Epileptic Encephalopathy, Early Infantile, 36

A number sign (#) is used with this entry because early infantile epileptic encephalopathy-36 (EIEE36) is caused by heterozygous mutation in the ALG13 gene (300776) on chromosome Xq23.

A hemizygous mutation in the ALG13 gene has been reported in 1 male infant with seizures and biochemical evidence of a congenital disorder of glycosylation (CDG1S).

Description

Early infantile epileptic encephalopathy-36 is an X-linked dominant neurodevelopmental disorder characterized by onset of seizures in infancy followed by delayed psychomotor development. Some patients may have dysmorphic features. Only females with this specific phenotype have been reported (summary by Dimassi et al., 2016).

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

For a discussion of the classification of CDGs, see CDG1A (212065).

Clinical Features

De Ligt et al. (2012) reported a 10-year-old girl who was born at 34 weeks' gestation and showed neonatal feeding problems, hypotonia, seizures, and severely delayed psychomotor development. She had a large head circumference (greater than 2.5 SD), and brain MRI showed hydrocephalus, myelination delay, and wide sulci. Other features included self-mutilation, sleep disturbance, and dysmorphic features, such as hypertelorism, broad coarse face, low-set ears, mild retromicrognathia, small hands and feet, joint contractures, and scoliosis. Isoelectric focusing of transferrin was not reported.

The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) reported 2 unrelated girls with early infantile epileptic encephalopathy. The patients had onset of seizures at ages 1 and 4 months, respectively. Both had severely delayed psychomotor development after onset of seizures and showed hypsarrhythmia on EEG. Isoelectric focusing of transferrin was not reported in these patients.

Michaud et al. (2014) reported a girl with EIEE36. She was diagnosed with focal infantile spasms at age 4 months. She had global developmental delay and severe intellectual disability. EEG showed hypsarrhythmia and multifocal discharges; brain MRI showed cerebral atrophy. Isoelectric focusing of serum transferrin was not reported.

Smith-Packard et al. (2015) reported a 7-year-old girl with EIEE36. She was diagnosed with cortical visual impairment at age 5 months and showed developmental regression at age 6 months. At age 8 months, she developed spasms associated with EEG abnormalities. The seizures remitted until age 5 years, when they became more severe and difficult to control. She had severe cognitive impairment with limited language (IQ range, 20-25), as well as feeding difficulties with gastric reflux. Isoelectric focusing of serum transferrin was normal, and Smith-Packard et al. (2015) suggested that the disease mechanism in females with ALG13 mutations may differ from that observed in males.

Dimassi et al. (2016) reported a 6-year-old girl who developed infantile spasms associated with hypsarrhythmia at age 2 months. She had severely delayed psychomotor development, was unable to sit, and had poor head control and limited eye contact. EEG showed slow background activity with multifocal spike and spike-wave discharges. Brain MRI showed global atrophy. She also had mild dysmorphic features, including hypertelorism, upturned nose, long philtrum, and adducted thumbs. Western blot analysis showed normally glycosylated transferrin isoforms.

Male Infant With Congenital Disorder Of Glycosylation Type 1S

Timal et al. (2012) reported a Caucasian boy with a severe multisystem disorder resulting in death at 1 year of age. He had refractory epilepsy with polymorphic seizures, hepatomegaly, swelling of hands, feet, and eyelids, recurrent infections, increased bleeding tendency, microcephaly, horizontal nystagmus, bilateral optic nerve atrophy, and extrapyramidal and pyramidal signs. Laboratory studies showed prolonged APPT. Transferrin isoelectric focusing showed abnormal N-glycosylation consistent with CDG type I.

Molecular Genetics

In a 10-year-old girl with EIEE36, de Ligt et al. (2012) identified a de novo heterozygous mutation in the ALG13 gene (N107S; 300776.0002). The patient was ascertained from a larger cohort of 100 patients with severe intellectual disability who underwent exome sequencing. The patient also carried a de novo heterozygous E89K variant in the KRT32 gene (602760) that was not thought to be pathogenic.

The Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous N107S mutation in the ALG13 gene in 2 unrelated girls with early infantile epileptic encephalopathy. The patients were part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. Functional studies of the variant were not performed.

Michaud et al. (2014) identified a de novo heterozygous N107S mutation in the ALG13 gene in a girl with EIEE36. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant were not performed. The girl also had a heterozygous 9p24.2 deletion inherited from her unaffected mother that was predicted to be benign. Michaud et al. (2014) postulated that ALG13 mutations in girls may represent either a dominant-negative or a gain-of-function effect.

Smith-Packard et al. (2015) identified a de novo heterozygous N107S mutation in the ALG13 gene in a girl with EIEE36. Functional studies of the variant were not performed.

Dimassi et al. (2016) identified a de novo heterozygous N107S mutation in a 6-year-old girl with EIEE36. Functional studies of the variant were not performed.

Male Infant With Congenital Disorder Of Glycosylation Type 1S

In a Caucasian boy with CDG1S, Timal et al. (2012) identified a hemizygous missense mutation in the ALG13 gene (K94E; 300776.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing. The mutation was not present in the blood of the mother, but was present on the maternally inherited allele, suggesting either maternal germline mosaicism or a de novo event. The ALG13 gene catalyzes the second step of lipid-linked oligosaccharide (LLO) synthesis, the incorporation of the second GlcNAc residue. Studies of patient-derived cells showed decreased enzyme activity, at about 17% of wildtype.