Epileptic Encephalopathy, Early Infantile, 80

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-80 (EIEE80), also known as glycophosphatidylinositol biosynthesis defect-20 (GPIBD20), is caused by homozygous or compound heterozygous mutation in the PIGB gene (604122) on chromosome 15q21.

Description

Early infantile epileptic encephalopathy-80 (EIEE80) is an autosomal recessive neurologic disorder characterized by onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019).

For a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

Clinical Features

Murakami et al. (2019) reported 16 patients from 10 unrelated families with EIEE80. Several of the families were consanguineous, and the severity of the disorder was somewhat variable. Eight of the 16 patients died in the first months or years of life. The patients had global developmental delay, severely impaired intellectual development, hypotonia, and feeding problems apparent from early infancy. All had onset of seizures in the first year of life, most of which were refractory to treatment. Five patients had evidence of a degenerative axonal neuropathy or demyelinating sensorimotor neuropathy, often with weak or absent reflexes. About half had impaired hearing and variable visual problems, such as poor fixation, pale optic discs, and decreased response to visual evoked potentials. Most patients had dysmorphic features, including coarse facies, hypertelorism, wide or broad nasal bridge, long smooth philtrum with tented upper lip, large or protruding tongue, ear anomalies with upturned earlobes, micrognathia, pointed chin, full cheeks, and broad nasal bridge. Distal skeletal abnormalities, which were observed in most patients, included short distal phalanges with hypoplastic nails, triphalangeal thumbs, tapering fingers, and pes equinovarus. Brain imaging showed variable abnormalities in about half of patients, including thin corpus callosum, enlarged ventricles, poor myelination, and nonspecific white matter abnormalities; 2 patients had polymicrogyria. Laboratory investigation in most patients showed increased serum alkaline phosphatase, a characteristic finding in GPIBD. Other variable and nonspecific abnormalities included polyhydramnios during the pregnancies, premature birth, congenital heart defects, anal stenosis, constipation, and dry or rough skin. One family (family 1), a nonconsanguineous family of Moroccan descent, had previously been reported by van Bever et al. (2007) as having a clinical diagnosis consistent with DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures; see 220500). The patients in this family also had increased 2-oxoglutaric acid, which was not observed in the other patients.

Inheritance

The transmission pattern of EIEE80 in the families reported by Murakami et al. (2019) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected individuals from 10 unrelated families with EIEE80, Murakami et al. (2019) identified homozygous or compound heterozygous mutations in the PIGB gene (see, e.g., 604122.0001-604122.0006). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Patient lymphocytes and fibroblasts showed variably decreased levels of cell surface GPI-anchored proteins, including CD16 (see, e.g., CD16A, 146740) and CD59 (107271). In vitro functional expression studies performed with some of the mutations in PIGB-null CHO cells showed that the mutant proteins were unable to fully restore expression of GPI-anchored surface proteins, consistent with a loss of function, although the mutations had variable effects.