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

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

HPO Terms

HP:0000020 Urinary incontinence HP:0000054 Micropenis HP:0000252 Microcephaly HP:0000407 Sensorineural hearing impairment HP:0000568 Microphthalmia HP:0000629 Periorbital fullness HP:0000637 Long palpebral fissure HP:0000729 Autistic behavior HP:0000752 Hyperactivity HP:0000817 Reduced eye contact HP:0001249 Intellectual disability HP:0001250 Seizure HP:0001252 Hypotonia HP:0001254 Lethargy HP:0001257 Spasticity HP:0001263 Global developmental delay HP:0001266 Choreoathetosis HP:0001272 Cerebellar atrophy HP:0001276 Hypertonia HP:0001285 Spastic tetraparesis HP:0001302 Pachygyria HP:0001332 Dystonia HP:0001336 Myoclonus HP:0001337 Tremor HP:0001347 Hyperreflexia HP:0001357 Plagiocephaly HP:0001510 Growth delay HP:0001763 Pes planus HP:0002015 Dysphagia HP:0002033 Poor suck HP:0002069 Bilateral tonic-clonic seizure HP:0002079 Hypoplasia of the corpus callosum HP:0002094 Dyspnea HP:0002119 Ventriculomegaly HP:0002121 Generalized non-motor (absence) seizure HP:0002123 Generalized myoclonic seizure HP:0002131 Episodic ataxia HP:0002188 Delayed CNS myelination HP:0002205 Recurrent respiratory infections HP:0002283 Global brain atrophy HP:0002307 Drooling HP:0002353 EEG abnormality HP:0002360 Sleep disturbance HP:0002373 Febrile seizure (within the age range of 3 months to 6 years)HP:0002376 Developmental regression HP:0002421 Poor head control HP:0002506 Diffuse cerebral atrophy HP:0002521 Hypsarrhythmia HP:0003487 Babinski sign HP:0007204 Diffuse white matter abnormalities HP:0007256 Abnormal pyramidal sign HP:0007359 Focal-onset seizure HP:0008733 Dysplastic testis HP:0008936 Axial hypotonia HP:0008947 Floppy infant HP:0010818 Generalized tonic seizure HP:0010819 Atonic seizure HP:0010850 EEG with spike-wave complexes HP:0010851 EEG with burst suppression HP:0010864 Severe intellectual disability HP:0011153 Focal motor seizure HP:0011167 Focal tonic seizure HP:0011169 Generalized clonic seizure HP:0011190 Uni- and bilateral multifocal epileptiform discharges HP:0011344 Severe global developmental delay HP:0011968 Feeding difficulties HP:0012448 Delayed myelination HP:0012469 Infantile spasms HP:0025357 Erratic myoclonus HP:0032792 Tonic seizure HP:0100660 Dyskinesia HP:0100716 Self-injurious behavior HP:0200134 Epileptic encephalopathy

Association

Mendelian

Locus

hg19chrX:25031766-25031814

hg38chrX:25013649-25013697

t2tchrX: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 mislocalization of mutant protein, increased with expansion length¹⁴.

Detection

Because these are small coding expansions, they have been sized using targeted exon 2 PCR with fragment analysis or targeted Sanger sequencing¹⁵.

Year

2002¹⁶

Location in Gene

Coding Exon 2, aa 110-115

Gene Strand

Alleles

Ref. Motif

GCN

Ranges

Benign (ref.)

–

Benign (gene)

–

Pathogenic (ref.)

NGC

Pathogen. (gene)

GCN

Unknown (ref.)

–

Unknown (gene)

–

Interruption (ref.)

–

Interrup. (gene)

–

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.

1omim: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

7omim:309510

8omim:300004

9omim: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

Checking your browser - reCAPTCHA

genereviews:NBK51932

A longer polyalanine expansion mutation in the ARX gene causes early infantile epileptic encephalopathy with suppression-burst pattern (Ohtahara syndrome).

Mitsuhiro,Kato, Shinji,Saitoh, Atsushi,Kamei, Hideaki,Shiraishi, Yuki,Ueda, Manami,Akasaka, Jun,Tohyama, Noriyuki,Akasaka, Kiyoshi,Hayasaka

American journal of human genetics · 2007-06-11

pmid:17668384

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)

Cannabidiol attenuates epileptic phenotype and increases survival in a mouse model of developmental and epileptic encephalopathy type 1.

Lucia,Verrillo, Fabio Arturo,Iannotti, Denise,Drongitis, Katiuscia,Martinello, Loredana,Poeta, Adriano,Barra, Gaetano,Terrone, Sergio,Fucile, Vincenzo,Di Marzo, Maria Giuseppina,Miano

Epilepsia · 2025-07-03

pmid:40608247

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

Locus EIEE1 ARX

Disease

Locus

Alleles

gnomAD

References

Additional Literature