effects, movement disorders, disturbances of body im-age, disturbances of thinking and emotion, and gastroin-testinal side effects. The first three were the side effectspatients and/or caregivers recognized the most as asso-ciated with NL use. We had considered that tardivedyskinesia would be a side effect of high patient concern,because of its potential irreversibility, but in fact, partic-ipants were not well informed about this potential ad-verse effect.

The decision to start a medication should be an in-formed one, a result of careful weighing of the benefitsand risks. Patient and caregiver empowerment presumesa strong informational base for decision making in con-junction with health-care personnel. Our data clearlyidentify a disturbing information gap with regard to NLsamong GTS subjects in the setting of a university prac-tice. This gap is surprising as it is standard practice inthis group to discuss medication options and potentialside effects with the patients before medication initiation.As one of our study aims was to identify educationalneeds, we believe a focus on medication options andpotential side effects should be a primary focus of futureprograms. The willingness of patients and families toparticipate in our project encourages us to promote edu-cational efforts in this patient population. Finally, a use-ful supplement of this study would be a questionnaire oftreating physicians from the community to document theexisting educational procedures and assess the needs forfuture educational efforts. The results of this study em-phasize the need for clinicians to inform their patientsabout potential adverse events when they initiate therapyin patients with tics and to reiterate this information infrequent intervals.

REFERENCES

1. Diagnostic and statistical manual of mental disorders. 4th ed. Wash-ington, DC: American Psychiatric Association; 1994.

2. Shapiro E, Shapiro AK, Fulop G, et al. Controlled study of halo-peridol, pimozide and placebo for the treatment of Gilles de laTourette’s syndrome. Arch Gen Psychiatry 1989;46:722–730.

3. Onofrj M, Paci C, D’Andreamatteo G, Toma L. Olanzapine insevere Gilles de la Tourette syndrome: a 52-week double-blindcross-over study vs. low-dose pimozide. J Neurol 2000;247:443–446.

4. Bruggeman R, van der Linden C, Buitelaar JK, et al. Risperidoneversus pimozide in Tourette’s disorder: a comparative double-blindparallel-group study. J Clin Psychiatry 2001;62:50–56.

5. Silva RR, Munoz DM, Daniel W, Barickman J, Friedhoff AJ.Causes of haloperidol discontinuation in patients with Tourette’sdisorder: management and alternatives. J Clin Psychiatry 1996;57:129–135.

6. Lang AE. Update on the treatment of tics. Adv Neurol 2001;85:355–362.

7. Mesulam MM, Petersen RC. Treatment of Gilles de la Tourette’ssyndrome: eight-year, practice-based experience in a predominantlyadult population. Neurology 1987;37:1828–1833.

Genetic Heterogeneity in PatientsWith Pantothenate Kinase–Associated

Neurodegeneration and ClassicMagnetic Resonance Imaging

Eye-of-the-Tiger PatternPaola Valentino, MD,1,2 Grazia Annesi, PhD,2

Innocenza C. Ciro Candiano, PhD,2

Ferdinanda Annesi, PhD,2 Donatella Civitelli, PhD,2

Patrizia Tarantino, PhD,2 Francesco Naso, MD,3

Patrizia Spadafora, PhD,2 Sara Carrideo, PhD,2

Elvira V. De Marco, PhD,2 Domenico Consoli, MD,3

Mario Zappia, MD,1,2 Antonio Gambardella, MD,1,2

and Aldo Quattrone, MD1,2*1Institute of Neurology, University Magna Graecia

Catanzaro, Catanzaro, Italy; 2Neurological Sciences,National Research Council, Piano Lago Mangone, Cosenza,

Italy; 3Neurologic Clinic, Ospedale Vibo Valentia, Italy

Abstract: We performed a detailed molecular study in twounrelated families with pantothenate kinase–associatedneurodegeneration (PKAN) and the specific magnetic res-onance imaging (MRI) eye-of-the-tiger pattern. In the firstfamily with classic PKAN, linkage analysis using polymor-phic markers from the PANK2 region ruled out linkagewith this locus, and no mutation of the PANK2 gene wasfound. In the second family with atypical PKAN, we iden-tified a novel homozygous C-to-T transition at nucleotide1069 of the PANK2 gene, which resulted in an arginine totryptophane substitution at codon 357. As far as we areaware, this is the first case of classic PKAN with the specificMRI eye-of-the-tiger pattern not carrying a PANK2 muta-tion. Therefore, the present observation reinforces the no-tion of the phenotypic and genetic heterogeneity in PKAN.© 2005 Movement Disorder Society

Key words: Hallervorden–Spatz syndrome; neurodegenera-tion; PANK2 gene

Pantothenate kinase–associated neurodegeneration(PKAN), formerly called Hallervorden–Spatz syndrome,is an autosomal recessive disorder characterized by pro-gressive dystonia, rigidity, choreoathetosis, spasticity,retinitis pigmentosa, optic atrophy, Parkinsonism or sei-zures, and iron accumulation in the brain.1 After the

*Correspondence to: Dr. Aldo Quattrone, Cattedra U.O. di Neurologia,Facolta di Medicina e Chirurgia, Universita Magna Graecia, Via T. Cam-panella, 115, Catanzaro, 88100 Italy. E-mail: a.quattrone@isn.cnr.it

Received 30 November 2004; Revised 3 May 2005; Accepted 5 May2005

Published online 7 September 2005 in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/mds.20681

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recent identification of mutations in the pantothenatekinase 2 (PANK2) gene on chromosome 20p12.3,2,3 ithas been claimed that patients with neurodegenerationwith brain iron accumulation who display classic disease(characterized by early onset with rapid progression)always carry PANK2 mutations, whereas this is the casein only a minority (approximately one third) of patientswith atypical disease who have later onset and a moreslowly progressive course.4 Most remarkable was theobservation of a one-to-one correlation between the mag-netic resonance imaging (MRI) eye-of-the-tiger patternand the presence of a PANK2 mutation, regardless of theseverity of the disease.4 We report here the clinicalfeatures and molecular findings of two unrelated familieswith PKAN phenotype.

PATIENTS

Both families originated in Calabria, southern Italy.One patient from the first family was affected. She is a21-year-old, right-handed woman, with a normal birthand normal achievement of early developmental mile-stones. Her parents are healthy and consanguineous (firstcousins). Her 31-year-old brother and her 32-year-oldsister are also healthy. Moreover, the brain MRI of theunaffected brother who shared the same haplotype withthe affected sister (see Molecular Study section) wasnormal. Around the age of 7 years, she developed fre-quent falls with gait and postural difficulties. From thetime of onset, progression of disease was severe, withappearance of progressive dystonia, rigidity and spastic-ity of the four limbs, particularly of the legs, togetherwith sphincter incontinence. At the age of 18 years, shewas unable to walk, and now she is seriously handi-capped and wheelchair-bound. In the past years, an in-tellectual decline associated with psychiatric distur-bances has emerged. The last neurological examinationdisclosed a spastic tetraparesis, particularly affecting thelower limbs with dystonic posturing of the extremities,dysarthria, diffuse brisk deep tendon reflexes, and bilat-eral Babinski sign. Visual acuity and funduscopy werenormal. Psychiatric examination revealed lability ofmood, mania, agitation, and delusion. There was also aprofound cognitive impairment, with failure to performeven easy neuropsychological tasks. Extensive labora-tory investigations, including cerebrospinal fluid analysiswere unremarkable. Brain MRI study revealed the spe-cific pattern of hyperintensity within the hypointensemedial globus pallidus (Fig. 1). On the basis of theclinical and neuroimaging features, a diagnosis of classicPKAN4 was made in this patient.

In the second family, 2 patients were affected. Theirparents are unrelated and healthy. The proband is a

55-year-old man who developed, at the age of 25,postural tremor in both hands and progressive gaitdifficulty. His sister is now 53 years old, and at the ageof 22, she developed a similar relentlessly progressivecourse. T2-weighted MRI of both patients showedthe classic eye-of-the-tiger pattern. On the basis of theage at onset, course of the symptoms, and neuroimag-ing findings, we formulated a diagnosis of atypicalPKAN.4

MOLECULAR STUDY

In both families, we performed the molecular study forPKAN. Primers were designed to amplify each of theseven exons of PANK2. Polymerase chain reaction–am-plified DNA was sequenced in both the forward and thereverse directions and compared with control DNA.3,4

No mutation in the coding regions of the PANK2 genewas found in the patient displaying classic PKAN. Thefailure to find a PANK2 mutation is negative data and isfurther weakened by the sensitivity of only 90% formutation identification in compelling cases of PKAN.Because of the well-established �90% sensitivity ofPANK2 mutation testing,3,4 we also performed linkageanalysis on the PANK2 gene region on 20p12.3-p13,which allowed us to rule out linkage with this locus(Fig. 2).

FIG. 1. T2-weighted magnetic resonance imaging scan of the patientshowing hypointensity with a central region of hyperintensity in themedial globus pallidus (the eye-of-the-tiger sign).

PKAN AND CLASSIC MRI EYE-OF-THE-TIGER PATTERN 253

Movement Disorders, Vol. 21, No. 2, 2006

In the 2 patients with atypical PKAN, we identifieda novel homozygous C-to-T transition at nucleotide1069 of the PANK2 gene, which resulted in an argi-nine to tryptophane substitution at codon 357. Thismissense mutation was not found in 200 control chro-mosomes.

DISCUSSION

Our findings illustrate that the specific MRI eye-of-the-tiger pattern is not always associated with mutationsin the PANK2 gene in patients with PKAN phenotype.As far as we are aware, this is the first case of classicPKAN with the specific MRI eye-of-the-tiger pattern notcarrying a PANK2 mutation. In a previous study,4 it wasaddressed that the MRI pattern of the eye-of-the-tigerwas highly predictive of PANK2 mutations, as all 79reported patients carrying PANK2 mutations, either withclassic or atypical disease, showed this peculiar patternon MRI, and it was not found in any of the 16 mutation-negative patients. In this way, the present observationreinforces the notion of the phenotypic and genetic het-erogeneity in PKAN.5

REFERENCES

1. Dooling EC, Schoene WC, Richardson EP Jr. Hallervorden–Spatzsyndrome. Arch Neurol 1974;30:70–83.

2. Taylor TD, Litt M, Kramer P, et al. Homozygosity mapping ofHallervorden–Spatz syndrome to chromosome 20p12.3-p13. NatGenet 1996;14:479–481.

3. Zhou B, Westaway SK, Levinson B, et al. A novel pantothenatekinase gene (PANK2) is defective in Hallervorden–Spatz syndrome.Nat Genet 2001;28:34–59.

4. Hayflick SJ, Westaway SK, Levinson B, et al. Genetic, clinical, andradiographic delineation of Hallervorden–Spatz syndrome. N EnglJ Med 2003;348:33–40.

5. Thomas M, Hayflick SJ, Jankovic J. Clinical heterogeneity of neu-rodegeneration with brain iron accumulation (Hallervorden–Spatzsyndrome) and pantothenate kinase-associated neurodegeneration.Mov Disord 2004;19:36–42.

Polysomnographic andPharmacokinetic Findings in

Levodopa-Induced Augmentationof Restless Legs Syndrome

Roberto Vetrugno, MD, PhD,*Manuela Contin, PharmD, Agostino Baruzzi, MD,Federica Provini, MD, Giuseppe Plazzi, MD, and

Pasquale Montagna, MD

Department of Neurological Sciences, University of Bologna,Bologna, Italy

Abstract: Augmentation, defined as a loss of circadian re-currence with progressively earlier daily onset and increasein the duration, intensity, and anatomy of symptoms, notcompatible with the half-life of the drug, is associated withdopaminergic treatment in restless legs syndrome (RLS)patients. The pathogenesis of augmentation is unclear. Wedescribe a patient with idiopathic RLS who developed aug-mentation after 8 months of levodopa treatment. Video-polysomnographic and pharmacokinetic studies with mon-itoring of plasma levodopa levels demonstrated markedmotor hyperactivity during augmentation, with anarchicdischarges of motor unit potentials, tonic grouped dis-charges and flexor spasms, associated with painful dyses-thesia. Symptoms and signs of augmentation were related tolow plasma levodopa levels, abating 75 minutes after orallevodopa administration and reappearing after 3 hours,closely mirroring the rapid rise and fall of plasma levodopaconcentration. This case is the first report in which RLSaugmentation is shown to be characterized by motor hy-perkinesias paralleling levodopa plasma pharmacokineticprofile. © 2005 Movement Disorder Society

Key words: restless legs syndrome; levodopa; augmenta-tion; polysomnography; pharmacokinetic

*Correspondence to: Dr. Roberto Vetrugno, Dipartimento di ScienzeNeurologiche dell’Universita di Bologna, Via Ugo Foscolo 7, 40123Bologna, Italy. E-mail: vetrugno@neuro.unibo.it

Received 30 March 2005; Revised 10 May 2005; Accepted 13 May2005

Published online 30 September 2005 in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/mds.20677

FIG. 2. Microsatellite markers from the 20p12.3-p13 region where thePANK2 gene has been localized, excluded linkage with this locus, asthe proband and his unaffected 31-year-old brother shared the samehaplotypes.

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