Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus.
BACKGROUND
ARX is a paired-type homeobox gene located on the X chromosome that contains five exons with four polyalanine (PolyA) tracts, a homeodomain, and a conserved C-terminal aristaless domain. Studies in humans have demonstrated remarkable pleiotropy: malformation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are associated with missense mutations outside of the homeobox and expansion of the PolyA tracts.


OBJECTIVE
To investigate the role of ARX, we performed mutation analysis in 115 boys with cryptogenic ISS. This included two pairs of brothers.


RESULTS
We found an expansion of the trinucleotide repeat that codes for the first PolyA tract from 10 to 17 GCG repeats (c.333_334ins[GCG]7) in six boys (5.2%) ages 2 to 14, from four families, including the two pairs of brothers. In addition to ISS, all six boys had severe mental retardation and generalized dystonia that appeared around the age of 6 months and worsened, eventually leading to stable severe quadriplegic dyskinesia within age 2 years. Three children experienced recurrent, life-threatening status dystonicus. In four children brain MRI showed multiple small foci of abnormal cavitation on T1 and increased signal intensity on T2 in the putamina, possibly reflecting progressive multifocal loss of tissue.


CONCLUSIONS
The phenotype of infantile spasms with severe dyskinetic quadriparesis increases the number of human disorders that result from the pathologic expansion of single alanine repeats. ARX gene testing should be considered in boys with infantile spasms and dyskinetic cerebral palsy in the absence of a consistent perinatal history.
Department of Pediatric Neurosciences, Pediatric Hospital A Meyer and University of Florence, Firenze, Italy. r.guerrini@meyer.it
R
R
Guerrini
F
F
Moro
M
M
Kato
A J
AJ
Barkovich
T
T
Shiihara
M A
MA
McShane
J
J
Hurst
M
M
Loi
J
J
Tohyama
V
V
Norci
K
K
Hayasaka
U J
UJ
Kang
S
S
Das
W B
WB
Dobyns
D000293:Adolescent; D000409:Alanine / Q000235:genetics; D001284:Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D001479:Basal Ganglia / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D020821:Dystonic Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005819:Genetic Markers / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013036:Spasms, Infantile / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
C469264:ARX protein, human; D005819:Genetic Markers; D018398:Homeodomain Proteins; D014157:Transcription Factors; D000409:Alanine