Developmental and Epileptic Encephalopathy 1

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/developmental-and-epileptic-encephalopathy-1

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.

genetic conditions

1. Introduction

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.

2. 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.

3. 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.

4. 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.

5. 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

References

Hrachovy RA, Frost JD Jr. Infantile epileptic encephalopathy withhypsarrhythmia (infantile spasms/West syndrome). J Clin Neurophysiol. 2003Nov-Dec;20(6):408-25. Review.
Kato M. A new paradigm for West syndrome based on molecular and cell biology. Epilepsy Res. 2006 Aug;70 Suppl 1:S87-95.
Kossoff EH. Infantile spasms. Neurologist. 2010 Mar;16(2):69-75. doi:10.1097/NRL.0b013e3181d1416c. Review.
Lee K, Ireland K, Bleeze M, Shoubridge C. ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmentaldeficit of calbindin-positive cortical GABAergic interneurons. Neuroscience. 2017Aug 15;357:220-231. doi: 10.1016/j.neuroscience.2017.06.010.
Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis ofARX mutations and X-linked infantile spasms. Curr Opin Neurobiol. 2012Oct;22(5):859-65. doi: 10.1016/j.conb.2012.04.006.
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-dependentkinase-like 5 and aristaless-related homeobox genes in epileptic encephalopathyof unknown etiology with onset in the first year of life. J Child Neurol. 2011Jun;26(6):683-91. doi: 10.1177/0883073810387827.

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Subjects: Genetics & Heredity

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Nicole Yin

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Update Date: 24 Dec 2020

Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The Gene Associated with Developmental and Epileptic Encephalopathy 1

4. Inheritance

5. Other Names for This Condition

References