ARX. This is the epilepsiome page for ARX, which is associated with a spectrum of overlapping neurological conditions, including X-linked intellectual disability, West syndrome, Partington syndrome, Ohtahara syndrome, Proud syndrome, and X-linked lissencephaly with abnormal genitalia [OMIM#300382]. These ARX-related conditions are characterized by variable features, including intellectual disability, epilepsy, movement disorders, EEG findings or brain abnormalities.
Here are the most recent blog posts on ARX
- The ARX problem – how an epilepsy gene escapes exome sequencing
- Three novel aspects about epilepsy gene panels
- The novel gene dilemma
- How genome sequencing in intellectual disability breaks the 50% boundary
In a nutshell. In 2002, three different groups of investigators identified pathogenic variants in ARX as the cause of five distinct phenotypes including X-linked lissencephaly with abnormal genitalia, Partington’s syndrome, X-linked infantile spasms, and non-syndromic X-linked intellectual disability. Thus, it was clear that from the start that ARX variants could cause a broad range of phenotypes. In 2009, two male cousins with the same ARX pathogenic variant were diagnosed with two different epilepsy syndromes, West syndrome and Ohtahara syndrome, indicating the degree of variable expressivity associated with ARX-related conditions, even with the same variant in the same family. Female carriers may have intellectual disability, epilepsy, and often display agenesis of the corpus callosum. This finding is consistent with X-linked inheritance with variable expression in females.
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Pathogenic ARX variants can cause a wide range of phenotypes, including those described below.
ARX-related epilepsy. Patients have been found to present with features consistent with a diagnosis of West syndrome, Partington syndrome, Ohtahara syndrome, Proud syndrome, X-linked lissencephaly with abnormal genitalia and nonsyndromic X-linked intellectual diability. In all conditions, intellectual disability is present and ranges from mild to profound. Seizures are present in all the syndromes listed, but there are variations in age of onset, type of seizures, severity of seizures, and treatment. Additional clinical features may include hypotonia, abnormal genitalia, and movement disorders.
Mutation Spectrum. Fewer than 100 unique disease-causing ARX variants have been reported in the scientific literature. Most variants are missense variants, but deletions, duplications and complex rearrangements have also been identified. Disease-causing variants have been reported throughout the gene. Some pathogenic ARX variants are unique to a single patient or family, but multiple recurrent variants have also been reported. The most common recurrent pathogenic variant, c.428_451dup (24bp), has been seen in over 50 individuals. Duplications in the ARX gene have been associated with infantile spasms. To view some of the variants that have been reported thus far, please see the ClinVar page for ARX.
Genotype-Phenotype Correlation. As discussed above, ARX-related disorders can have significant variable expressivity, even with the same variant within the same family; however, some genotype-phenotype correlations have been identified. Phenotypes involving malformations of the brain, such as X-linked lissencephaply with abnormal genitalia and Proud syndrome, are associated with truncating variants and missense variants in the homeobox domain. Non-malformation phenotypes are associated with missense mutations outside of the homeobox domain or expansions in the polyalanine tracts, and include West syndrome, Partington syndrome, Ohtahara syndrome, and X-linked intellectual disability.
General Considerations for Variant interpretation. When reviewing a genetic variant to determine its significance for a given patient, it is important to weigh multiple pieces of evidence:
Considerations for gene level interpretation. First, it is important to establish the strength of the evidence showing that the gene is associated with epilepsy. Some genes may only have one variant reported in a single individual with epilepsy, while other genes may have multiple variants reported in many large families with an autosomal dominant pattern of epilepsy. For ARX, there is moderate evidence for its role in human epilepsy.
Considerations for variant level interpretation. When reviewing the significance of a variant, it is important to consider the impact on the gene and the presence of the variant in previously described patient and control populations. Many clinical genetic testing laboratories classify genetic variants into different categories, ranging from benign to pathogenic. Variants that are common in control populations and would not be predicted to have a major impact on the gene/protein are generally classified as benign. Variants are more likely to be classified as pathogenic if the variants are rare or not present in the control population, reported in multiple individuals or families with disease, and likely to have a higher impact on the gene/protein based on the type of mutation or functional studies. Variants with uncertain or limited available evidence may be classified as variants of uncertain significance (VUS), indicating that further information is required in order for the variant to be further defined. In some cases, testing additional family members can be helpful, as it allows the lab to determine whether or not the variant was inherited (versus de novo) and how the variant segregates with disease in the family. This is particularly true for ARX variants, as most disease-causing variants would be expected to be de novo. Sometimes further classification of a VUS requires waiting for the identification of additional patients or families with similar or nearby variants.
Inheritance, Penetrance & Prevalence. ARX-related conditions are inherited in an X-linked recessive manner. Female carriers are generally asymptomatic or may be mildly affected, depending on the genetic variant and condition. The most common conditions caused by disease-causing variants in the ARX gene are West syndrome and X-linked intellectual disability. The prevalence of West syndrome is 1 in 100,000 individuals, but includes individuals with a CDKL5 variant and other causes of infantile spasms. The exact prevalence of ARX-related disorders is unknown, although it appears to be a common cause of intellectual disability.
Mechanism.The ARX gene encodes one of the homeoproteins in the paired class. This class of homeobox genes are thought to be important regulators of essential events during embryogenesis, including the development of the pancreas, testes, brain and skeletal muscles. The ARX protein helps to regulate the process by which cells differentiate and migrate, in particular interneurons. The protein also contains an aristaless domain that is linked to major developmental functions.
Recurrence risk & testing of family members. ARX variants can be de novo or inherited in an X-linked pattern. Each child of a mother who carries a disease-causing variant has a 50% (1 in 2) chance of inheriting the variant. All female children of males who carry a disease-causing variant will inherit the variant. It is appropriate to test a seemingly unaffected mother of an affected proband for the same disease-causing variant due to the possibility of skewed X-inactivation. If the disease-causing variant is not identified in the mother, the risk to future pregnancies is low, but germline mosaicism of ARX variants has been reported, making the recurrence risk for families with one child with an ARX variant higher than the general population risk.
Therapy. A specific therapy recommendation has not yet been proposed for ARX-related epilepsy. Treatment of ARX-related conditions is focused on symptoms and optimizing the individual’s abilities. Individuals with ARX-related epilepsy may experience refractory seizures.
The current section on therapy is a brief overview, and, from the therapeutic perspective, does not represent a comprehensive review of the literature. It should therefore not be used for clinical decision-making without input from a health care provider with relevant expertise in the field.
Research studies, patient registries, and family connections. The Epilepsiome team is happy to facilitate if you have questions or a specific interest in this gene. There are a number of groups/websites that provide relevant information and support for individuals and families with ARX-related conditions, including the groups listed below.
- American Epilepsy Society
- Epilepsy Foundation
- Epilepsy Action UK
- National Organization for Rare Disorders (NORD) – West Syndrome
- National Organization for Rare Disorders (NORD) – Lissencephaly