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NEUROLOGY 2007;69:427-433
© 2007 American Academy of Neurology

Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus

R. Guerrini, MD, F. Moro, PhD, M. Kato, MD, PhD, A. J. Barkovich, MD, T. Shiihara, MD, M. A. McShane, MD, J. Hurst, MD, M. Loi, MD, J. Tohyama, MD, V. Norci, BS, K. Hayasaka, MD, U. J. Kang, MD, PhD, S. Das, PhD and W. B. Dobyns, MD

From the Department of Pediatric Neuroscience (R.G., V.N.), Pediatric Hospital A. Meyer and University of Florence, Research Institute I.R.C.C.S. Stella Maris Foundation (R.G., F.M.), Pisa, and Azienda Ospedaliera G. Brotzu (M.L.), Servizio di Neuropsichiatria Infantile, Cagliari, Italy; Department of Pediatrics (M.K., T.S., J.T., K.H.), Yamagata University School of Medicine, Japan; Department of Radiology (A.J.B.), University of California, San Francisco, and Departments of Neurology and Neurobiology, Pharmacology, and Physiology (U.J.K.) and Human Genetics (S.D., W.B.D.), University of Chicago, IL; and Paediatric Neurology (M.A.McS.), Oxford Radcliffe Hospitals, and Department of Clinical Genetics (J.H.), Churchill Hospital, Oxford, UK.

Address correspondence and reprint requests to Dr. R. Guerrini, Clinical Pediatric Neurology, Department of Pediatric Neurosciences, University of Florence, and Pediatric Hospital A Meyer, via Bonvicini 62, 50132 Firenze- Italy r.guerrini{at}meyer.it

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.

Conclusion: 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.

Editorial, see page 421

Supplemental data at www.neurology.org

Funded partly by the Italian League Against Epilepsy (to R. Guerrini) and by a collaborative study group for West syndrome in Japan and supported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the Japan Epilepsy Research Foundation (to M. Kato).

Disclosure: The authors report no conflicts of interest.

Received December 7, 2006. Accepted in final form March 19, 2007.


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