Malignant migrating focal seizures of infancy (ORPHA:293181)
A rare epileptic and developmental encephalopathy characterized by seizure onset during the first months of life, focal seizures arising independently in both hemispheres, marked drug resistance, and severe, long-term cognitive disability.
Epidemiology
The estimated prevalence of Epilepsy of infancy with migrating focal seizures (EIMFS) is approximately 1/900,000 children. Both sexes are equally affected.
Clinical description
Seizures start during the first 6 months of life, typically in the neonatal period. Seizures are initially infrequent and consist of focal motor, tonic or clonic seizures, showing in some patients as subtle seizures reported as behavioral arrest with minor motor signs, and prominent autonomic features. Seizure frequency rapidly increases and status epilepticus is common. At onset, focal seizures arise independently in both hemispheres and can migrate from one region to another. Seizures show a marked drug resistance. Neurological status progressively deteriorates with worsening seizures and leads to progressive hypotonia, loss of visual contact, and lack or regression of psychomotor achievements. Most patients develop microcephaly by 1 year of age.
Etiology
The genetic etiology is variable. 70% of children have an identified genetic etiology. Half of them present gain-of-function mutations affecting the KCNT1 gene, located on 9q34.4. In other cases, the genes involved may include SCN2A (2q24.3), KCNQ2 (20q13.33), PLCB1 (20p12.3), TBC1D24 (16p13.3),PIGA (Xp22.2), SCN1A (2q24.3), SLC25A22 (11p15.5), and SLC12A5 (20q13.12). The following genes have been reported in single cases: GABRA1, GABRB1, ATP1A3, CDKL5, and ITPA.
Diagnostic methods
Diagnosis is based on clinical and electroencephalographic (EEG) findings. The EEG background can be normal at onset; however, diffuse slowing of the background occurs with time. At onset, seizures may be subtle and video-EEG recordings are necessary to identify the seizures and the ictal EEG pattern. This is characterized by rhythmic theta discharges that affect different cortical regions consecutively in the same single seizure event giving the eponym ''migrating'' to EIMFS. Multifocal discharges appear with time in all cases. Rarely hypsarrhythmia is reported. Brain magnetic resonance imaging (MRI) is usually normal at onset and may show diffuse brain atrophy as the condition progresses. Delayed myelination with white matter hyperintensity on MRI and decreased N-acetyl aspartate on magnetic resonance spectroscopy are often reported early during the first months of the disease onset. Molecular genetic testing should be proposed in order to identify the causal pathogenic variant.
Differential diagnosis
Differential diagnosis includes other epileptic and developmental encephalopathies starting during the neonatal period, in particular when multifocal seizures and EEG abnormalities are present.
Antenatal diagnosis
Prenatal genetic diagnosis can be performed in families with a known mutation.
Genetic counseling
In the majority of patients, KCNT1 mutations arise de novo. In a few families with a known KCNT1 mutation, inheritance is autosomal dominant with variable penetrance and expressivity. Genetic counselling is highly recommended in all patients with known genetic etiology. According to the gene involved, the disorder may be autosomal dominant, autosomal recessive, or X-linked.
Management and treatment
Seizures are often difficult to treat and may continue into adulthood despite anti-seizures medications. Currently, there is no anti-seizures medication that has been proven to be more efficient to reduce seizure frequency and duration. Overtreatment should be avoided and follow-up by a reference center recommended.
Prognosis
Prognosis is poor with on-going drug resistant seizures, severe neurological disability, acquired microcephaly and reduced life expectancy, although a milder evolution has been reported in a few children. Some patients are also affected by severe gastrointestinal dysmotility and movement disorder.

                            Last update: 
                            June 2021


                            - Expert reviewer(s): 
                            Dr Giulia BARCIA | EpiCARE* - Dr Amy MC TAGUE  - Pr Rima NABBOUT | EpiCARE*


                                * European Reference Network