machado joseph disease maps to the same region of

J Med Genet 1995;32:25-31

Machado Joseph disease maps to the sameregion of chromosome 14 as the spinocerebellarataxia type 3 locus

Elspeth C Twist, Leanne K Casaubon, Martin H Ruttledge, Valluri S Rao, Patrick MMacleod, Joao Radvany, Zuyun Zhao, Roger N Rosenberg, Lindsay A Farrer, Guy ARouleau

Centre for Research inNeuroscience, McGillUniversity and theMontreal GeneralHospital ResearchInstitute, 1650 CedarAvenue, Montreal,Quebec H3G 1A4,CanadaE C TwistL K CasaubonM H RuttledgeG A Rouleau

Department ofNeurology, BostonUniversity School ofMedicine, 80 EastConcord Street,Boston, USAV S RaoL A Farrer

Section of Genetics,Department ofLaboratory Medicine,Victoria GeneralHospital, Victoria,British ColumbiaV8Z 6R5, CanadaP M Macleod

Neurologia HospitalIsraelita AlbertEinstein, Sao Paulo,BrazilJ Radvany

Department of HumanGenetics, University ofUtah, Salt Lake City,Utah 84112, USAZ Zhao

Department ofNeurology, Universityof Texas SouthWestern MedicalCenter, Dallas, Texas,USAR N Rosenberg

School of PublicHealth, BostonUniversity School ofMedicine and theDepartment ofNeurology, HarvardUniversity School ofMedicine, Boston,USAL A Farrer

Correspondence to:Dr Twist.

Received 24 June 1994Revised version accepted forpublication 15 August 1994

AbstractMachado Joseph disease (MJD) is anautosomal dominantly inherited neuro-degenerative disorder primarily affect-ing the motor system. It can be dividedinto three phenotypes based on thevariable combination ofa range of clinicalsymptoms including pyramidal and extra-pyramidal features, cerebellar deficits,and distal muscle atrophy. MJD is thoughtto be caused by mutation of a single genewhich has recently been mapped, usinggenetic linkage analysis, to a 29 cM regionon chromosome 14q24.3-q32 in five Jap-anese families. A second disorder, spino-cerebellar ataxia type 3 (SCA3), whichhas clinical symptoms similar to MJD, hasalso been linked to the same region ofchromosome 14q in two French families.In order to narrow down the region ofchromosome 14 which contains the MJDlocus and to determine if this region over-

laps with the predisposing locus for SCA3,we have performed genetic linkage ana-

lysis in seven MJD families, six ofPortuguese/Azorean origin and one ofBrazilian origin, using nine microsatellitemarkers mapped to 14q24.3-q32. Our res-

ults localise theMJD locus in these familiesto an 11 cM interval flanked by the markersD14S68 and AFM343vfl. In addition we

show that this 11 cM interval maps withinthe 15cM interval containing the SCA3locus, suggesting that these diseases areailelic.

(JMed Genet 1995;32:25-31)

Machado Joseph disease (MJD) is an inheritedneurodegenerative disorder which primarilyaffects the motor system.' It shows an auto-somal dominant pattern of transmission anda mean age of onset of 37-4 years (SD 14-1).Pathologically, there is neuronal loss in thedentate nucleus of the cerebellum as well as

progressive loss of neurones and gliosis in thesubstantia nigra and basis pontis. In addition,there is significant motor neurone loss in theanterior horn of the spinal cord and in motorcranial nerve nuclei.2-7 The spinal cord alsoshows demyelination and there is atrophy ofthe spinocerebellar tracts. These morphologicalchanges give rise to a wide range of clinicalsymptoms including cerebellar ataxia, pro-

gressive external ophthalmoplegia, pyramidalsigns, dystonia, rigidity, amyotrophy, and peri-pheral neuropathy.3589Based on the variable combination of these

clinical symptoms in different persons, MJDcan be divided into three phenotypes: typeI begins in the second or third decade withpyramidal and extrapyramidal features and hasa rapid clinical course; type II occurs mostfrequently in the second to fourth decade withpredominantly cerebellar deficits; and type IIIbegins in the fifth to seventh decade with distalmuscle atrophy being the prominant feature.9The reasons for such variation in clinical pre-sentation remain to be established but geneticheterogeneity seems unlikely since differentsubtypes are frequently seen within the samefamily.9"0 In addition, the phenotype is notfixed but can change over time.59 Thus, itappears that MJD is the result of a single genemutation which results in variable expressionof the disease.'0MJD was initially described in three Am-

erican families of Portuguese/Azorean des-cent.28"2 The disease is most prevalent (1:4000) in the Portuguese islands of the Azores,as well as in Portuguese Americans from NewEngland and California. It is now generallyaccepted, however, that the disease alsoexists in other ethnic groups, for example,Japanese,7"" Aboriginal Australians,"8 blackAmericans,'920 and Italian,2122 Spanish, Rus-sian, and Chinese kindreds from the USA aswell as Spanish and Chinese kindreds frommainland Spain and China.23 It is possible thatthese populations have links with Portugal or,alternatively, MJD may have arisen in thesegroups as a result of different ancestral mut-ations of the MJD gene.The gene for MJD has recently been mapped

to a 29 cM interval on chromosome 14q24.3-q32 in five Japanese kindreds."4 Subsequently,a second disorder, spinocerebellar ataxia type3 (SCA3), has been mapped to the same regionof chromosome 14q in two French families.24In order to narrow down the region of chro-mosome 14 which contains the MJD locus andto determine if this region overlaps with thepredisposing locus for SCA3, we have per-formed genetic linkage analysis in seven familiessegregating MJD, six Portuguese/Azorean fam-ilies, and one Brazilian family, using ninemicrosatellite markers mapped to 14q24.3-q32. Our results show that the MJD locus islocalised to an 11 cM interval flanked by the

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Twist, Casaubon, Ruttledge, Rao, Macleod, Radvany, Zhao, Rosenberg, Farrer, Rouleau

Table 1 Machado J7oseph families used for linkage analysis

Pedigree identification No ofpersons No ofpersons No ofpersonssampled affected at risk

MJD-1 19 11 5MJD-2 18 10 5MJD-3A 9 3 4MJD-3B 22 12 6MJD-4 11 3 5MJD-11 13 5 6MJD-B1 101 32 56Total 193 76 87

markers D14S68 and AFM343vfl. In additionwe show that this 11 cM interval lies withinthe 15 cM interval containing the SCA3 locus,indicating that these diseases may be allelic.

Materials and methodsSeven pedigrees of known Portuguese/Azoreandescent which were segregating MJD were se-

lected for linkage analysis: five from New Eng-land (identified as MJD-1, MJD-2, MJD-3A,MJD-3B, and MJD-4), one from California(identified as MJD-1 1), and one from SantaCatarina, Brazil (identified as MJD-B1). Allseven pedigrees have been described pre-viously.25-27 Blood was collected from 193 per-

sons, 76 ofwhom are affected and 87 ofwhomare at risk (table 1). DNA was extracted as

previously described28 and, in addition,lymphoblastoid cell lines were established byEpstein Barr virus transformation.28

Linkage analysis was carried out using a

range of highly informative di- and tetra-nucleotide repeat polymorphic markers (fig1). Polymerase chain reaction (PCR) am-

plification of the desired fragments was carriedout as described previously.29 PCR reactionswere subjected to a hot start of 94°C for two

cM

2

7

1

1

10

9

D14S43 -

D14S74

D14S55D14S128

D14S124/D14S48D14S68

D14S256

AFM343vf1

D14S51

Figure 1 Linkage map of markers on chromosome 14q in the region of the M7D locus.Markers used in this study are highlighted in bold print.

minutes followed by 30 cycles of denaturingfor one second at 94°C and then one minute at92°C, annealing for 45 seconds at temperaturesranging from 52°C to 57°C depending on theprimer pairs, and elongation for one minute at72°C followed by a final extension of five min-utes at 72°C and then cooling of the productto 4°C. DNA fragments were resolved on 5%or 6% polyacrylamide denaturing sequence gelsfor varying lengths of time depending on thesize of the DNA fragment. Gels were dried andexposed to x ray film for three days.Linkage between the MJD locus and the

chromosome 14 markers was analysed by thecomputer program LIPED30 using an age atonset correction function3' which assumed anormal distribution with a mean of 37-4 (SD14-1),9 autosomal dominant transmission ofMJD, and mutant allele frequency of 0-0005.Allele frequencies for the markers were cal-culated from genotype analysis of a sample of30 spouses of family members.The genetic map of chromosome 14 used to

position the MJD locus (fig 1) was based onthe Genethon map32 and the map accordingto Takiyama et al.14 Two additional markers,D14S124 and D14S128, were inserted intothe map by multilocus linkage analysis. CEPHreference pedigree data were obtained fromthe Utah and Collaborative Human LinkageCenter data bases. Odds for marker order anddistances were estimated using the CRIMAPprogram.33 The marker order D14S74-D14S55-D14S128-D14S124-D14S48-D14S51was equally likely as the order D 14S74-D14S55-D14S128-D14S48-D14S124-D14S5 1.However, haplotype analysis in the MJD fam-ilies favoured the former order. This markerorder was 1000:1 times more likely than anyother possible order.33 DI4S68 was positionedaccording to Stevanin et al.24

Evaluation ofthe support for linkage ofMJDwithin each interval on the genetic map (fig 1)was carried out by multilocus linkage analysisusing the LINKMAP program (version 4.9)from the LINKAGE package.34 In these ana-lyses, age dependent penetrance of MJD wasdefined as a step function based on 15 ageintervals corresponding as closely as possibleto the function used in the LIPED analyses.D14S48 and D 14S 124 were treated as a haplo-type since recombination has not been observedbetween them. Computer analyses were fa-cilitated by reducing the observed alleles foreach marker to four using the scheme ofBraver-man35 which is an implementation of a methodproposed by Ott.36 Allele reductions were doneby hand. A series of overlapping four loci (MJDplus three marker loci) were carried out in amanner previously described,37 which allowedcomparison of results over all intervals andefficient computation. Because an age cor-rection function may not adequately accountfor non-penetrance in some persons, analyseswere repeated after changing the disease pene-trance in all at risk persons to zero (that is, azero penetrance model). This latter model issimilar to an "affecteds only" model in thatnormal offspring contribute no linkage in-formation with regard to MJD; however, they

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27Machado J7oseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus

Table 2 Pairwise lod scores between chromosome 14 markers and the Machado J7oseph disease locus for individualfamilies

0 00 0 01 0-05 0 10 0-20 0 40 Zmax (0)

2-82-1-03

1-210-63-x0-040-87-X

4.49

-X-x

-0-050-89- DC

- .

-X-0-46-X

-0-73-0-28-X

-Xc-x2-070-63

-1-11-Xc-X- Xc

-0-23-0-97

1-690-73

-0-191-822-84

-X-0-702-880-63-x-x2-32- Xc

3-80-0-53

1-200-62

-1-120-050-863-88

4-40-0-73-1-78-3-850-000-87

-1-09

0-42-3-99-0-43-2-48-0-67-0-27-7-42

1-10-0-592-010-62

-1-05- 1-29-3-17-2-39

0-890-071-650-71

-0-141-784-96

1-790-442-830-62

- 1-12-0-822-276-01

8-32 8-162-06 2-041-06 1-040-63 0-62-xc -1-790-64 0-610-30 0-29-xc 10-94

3-58 5-091-70 1-682-88 2-83-cx -1-670-45 0-430-99 1-04-x 9-40

1-51 0-29-0-58 -0-05-0-07 0-000-23 0-05-0-21 -0-05-0-14 -0-020-74 0-22

1-68 0-390-26 0-101-10 0-150-41 0-160-36 0-07-0-14 -0-01-0-46 -0-033-21 0-83

0-76 0-120-77 0-281-00 0-230-36 0-040 11 0-041-01 0-164-01 0-87

3-61 0-961-05 0-201-74 0-380-25 0-100-18 0-020-87 0-177-70 1-83

6-25 0-07

3-41 0-10

3-41 0-20

3-35 0-18

5-71 0-05

9-13 0-08

11-07 0-02

10-45 0-05

provide valuable information about the markergenotype and linkage phase between markersin their parents, many of whom were un-

available for study.

ResultsWe have analysed nine di- and tetranucleotiderepeat polymorphic markers spanning the29 cM region of chromosome 14q24.3-q32.2,reported by Takiyama et al14 to contain thegene responsible for MJD (fig 1).

Two point lod scores between the MJD locusand each marker for all seven families examinedare shown in table 2. The marker D14S68 isnot included in the table since it was analysedin family MJD-B1 only, yielding a maximumlod score of 5 03 at a recombination fractionof 0-03. The cumulative lod scores for eachmarker was greater than + 3 with the exceptionof D14S55 which was not very informative.Dl14S256 showed the highest lod score of 11 -07at a recombination fraction of 0-02. The max-

imum likelihood estimates of recombination

3-000-390-780-41

-0-080-050-515-06

2-530-59

-0-11-0-320-170-523-38

0-980-230-190-16

-0-010-000-071-62

0-610-200-000-030-000-110-95

D14S48MJD-B1MJD-1MJD-2MJD-3AMJD-3BMJD-4MJD- 11Total

D14S51MJD-B1MJD-1MJD-2MJD-3BMJD-4MJD- 11Total

D14S55MJD-B1MJD-1MJD-2MJD-3BMJD-4MJD-l1Total

D14S74MJD-B1MJD-1MJD-2MJD-3AMJD-3BMJD-4MJD-llTotal

D14S124MJD-BlMJD-1MJD-2MJD-3BMJD-4MJD- 11Total



AFM343vflMJD-BIMJD-1MJD-2MJD-3BMJD-4MJD- 11Total

4-060-011-150-58

-0-500-060-816-17

4-050-11

-0-83-1-940-120-812-32

1-35-2-38-0-30- 1-29-0-49-0-26-3-37

2-050-021-830-58

-0-33-0-63-1-85

1-67

1-270-671-530-64

-0-021-635-71

3-281-032-610-58

-0-51-0-202-078-86

7-501-950-940-58

-0-940-530-2610-82

5-221-592-61

-0-460-371-12

10-45

3-820-241-050-53

-0-260-070-726-17

3-560-45

-0-42- 1-070-170-723-41

1-62- 1-42-0-19-0-73-0-36-0-22-1-30

2-120-201-610-530-13

-0-37-1-173-05

1-190-831-360-550-061-435-42

3-461-172-340-53

-0-280-011-829-05

6-661-800-810-53

-0-520-430-219-92

4-801-432-34

-0-010-301-109-96

2-841-031-740-41

-0-120-131-297-32

4-891-380-560-41

-0-160-250-127-45

0-680-310-390-16

-0-030-060-211-78

1-290-380-090-160-000-040-021-98

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22 F

20K

18K

16K

14 -

12

10 e-

8

6

4

00

CN~~~~~~~~~~Y(1) CY)Sfin Un'e/n <:

l I

5 10 15 20

Map position (cM)

Figure 2 Support for position of the MJD locus with respect to chromosome 14 markerloci. The position of D14S74 was arbitrarily set at 0 00 and the positions of the other lociwere fixed according to the genetic map in fig 1. The solid line indicates the supportassuming age dependent penetrance and the dashed line indicates the support assumingincomplete penetrance in at risk persons.

for all other markers were greater than 0-02.Inspection of the lod scores by family showsthat pedigree MJD-B1 is significantly linked(lod greater than 3-0) to D14S48, D14S128,D14S256, AFM343vfl, and D14S51. Lodscores greater than 2-0 were obtained in ped-igrees MJD-1 (D14S256) and MJD-2(D14S74, D 14S 128, D 14S256, andAFM343vfl). The other pedigrees, which hadfewer meiotic events, yielded positive lod scores

greater than 0 5 with at least one marker. Therewas no evidence of linkage heterogeneity. Mul-tilocus analysis was carried out using the geneticlinkage map shown in fig 1, to determine theprecise location of the MJD gene among thegroup of chromosome 14q markers analysed.The most likely location for the MJD gene isat a position 2 cM distal to D14S256 and 8 cMproximal to AFM343vfl. However, assuminga one lod unit confidence interval, the MJDgene is not excluded from any of the testedlocations between these two flanking markers.The statistical support favouring each order ispresented in fig 2. Odds against the secondmost likely order (the MJD gene being in theinterval immediately proximal to D 14S256) are

11 to 1. The other possible orders are muchless likely ranging from 288 to 1 (the MJDgene being in the interval between AFM343vfland D14S51) to 5-75 x 1010 to 1 (the MJDgene being in the interval between D14S55 andD 14S128). The final conclusion and relativeposition of the MJD gene between the flankingmarkers was unchanged if zero penetrance inat risk persons was assumed.Haplotype analysis was carried out on all

seven families. The most informative re-

combinants are shown in fig 3A and B whichdepict different branches of the largest ped-igree, MJD-B1. Fig 3A shows recombination

of the chromosome inherited from the affectedmother below the marker D14S256 in bothsubjects 24 and 86. In fig 3B, subject 538(whose DNA has not been obtained) appearsto have only inherited that portion of the chro-mosome from her affected parent below themarker D14S68. This can be inferred since heraffected daughter, subject 98, only inheritedthis portion ofthe "affected" chromosome fromher. In addition, her affected son, subject 540(whose DNA has also not been obtained), hasalso inherited this portion of the "affected"chromosome as inferred from his affecteddaughter, subject 65. Thus, from these persons,the MJD gene can be localised to that intervalbelow D14S68 and above AFM343vfl, a gen-etic distance of approximately 11 cM. Thereare, however, a number of persons who inherit

LO, this region of chromosome 14 from their affec-ted parent but who are at present asympto-matic. These persons are below the mean age

25 30 35 of onset, that is, below 37 years of age, withthe exception of subject 26 who is 38 years.

DiscussionIn this paper we show that MJD segregatingin seven Portuguese/Azorean families currentlyliving in the United States and one Brazilianfamily is linked to chromosome 14q24.3-q32,confirming the findings of Takiyama et al. 4 Intheir study, they found tight linkage of MJDto the markers D14S55 and D14S48 in fiveJapanese families. Multiple recombinationevents were observed between the more cen-

tromeric marker D14S53 and the MJD lociand between the more telomeric markerD14S45 and the MJD locus. Thus the gene

for MJD was postulated to lie within a 29 cMregion flanked by these two markers.

In our families a cumulative two point lodscore of +6-25 and +0 74 was obtained withthe markers D14S48 and D14S55 respectivelywith multiple recombination events being ob-served between both markers and the MJDlocus. Our data suggest that the MJD gene islocated 8 cM centromeric to AFM343vfl and2 cM telomeric to D14S256. From haplotypeanalysis it can be shown that the MJD locusmaps within a 11 cM region flanked by themarkers D14S68 and AFM343vfl. At least onerecombination event is seen between D14S256and the MJD locus in family MJD-3B, tent-atively placing the MJD locus telomeric to thismarker. However, since there are a number ofgenerations ofuntyped persons in this pedigree,reconstruction of the recombinant haplotypesis problematical at present.

In this study, we did not find linkage dis-equilibrium with any of the marker loci tested.The evidence for linkage disequilibrium re-

ported by Takiyama et al14 is misleading sinceit appears that they included chromosomesfrom multiple members (affected and un-

affected) from every MJD family. Their sample,which contains only five unrelated MJD chro-mosomes, is not sufficient for linkage dis-equilibrium studies. This fact notwithstanding,the multilocus one lod unit confidence intervalfor the most likely location of MJD in the

UL)0cnV0-j

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Machado J'oseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus

A

D 14S74D 1 4S55D 1 4S 128D 1 4S 124D 14S64D 14S68D 14S256AfF343vf ID 14SS1

514 1

6 63 3

1148145

1841L27i4 43 24 4

2 22 31 6S S3 3

L9i3 47 44 6

-5*526 13s 525 16

26 2 6 26

23I3 1- 2 3

1 14 6 14 9 - 18a5 5 5 4 5 - 5 4

34 38 3- 38

9 7 9 22

3- 34432-

73

14 6,4 -1 J

_ ^___11---ik r% -- __-1S23 1 323 1 3

17 9 7

5 6 5 5

3 3 3 69 4 6 5

7 6 2 74f4 7 6

( 101

131397563364182674

90 J37

2

99 9

27 74 4Lj 1

60

3 23 31645 76 6

4 92 47 6

I32 3333 3 63 3 316 4 147 7 46 6 80 8 29 9 44 4 36 6 4

15 j17 se 14

2 6 26 2 62 3 2 3 33 2 3114 1 4 6 _ _5

4 5 4 55 S 53 8 3 34 39 2 9 2 9 7 9 2

34 34 4 4 I-I-

7 3 7 3 42 _4± 4 4 4 4 4 4j 4

(1122i151343L

OT34 I;61353 2 63 3 34 4147 7 46 6 80 8 29 9 44 4 36 6 4

{64

2 331

8639442749

*24 *27 i25 961 n26 6)29 830 631 6)223 73 36 36 36 36 265 72 36211 1213 13 13 13 13 33 23 1 3118 1116 8 88 8 88 68 16 a

856 55 65 65 65 65 55 55 6316 1318 68 68 68 68 a8 38 6334434 44 44 44 44 44 34 4337 72 73 27 73 73 23 72 774 9 44 44 44 94 94 44 44 9

B

998

D14S74D14S55D14S 128D14S 124D14S48D 1 4S68D14S256AMF343vf 1

D 1451

2 6 2 2 2 23 1 3 3 3 3 3 27 11 7 8 7 4 86 6

55 5 5 5 56 8 6 3 6 6 1 6 6

5 72 177 62

2

45 4 7 4 3 5~~~

33[3 29 6

156

3 36 2

58BI69 D714 2 33 2 3a I 95 5 5

3 62 9 73 3 37 7 64 14 S

Figure 3A and B Haplotype analysis ofpart of the MJD-BI kindred indicating a centromeric and a telomeric markerflanking the interval containing the MJD locus. The haplotype segregating with the disease is surrounded by a box.Bracketed haplotypes have been inferred from offspring. Age of at risk persons (where this information is available) isindicated within the symbol denoting sex.

527

3 4171411663 3

a 36 5

* 862142 3

7

3 39 4Ia

2 64 4

0363 63 37 146 53 4

8 46 24 4

J85 11874 6 4 64 3 4 314 14 14 146 5 6 53 4 3 4

3 4 3 45 2 5 25 4 5 4

29

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Japanese families includes the most likely loc-ation for MJD in our group of families.

Recently, another type of autosomal dom-inant cerebellar ataxia, SCA3, has been linkedto the same region of chromosome 14q asMJD.24 The autosomal dominant cerebellarataxias (ADCA) are clinically and geneticallya heterogeneous group and, according to Hard-ing,38 can be divided into three types: ADCAtype 1 can be further subdivided to includeMJD, chromosome 6 linked SCA1, chro-mosome 12 linked SCA2, and SCA3. Linkageof SCA3 to chromosome 14q was found intwo French families using an array of markersspanning the MJD region.24 For the markersD14S55 and D14S48, cumulative positive lodscores of 1-73 for a recombination fraction of0 I and 1 -29 for a recombination fraction of 0-2were obtained respectively. Thus, in agreementwith our data, the SCA3 loci was found not tobe tightly linked to either D14S55 or D14S48.From multilocus and haplotype analysis thepredisposing SCA3 locus is thought to be loc-ated in a 15 cM interval flanked by the markersD14S68 and D14S81. Since MJD and SCA3have been localised to the same region of chro-mosome 14 by linkage analysis it is possiblethat these two disorders are allelic. This hy-pothesis is further supported by the clinicalsimilarity between the two diseases. From astudy by Stevanin et al,24 the mean age of onsetand the mean disease duration was shown tobe similar between a group of 18 SCA3 patientsand 12 MJD patients. In addition, the fre-quency of the cerebellar signs associated withcerebellar ataxia was not significantly differentbetween the SCA3 patients and the MJDpatients with the exception of faciolingualmyokymia which was always present in MJDbut never in SCA3, and dystonia which was

significantly more frequent in MJD comparedto SCA3 (p<005). However, the clinical symp-toms of SCA3 more closely resemble those ofSCA1,24 the locus of which is known to beon chromosome 6, suggesting that clinicalsimilarity is not necessarily indicative of genetichomogeneity.A third autosomal dominant neurode-

generative disease, dentatorubropallidoluysianatrophy (DRPLA) has recently been reportedto be linked to chromosome 14q24.3-qter.4°However, two independent reports have re-

cently identified an expanded unstable CAGrepeat on chromosome 12p in DRPLA patientsfrom Japan,4142 a finding which has recentlybeen confirmed in a British DRPLA kindred.43Thus, it is possible that there are two genesresponsible for DRPIA located on differentchromosomes, although it is more probablethat the chromosome 14 linked DRPIA is infact MJD.

In conclusion, we have shown linkage ofMJD to chromosome 14q in six American fam-ilies of Portuguese/Azorean descent and in oneBrazilian family indicating that MJD se-

gregating in these families is the same as MJDdescribed in Japan. In addition we have nar-

rowed the region of chromosome 14q con-

taining the MJD gene locus from 29cM to

11 cM, an interval which maps within the re-

gion of chromosome 1 4q containing the SCA3locus.

We would like to thank the families for their willingness toparticipate in this study and Drs B White and J Holden forassistance with lymphoblastoid transformation of cell lines fromseveral American kindreds. We would also like to thank Dr SMarc for information regarding the marker AFM343vfl. ElspethC Twist is the holder of a Unisource Canada/Alzheimer Societyof Canada/MRC fellowship award, Lindsay A Farrer was sup-ported by a fellowship from the Sloan Foundation, and Guy ARouleau is supported by the Medical Research Council ofCanada and the Fonds de Recherches en Sante du Quebec andthe National Institute of Health.

1 McKusick VA. Mendelian inheritance in man. Catalogs ofautosomal dominant, autosomal recessive and X-linkedpheno-types. 9th ed. Baltimore: The Johns Hopkins UniversityPress, 1990:117.

2 Woods BT, Schaumburg HH. Nigrospinodendal de-generation with nuclear ophthalmoplegia. A unique andpartially treatable clinicopathological entity. J Neurol Sci1972;17: 149-66.

3 Romanul FCA, Fowler HL, Radvany J, Feldman RG, Fein-gold M. Azorean disease of the nervous system. N EnglJMed 1977;296:1501-8.

4 Rosenberg RN, Nyhan WL, Coutinho P, Bay C. Josephdisease: an autosomal dominant neurological disease inthe Portuguese of the United States and the Azores Islands.Adv Neurol 1978;21:33-57.

5 Coutinho P, Sequeiros J. Aspects clinique et pathologiquede la maladie de Machado-Joseph. JfGenet Hum 1981;29:203-9.

6 Sachdev HS, Fomo LS, Kane CA. Joseph disease: a mul-tisystem degenerative disorder of the nervous system.Neurology 1982;32:192-5.

7 Sakai T, Ohta M, Ishino H. Joseph disease in a non-

Portuguese family. Neurology 1 983;33:74-80.8 Rosenberg RN, Hyhan WL, Bay C, Shore C. Autosomal

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