Overview

• Early myoclonic encephalopathy is a syndrome characterized by:
  • Frequent intractable seizures
  • Severe early encephalopathy
  • Limited development and reduced life expectancy
• Frequent myoclonic seizures distinguish this syndrome from Ohtahara syndrome.
• Early exclusion of treatable metabolic etiologies (especially pyridoxine and pyridoxal-5-phosphate disorders) is crucial.

Clinical Context

• Onset of seizures typically occurs within the first two months of life.
  • More than half of the cases have seizure onset by 10 days of life.
• Both sexes are equally affected.
• Antecedent and birth history is usually normal.
• Neurological examination reveals severe neurological impairment.
• Abnormal neurological behavior may be present before the onset of seizures.
• Head size is typically normal at onset; microcephaly may develop over time.
• Severe developmental delay is common, with or without regression.

Causes

• Overlap exists between the etiologies of Ohtahara syndrome and early myoclonic encephalopathy:
  • Metabolic etiologies are common:
    • Non-ketotic hyperglycinemia (most common cause)
    • Amino and organic acidopathies
    • Urea cycle disorders
    • Mitochondrial disorders
    • Pyridoxine and pyridoxal-5-phosphate disorders
    • Molybdenum cofactor deficiency
    • Sulfite oxidase deficiency
    • Menke syndrome
    • Zellweger syndrome
    • Other disorders
  • Structural brain abnormalities are rare.
  • Genetic causes
    • ErbB4, SLC25A22

Seizures

• All patients experience frequent (near-continuous), fragmentary erratic myoclonus.
• Myoclonus migrates from body part to body part asynchronously, asymmetrically, and randomly.
• The face and limbs are commonly affected.
• Myoclonus can be highly localized (e.g., to a finger, toe, eyelid, or lip).

• Other Seizures:
  • After the onset of myoclonus, focal seizures and later epileptic spasms or tonic seizures (generalized tonic or focal tonic) may occur.
  • Focal seizures are often subtle and may be accompanied by tonic eye version and autonomic features (e.g., apnea or facial flushing).
  • Massive, usually bisynchronous, axial myoclonic jerks may occur.

Background/Interictal EEG

• The background EEG is abnormal in all states, displaying a suppression-burst pattern.
• High voltage bursts (150-300 µV) of spikes or sharp and slow waves, lasting 1-5 seconds, are seen with inter-burst intervals of 3-10 seconds.
• EEG may evolve to a hypsarrhythmia pattern in children who develop West syndrome or to a pattern of multifocal spikes and sharp waves at 3-4 months of age.

Ictal EEG

• Erratic myoclonus usually does not have an ictal EEG pattern but may follow bursts on the EEG.
• Focal seizures are associated with focal ictal discharges, often superimposed on the suppression-burst background.

Imaging

• Neuroimaging findings depend on the underlying cause.
• Imaging is often normal at onset, but cerebral atrophy commonly develops over time.

Genetics

• Pattern of Inheritance:
  • The condition is usually de novo, but this depends on the underlying etiology as metabolic disorders may be inherited in Mendelian fashion.
• Known Genes:
  • ErbB4, SLC25A22 (Cohen R et al., 2014), STXBP1 and SPTAN1 (Nicita et al., 2015), GABRB2 (Ishii A et al., 2017)
• Family History of Seizures/Epilepsy:
  • Family history of seizures or epilepsy is usually absent.
  • A positive family history should prompt a search for a genetic or metabolic etiology.

Differential Diagnosis

• Ohtahara syndrome

References

Cohen R, Basel-Vanagaite L, Goldberg-Stern H, Halevy A, Shuper A, Feingold-Zadok M | display-authors=etal (2014) Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22. Eur J Paediatr Neurol 18 (6):801-5. DOI: 10.1016/j.ejpn.2014.06.007 PMID: 25033742.

Nicita F, Ulgiati F, Bernardini L, Garone G, Papetti L, Novelli A | display-authors=etal (2015) Early myoclonic encephalopathy in 9q33-q34 deletion encompassing STXBP1 and SPTAN1. Ann Hum Genet 79 (3):209-17. DOI: 10.1111/ahg.12106 PMID: 25779878.

Ishii A, Kang JQ, Schornak CC, Hernandez CC, Shen W, Watkins JC | display-authors=etal (2017) A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy. J Med Genet 54 (3):202-211. DOI: 10.1136/jmedgenet-2016-104083 PMID: 27789573.