Boltshauser, Eugen

Gross, Claudia

Hehr, Ute

Schmitt, Bernhard

Uyanik, Goekhan

Winkler, Jürgen

Wohlrab, Gabriele

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SHORT REPORTGabriele Wohlrab Æ Goekhan Uyanik Æ Claudia GrossUte Hehr Æ Ju¨rgen Winkler Æ Bernhard SchmittEugen BoltshauserFamilial West syndrome and dystonia caused by an Aristaless relatedhomeobox gene mutationReceived: 9 September 2004 / Accepted: 15 December 2004 / Published online: 22 February 2005 Springer-Verlag 2005Boys with unexplained West syndrome should beexamined for a mutation in the Aristaless relatedhomeobox gene, especially, when the family history ispositive for mental retardation and epilepsy.X-linked West syndrome is very rare. We report ontwo brothers with West syndrome and dystonia withpolyalanine expansion of the Aristaless related homeo-box gene (ARX).The index patient (Fig. 1a; III-2) was the second childof non-consanguineous parents, born in 2001 at term,after an uneventful pregnancy and delivery (birth weight3659 g, 75th percentile; length 51 cm, 75th percentile;head circumference 35 cm, 50th percentile). At the ageof 3 months he developed infantile spasms and a hyp-sarrhythmic EEG pattern. He promptly responded tovigabatrin therapy. At 5 months a generalised dystonia,i.e. increased muscle tone with dystonic posturing oflimbs, was evident. At the age of 3 years, he is able towalk a few steps with help and grasping objects is verydiﬃcult. He has no expressive speech.The elder brother of the index patient (Fig. 1a; III-1)was born in 1996 by caesarean section because of neo-natal macrosomia (birth weight 4200 g, 90th percentile;length 53 cm, 90th percentile; head circumference 38 cm,>90th percentile). At the age of 3 months he showeddystonic movements and marked truncal hypotonia.One month later he developed infantile spasms and ahypsarrhythmic EEG pattern. He did not respond tovigabatrin, but to ACTH. At the age of 8 years he iswheel-chair bound, not talking, grasping objects is notpossible.In both children metabolic tests and neuroimaging(MRI) were normal. Actually, both brothers suﬀer froma severe dystonia, mental impairment and rare general-ised tonic-clonic seizures (the older brother), treatedwith valproic acid.The family history was remarkable. In the maternaluncle (Fig. 1a; II-3, now 37 years old), spastic tetraple-gia, mental retardation and epilepsy have been presentsince early infancy. In retrospect, the epilepsy syndromecould not be classiﬁed. MRI was not performed in thisuncle, the mother or the grandmother.From the pedigree and the clinical ﬁndings we sus-pected a mutation in the ARX gene. Following informedconsent, a sequence analysis of the coding region andﬂanking intronic sequences of the ARX gene was per-formed. The male proband (index patient; Fig. 1a; III-2)as well as his brother and uncle were found to behemizygous for a 21 bp GCG repeat expansion in exon 2of the ARX gene c.333_334ins(GCG)7, which expandsthe ﬁrst of four alanine tracts from normally 16 to 23alanine residues (Fig. 1b,c). Both the mother (Fig. 11;II-2) and the maternal grandmother (Fig. 1a; I-2) wereidentiﬁed as heterozygous mutation carriers using anoptimised ﬂuorescence-based PCR assay.Mutations in the ARX gene have been found in abroad spectrum of disorders including X-linkedinfantile spasms (ISSX)/West syndrome, mental retar-dation [2], ataxia and dystonia (Partington syndrome),syndromic and non-syndromic forms of mental retar-dation, myoclonic epilepsy and X-linked lissencephalywith abnormal genitalia (XLAG) [5, 6,8]. The muta-tion found in our Swiss family, which is not related topreviously reported families, has been described beforein boys with infantile spasms and normal MRI, severemental and motor retardation [7]. In addition to Par-tington syndrome, dystonia was described in a fewunpublished Australian and Norwegian cases [6], butG. Wohlrab (&) Æ B. Schmitt Æ E. BoltshauserDepartment of Neuropaediatrics and Neurophysiology,University Children’s Hospital, Steinwiesstrasse 75, 8032Zurich, SwitzerlandE-mail: gabriele.wohlrab@kispi.unizh.chTel.: +41-1-2667701Fax: +41-1-2667165G. Uyanik Æ J. WinklerDepartment of Neurology, University of Regensburg,Regensburg, GermanyC. Gross Æ U. HehrCentre for Gynaecological Endocrinology,Reproductive Medicine and Human Genetics,Regensburg, GermanyEur J Pediatr (2005) 164: 326–328DOI 10.1007/s00431-005-1622-2other ARX mutations can result in a similar pheno-type [1,3]. Present observations suggest some genotype-phenotype correlation: The more severe inactivatingmutations such as early truncation mutations or mis-sense mutations in the evolutionary conserved domainscause the more severe phenotype of XLAG.To our knowledge this is the ﬁrst family presentingwith typical features of X-linked West syndrome plusdystonia plus palsy resulting from expansion of theﬁrst of the four polyalanine tracts, which previouslyhad only been associated with pure West syndrome.Critical re-evaluation of the known West syndromefamilies with similar mutations might reveal whethersome of the aﬀected family members indeed alsopresent with those additional symptoms. With theidentiﬁcation of causal ARX mutations in aﬀectedfamilies, the previously described allelic clinical entitiesneed to be reconsidered, as many of the families likethe one reported here present with an overlappingphenotype.In mice, ARX is expressed in a signiﬁcant proportionof neurons in the cortex, the striatum, the ganglioniceminences and also in the spinal cord. In adult mice,ARX expression is restricted to regions known to be richin GABAergic neurons such as the amygdala and theolfactory bulb [4]. This could explain the occurrence ofseizures in the majority of patients with an ARXmutation due to mislocalisation or dysfunction ofGABAergic neurons. Anticonvulsant drugs increasingthe neuronal GABA level, for instance valproic acid,vigabatrin, and tiagabine, might theoretically be eﬀec-tive in these patients.Based on our observation and the data published byStrømme et al. [6,7] and Kato et al. [1], we conclude thatARX mutations should be taken into consideration inboys with otherwise unexplained West syndrome.Fig. 1 a Family pedigree. Blacksymbols refer to patients with ahemizygous ARX mutation,dotted circles to heterozygousfemale carriers. b Schematicdrawing of the ARX geneindicating the polyalaninedomain in exon 2 (in green).c Sequencing in exon 2 ofpatient III.1 showing thent333_334ins(GCG)7 withexpansion of the ﬁrst of fouralanine tracts from 16 to 23alanine residues327References1. Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB (2003)Polyalanine expansions of ARX associated with cryptogenicWest syndrome. Neurology 61: 267–2682. Mandel JL, Chelly J (2004) Monogenic X-linked mental retar-dation: Is it as frequent as currently estimated? The paradox ofthe ARX (Aristaless X) mutations. Eur J Hum Genet 12: 689–6933. Patterson M, Zoghbi H (2003) Mental retardation: X marks thespot. Neurology 61: 156–1574. Poirier K, Van Esch H, Friocourt G, Saillour Y, Bahi N, BackerS, Souil E, Castelnau-Ptakhine L, Beldjord C, Francis F, Bien-venu T, Chelly J (2004) Neuroanatomical distribution of ARX inbrain and its localisation in GABAergic neurons. Brain Res MolBrain Res 122: 35–465. Sherr EH (2003) The ARX story (epilepsy, mental retardation,autism, and cerebral malformations): one gene leads to manyphenotypes. Curr Opin Pediatr 15: 567–5716. Strømme P, Mangelsdorf ME, Scheﬀer IE, Ge´cz J (2002)Infantile spasms, dystonia, and other X-linked phenotypescaused by mutations in Aristaless related homeobox gene, ARX.Brain Dev 24: 266–2687. Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, LewisME, Bruyere H, Lu¨tcherath V, Gedeon AK, Wallace RH,Scheﬀer IE, Turner G, Partington M, Frints SGM, Fryns JP,Sutherland GR, Mulley JC, Ge´cz J (2002) Mutations in thehuman ortholog of Aristaless cause X-linked mental retardationand epilepsy. Nat Genet 30: 441–4458. Uyanik G, Aigner L, Martin P, Gross C, Neumann D, Mars-chner-Scha¨fer H, Hehr U, Winkler J (2003) ARX mutations inX-linked lissencephaly with abnormal genitalia. Neurology 61:232–235328

Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation

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Familial West syndrome and dystonia caused by an Aristaless related homeobox gene mutation

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