Differential Diagnosis
Epileptic encephalopathies presenting with seizures as prominent/unique symptom
Vitamin or enzymatic cofactor dependency- Pyridoxine dependent epilepsy
- Folinic acid responsive epilepsy
- Pyridoxal-5′-phosphate responsive epilepsy
Channellopathies
- 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)
Chromosomopathies
- 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 associated with Movement disorders
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 involvement
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 investigations
Biochemical
Urine
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 Elevations
| Common Aminoacidopathies | Elevated 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 Guanidinoacetate
- 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
- 5-MHTF:5-methyltetrahydrofolate
- 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 Levels
- Lower-than-normal ceruloplasmin levels:
- Chronic liver disease
- Intestinal malabsorption
- Malnutrition
- Menkes' syndrome (Menkes' kinky hair syndrome)
- Nephrotic syndrome
- Wilson's copper storage disease
- Higher-than-normal ceruloplasmin levels:
- Acute and chronic infections
- Lymphoma
Blood lactate/pyruvate ratio
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 substances
- 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
| Deficiency | Guanidinoacetate(GAA) Concentration | Creatine Concentration** | 24-Hour Creatinine Excretion | Creatine / 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 studies
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 seizures
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)
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
- 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) 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.
Cite this: ICNApedia contributors.Investigations in Epileptic Encephalopathies. ICNApedia, The Child Neurology Knowledge Environment. 24 June 2024. Available at: https://icnapedia.org/knowledgebase/articles/investigations-in-epileptic-encephalopathies Accessed 24 June 2024.
