A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-47 (DEE47) is caused by heterozygous mutation in the FGF12 gene (601513) on chromosome 3q28.

Developmental and epileptic encephalopathy-47 (DEE47) is a neurologic disorder characterized by onset of intractable seizures in the first days or weeks of life. EEG shows background slowing and multifocal epileptic spikes, and may show hypsarrhythmia. Most patients have developmental regression after seizure onset and show persistent intellectual disability and neurologic impairment, although the severity is variable. Treatment with phenytoin, a voltage-gated sodium channel blocker, may be beneficial (summary by Guella et al., 2016).

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

Siekierska et al. (2016) reported 2 sibs, born of unrelated Caucasian parents, with early infantile epileptic encephalopathy resulting in death at ages 7 and 3.5 years. The proband developed tonic seizures at age 14 days, and her younger brother had onset of seizures at age 4 weeks. The seizures developed into severe refractory epilepsy associated with EEG abnormalities, including severe background slowing, multifocal epileptic abnormalities, and hypsarrhythmia. This was followed by severely delayed psychomotor development with profound intellectual disability, inability to stand or walk, cerebral visual impairment, feeding difficulties necessitating tube feeding, and absent speech development. Other features included acquired microcephaly, axial hypotonia, and limb ataxia. Funduscopy was normal initially, but later showed pale optic discs. Brain imaging was normal in early infancy, but later showed cerebellar atrophy. The findings were consistent with a progressive and degenerative process.

Al-Mehmadi et al. (2016) reported 3 unrelated patients with DEE47. The patients had a slightly different disease course, despite sharing the same de novo heterozygous mutation (R52H; 601513.0001). Patient 1 was a 3-year-old boy who had onset of intractable seizures on the second day of life, with frequent status epilepticus. EEG showed background slowing and multifocal discharges. He had severe global developmental delay and was nonverbal with poor visual and social interaction, hypotonia with head lag, and could only sit with support. He was tube-fed and had chronic constipation. Brain imaging was normal at onset, but showed enlarged ventricles at age 2 years. Treatment included a ketogenic diet and medications; phenytoin was not used. The second patient was a 16-year-old girl who developed seizures at age 6 weeks, had severe cognitive impairment with single words, but showed normal motor development and could ambulate. Seizures included generalized tonic-clonic and partial seizures. She was started on phenytoin at age 6, with some improvement. Since age 7, she developed transient ataxia after seizures. Vagal nerve stimulation improved the frequency and intensity of seizures and ataxia. Brain imaging at age 16 months was normal, but showed cerebellar atrophy at age 8 years. She had chronic constipation and required help with all activities of daily living. Patient 3 was an 18-year-old girl had intractable epilepsy since day 2 of life associated with EEG abnormalities. She had moderate intellectual disability, but could read simple books and ambulate with an abnormal gait. She had chronic constipation, hypohidrosis, and reduced lacrimation, suggesting autonomic dysfunction. Brain imaging showed mesial temporal sclerosis and mild prominence of the cerebellar folia. She was treated with phenytoin and vagal nerve stimulation.

Guella et al. (2016) reported a 15-year-old girl with DEE47 who developed tonic seizures on the second day of life. EEG showed background slowing and multifocal spikes. The seizures did not respond to several medications, and she had an allergic reaction to carbamazepine; phenytoin was never used. She had developmental delay with regression at times of increased seizure frequency, moderate intellectual disability with speech delay, and autism. Brain imaging showed an incidental Chiari I malformation.

Guella et al. (2016) reported an 11-month-old girl who developed seizures on the third day of life and was found to carry a de novo heterozygous R52H mutation in the FGF12 gene. Initial interictal EEG showed multifocal spikes, and continuous EEG monitoring showed multiple seizures, including during sleep. The seizures were unresponsive to several medications at first, but she did respond to phenytoin on day 20. She had normal development and a normal neurologic examination at age 11 months. Brain imaging on day 4 of life was normal. Guella et al. (2016) noted that the phenotype in this patient was significantly milder than that observed in other patients with the same mutation.

Takeguchi et al. (2018) identified 2 unrelated Japanese patients with DEE47. Patient 1 was diagnosed with early infantile epileptic encephalopathy, and patient 2 was diagnosed with epilepsy of infancy with migrating focal seizures. Seizures in patient 1 were resistant to several antiepileptic medications, whereas patient 2 responded well to phenytoin and high-dose phenobarbital. MRI in patient 1 was normal at age 7 years, with mildly enlarged lateral ventricles on an MRI at age 14 years. MRI in patient 2 showed mild cerebral atrophy at 7 months of age. Both patients had severely impaired intellectual development. The authors emphasized that DEE47 might exhibit diverse phenotypes and may respond to sodium channel blockers or high-dose phenobarbital.

The heterozygous mutations in the FGF12 gene that were identified in patients with DEE47 by Al-Mehmadi et al. (2016) and Guella et al. (2016) occurred de novo. The mutation in patient 1 of Takeguchi et al. (2018) was inherited from a mosaic parent.

In 2 sibs with DEE47, Siekierska et al. (2016) identified a de novo heterozygous missense mutation in the FGF12 gene (R114H; R52H in the B isoform; 601513.0001). The mutation, which was found by exome sequencing, was not present in either parent, suggesting germline mosaicism. In vitro functional expression studies in neuronal cells showed that the mutation changed the voltage dependence of inactivation gating of sodium channels, resulting in a gain-of-function effect and increased neuronal excitability. Transfection of the orthologous mutation in zebrafish caused epileptiform activity in larval optic tecta.

Al-Mehmadi et al. (2016) identified a de novo heterozygous R52H mutation in the FGF12 gene in 3 unrelated patients with DEE47. The mutations were found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the authors noted that their findings, combined with the report of Siekierska et al. (2016), suggested that DEE47 is an FGF12 R52H mutation-specific disease.

Guella et al. (2016) identified a de novo heterozygous R52H mutation in 2 unrelated patients with DEE47. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed. Guella et al. (2016) noted that 1 of the patients had normal development and neurologic examination at age 11 months, which may have resulted from early successful treatment with phenytoin at 20 days of age. The findings significantly expanded the phenotype associated with this specific mutation, suggesting that other genetic and/or environmental factors may be involved.

Using whole-exome sequencing in 2 unrelated Japanese patients with epileptic encephalopathy, Takeguchi et al. (2018) identified heterozygosity for the R114H mutation in the FGF12 gene. Both patients started having seizures a few days after birth; patient 1 was diagnosed with early infantile epileptic encephalopathy, and patient 2 was diagnosed with epilepsy of infancy with migrating focal seizures, which responded well to phenytoin and high-dose phenobarbital. The phenotypically normal mother of patient 1 was found to be mosaic for the mutation. The mutation in patient 2 occurred de novo. The authors noted that DEE47 is associated with diverse phenotypes and may respond to sodium channel blocker or high-dose phenobarbital.