heritable essential tremor-idiopathic normal pressure hydrocephalus (etinph)

� 2008 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 146A:433–439 (2008)

Heritable Essential Tremor-Idiopathic NormalPressure Hydrocephalus (ETINPH)

Jun Zhang,1* Michael A. Williams,2 and Daniele Rigamonti31Department of Neurosurgery, University of Mississippi Medical Center, Jackson, Mississippi

2Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland3Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Received 7 December 2006; Accepted 26 June 2007

In this report, we identified a large five-generation distinctivekindred with essential tremor (ET) presenting during theteen years and the consequent appearance of idiopathicnormal pressure hydrocephalus (iNPH) when elderly(>65 years), in an autosomal dominant fashion. Throughclinical and genetic analysis, we defined this kindred as anew essential tremor-idiopathic normal pressure hydro-cephalus (ETINPH) disorder. One of the most commonneurological disorders, ET comprises uncontrollable tremor,most commonly the upper limbs. Molecular genetic studiesin hereditary ET have been initiated, but only with negativeresults so far. iNPH is an adult-onset hydrocephaluscharacterized by ventricular enlargement in the absenceof significant elevations of intracranial pressure. iNPHpatients usually have a triad of clinical symptoms: gaitimpairment, incontinence, and dementia, which is amongthe most common medical problems in the older population.The genetic etiology of iNPH is totally unknown. Wehypothesize that ET is the consequence of the abnormalfunction of a specific neuronal gene, and that the same gene

causes tremor at an early age eventually leading to thedevelopment of iNPH later in life. An understanding of thegenetic components of this disorder may offer us significantinsights into the molecular pathogenesis of ET, iNPH,and other related neurological conditions. In our geneticanalysis of this family, array-based comparative genomichybridization (aCGH) was carried out, and we could notidentify any possible copy number changes of the genomicfragment along the whole-genome in ETINPH patient.Candidate gene linkage analysis was also performed, andwe excluded this disorder from several established lociassociated with tremor. We conclude that the pedigreereported here is a new autosomal dominant genetic disorderETINPH. The characterization of the gene that causesETINPH will certainly enhance our understanding of motordiseases in general. � 2008 Wiley-Liss, Inc.

Key words: essential tremor; idiopathic normal pressurehydrocephalus; ETINPH; aCGH; linkage analysis

How to cite this article: Zhang J, Williams MA, Rigamonti D. 2008. Heritable essential tremor-idiopathicnormal pressure hydrocephalus (ETINPH). Am J Med Genet Part A 146A:433–439.

INTRODUCTION

Essential tremor (ET) is the most common move-ment disorder that interferes with the performanceof daily activities of patients [Louis et al., 2001a;Benito-Leon and Louis, 2006]. The prevalence of ETis as much as 5–6% of the population [Murray,1981; Louis et al., 2001a]. ET occurs 20 times morefrequently than Parkinson disease (PD), affecting upto 10 million people in the United States [Larsson andSjogren 1960; Ashenhurst 1973; Murray, 1981; Larsenand Calne, 1983; Hubble et al., 1989; Metzer, 1994;Louis, 2000; Jankovic et al., 2004; Louis, 2005; Benito-Leon and Louis, 2006]. Epidemiological data providestrong evidence that ET is a genetic disease, with apositive family history in 50–96% [Sutherland et al.,1975; Hubble et al., 1989; Louis and Ottman, 1996;Louis et al., 1997, 2001b; Jankovic et al., 2004], which

probably led to initial descriptions of ET as familialtremor [Schade, 1956; Metzer, 1994; Louis, 2000;Lorenz et al., 2004].

Idiopathic normal pressure hydrocephalus (iNPH)is an adult-onset hydrocephalus disorder of theelderly characterizedbygait impairment, incontinence,and dementia, and by ventricular enlargement inthe absence of elevated intracranial pressure. While

*Correspondence to: Jun Zhang, Department of Neurosurgery,University of Mississippi Medical Center, 2500 N. State Street, Jackson,MS 39216-4505. E-mail: [email protected]

DOI 10.1002/ajmg.a.31958

about 40% of all cases of congenital hydrocephalusare believed to have a possible genetic etiology, noknown genetic etiology for iNPH has been reported inthe literature [Zhang et al., 2006]. Tremor has occasion-ally been reported as a symptomof iNPH, but is usuallyconsidered to be a Parkinsonian-type tremor [Lieber-man, 1974; Kandel and Mirkiev, 1979; Gabellini et al.,1990; Relkin et al., 2005].

Although we have occasionally encounteredpatients displaying symptoms of both ET andiNPH, nevertheless, we have considered them tobe unrelated and coincidental. Indeed, a searchof PubMed (‘‘essential tremor’’[All Fields] AND‘‘hydrocephalus’’[All Fields]) revealed no publishedreports of ETand iNPH.However, oneof our patientswith iNPH and ET reported to us that his oldersister had been treated for iNPH and also had ET,and many in the family also displayed ET. Wereport on the results of our investigation of thisfamily and describe a new autosomal dominantgenetic disorder, essential tremor-idiopathic normalpressure hydrocephalus (ETINPH).

MATERIALS AND METHODS

Subjects

All research subjects are related to each otherwithin a large kindred in which ET segregated as anautosomal dominant trait within the span of fivegenerations. In addition, iNPH also developedexclusively among all affected subjects older than65 years (three affected subjects in the secondgeneration). While the onset age of ET ranges from16 to 44 years, the onset of iNPH occurs in affected

subjects older than 65 years. Informed consentwas obtained from every human research subjectin accordance with a protocol approved by theInstitutional Review Board at the Johns HopkinsSchool of Medicine.

Confirmation of Diagnosis

Blood samples and confirmatory interviewswere successfully obtained from five generations,yielding a total of 26 individuals in a large family thatincluded 13 ET affected individuals and 2 iNPHaffected individuals (numbered individuals, Fig. 1).All subjects completed a questionnaire that coversmost clinical aspects regarding ET and iNPH, such astremor, gait impairment, incontinence, dementia,and head circumference, as well as others. The ETquestions were adapted from a standardized surveydeveloped at Johns Hopkins Neurological Clinics.The diagnosis of ET was confirmed by our analysis ofthe questionnaires and by the clinical exams duringtheir family reunions and phone interviews. Thediagnosis of iNPH was confirmed in two affectedsubjects by virtue of characteristic iNPH symptomsthat responded to shunt surgery. One of thesesubjects (II-2) was originally diagnosed at theJohns Hopkins Adult Hydrocephalus Program onthe basis of his response to controlled CSF drainagevia spinal catheter [Marmarou et al., 2005; McGirtet al., 2005; Relkin et al., 2005]. The diagnosis ofiNPH in the second subject (II-3) was confirmedby significant improvement after shunting. Thediagnosis of an additional third iNPH patient (siblingof II-2 and II-3, deceased) was determined fromfamily interviews.

FIG. 1. The pedigree of a five-generation essential tremor family recruited in JHU. Blood samples have been collected from the numbered individuals. The circlesymbols are female, the square symbols are male, black symbols are affected individuals, white symbols are normal individuals, and gray symbols are individuals withunknown affection status.

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American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

Sample Collection

Blood samples were collected from recruitedmembers of this family, and DNA was extracted fromthese blood samples.

aCGH Hybridization

Before performing candidate gene linkage ana-lysis, we used array-based comparative genomichybridization (aCGH) that measures copy-numbervariations at the whole-genome level to screen ourpatients. High-resolution Agilent Human GenomeCGH 44B microarray was used to screen whetherthere are any copy number changes (duplications ordeletions) along the genome of the patients.

DNA Genotyping

The genetic localization and allele frequencies ofeach microsatellite marker and the relevant geneticmaps for each candidate locus were from publiclyavailable databases. The markers were PCR ampli-fied using standard protocols provided by manu-facturer (Invitrogen, Carlsbad, CA). The PCRproducts were separated on an ABI 377 AutomaticSequencer and the genotypes were determinedusing GenescanTM and GenoTyperTM software(Applied Biosystems, Foster City, CA).

Linkage Analysis

We used microsatellite markers for candidate genelinkage analysis to identify the possible diseaselocus. For the analysis, as implemented in FASTLINK[Cottingham et al., 1993], model-dependent linkageanalysis was performed, assuming an underlyingcomplete penetrance and an autosomal dominantmodeof inheritance, equal allele frequencies, andnoage of onset curve (simplest model).

RESULTS

Clinical Description

The five-generation pedigree shown in Figure 1details 15 affected subjects with ET, of whom 3 inthe second generation also displayed iNPH (gener-ation II, Fig. 1). All 3 with iNPH were over age 65 atthe time their iNPH symptoms became evident.

The index patient (II-2) was initially seen inthe Johns Hopkins Movement Disorder Clinic atage 75 for difficulty walking and tremor. Hishistory was significant for bilateral upper extremitytremor that had worsened progressively over theprevious 10 years and also for a several-yearhistory of difficult walking, which he described asshuffling and needing to walk faster and fasterto maintain momentum. His presentation was

considered consistent with ET. He was seen in theAdult Hydrocephalus Program at Johns Hopkins18months later at age 76 years complaining chiefly ofstumbling, falling, and extreme inability to walk.During the preceding month, he had used a cane,a walker with wheels, and an electric scooterwhen shopping. Clinical evaluation of his gaitnoted cautious, tiny, stuttering steps. The Tinettiassessment tool revealed a balance score of 9/16 anda gait score of 6/12 for a total score of 15/28, which isconsistent with an increased risk of falling [Tinetti,1986]. His head circumference was 61.5 cm, whichexceeded the 97th centile for an adult man of hisheight [Bushby et al., 1992], which is consistent withthe diagnosis of congenital hydrocephalus withlate decompensation [Wilson and Williams, 2007]. Abrain MRI done 2 weeks before this evaluationrevealed enlarged ventricles with a frontal horn spanof 5.1–5.5 cm, a third ventricle span of 11–15 mm,and a patent Sylvian aqueduct. During this visit hereported that his older sister had received a shunt forhydrocephalus 20 years ago and had improvedsignificantly; moreover, she also displayed the samefamilial tremor. When he was evaluated 3 monthsafter shunt surgery, the Tinetti assessment tooldocumented a balance score of 14/16, and a gaitscore of 12/12 yielding a total score of 26/28 whichindicated substantial improvement. He no longerused a cane or other assistive device. He also notedthat his handwriting had improved since hisshunt surgery and that his tremor had diminishedmarkedly, despite no change in his medication(primidone 50 mg TID).

aCGH Analysis

No copy number changes (duplications or dele-tions) were found in the genome of the ETINPHpatients using aCGH analysis (Fig. 2). Although thereare several suspicious spots,where several fragmentsshowed at least onefold or more changes (increaseor decrease), further examination of the flankingfragments rejected these suspicions.

Simulation

We performed a power analysis with 3,000 repli-cates simulation using the computer program SLINK.We found good power to detect linkage (expectedLOD > 3 if y is 0.17 or less). The simulation alsoshowed that given the structure of the pedigree,the probability of observing a lodscore of 3.0 aty¼ 0.02 by chance was 43%.

Linkage Analysis

We found that the genetic defect in this family waslinked to neither of three established ET loci (ETM1,ETM2, and ETM3) [Gulcher et al., 1997; Higgins et al.,

HERITABLE ETINPH 435


1997; Shatunov et al., 2006], nor to one Parkinsondisease locus associated with postural tremorsimilar to ET (PARK4) [Farrer et al., 1999] nor toother Parkinson disease loci associated with tremors(PARK1, 3, 8) [Gwinn-Hardy, 2002]. Maximumlodscore (Max Lodscore) and their recombinationfraction (y) obtained by linkage analysis suggest theexistence of new ETINPH gene for this distinctautosomal dominant disorder (Table I).

DISCUSSION

Because the elderly ET patients in this familyinevitably develop iNPH, it seems extremely unlikelythat these two disorders coincidently segregateindependently in this large family. The fact that theindex patient most likely has congenital hydro-cephalus with late decompensation, also raisesthe possibility that the iNPH and ET are linked.

TABLE I. Candidate Gene Linkage Analysis of this ETINPH Locus to Known ET Loci and SeveralEstablished Loci Associated With Tremor

Marker Locus CHROMGenetic distance inthe interval (cM) Max Lodscore y

D3S1278 ETM1 3q13 0 0 0.5D3S2460 ETM1 3q13 4.91 0 0.5D3S3515 ETM1 3q13 1.68 0 0.5D3S1267 ETM1 3q13 2.8 0 0.5D2S2233 ETM2 2p24 0 0 0.5D2S220 ETM2 2p24 2.72 0.236 0.233D2S2221 ETM2 2p24 1.44 0 0.5D2S2168 ETM2 2p24 1.21 0.044 0.394D6S289 ETM3 6p23 0 0.259 0.257D6S274 ETM3 6p23 3.24 0.039 0.41D6S938 ETM3 6p23 2.16 0.101 0.387D4S1534 PARK1 4q21 0 0 0.5D4S2461 PARK1 4q21 4 0 0.5D4S414 PARK1 4q21 1.6 0.15 0.342D2S2977 PARK3 2p13 0 0.165 0.323D2S1394 PARK3 2p13 1.1 0.125 0.361D4S2397 PARK4 4p16.3-p15.2 0 0 0.5D4S1609 PARK4 4p16.3-p15.2 1.4 0.035 0.42D4S230 PARK4 4p16.3-p15.2 0.5 0.026 0.3D4S2408 PARK4 4p16.3-p15.2 1.3 0 0.5D12S1048 PARK8 12p 0 0 0.5D12S1668 PARK8 12p 0.5 0 0.5D12S1301 PARK8 12p 0.9 0 0.5

FIG. 2. No copy number changes (duplications or deletions) along the genome of the ETINPH patients were found in array-based comparative genomichybridization analysis (aCGH) using high-resolution Agilent Human Genome CGH 44B Microarray. [Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

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We hypothesize that ET is the consequence of theabnormal function of a specific neuronal gene, andthat the same gene causes tremor at an earlyage, eventually leading to the development of iNPHlater in life. This plausible pathogenic model forthis distinct disorder can be further evaluatedonly by identifying the disease gene. Understandingthe genetic components of this disorder mayalso offer us significant insights into the molecularpathogenesis of ET, iNPH, and other related neuro-logical conditions.

Duringagenomescan for familial ET in16 Icelandickindreds with 75 affected members, the first ET locus(FET1 or ETM1)was localized to chromosome3q13.1[Gulcher et al., 1997]. A second ET locus (ETM2) wasthen mapped to chromosome 2p22-p25 in thelinkage study of a large American kindred of Czechdescent in whom ET affected 18 of 67 familymembers [Higgins et al., 1997, 1998, 2003, 2004a].Additional ET loci have also been suggested duringgenetic linkage analysis of ET [Kovach et al., 2001;Illarioshkin et al., 2002] and during clinical studies[Jankovic, 2002; Karmody et al., 2005]. A new ETlocus (ETM3) has been recently identified onchromosome 6p23 through a genome-wide linkagestudy of seven large North American familiesincluding 65 ET patients [Shatunov et al., 2006].However, no gene has yet been identified for ET.Furthermore, no animal model has yet beengenerated that exactly recreates all features ofany of the known tremor disorders in humans[Wilms et al., 1999; Jankovic and Noebels, 2005]. Ina series of efforts to try to identify ETM2 gene, amissense mutation (C/G) causing a glycine for analanine substitution (A265G variant) in the HS1binding protein-3 gene (HS1BP3) was identified inthe minimal critical region (MCR) at the ETM2 locusand was defined to be associated with ET among twoET families linked to this locus [Higgins et al., 2005].However, further reexamination of one of thesetwo ET families and other families linked to thisregion has concluded there is no association ofET with A265G variants of HS1BP3 [Deng et al., 2005;Shatunov et al., 2005]. In the same MCR, bothpolymorphic etm1231 and etm1234 loci were foundto be associated with ET among American patients.Both etm1234 and APOB loci were found to beassociated with ET; the ET locus critical region wasfurther narrowed near or within a 100 kb intervalbetween etm12312 and APOB among Asian ETfamilies [Higgins et al., 2004b; Kim et al., 2005].

For genetic association study on ET candidategenes, lack of association between ET with respectto the FMR1 permutation genotype [Deng et al.,2004; Garcia et al., 2004], to hSKCa3 and CACNL1A4permutation genotype [Pigullo et al., 2001], toNACP-Rep1 allele within the a-synuclein promoter[Pigullo et al., 2003], to SCA-12permutation genotype[Nicoletti et al., 2002], to cytochrome P450IID6

(CYP2D6) [Agundez et al., 1997], to parkin [Pigulloet al., 2004], and to a2 macroglobulin [Xiao andZhang 2006] was reported. The association of ETwith the 263 bp allele of the nonamyloid componentof plaques (NACP)-Repl [Tan et al., 2000], alleles677(T/C) and 1298(C/A) and their compoundgenotypes of methylenetetrahydrofolate reductase(MTHFR) [Sazci et al., 2004], ALAD-2 allele ofd-amino-levulinic acid dehydratase (ALAD) in thepresenceof increased circulatingBPb concentrations[Louis et al., 2005] was described. However, theseresults suggesting positive association will alwaysremain controversial due to the possible type-1error generated from experiment design withrespect to homogeneity, sample size, and age-relatedpenetrance of patient and control groups in thesespecific reports unless these issues are fully evaluat-ed and addressed.

As a progressive neurological disorder, ET has aclearly negative impact on social, physical, andpsychological ability, and quality of life amongpatients, and leads to substantial disability in somepatients. In a recent study, a majority of ET patients(73%) reported experiencing disability in multiplefunctional domains [Ashenhurst, 1973; Sutherlandet al., 1975; Murray, 1981; Larsen and Calne, 1983;Hubble et al., 1989; Metzer, 1994; Louis, 2000].However, the etiology and pathogenesis of ET areas yet unknown. Tremor is defined as a rhythmic,involuntary, oscillatory movement of body parts. ETis characterized primarily by a slowly progressiveaction and postural tremor that most often affects thehands and arms but that sometimes affects otherbody parts. ET is absent at rest, maximal duringmaintenance of a posture, attenuated during move-ment, and usually accentuated at the terminationof movement [Ashenhurst, 1973; Sutherland et al.,1975; Murray, 1981; Larsen and Calne, 1983; Hubbleet al., 1989; Metzer, 1994; Louis, 2000]. The ETtypically consists of postural or kinetic tremor, orsometimes both with the frequency of 4–12 Hz[Metzer, 1994; Pahwa and Lyons, 2003]. Due todifferences in diagnostic criteria and patient attend-ances, the estimated prevalence of ET varies from 1%to 6% [Sullivan et al., 2004]. It has been estimatedthat the mean age of tremor onset is 15 years. Thepenetrance of ET increases with age and is virtuallycomplete by the age of 65 years [Bain et al., 1994].

ET affects all ethnic and geographic populationswithout gender bias. Although the disorder mayinitially become apparent during childhood oradolescence, onset occurs most often during adult-hood. Although there is no known cure for ET yet,medical treatment can provide some benefit byreducing or eliminating functional disability. Currenttreatment with primidone or beta-blockers, suchas propranolol, is not completely satisfactory [Pahwaand Lyons, 2003; Louis, 2005]. Because ET isboth clinically and genetically heterogeneous, it



overlaps with other disorders [Findley, 2000], such asdystonia [Martinelli and Gabellini, 1982; Jankovicet al., 2004], Parkinsonism [Jankovic, 1989; Jankovicet al., 1993], peripheral neuropathy [Brin and Koller,1998], migraine [Biary et al., 1990; Bain et al., 1994],and restless leg syndrome [Ondo and Lai, 2005]. Lackof a clear definition of the ET phenotype plaguesresearch in this area. For example, ET shares severalphenotypic features with genetic heterogeneousautosomal dominant idiopathic torsion dystonia(ITD, or DYT loci) [Durr et al., 1993]. Throughseveral linkage studies, ET and ITD have beenproven to be distinct genetic disorders [Conwayet al., 1993; Durr et al., 1993]. Advances in under-standing the genetic and molecular underpinnings ofET should provide additional tools to unravel theclinical phenotype, genotype–phenotype correla-tions, and the epidemiology of ET.

In this work, through clinical and genetic analysis,we have defined a new ETINPH disorder. Ultimately,cloning of the ETINPH gene will pave the way forfurther research into the neuronal gene function andits relationship in neuronal networks, into thepathogenesis and perhaps the molecular and cellularetiology of ET and iNPH, and into other relatedneurological conditions. The identification of thedisease gene can also result in the possibility ofimproved diagnosis and more widespread availabil-ity of predictive genetic testing.

ACKNOWLEDGMENTS

We wish to thank Siddharth Kharkar at JohnsHopkins University Hydrocephalus Research Centerfor his kind help during the patient recruitment andevaluation, Lucia Griffin and Becky Nichols at UMCNeurosurgery for their help in the preparation of thismanuscript.

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heritable essential tremor-idiopathic normal pressure hydrocephalus (etinph)

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