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Description
Developmental and epileptic encephalopathy 1 (DEE1) is a seizure disorder characterized by a type of seizure known as infantile spasms. The spasms usually appear before the age of 1. Several types of spasms have been described, but the most commonly reported type involves bending at the waist and neck and extending the arms and legs (sometimes called a jackknife spasm). Each spasm lasts only seconds, but they occur in clusters several minutes long. Although individuals do not usually have spasms while they are sleeping, the spasms commonly occur just after awakening. Infantile spasms usually stop by age 5, but many children then develop other types of seizures that recur throughout their lives.
Most babies with DEE1 have characteristic results on an electroencephalogram (EEG), a test used to measure the electrical activity of the brain. The EEG of these individuals typically shows an irregular pattern known as hypsarrhythmia, and this finding can help differentiate infantile spasms from other types of seizures.
Early in life, babies with DEE1 stop developing normally and begin to lose skills they have acquired (developmental regression), such as sitting, rolling over, and babbling. Most affected individuals also have intellectual disability throughout their lives.
Frequency
Infantile spasms are estimated to affect 1 to 1.6 in 100,000 individuals. This estimate includes DEE1 as well as infantile spasms that have other causes.
Causes
DEE1 is caused by mutations in the ARX gene. The protein produced from this gene plays a role in the normal functioning of the brain by regulating other genes that contribute to brain development. Research suggests that mutations in the ARX gene reduce the amount or function of the ARX protein. A shortage of ARX function is thought to disrupt normal brain development, leading to seizures and intellectual disability.
It is likely that mutations in other genes that have not been identified cause rare cases of DEE1. Infantile spasms can also have nongenetic causes, such as brain malformations, other disorders that affect brain function, or brain damage. In addition, changes in genes that are not located on the X chromosome cause infantile spasms in rare cases.
Inheritance
DEE1 is inherited in an X-linked recessive pattern
. The ARX gene is located on the X chromosome, which is one of the two sex chromosomes
. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would usually have to occur in both copies of the gene to cause the disorder. However, in some instances, one altered copy of the ARX gene is sufficient because the X chromosome with the normal copy of the ARX gene is turned off through a process called X-inactivation
. Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell.
Usually X-inactivation occurs randomly, such that each X chromosome is active in about half of the body cells. Sometimes X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation. Some ARX gene mutations may be associated with skewed X-inactivation, which results in the inactivation of the X chromosome with the normal copy of the ARX gene in most cells of the body. This skewed X-inactivation causes the chromosome with the mutated ARX gene to be expressed in more than half of cells, causing DEE1.
A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
Other Names for This Condition
- Early infantile epileptic encephalopathy-1
- EIEE1
- Epileptic encephalopathy, early infantile, 1
- Infantile epileptic-dyskinetic encephalopathy
- ISSX
- ISSX1
- X-linked infantile spasm syndrome
- X-linked infantile spasm syndrome 1
- X-linked Ohtahara syndrome
- X-linked West syndrome
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Clinical Trials
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy with hypsarrhythmia (infantile spasms/West syndrome). J Clin Neurophysiol. 2003 Nov-Dec;20(6):408-25. doi: 10.1097/00004691-200311000-00004. Citation on PubMed
- Kato M. A new paradigm for West syndrome based on molecular and cell biology. Epilepsy Res. 2006 Aug;70 Suppl 1:S87-95. doi: 10.1016/j.eplepsyres.2006.02.008. Epub 2006 Jun 23. Citation on PubMed
- Kossoff EH. Infantile spasms. Neurologist. 2010 Mar;16(2):69-75. doi: 10.1097/NRL.0b013e3181d1416c. Citation on PubMed
- Lee K, Ireland K, Bleeze M, Shoubridge C. ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. Neuroscience. 2017 Aug 15;357:220-231. doi: 10.1016/j.neuroscience.2017.06.010. Epub 2017 Jun 13. Citation on PubMed
- Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Curr Opin Neurobiol. 2012 Oct;22(5):859-65. doi: 10.1016/j.conb.2012.04.006. Epub 2012 May 5. Citation on PubMed or Free article on PubMed Central
- Sartori S, Polli R, Bettella E, Rossato S, Andreoli W, Vecchi M, Giordano L, Accorsi P, Di Rosa G, Toldo I, Zamponi N, Darra F, Dalla Bernardina B, Perilongo G, Boniver C, Murgia A. Pathogenic role of the X-linked cyclin-dependent kinase-like 5 and aristaless-related homeobox genes in epileptic encephalopathy of unknown etiology with onset in the first year of life. J Child Neurol. 2011 Jun;26(6):683-91. doi: 10.1177/0883073810387827. Epub 2011 Apr 11. Citation on PubMed
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