EIEE1 ARX

Developmental and epileptic encephalopathy-1 (DEE1) is a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases¹.

Prevalence

Found in individuals of multiple ethnicities, including European and Asian ancestry².

Age of Onset Details

Typical: 0^3,4; Range: 0-4; 70% of cases involve infantile spasms, leading to seizures by 3 or 4 years⁵.

Locus

hg19

chrX:25031766-25031814

hg38

chrX:25013649-25013697

t2t

chrX:24597886-24597934

Details

ARX expansions⁶result in a phenotypic spectrum of conditions including Partington syndrome⁷, Early Infantile Epileptic Encephalopathy¹, Agenesis of Corpus Callosum with Abnormal Genitalia⁸, and X-Linked Lissencephaly with Ambiguous Genitalia⁹, described in the literature^10,11.

Mechanism

LoF

Polyalanine expansions lead to reduction in protein product through unclear mechanism^12,13. Apparent aggregation and mis-localisation of mutan protein, increased with expansion length¹⁴.

Year

2002¹⁵

Location in Gene

Exon 2, aa 110-115

Gene Strand

Alleles

Ref. Motif

NGC

Pathogenic (ref.)

NGC

Pathogenic (gene)

CNG

gnomAD

Pathogenic genotype frequency data is not displayed for this locus because a substantial number of large alleles failed manual review by the gnomAD team.

References

Direct supporting references for info on this page.

omim:308350

Polyalanine expansion of ARX associated with cryptogenic West syndrome.

M,Kato, S,Das, K,Petras, Y,Sawaishi, W B,Dobyns

Neurology · 2003-07-22

pmid:12874418

ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia.

Mireille,Cossée, Laurence,Faivre, Christophe,Philippe, Heifa,Hichri, Anne,de Saint-Martin, Vincent,Laugel, Nadia,Bahi-Buisson, Jean-François,Lemaitre, Bruno,Leheup, Bruno,Delobel, Bénédicte,Demeer, Karine,Poirier, Valérie,Biancalana, Jean-Michel,Pinoit, Sophie,Julia, Jamel,Chelly, Didier,Devys, Jean-Louis,Mandel

American journal of medical genetics. Part A · 2011-01-01

pmid:21204215

The X-linked infantile spasms syndrome (MIM 308350) maps to Xp11.4-Xpter in two pedigrees.

S,Claes, K,Devriendt, L,Lagae, B,Ceulemans, L,Dom, P,Casaer, P,Raeymaekers, J J,Cassiman, J P,Fryns

Annals of neurology · 1997-09-01

pmid:9307258

A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment.

Maureen G,Price, Jong W,Yoo, Daniel L,Burgess, Fang,Deng, Richard A,Hrachovy, James D,Frost, Jeffrey L,Noebels

The Journal of neuroscience : the official journal of the Society for Neuroscience · 2009-07-08

pmid:19587282

Resources for Genetics Professionals — Genetic Disorders Caused by Nucleotide Repeat Expansions and Contractions

Stephanie E.,Wallace, Lora JH,Bean

GeneReviews® [Internet] · 2022-10-20

genereviews:NBK535148

omim:309510

omim:300004

omim:300215

Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach.

Isabel,Marques, Maria João,Sá, Gabriela,Soares, Maria do Céu,Mota, Carla,Pinheiro, Lisa,Aguiar, Marta,Amado, Christina,Soares, Angelina,Calado, Patrícia,Dias, Ana Berta,Sousa, Ana Maria,Fortuna, Rosário,Santos, Katherine B,Howell, Monique M,Ryan, Richard J,Leventer, Rani,Sachdev, Rachael,Catford, Kathryn,Friend, Tessa R,Mattiske, Cheryl,Shoubridge, Paula,Jorge

Molecular genetics & genomic medicine · 2015-02-25

pmid:26029707

ARX spectrum disorders: making inroads into the molecular pathology.

Cheryl,Shoubridge, Tod,Fullston, Jozef,Gécz

Human mutation · 2010-08-01

pmid:20506206

Clinical and neuroimaging review of triplet repeat diseases.

Ryo,Kurokawa, Mariko,Kurokawa, Akihiko,Mitsutake, Moto,Nakaya, Akira,Baba, Yasuhiro,Nakata, Toshio,Moritani, Osamu,Abe

Japanese journal of radiology · 2022-09-28

pmid:36169768

Sequence composition changes in short tandem repeats: heterogeneity, detection, mechanisms and clinical implications.

Indhu-Shree,Rajan-Babu, Egor,Dolzhenko, Michael A,Eberle, Jan M,Friedman

Nature reviews. Genetics · 2024-03-11

pmid:38467784

POLYALANINE TRACT DISORDERS AND NEUROCOGNITIVE PHENOTYPES

Cheryl,Shoubridge, Jozef,Gecz

Madame Curie Bioscience Database [Internet] · 2013-01-01

genereviews:NBK51932

Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy.

Petter,Strømme, Marie E,Mangelsdorf, Marie A,Shaw, Karen M,Lower, Suzanne M E,Lewis, Helene,Bruyere, Viggo,Lütcherath, Agi K,Gedeon, Robyn H,Wallace, Ingrid E,Scheffer, Gillian,Turner, Michael,Partington, Suzanna G M,Frints, Jean-Pierre,Fryns, Grant R,Sutherland, John C,Mulley, Jozef,Gécz

Nature genetics · 2002-03-11

pmid:11889467

Additional Literature

Additional literature related to this locus.

Raw PubMed search results
(All PubMed results returned by searching for this gene, tandem repeats, and disease, in medline format)

Infantile Epileptic Spasms Syndrome: Unveiling clinical and genetic variability in a case series from Argentina.

María Eugenia,Martín, Lenin,Intriago, Mariana,Loos, Gabriela,Reyes Valenzuela, Gabriel,Veneruzzo, María Eugenia,Foncuberta, Gabriela,Zelaya, Giovanna,Aschettino, Francisco,García, Giovanna,Flores, Roberto,Caraballo, Cristina,Alonso, Matías,Juanes

Seizure · 2025-01-31

pmid:39933386

Exploring unsolved cases of lissencephaly spectrum: integrating exome and genome sequencing for higher diagnostic yield.

Shogo,Furukawa, Mitsuhiro,Kato, Akihiko,Ishiyama, Tomohiro,Kumada, Takeshi,Yoshida, Eri,Takeshita, Pin Fee,Chong, Hideo,Yamanouchi, Yuko,Kotake, Takayoshi,Kyoda, Toshihiro,Nomura, Yohane,Miyata, Mitsuko,Nakashima, Hirotomo,Saitsu

Journal of human genetics · 2024-08-09

pmid:39123069

Clinical and genetic study of developmental and epileptic encephalopathy in Argentinean pediatric patients.

Matías,Juanes, Mariana,Loos, Gabriela,Reyes, Gabriel,Veneruzzo, Francisco Martín,García, Giovanna,Aschettino, Silvana,Calligaris, María Eugenia,Martín, María Eugenia,Foncuberta, Cristina N,Alonso, Roberto H,Caraballo

Medicina · 2022-01-01

pmid:36571524

Different types of disease-causing noncoding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability.

Michael J,Field, Raman,Kumar, Anna,Hackett, Sayaka,Kayumi, Cheryl A,Shoubridge, Lisa J,Ewans, Atma M,Ivancevic, Tracy,Dudding-Byth, Renée,Carroll, Thessa,Kroes, Alison E,Gardner, Patricia,Sullivan, Thuong T,Ha, Charles E,Schwartz, Mark J,Cowley, Marcel E,Dinger, Elizabeth E,Palmer, Louise,Christie, Marie,Shaw, Tony,Roscioli, Jozef,Gecz, Mark A,Corbett

Human mutation · 2021-05-03

pmid:33847015

Meagan S,Siehr, Cory A,Massey, Jeffrey L,Noebels

Disease models & mechanisms · 2020-03-30

pmid:32033960

ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons.

K,Lee, K,Ireland, M,Bleeze, C,Shoubridge

Neuroscience · 2017-06-13

pmid:28627419

Extensive phenotyping of two ARX polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy.

Matilda R,Jackson, Kristie,Lee, Tessa,Mattiske, Emily J,Jaehne, Ezgi,Ozturk, Bernhard T,Baune, Terence J,O'Brien, Nigel,Jones, Cheryl,Shoubridge

Neurobiology of disease · 2017-06-08

pmid:28602636

Embryonic forebrain transcriptome of mice with polyalanine expansion mutations in the ARX homeobox gene.

Tessa,Mattiske, Kristie,Lee, Jozef,Gecz, Gaelle,Friocourt, Cheryl,Shoubridge

Human molecular genetics · 2016-12-15

pmid:27798109

Polyalanine expansions drive a shift into α-helical clusters without amyloid-fibril formation.

Saskia,Polling, Angelique R,Ormsby, Rebecca J,Wood, Kristie,Lee, Cheryl,Shoubridge, James N,Hughes, Paul Q,Thomas, Michael D W,Griffin, Andrew F,Hill, Quill,Bowden, Till,Böcking, Danny M,Hatters

Nature structural & molecular biology · 2015-11-16

pmid:26571108