Clinical review of genetic epileptic encephalopathies

Abstract

Seizures are a frequently encountered finding in patients seen for clinical genetics evaluations. The differential diagnosis for the cause of seizures is quite diverse and complex, and more than half of all epilepsies have been attributed to a genetic cause. Given the complexity of such evaluations, we highlight the more common causes of genetic epileptic encephalopathies and emphasize the usefulness of recent technological advances. The purpose of this review is to serve as a practical guide for clinical geneticists in the evaluation and counseling of patients with genetic epileptic encephalopathies. Common syndromes will be discussed, in addition to specific seizure phenotypes, many of which are refractory to anti-epileptic agents. Divided by etiology, we overview the more common causes of infantile epileptic encephalopathies, channelopathies, syndromic, metabolic, and chromosomal entities. For each condition, we will outline the diagnostic evaluation and discuss effective treatment strategies that should be considered.

Fig. 1

FOXG1 Deletion. Frontal and side profile depicting microcephaly, wide and round face, sloping forehead, bitemporal narrowing, full cheeks, flat midface, large ears, and micrognathia.

Fig. 2

Mowat Wilson Syndrome. Characteristic facial features include bitemporal narrowing, hypertelorism with downslanting palpebral fissures, square jaw with micrognathia, pointed chin, malar hypoplasia, open mouth, rounded nasal tip, broad nasal bridge, columella extended below nasal tip, unusual ears with thick cupped helices and upturned fleshy lobes.

Fig. 3

Microcephaly Capillary Malformation Syndrome. Multiple round 1–2 cm capillary malformations (port wine stains) on the skin at birth. Facial features can include ptosis, hypertelorism, short nose, and downturned mouth, a low frontal hairline, flat nasal bridge, bilateral epicanthus, hypertelorism, thin upper lip and interrupted eyebrows. MRI shows a very simplified gyral pattern with widened extra-axial spaces suggesting atrophy, relative sparing of the cerebellum, severe hypomyelination, thin corpus callosum, and thin optic tracts.

Fig. 4

MCAP Syndrome Neuroimaging. A. Megalencephaly with thick corpus callosum. Cerebellar tonsillar ectopia after surgical decompression. B. Bilateral perisylvian polymicrogyria. C. MCAP Syndrome features a spectrum of anomalies including primary megalencephaly, prenatal overgrowth, brain and body asymmetry, cutaneous vascular malformations, digital anomalies (primarily syndactyly and/or postaxial polydactyly), and connective tissue dysplasia involving the skin, subcutaneous tissue, and joints.

Fig. 5

Ring Chromosome 14 Syndrome. Distinct facial features included a long face, full cheeks, high forehead, downslanting short palpebral fissures, hypertelorism, short nose with bulbous tip, long philtrum and small mouth with downturned corners.