosinemia Tyrosine
Secondary Aminoacidopathies  
Hyperammonemia Glutamine
Lactic acidosis Alanine
Organic acidurias selected Glycine
Transient tyrosinemia of the newborn Tyrosine

Increased Serum Guanidinoacetateback-to-top-icon

S-adenosylhomocyteine Hydrolase
Argininemia; Hyperargininemia, Arginase deficiency

Increased serum and urine Guanidinoacetate

Creatine Deficiency; Guanidioacetate Methyltransferase deficiency

Decreased Serum and Urine Guanidinoacetate

L-Arginine: Glycine Amidinotransferase deficiency

CSF Neurotransmitters

BH2 Dihydrobiopterin
BH4 Tetrahydrobiopterin
5-HIAA 5hydroxyindoleacetic acid
HVA Homovanillic acid
OMD 3-Ortho-methyldopa

Note: While interpreting CSF neurotransmitter assays, the HVA/HIAA ratio should always be considered to detect imbalances between the dopaminergic and the serotoninergic systems. However when both pathways are involved as in pterin defects or AADC deficiency, the ratio could be normal

Ceruloplasmin Levelsback-to-top-icon

Lower-than-normal ceruloplasmin levels:

Chronic liver disease
Intestinal malabsorption
Menkes' syndrome (Menkes' kinky hair syndrome)
Nephrotic syndrome
Wilson's copper storage disease

Higher-than-normal ceruloplasmin levels:
Acute and chronic infections

Blood lactate/pyruvate ratioback-to-top-icon

The normal lactate (0.8 to 2.2 mmol/L) to pyruvate (0.04 to 0.01 mmol/L) blood concentration ratio is less than 25 (lactate 25: pyruvate 1). The lactate/pyruvate ratio depends on the state of tissue oxygenation (lactate = pyruvate multiplied by the state of tissue oxygenation [t]).

The state of tissue oxygenation t depends on the amount of NADH2 and NAD in the cytosol (NADH2/NAD). So a metabolic disorder associated with lactic acidosis and a high number in t will have a high serum lactate level despite low serum pyruvate levels (increased lactate/pyruvate ratio [lactate >35: pyruvate 1]);

whereas diseases with lactic acidosis and a lower t will have a high serum lactate level at the expense of a high pyruvate level (low lactate/pyruvate level [lactate

CSF-to-Plasma glycine ratio

An increase in CSF glycine concentration together with an increased CSF-to-plasma glycine ratio suggests the diagnosis of Non-ketotic Hyperglycinemia or Glycine encephalopathy

Urine reducing substancesback-to-top-icon

A positive result indicates that reducing substances are present in the urine. Reducing substances include glucose, fructose, galactose, xylose, maltose, etc.

False positive results are produced by large amounts of ampicillin or similar penicillin derivatives as well as drugs that are excreted as glucuronides. Ascorbic acid (vitamin C) will give a positive test.

Urinary Metabolites by CCDS Disorder

DeficiencyGuanidinoacetate(GAA) ConcentrationCreatine Concentration**24-Hour Creatinine ExcretionCreatine / Creatinine Ratio
GAMT High (pathognomonic) Low Low to normal Normal
AGAT In or below the low normal range Low Low Normal
SLC6A8 Males Normal to slightly increased * High normal to high Low High(Diagnostic)
SLC6A8 Females Normal Normal to mildly elevated Unknown Normal to mildly elevated

**Urinary creatinine excretion is directly related to the intracellular creatine pool, which is diminished in disorders of creatine synthesis and creatine transport. Although assessment of the creatinine excretion in 24-hour urine samples may be helpful in the diagnosis of CCDS, this test reflects a nonspecific reduction of the body creatine pool and, thus, may not be reliable in individuals with reduced muscle mass (e.g., newborns; very young infants; and persons with muscle disease).

*If GAA is presented as guanidinoacetate mmol/mol creatinine, the values may appear slightly increased because of the generally lower creatinine values in males with SLC6A8 deficiency.

Plasma Concentration of Metabolites by CCDS Disorder

Deficiency GAA 1 Creatine Creatinine
GAMT 20-30x normal Low  
AGAT Less than age-related lowest level Normal Low to normal*
SLC6A8 Males Normal Normal to high  
SLC6A8 Females Normal Unknown  

*Determination of plasma creatinine concentration alone cannot identify a CCDS

CSF Concentration of Metabolites by CCDS Disorder

Deficiency GAA Creatine Creatinine
GAMT 100-300x normal Low  
AGAT No data Normal  
SLC6A8 Males No data Normal Reduced
SLC6A8 Females No data Unknown  

Molecular Genetic studiesback-to-top-icon

Aldehyde dehydrogenase (ALDH7A1 / ALDH4A1)

  • Hyperprolinemia, Type II

Pyridoxine-dependent epilepsy and folinic acid seizures are potentially reversible causes of neonatal seizures that have both been attributed to mutations of the ALDH7A1 (antiquitin) gene. This mutation results in the deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase, an enzyme that is important in lysine degradation

Pyridoxamine 5- phosphate oxidase (PNPO) 

  • Pyridoxamine 5-Prime-Phosphate Oxidase Deficiency
  • Pyridoxine-dependent epilepsy and
  • folinic acid seizuresback-to-top-icon

ARX- ARX-Related Disorders 

Includes: Agenesis of Corpus Callosum with Abnormal Genitalia | Epileptic Encephalopathy, Early Infantile, 1 | Partington X-Linked Mental Retardation Syndrome | X-Linked Lissencephaly with Ambiguous Genitalia | X-Linked Mental Retardation

Syntax binding protein 1 (STXBP1)

[Epileptic Encephalopathy, Early Infantile, 4]. Defects in STXBP1 are the cause of epileptic encephalopathy early infantile type 4 (EIEE4) [MIM:612164]. Affected individuals have neonatal or infantile onset of seizures, suppression-burst pattern on EEG, profound mental retardation, and MRI evidence of hypomyelination

Solute Carrier family 25 member 22 (SLC25A22) back-to-top-icon

Epileptic Encephalopathy, Early Infantile, 3

Phospholipase C-Beta1 Defects in PLCB1 are the cause of epileptic encephalopathy early infantile type 12 (EIEE12) [MIM:613722]. EIEE12 is a form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG


  • SCN1A Related Seizure disorders
    • SCN1A- Related Generalized Epilepsy with Febrile Seizures Plus
    • SCN1A-Related Intractable Childhood Epilepsy with Generalized Tonic-Clonic Seizures
    • SCN1A-Related Intractable Infantile Partial Seizures
    • SCN1A-Related Myoclonic-Astatic Epilepsy
    • SCN1A-Related Severe Myoclonic Epilepsy in Infancy
    • SCN1A-Related Simple Febrile Seizures

Protocadherin 19 (PCDH19)back-to-top-icon Epileptic Encephalopathy, Early Infantile, 9

PAH Phenylalanine Hydroxylase Deficiency]

LISX2 Lissencephaly X-linked 2

ATP7A Menkes Disease

ADSL Adenylosuccinase Deficiency

DPYS Dihydropyrimidinase Deficiency

DPYD Dihydropyrimidine Dehydrogenase Deficiency

MECP2 Classic Rett Syndrome ; MECP2-Related Severe Neonatal Encephalopathy PPM-X Syndrome

CDKL5 CDKL5-Related Angelman-like Syndrome, Epileptic Encephalopathy, Early Infantile, 2

FOXG1 Rett Syndrome, Congenital Variant

UBE3A Angelman Syndrome


Algorithm adapted from:
Mastrangelo M, Celato A, Leuzzi V (2012) A diagnostic algorithm for the evaluation of early onset genetic-metabolic epileptic encephalopathies.Eur J Paediatr Neurol 16 (2):179-91. DOI: 10.1016/j.ejpn.2011.07.015 PMID: 21940184.


Approach to Epileptic Encephalopathies

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