#619606
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-99 (DEE99) is caused by heterozygous mutation in the ATP1A3 gene (182350) on chromosome 19q13.
Developmental and epileptic encephalopathy-99 (DEE99) is characterized by onset of seizures in early childhood associated with global developmental delay and severely impaired intellectual development. Other features may include hypotonia, quadriparesis, nystagmus, and apnea. Brain imaging may be normal or show nonspecific and variable abnormalities, including cerebral atrophy and polymicrogyria. The severity is variable; some patients die of refractory status epilepticus (summary by Vetro et al., 2021).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Vetro et al. (2021) reported 14 unrelated children and one mother/son pair (patients 14 and 15), ranging from infancy to 32 years of age, with onset of various types of seizures between birth and 4 years, although most had onset in early infancy. Seizure types included focal, multifocal, clonic, tonic, migrating focal seizures, and generalized tonic-clonic seizures. Some had apnea, hypertonic posturing, eye deviation, or dyscognitive seizures. Six patients died in childhood mainly due to respiratory complications of refractory status epilepticus. EEG was abnormal in all patients, demonstrating multifocal discharges and slow background activity. One patient (patient 11) had a burst-suppression pattern. Most patients had severe developmental delay with intellectual disability and hypotonic quadriparesis. Less common features included tube feeding, microcephaly, optic atrophy, nystagmus, poor or absent speech, and dyskinesia. Brain imaging was normal in 4 patients, but showed variable abnormalities in the others, including cerebral atrophy, dilated ventricles, and thin corpus callosum. Polymicrogyria was observed in 9 patients. The only patient without overt seizures was the mother (patient 15): she did have EEG abnormalities, mild intellectual disability, dyspraxia, migraine, and polymicrogyria with a thick corpus callosum on brain imaging.
Most of the heterozygous mutations in the ATP1A3 gene that were identified in patients with DEE99 by Vetro et al. (2021) occurred de novo. One mutation was transmitted from an unaffected man to his mildly affected daughter and severely affected grandson, indicating incomplete penetrance and variable expressivity.
In 16 patients from 15 families with DEE99, Vetro et al. (2021) identified 14 heterozygous mutations in the ATP1A2 gene (see, e.g., 182350.0019-182350.0021). The mutations occurred de novo in all except for a mother and son pair (patients 14 and 15). Most mutations were missense, with a few small in-frame deletions or insertions. All occurred at conserved residues, and none were present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. Vetro et al. (2021) estimated that about 12% of ATP1A3 mutations may be associated with DEE. Polymicrogyria was estimated to be observed in about 5.5% of patients with ATP1A3 mutations.
Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. Brain 144: 1435-1450, 2021. [PubMed: 33880529, related citations] [Full Text]
ORPHA: 442835; DO: 0070385;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
19q13.2 | Developmental and epileptic encephalopathy 99 | 619606 | Autosomal dominant | 3 | ATP1A3 | 182350 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-99 (DEE99) is caused by heterozygous mutation in the ATP1A3 gene (182350) on chromosome 19q13.
Developmental and epileptic encephalopathy-99 (DEE99) is characterized by onset of seizures in early childhood associated with global developmental delay and severely impaired intellectual development. Other features may include hypotonia, quadriparesis, nystagmus, and apnea. Brain imaging may be normal or show nonspecific and variable abnormalities, including cerebral atrophy and polymicrogyria. The severity is variable; some patients die of refractory status epilepticus (summary by Vetro et al., 2021).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Vetro et al. (2021) reported 14 unrelated children and one mother/son pair (patients 14 and 15), ranging from infancy to 32 years of age, with onset of various types of seizures between birth and 4 years, although most had onset in early infancy. Seizure types included focal, multifocal, clonic, tonic, migrating focal seizures, and generalized tonic-clonic seizures. Some had apnea, hypertonic posturing, eye deviation, or dyscognitive seizures. Six patients died in childhood mainly due to respiratory complications of refractory status epilepticus. EEG was abnormal in all patients, demonstrating multifocal discharges and slow background activity. One patient (patient 11) had a burst-suppression pattern. Most patients had severe developmental delay with intellectual disability and hypotonic quadriparesis. Less common features included tube feeding, microcephaly, optic atrophy, nystagmus, poor or absent speech, and dyskinesia. Brain imaging was normal in 4 patients, but showed variable abnormalities in the others, including cerebral atrophy, dilated ventricles, and thin corpus callosum. Polymicrogyria was observed in 9 patients. The only patient without overt seizures was the mother (patient 15): she did have EEG abnormalities, mild intellectual disability, dyspraxia, migraine, and polymicrogyria with a thick corpus callosum on brain imaging.
Most of the heterozygous mutations in the ATP1A3 gene that were identified in patients with DEE99 by Vetro et al. (2021) occurred de novo. One mutation was transmitted from an unaffected man to his mildly affected daughter and severely affected grandson, indicating incomplete penetrance and variable expressivity.
In 16 patients from 15 families with DEE99, Vetro et al. (2021) identified 14 heterozygous mutations in the ATP1A2 gene (see, e.g., 182350.0019-182350.0021). The mutations occurred de novo in all except for a mother and son pair (patients 14 and 15). Most mutations were missense, with a few small in-frame deletions or insertions. All occurred at conserved residues, and none were present in the gnomAD database. In vitro functional expression studies showed that all of the mutations caused variable functional defects in the Na+/(K+)ATPase. Variants with more severe functional deficits were associated with a more severe phenotype. The findings were consistent with a loss-of-function effect. Vetro et al. (2021) estimated that about 12% of ATP1A3 mutations may be associated with DEE. Polymicrogyria was estimated to be observed in about 5.5% of patients with ATP1A3 mutations.
Vetro, A., Nielsen, H. N., Holm, R., Hevner, R. F., Parrini, E., Powis, Z., Moller, R. S., Bellan, C., Simonati, A., Lesca, G., Helbig, K. L., Palmer, E. E., and 18 others. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria. Brain 144: 1435-1450, 2021. [PubMed: 33880529] [Full Text: https://doi.org/10.1093/brain/awab052]
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