Epileptic Encephalopathy, Early Infantile, 5

A number sign (#) is used with this entry because of evidence that early infantile epileptic encephalopathy-5 (EIEE5) is caused by heterozygous mutation in the SPTAN1 gene (182810) on chromosome 9q34.

For a general phenotypic description and a discussion of genetic heterogeneity of EIEE, see EIEE1 (308350).

Tohyama et al. (2008) reported 2 unrelated Japanese infants, a girl and a boy, with early infantile epileptic encephalopathy. Both had onset of intractable seizures associated with hypsarrhythmia at age 3 months. Both had profound mental retardation with lack of visual attention and speech development, as well as spastic quadriplegia. Brain MRI showed diffuse hypomyelination and widespread brain atrophy affecting the cortex, corpus callosum, brainstem, and cerebellum. Progressive microcephaly was also observed.

Hamdan et al. (2012) reported an 11-year-old French Canadian boy with EIEE5 and severe intellectual disability. Although he did not present with early infantile spasms, he had febrile seizures at age 16 months and later developed mild generalized epilepsy. He could not walk or speak, but did understand a few commands and was able to communicate with a few signs. He had hypotonia, but no microcephaly or dysmorphic features. Brain MRI showed severe atrophy of the cerebellum and mild atrophy of the brainstem, without any hypomyelination or other structural defects. Overall, the phenotype in this patient was less severe than that of the patients reported by Saitsu et al. (2010).

Writzl et al. (2012) reported an 8-month-old Slovenian girl with EIEE5. Significant hypotonia had been apparent since birth. She had no visual contact, and ophthalmologic examination revealed bilateral coloboma-like optic discs. An abnormal EEG was noted on the third day of life; the patient subsequently developed intractable seizures with hypsarrhythmia and suppression burst-like pattern on EEG. Psychomotor development was severely impaired. Brain MRI showed hypomyelination, reduction of deep and subcortical white matter, and thin corpus callosum. Dysmorphic features included small anterior fontanel, low-set ears, and high-arched palate.

Nonoda et al. (2013) reported a 12-month-old Japanese boy with EIEE5 who developed seizures associated with hypsarrhythmia at 3 months of age. Brain imaging showed progressive atrophy of the brain, predominantly at the brainstem and cerebellum, and severe hypomyelination. He had progressive microcephaly (-3.2 SD at 7 months of age), severely impaired psychomotor development, no visual attention, and rigospastic tetraplegia. Genetic analysis identified a de novo heterozygous mutation in the SPTAN1 gene (182810.0005).

In 2 unrelated Japanese patients with EIEE5, previously reported by Tohyama et al. (2008), Saitsu et al. (2010) identified different de novo heterozygous mutations (182810.0001-182810.0002) in the SPTAN1 gene. In vitro functional expression studies suggested a dominant-negative effect of the mutations on spectrin heterodimer stability, as well as perturbation of the axon initial segment. Another unrelated patient with a similar disorder, previously reported by Tohyama et al. (2008) and Saitsu et al. (2008), was found to have a 2.25-Mb microdeletion encompassing both the STXBP1 (602926) and SPTAN1 genes. This patient had a slightly milder phenotype with well-controlled seizures and only mildly decreased white matter with no structural brain anomalies. Although she had hypomyelination at 12 months, she showed progression of myelination at age 4 years. Saitsu et al. (2010) hypothesized that this patient's phenotype was due more to haploinsufficiency of STXBP1 (see EIEE4; 612164), but that haploinsufficiency of SPTAN1 may have had some effect on myelination.

In an 11-year-old French Canadian boy with EIEE5, Hamdan et al. (2012) identified a de novo heterozygous mutation in the SPTAN1 gene (182810.0003). In vitro expression of the mutation in primary mouse cortical neurons caused formation of spectrin aggregates in about 20% of cells.