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Expansion of the first PolyA tract ofARX causes infantile spasms andstatus dystonicus ABSTRACT 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: mal- A.J. Barkovich, MD formation phenotypes are associated with protein truncation mutations and missense mutations in the homeobox; nonmalformation phenotypes, including X-linked infantile spasms (ISS), are as- sociated 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 trinu-
cleotide 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 U.J. Kang, MD, PhD 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 consis-
tent perinatal history. NEUROLOGY 2007;69:427–433
Address correspondence andreprint requests to Dr. R.
Guerrini, Clinical Pediatric ARX (aristaless-related homeobox) is a paired-class homeobox gene comprising five ex- Neurology, Department of ons that contains highly conserved octapeptide, homeobox, and C-terminal domains as Pediatric Neurosciences,University of Florence, and well as four PolyA tracts.1 It is expressed in embryonic brain, endocrine pancreas, testes, Pediatric Hospital A Meyer,via Bonvicini 62, and probably other tissues as well as in adult brain, heart, skeletal muscle, and liver.1-4 50132 Firenze- Italy Studies in humans have demonstrated remarkable pleiotropy, as several apparently unre- lated disease phenotypes have been associated with mutations of this gene, includingsyndromes with and without brain malformations. The former include X-linked lissen-cephaly with abnormal genitalia (XLAG), severe hydrocephalus, and Proud syndrome(agenesis of the corpus callosum with abnormal genitalia), whereas the latter includeX-linked infantile spasms (ISS), Partington syndrome, which consists of mental retarda-tion with mild distal dystonia, and nonspecific X-linked mental retardation.3,5-10 In gen-eral, the malformation phenotypes are associated with protein truncation mutations andmissense mutations in the homeobox, whereas the nonmalformation phenotypes are as-sociated with missense mutations outside of the homeobox and expansion of the PolyA Editorial, see page 421
While investigating the role of ARX as the causative gene for cryptogenic infantile spasms, we found an expansion of the trinucleotide repeat that codes for the first PolyA From the Department of Pediatric Neuroscience (R.G., V.N.), Pediatric Hospital A. Meyer and University of Florence, Research InstituteI.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, andDepartment of Clinical Genetics (J.H.), Churchill Hospital, Oxford, UK.
Funded partly by the Italian League Against Epilepsy (to R. Guerrini) and by a collaborative study group for West syndrome in Japan andsupported by a grant from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the Japan Epilepsy ResearchFoundation (to M. Kato).
Disclosure: The authors report no conflicts of interest.
Copyright 2007 by AAN Enterprises, Inc.

in 115 boys (68 from Pisa, 31 from Yamagata, and 16 from Pedigrees, schematic representation of genomic structure, and Chicago) with ISS and developmental delay, all of whom had normal brain imaging and no recognized etiology. This in-cluded two pairs of brothers. We defined ISS as an electro-clinical syndrome of flexor, extensor, or flexor– extensorspasms, appearing in clusters and accompanied on the EEGby a bilateral electrodecremental event or biphasic slowwave with superimposed low voltage fast rhythms, with orwithout interictal hypsarrhythmia.12 We found a (GCG)10 ⫹ 7PolyA expansion of the ARX gene in six boys (5.2%). One-third of the patients, including all six described here, wereclinically examined; for the remaining patients, clinical in-formation was obtained from the referring physiciansthrough a standard questionnaire. For all six boys, informedparental consent was obtained for videotaping.
After noticing that all six boys carrying the (GCG)10 ⫹ 7 PolyA expansion had severe dystonia and that three of themhad experienced status dystonicus, we decided to investigatewhether ARX mutations might be a frequent cause of statusdystonicus. However, we found no ARX gene mutations inseven additional boys who had had status dystonicus of un-known etiology that had not been preceded by ISS.
DNA extraction, PCR amplification, and mutation
Blood or DNA samples were obtained from all
patients after informed parental consent. Genomic DNA
was extracted from blood samples using standard proto-
cols.13 PCR amplification was performed with 50 ng of
genomic DNA template using Taq Gold DNA polymerase
(Applied Biosystems). The primers used to amplify the cod-
ing and flanking noncoding regions of ARX (GenBank no.
AY038071.1) were designed using Primer 3 software (http://
primer3_www.cgi). PCR primer sequences are described in
table E-1 on the Neurology Web site (
Because of the high GC content of exon 2, we optimized the
(A and B) Pedigrees of the Italian and Japanese families. A-III:1 ⫽ Patient 1; A-III:2 ⫽ Patient amplification conditions using KOD-Plus-DNA polymerase 2; B-II:1 ⫽ Patient 5; B-II:2 ⫽ Patient 6. Squares ⫽ males; circles ⫽ females, arrows ⫽ (TOYOBO-Novagen). PCR products were analyzed using probands; filled black symbols ⫽ patients with infantile spasms and dyskinetic quadriparesis; denaturing high performance liquid chromatography (DH- right side quarter-filled symbols ⫽ early seizures and severe neurologic impairment; dotted PLC), followed by direct sequencing of PCR fragments that circles ⫽ carriers of ARX mutation; white symbols ⫽ unaffected individuals; dashed showed abnormal DHPLC profiles on automated capillary symbols ⫽ deceased individuals. (C) Schematic representation of the genomic structure of sequencer (ABI Prism 310; Applied Biosystems). DHPLC ARX and DNA sequence electropherograms showing the (c.333_334ins[GCG]7) mutation conditions were chosen according to the Wavemaker pro- located in the first PolyA tract. The electropherograms show the sequence of the first gram (Transgenomic). With the exception of exon 2, primers PolyA tract (black lines) in a wild-type (WT) individual and the sequence with the expansion used for PCR and sequencing were the same.
(black arrow) in the probands. This mutation introduces seven extra alanine (A) residues in the ARX protein.
Clinical reports. Patient 1. This 15-year-old boy from a
Sardinian family was born after a normal pregnancy with
tract in the protein from 10 to 17 GCG re- birth head circumference 34 cm (50th percentile) (figure 1, peats (c.333_334ins[GCG]7) in six boys AIII:1). Two maternal uncles and two aunts who had diedbetween the 16th and 20th months of life were reported to from four families. All shared a severe clin- have severe developmental delay and intractable seizures.
ical picture of early infantile spasms with Delayed milestones were noticed in the first months of generalized dystonia that appeared around life. He had onset of ISS with hypsarrhythmia at 3 months, age 6 months and worsened, eventually which proved refractory to treatment. The spasms ceased by8 months, but generalized dystonia and chorea appeared and leading to severe quadriplegic dyskinesia progressed in severity until 2 years. Exam demonstrated in- within age 2 years, accompanied in three creased tone and brisk tendon reflexes. He began to have by relentless episodes of devastating gener- prolonged episodes of status dystonicus lasting days at atime, with worsening of his dyskinesia, dyspnea, and inabil- ity to swallow that prompted frequent hospital admissions.
These were treated with anticholinergic drugs with no bene-fit and with apomorphine and benzodiazepines with limited METHODS Patients. To investigate the role of ARX mu-
benefit. He also had infrequent focal seizures. EEG showed tations in cryptogenic ISS, we performed mutation analysis multifocal epileptiform abnormalities. Brain MRI at age 10

nia, coagulopathy, and elevated creatinine and creatine Imaging features in Patients 3 and 4 kinase levels (52,590 U/dL). Treatment with haloperidol andtetrabenazine probably triggered malignant neuroleptic syn-drome, with life-threatening acidosis, disseminated intravas-cular coagulation, and renal failure. His course remainedstormy with recurrent episodes of status dystonicus. Treat-ment with carbamazepine, baclofen, diazepam, morphine,nasal midazolam, and deep brain stimulation were of limitedbenefit. Head circumference at birth and afterward was al-ways at the 50th centile.
Patient 4. This 14-year-old boy has severe mental retar-
dation, dyskinetic movements, and intractable epilepsy.
Family history is negative. He was born at term with normalhead circumference. Perinatal history was unrevealing. Hehad the onset of ISS at 2 months when an EEG showed mul-tifocal spike or polyspike and wave activity, followed byelectrodecremental responses. He was started on adrenocor-ticotropic hormone (ACTH) in addition to phenobarbitaland clonazepam. Spasms were transiently controlled but re-lapsed at 6 months after stopping ACTH, and he was treatedwith phenytoin. Over the next several months, the ISS finally (A) Axial T1-weighted showed multiple small areas of high T2 signal in the poste- stopped, and his EEG improved; however, he went on to inversion recovery image of rior inferior regions of both basal ganglia that appeared to be have drug-resistant focal seizures and since age 12 he has had Patient 3 shows lucencies(arrows) in the posterior of CSF intensity on T1-weighted spin echo and inversion re- multiple seizure types per day. During infancy and early lentiform nuclei. Foci of covery (IR) sequences, as well as mildly enlarged ventricles.
childhood, continuous choreoathetotic and dystonic move- Biochemical screening for a wide range of metabolic disor- ments developed. He learned to walk on his knees, but al- are seen in the cerebral ders and muscle biopsy were normal. At age 15, he had mild most constant twisting or writhing movements largely peduncles; these are of microcephaly (–2 SD), severe mental retardation with absent prevent normal hand use (see video 4). MRI scan at 5 years unknown significance. (B) speech, and severe dystonia (see video 1 on the Neurology showed multiple small areas of high T2 signal in both basal Axial T2-weighted image of Web site). He was assigned the diagnostic label of "dyski- ganglia that appear to be small cysts based on T1-weighted Patient 4 shows multiple netic cerebral palsy." Brain MRI in his mother and maternal spin echo and IR sequences, as well as mildly enlarged ven- hyperintense foci aunt were normal.
tricles (figure 2B). His head circumference was 54.6 cm (50th (arrowheads) in the Patient 2. The 9-year-old brother of Patient 1 had a sim-
percentile) at 14 years.
posterior putamina. There isoverall increase in the size ilar clinical history with onset of infantile spasms at 3 Patient 5. This 3-year 6-month-old Japanese boy was
of ventricles and cisterns, months and onset of generalized dystonia and chorea at 5 born at term as the first child of healthy and unrelated par- suggesting cerebral volume months that progressed in severity until 2 years (figure 1, ents (figure 1B, II:1). Head circumference at birth was 33.0 AIII:2). Recurrent status dystonicus was also observed. Brain cm (about 10th percentile). His early development was MRI at 5 years demonstrated multiple small cystic areas in mildly delayed with visual tracking and smiling noted at 2 the basal ganglia as well as mildly enlarged ventricles. At age months, but he never acquired good head control. He had 9 he had continuous severe dystonia (see video 2). His head the onset of brief clonic seizures at 3 months, followed by ISS circumference was 47 cm (50th percentile) at 1 year and 52 several weeks later that were associated with loss of develop- cm (25th to 50th percentile) at 9 years.
mental milestones. An EEG showed hypsarrhythmia, Patient 3. This 8-year-old British boy was first brought
whereas brain MRI at 4 months was normal. After treatment to medical attention at 5 months with motor delay, fisting, with several antiepileptic drugs was ineffective, ACTH con- and ISS. Family and perinatal history were negative. He was trolled the spasms at age 8 months, but they relapsed at 11 born at term with normal head circumference. By 1 year, months, at which time generalized dystonic movements first dystonic posturing was noted that progressed to generalized appeared. A second cycle of ACTH was effective in control- dyskinesia over the following months, and a tentative diag- ling the spasms. At age 2 years, he had microcephaly (–2.4 nosis of "dyskinetic cerebral palsy" was assigned. At 3 years, SD), poor head control, axial hypotonia, spasticity, and se- he experienced his first episode of status dystonicus, lasting vere dystonic movements. He was not able to roll, and his several days. Baclofen, benxhezol, benzodiazepines, and tet- development was estimated at a 5 months' level.
rabenazine were of little benefit. Focal seizures appeared at Patient 6. This 2-year-old boy is the younger brother of
this time and were treated with valproate and subsequently Patient 5 (figure 1B, II:2) . He was delivered by cesarean sec- carbamazepine monotherapy, which slightly improved the tion at 38 weeks' gestation. His birth weight was 2.858 kg involuntary movements. Brain MRI at 6 years showed small and head circumference was 34.0 cm (50th percentile). He areas of T1 hyperintensity in the mesencephalon (figure 2A) smiled at 2 months but had poor head control. Tonic sei- as well as multiple small areas of high T2 signal in both basal zures began at 4 months and were temporarily controlled by ganglia (not shown) that appeared to be small cysts on T1 phenobarbital. His EEG and brain MRI at age 6 months and IR sequences (figure 2A) and mild ventricular enlarge- were normal. He had axial hypotonia, limb spasticity, and ment. The nature of these is uncertain, but possibilities in- diffuse dystonia most prominent in the neck (see video 5). At clude foci of calcification, lipid, and proteinaceous fluid.
16 months, his head circumference was 48 cm (50th percen- After 4 years of clinical stability, involuntary movements tile). He had the onset of ISS at 17 months. His EEG showed evolved again into status dystonicus (see video 3) with hyper- thermia, acidosis, hypernatremia, uremia, thrombocytope- Neurology 69 July 31, 2007

Phenotypes and genotypes associated with ARX mutations Phenotype (gender) ARX genotypes XLAG with HYD (M) Proud syndrome (ACC-AG) (M) Large intragenic deletions,frameshifts or null mutations(exons 1–4), nonconservativemissense mutations in homeobox ACC with MR, seizures (F) ACC with normal intelligence (F) Syndromes without PolyA expansion (1st PolyA tract [GCG]7) encephalopathy (this report) (M) Infantile spasms (M) PolyA expansion (1st [GCG]7 and 2ndPolyA tracts), deletion of exon 5 Rarely, conservative missense mutationsin homeobox Partington syndrome (XLMR, PolyA expansion (2nd PolyA tract) seizures, mild distal dystonia) (M) XLMR with or without seizures (M) PolyA expansion (1st [GCG]1, 2, 3 and2nd PolyA tracts), missense mutations outsidehomeobox PolyA expansion, missense mutation ACC ⫽ agenesis of the corpus callosum; AG ⫽ abnormal genitalia; HYD ⫽ hydrocephalus; XLMR ⫽ X-linked mental retarda-tion; XLAG ⫽ X-linked lissencephaly with abnormal genitalia; XMESID ⫽ X-linked myoclonic epilepsy with spasticity and in-tellectual disability.
RESULTS Mutation analysis of ARX gene. DH-
most severe in the neck and arms, whereas three PLC analysis of the ARX gene in Patients 1 to 3 (Patients 1 to 3) had recurrent status dystonicus.
showed an altered profile in exon 2, promptingdirect DNA sequencing of the PCR product. Pa- DISCUSSION Previous reports have described re-
tient 4 to 6 were sequenced directly. In all six markable pleiotropy among the phenotypes asso- boys, sequencing demonstrated an insertion of ciated with mutations of ARX, including several seven tandem GCG repeats within the normal syndromes with and without malformations of stretch of 10 GCG triplet repeats in the 5= end of the brain and introducing interneuronopathies as exon 2 (c.333_334ins[GCG]7) (figure 1C). This a new class of developmental disorders.14,15 Here insertion results in expansion of the first PolyA we extend the pleiotropy by demonstrating a con- tract (amino acids [aa] 100 to 115) from 16 to 23 sistent phenotype among males with expansion of residues. This change is not present in the control the first PolyA tract, which consists of severe population9 and was not found in a total of 300 mental retardation, early-onset ISS, and a severe controls, 100 of which were tested in each of three form of generalized dystonia that has a progres- laboratories (Pisa, Chicago, Yamagata). Sequenc- sive course in the first years of life before reaching ing of ARX exon 2 in the mother and maternal a plateau and that may be associated with recur- aunt of Patients 1 and 2 and the mother of Pa- rent life-threatening status dystonicus. We desig- tients 5 and 6 revealed that they were heterozy- gous carriers of the expansion; mutation analysis encephalopathy. This appears to be the most se- in the mothers of Patients 3 and 4 were normal.
vere of the nonmalformation phenotypes recog- The maternal aunt of Patients 1 and 2 gave birth nized to date, as we will review below, although to an healthy boy after prenatal testing on amnio- one could argue that the basal ganglia cysts ob- cytes had ruled out the (c.333_334ins[GCG]7) served in some patients represent a subtle Phenotype summary. All six boys in this study had
Including our report, about 10 different syn- ISS and severe mental retardation. In four of six, dromes have been associated with mutations of onset of ISS was at 2 to 3 months of age, which is ARX, divided into syndromes with and without earlier than usual for this type of seizure. All six brain malformations that differ between males had severe, generalized dystonia that seemed and females (table). Males with less severe muta-

tions have one of several overlapping nonmalfor- companied in two by ISS, other types of epilepsy, spastic quadriparesis, and dystonic movements.22 retardation, epilepsy, especially ISS or myoclonic Our observations contribute to delineating a seizures, and sometimes dyskinesia, as identified particularly severe phenotype that is associated previously.9 Expansions of the first (aa 100 to 115) with the A16¡A23/PolyA expansion, including or second (aa 144 to 155) of the four PolyA tracts frequent early lethality, profound delay, and epi- have proved to be the most common ARX muta- lepsy in all patients, infantile spasms in most, and tions.5,6,9,13,16,17 The first reports in multiplex fam- dystonia with an initially progressive course lead- ilies suggested that duplication of the second ing to a severe dyskinetic syndrome in those who PolyA tract was the most common mutation of survive beyond infancy. The observation that the gene,5,9 but our experience suggests that ex- small in-frame insertion c.333_334(GCG) muta- pansion of the first PolyA tract may be more com- tions leading to one to three amino acid expan- mon in sporadic patients. We report details of a sions of the first PolyA tract caused only mild to series of males with expansion of the first PolyA moderate nonsyndromic mental retardation with tract. In contrast to the more severe malformation no neurologic signs5,23 suggests that the longer the syndromes, all female heterozygotes for less se- PolyA expansion, the earlier the onset and sever- vere mutations have had a normal phenotype.
ity of clinical manifestations. The fact that none Expansions of the second PolyA tract cause a of the carrier women recognized so far, including variable phenotype but are not associated with three women in our study, had any clinical signsuggests loss of function resulting from the PolyA brain abnormalities on neuroimaging. In particu- lar, the 24-bp duplication (c.428_451dup) that re- Similarities between the phenotypes of PolyA sults in the expansion of 12 alanine residues to 20 expansion mutations and null alleles suggest that (A155_W156insAAAAAAAA) is considered a the PolyA-expanded proteins are at least partial mutational hotspot as it was identified in 24 of 59 loss of function mutations.24 An Arx construct families with any mutation of ARX.14 To date, 89 that contains the 16¡23 expansion correspond- patients have been described having this muta- ing to that found in our patients forms intranu- tion, most from multiplex families. Phenotypes clear aggregation of mutant protein and causes included familial nonsyndromic X-linked mental cell death in cultured cortical neurons.25 In oculo- pharyngeal muscular dystrophy, PolyA expan- (ISSX),9,17,18 familial mental retardation with hyp- sions result in nuclear inclusions of mutant sarrhythmia,9 and Partington syndrome.7,19,20 The protein with an increase in cell death.26 latter syndrome is characterized by mild to mod- Status dystonicus is a rare condition with vari- erate mental retardation in boys, of which about ous etiologies.11 Infections and drug treatments 60% also have episodic dystonic movements of that produce inhibition of GABAergic transmis- the hands, which become more prominent in sion in the basal ganglia are potential precipitants childhood.7,19,20 Mild dystonia was also reported in patients with pre-existing dystonia.11 Urgent in some members of two additional families with hospital admission is mandatory as the risk of syndromic and nonsyndromic X-linked mental mortality is high mainly due to bulbar and respi- retardation, and the c.428_451dup mutation.10 ratory complications, exhaustion, pain, and rhab- Altogether, dystonia has never comprised a severe domyolysis with subsequent acute renal failure.
clinical feature in patients with expansion of the Management is difficult. Benzhexol, tetrabena- second PolyA tract.
zine, haloperidol, baclofen, and benzodiazepines The A16¡A23/PolyA expansion of the first were not effective in our patients. We observed PolyA tract that we found in our patients was pre- only mild and transient improvement of dystonia viously reported in three families. In two families, in Patients 1 and 2 after apomorphine infusion 11 boys had ISSX and severe mental retarda- and in Patient 3 with carbamazepine treatment.
tion.10,18,21 Six of the 11 boys died early in life and ARX mutation analysis in our patients was for the remaining boys, data were either missing prompted by a study investigating the role of this or reported at a very early age, when severe dysto- gene in infantile spasms; the correlation with se- nia might not have been manifest yet, although vere dystonic quadriparesis would have otherwise "roving eye movements," "bilateral hand fisting," and "spastic jerking movements" of the hands workup for inborn errors of metabolism that may were reported in some children.18 In the third be accompanied by dyskinetic movements start- family, three males had mental retardation, ac- ing in infancy was unrevealing, and arrest of pro- Neurology 69 July 31, 2007 gression was at odds with the usually inexorably death of interneurons in the striata, due to the progressive course of such disorders. A tentative formation of intranuclear aggregates.25 diagnosis of cerebral palsy was assigned indepen-dently in various centers, although without clini- cal or neuroimaging evidence of perinatal injury.
The authors thank A. Ramazzotti for carrying some of the sequences Indeed, appearance of abnormal movements even of the ARX gene and T. Pisano for retrieving early clinical informa- tion for Patients 1 and 2.
several months or years after birth with subse-quent partial progression is not unusual in dyski- Received December 7, 2006. Accepted in final form March netic cerebral palsy.27 One possible explanation for this is that involuntary movements require ananatomic substrate that may not be sufficiently developed at birth to cause symptoms. The same Miura H, Yanazawa M, Kato K, Kitamura K. Expres- likely applies to our patients, in whom cellular sion of a novel aristaless related homeobox gene ‘Arx' neuropathology caused by the PolyA expansion is in the vertebrate telencephalon, diencephalon and floorplate. Mech Dev 1997;65:99–109.
presumably present at birth and causes early in- Colombo E, Galli R, Cossu G, Gecz J, Broccoli V.
fantile spasms but only produces dyskinesia later, Mouse orthologue of ARX, a gene mutated in several when the anatomic substrate becomes function- X-linked forms of mental retardation and epilepsy, is a ally expressed.
marker of adult neural stem cells and forebrain The ARX gene is highly expressed in the devel- GABAergic neurons. Dev Dyn 2004;231:631–639.
Kitamura K, Yanazawa M, Sugiyama N, et al. Muta- oping cerebral cortex and ganglionic eminence tion of ARX causes abnormal development of fore- where it regulates proliferation and migration of brain and testes in mice and X-linked lissencephaly GABAergic interneurons.3 Arx-deficient mice with abnormal genitalia in humans. Nat Genet 2002; show aberrant migration and differentiation of GABAergic interneurons in the ganglionic emi- Ohira R, Zhang YH, Guo W, et al. Human ARX gene: nence and neocortex.3 Expression studies in the genomic characterization and expression. Mol GenetMetab 2002;77:179–188.
murine brain provide several lines of evidence Bienvenu T, Poirier K, Friocourt G, et al. ARX, a novel suggesting that Arx is involved in the commit- Prd-class-homeobox gene highly expressed in the telen- ment of proliferating neuroblasts to a GABAergic cephalon, is mutated in X-linked mental retardation.
neuronal fate.2 Neuropathologic studies of the Hum Mol Genet 2002;11:981–991.
brain in boys with the XLAG show that the basal Kato M, Das S, Petras K, et al. Mutations of ARX areassociated with striking pleiotropy and consistent ganglia are poorly delineated and atrophic, with genotype-phenotype correlation. Hum Mutat 2004;23: disorganized internal structure and multiple small cavitations.28 No neuropathologic study of boys Partington MW, Turner G, Boyle J, Gecz J. Three new with PolyA expansion mutation of ARX has been families with X-linked mental retardation caused by performed. However, neuroimaging in four of the 428-451dup(24bp) mutation in ARX. Clin Genet2004;66:39–45.
our patients revealed subtle areas of abnormally Scheffer IE, Wallace RH, Phillips FL, et al. X-linked increased signal intensity in the putamina, having myoclonic epilepsy with spasticity and intellectual dis- signal characteristics of CSF (hyperintense on T2- ability: mutation in the homeobox gene, ARX. Neurol- weighted images, hypointense on T1-weighted images and fluid-attenuated IR [FLAIR] images).
Stromme P, Mangelsdorf ME, Shaw MA, et al. Muta-tions in the human ortholog of Aristaless cause The absence of hyperintense signal on the FLAIR X-linked mental retardation and epilepsy. Nat Genet images argues against the presence of astrogliosis and suggests that these foci are dilated perivascu- Stromme P, Mangelsdorf ME, Scheffer IE, Gecz J. In- lar spaces and not focal areas of necrosis, as the fantile spasms, dystonia, and other X-linked pheno- latter would be expected to incite an astroglial re- types caused by mutations in Aristaless relatedhomeobox gene, ARX. Brain Dev 2002;24:266–268.
sponse that would be manifested as hyperinten- Manji H, Howard RS, Miller DH, et al. Status dystoni- sity on these sequences. The observation that cus: the syndrome and its management. Brain 1998;121: these lesions were not present in the two boys who had MRI scan studies at ages 4 to 6 months Guerrini R. Epilepsy in children. Lancet 2006;367:499– and that dystonia has had a progressive course in the first 2 years of life might suggest progressive Chomczynski P, Mackey K, Drews R, Wilfinger W.
DNAzol: a reagent for the rapid isolation of genomic multifocal loss of tissue within the putamina.
DNA. Biotechniques 1997;22:550–553.
We postulate that the areas of cavitation or en- Ge´cz J, Cloosterman D, Partington M. ARX: a gene for larged perivascular spaces might result from all seasons. Curr Opin Genet Dev 2006;16:308–316.
Kato M, Dobyns WB. X-linked lissencephaly with ab- Xp11.4-Xpter in two pedigrees. Ann Neurol 1997;42: normal genitalia (XLAG) as a tangential migration dis- order causing intractable epilepsy—proposal for a new Wohlrab G, Uyanik G, Gross C, et al. Familial West syn- term "interneuronopathy." J Child Neurol 2005;20: drome and dystonia caused by an Aristaless related ho- meobox gene mutation. Eur J Pediatr 2005;164:326–328.
Turner G, Partington M, Kerr B, Mangelsdorf M, Gecz Gronskov K, Hjalgrim H, Nielsen IM, Brondum- J. Variable expression of mental retardation, autism, Nielsen K. Screening of the ARX gene in 682 retarded seizures, and dystonic hand movements in two families males. Eur J Hum Genet 2004;12:701–705.
with an identical ARX gene mutation. Am J Med Brown LY, Brown SA. Alanine tracts: the expanding story of human illness and trinucleotide repeats.
Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB.
Trends Genet 2004;20:51–58.
PolyAlanine expansion of ARX associated with crypto- Nasrallah IM, Minarcik JC, Golden JA. A PolyAnine genic West syndrome. Neurology 2003;61:267–276.
tract expansion in Arx forms intranuclear inclusions Bruyere H, Lewis S, Wood S, MacLeod PJ, Langlois S.
and results in increased cell death. J Cell Biol 2004;167: Confirmation of linkage in X-linked infantile spasms (West syndrome) and refinement of the disease locus to Fan X, Dion P, Laganiere J, Brais B, Rouleau GA. Oli- Xp21.3-Xp22.1. Clin Genet 1999;55:173–181.
gomerization of polyalanine expanded PABPN1 facili- Partington MW, Mulley JC, Sutherland GR, Hockey tates nuclear protein aggregation that is associated A, Thode A, Turner G. X-linked mental retardation with cell death. Hum Mol Genet 2001;10:2341–2351.
with dystonic movements of the hands. Am J Med Trinidad KS, Kurlan R. Chorea, athetosis, dystonia, tremor and parkinsonism. In: Robertson MM, Eapen Frints SG, Froyen G, Marynen P, Willekens D, Legius V, eds. Movement and allied disorders in childhood.
E, Fryns JP. Re-evaluation of MRX36 family after dis- Chicester, UK: Wiley, 1995:105–147.
covery of an ARX gene mutation reveals mild neuro- Bonneau D, Toutain A, Laquerriere A, et al. X-linked logical features of Partington syndrome. Am J Med lissencephaly with absent corpus callosum and ambig- uous genitalia (XLAG): clinical, magnetic resonance Claes S, Devriendt K, Lagae L, et al. The X-linked in- imaging, and neuropathological findings. Ann Neurol fantile spasms syndrome (MIM 308350) maps to Report on Quality Measures to Earn 1.5% Bonus
Medicare will pay a 1.5% bonus to physicians who report their data from July 1, 2007, toDecember 31, 2007, through the Physician Quality Reporting Initiative (PQRI). Physicianreporting thresholds apply to qualify for the bonus. The program currently includesneurology-specific measures in stroke (8) and for risk of falls (1). Visit more information.
Neurology 69 July 31, 2007 Expansion of the first PolyA tract of
causes infantile spasms and status
R. Guerrini, F. Moro, M. Kato, A. J. Barkovich, T. Shiihara, M. A. McShane, J. Hurst, M. Loi, J. Tohyama, V. Norci, K. Hayasaka, U. J. Kang, S. Das and W. B. Dobyns 2007;69;427-433 DOI: 10.1212/01.wnl.0000266594.16202.c1 This information is current as of August 1, 2007
The online version of this article, along with updated information and services, is located on the World Wide Web at: ® is the official journal of the American Academy of Neurology. Published continuously Neurologysince 1951, it is now a weekly with 48 issues per year. Copyright 2007 by AAN Enterprises, Inc. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Expansion of the first PolyA tract of
causes infantile spasms and status
R. Guerrini, F. Moro, M. Kato, A. J. Barkovich, T. Shiihara, M. A. McShane, J. Hurst, M. Loi, J. Tohyama, V. Norci, K. Hayasaka, U. J. Kang, S. Das and W. B. Dobyns 2007;69;427-433 DOI: 10.1212/01.wnl.0000266594.16202.c1 This information is current as of August 1, 2007
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