Marked Phenotypic Heterogeneity Associated with Expansion of a CAG Repeat Sequence at the Spinocerebellar Ataxia 3/Machado-Joseph Disease Locus

The spinocerebellar ataxia 3 locus (SCA3) for type I autosomal dominant cerebellar ataxia (ADCA type I), a clinically and genetically heterogeneous group of neuro-degenerative disorders, has been mapped to chromosome 14q32.1. ADCA type I patients from families segregating SCA3 share clinical features in common with those with Machado-Joseph disease (MJD), the gene of which maps to the same region. We show here that the disease gene segregating in each of three French ADCA type I kindreds and in a French family with neuropatho-logical findings suggesting the ataxochoreic form of dentatorubropallidoluysian atrophy carries an expanded CAG repeat sequence located at the same locus as that for MJD. Analysis of the mutation in these families shows a strong negative correlation between size of the expanded CAG repeat and age at onset of clinical disease. Instability of the expanded triplet repeat was not found to be affected by sex of the parent transmitting the mutation. Evidence was found for somatic and gonadal mosaicism for alleles carrying expanded trinucleotide repeats.     

Refinement by linkage analysis in two large families of the candidate region of the third locus (SCA3) for autosomal dominant cerebellar ataxia type I

The autosomal dominant cerebellar ataxias (ADCA) are clinically and genetically heterogeneous. To date, several loci (SCAI-V) have been identified for ADCA type I. We have studied two large families from the northern part of The Netherlands with ADCA type I with a broad intra-familial variation of symptoms. In both families significant linkage is shown of the disease to the markers of the SCA3 locus on chromosome 14. Through recombinations, the candidate region for SCA3 could be refined to a 13-cM range between D14S256 and D14S81. No recombinations were detected with the markers D14S291 and D14S280, which suggests that the SCA3 gene lies close to these loci. This finding will benefit the individuals at risk in these two families who are seeking predictive testing or prenatal diagnosis.     

Molecular heterogeneity of autosomal dominant cerebellar ataxia: analysis of flanking microsatellites of the spinocerebellar ataxia 1 locus in a northern European family unequivocally demonstrates non-linkage

This study addresses the question whether the different forms of autosomal dominant cerebellar ataxia (ADCA) are related to different ethnic/geographical regions in Europe. One mutation in families originating from Holland, Prussia and Italy has previously been localized to chromosome 6p (SCA1 locus), whereas the mutation in families of Iberic origin has been excluded from chromosome 6p. In a Danish five-generation pedigree with ADCA and in which previous HLA-serotyping had shown inconclusive linkage results, the present study shows unequivocal exclusion from the SCA1 locus, firstly through the use of the new, highly informative microsatellites D6S89 and D6S109, which closely flank the SCA1 locus, and secondly through the manifestation of disease in four pedigree members previously scored as unaffected. Additional molecular genetic analysis of the HLA DRbeta and F13A polymorphisms also argue against a cluster of ADCA genes on chromosome 6p. Since this study demonstrates the existence of non-SCA1 families and therefore heterogeneity in the North-European population, molecular family counselling remains restricted to the few known SCA1 families.     

The gene for spinal cerebellar ataxia 3 (SCA3) is located in a region of approximately 3 cM on chromosome 14q24.3-q32.2.

SCA3, the gene for spinal cerebellar ataxia 3, was recently mapped to a 15-cM interval between D14S67 and D14S81 on chromosome 14q, by linkage analysis in two families of French ancestry. The SCA3 candidate region has now been refined by linkage analysis with four new microsatellite markers (D14S256, D14S291, D14S280, and AFM343vf1) in the same two families, in which 19 additional individuals were genotyped, and in a third French family. Combined two-point linkage analyses show that the new markers, D14S280 and AFM343vf1, are tightly linked to the SCA3 locus, with maximal lod scores, at recombination fraction, (theta) = .00, of 7.05 and 13.70, respectively. Combined multipoint and recombinant haplotype analyses localize the SCA3 locus to a 3-cM interval flanked by D14S291 and D14S81. The same allele for D14S280 segregates with the disease locus in the three kindreds. This allele is frequent in the French population, however, and linkage disequilibrium is not clearly established. The SCA3 locus remains within the 29-cM region on 14q24.3-q32.2 containing the gene for the Machado-Joseph disease, which is clinically related to the phenotype determined by SCA3, but it cannot yet be concluded that both diseases result from alterations of the same gene.     

Mutation detection in Machado-Joseph disease using repeat expansion detection.

BACKGROUND: Several neurological disorders have recently been explained through the discovery of expanded DNA repeat sequences. Among these is Machado-Joseph disease, one of the most common spinocerebellar ataxias (MJD/SCA3), caused by a CAG repeat expansion on chromosome 14. A useful way of detecting repeat sequence mutations is offered by the repeat expansion detection method (RED), in which a thermostable ligase is used to detect repeat expansions directly from genomic DNA. We have used RED to detect CAG expansions in families with either MJD/SCA3 or with previously uncharacterized spinocerebellar ataxia (SCA). MATERIALS AND METHODS: Five MJD/SCA3 families and one SCA family where linkage to SCA1-5 had been excluded were analyzed by RED and polymerase chain reaction (PCR). RESULTS: An expansion represented by RED products of 180-270 bp segregated with MJD/SCA3 (p < 0.00001) in five families (n = 60) and PCR products corresponding to 66-80 repeat copies were observed in all affected individuals. We also detected a 210-bp RED product segregating with disease (p < 0.01) in a non-SCA1-5 family (n = 16), suggesting involvement of a CAG expansion in the pathophysiology. PCR analysis subsequently revealed an elongated MJD/SCA3 allele in all affected family members. CONCLUSIONS: RED products detected in Machado-Joseph disease families correlated with elongated PCR products at the MJD/SCA3 locus. We demonstrate the added usefulness of RED in detecting repeat expansions in disorders where linkage is complicated by phenotyping problems in gradually developing adult-onset disorders, as in the non-SCA1-5 family examined. The RED method is informative without any knowledge of flanking sequences. This is particularly useful when studying diseases where the mutated gene is unknown. We conclude that RED is a reliable method for analyzing expanded repeat sequences in the genome.     

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.     

Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3.

Autosomal dominant cerebellar ataxia type III (ADCA III) is a relatively benign, late-onset, slowly progressive neurological disorder characterized by an uncomplicated cerebellar syndrome. Three loci have been identified: a moderately expanded CAG trinucleotide repeat in the SCA 6 gene, the SCA 5 locus on chromosome 11, and a third locus on chromosome 22 (SCA 10). We have identified two British families in which affected individuals do not have the SCA 6 expansion and in which the disease is not linked to SCA 5 or SCA 10. Both families exhibit the typical phenotype of ADCA III. Using a genomewide searching strategy in one of these families, we have linked the disease phenotype to marker D15S1039. Construction of haplotypes has defined a 7.6-cM interval between the flanking markers D15S146 and D15S1016, thereby assigning another ADCA III locus to the proximal long-arm of chromosome 15 (SCA 11). We excluded linkage of the disease phenotype to this region in the second family. These results indicate the presence of two additional ADCA III loci and more clearly define the genetic heterogeneity of ADCA III.     

Identification of a novel SCA locus ( SCA19) in a Dutch autosomal dominant cerebellar ataxia family on chromosome region 1p21-q21

We present a linkage study in a four-generation autosomal dominant cerebellar ataxia (ADCA) family of Dutch ancestry. The family shows a clinically and genetically distinct form of ADCA. This neurodegenerative disorder manifests in the family as a relatively mild ataxia syndrome with some additional characteristic symptoms. We have identified a SCA19 locus, approved by the Human Genome Nomenclature Committee that can be assigned to the chromosome region 1p21-q21. Our mutation analysis failed to identify any mutations in the known spinocerebellar ataxia ( SCA) genes and linkage analysis excluded the remaining SCA loci. We therefore performed a genome-wide scan with 350 microsatellite markers to identify the location of the disease-causing gene in this family. Multi-point analysis was performed and exclusion maps were generated. Linkage and haplotype analysis revealed linkage to an interval located on chromosome 1. The estimated minimal prevalence of ADCA in the Netherlands is about 3:100,000. To date, sixteen different SCA loci have been identified in ADCA ( SCA1-8 and SCA10-17). However, mutation analysis has been commercially available only for the SCA1, 2, 3, 6 and 7 genes. So far, a molecular analysis in these SCA genes cannot be made in about one-third of the ADCA families. Thus, the identification of this new, additional SCA19 locus will contribute to expanding the DNA diagnostic possibilities.     

Autosomal dominant cerebellar ataxia type I in Martinique (French West Indies): Genetic analysis of three unrelated SCA2 families

Autosomal dominant cerebellar ataxias (ADCAs) are a group of neurodegenerative disorders that are clinically and genetically heterogeneous. We report here a genetic linkage study, with five chromosome 12q markers, of three Martinican families with ADCA type I, for which the spinocerebellar ataxia 1 (SCA1) locus was excluded. Linkage to the SCA2 locus was demonstrated with a maximal lod score of 6.64 at = 0.00 with marker D12S354. Recombinational events observed by haplotype reconstruction demonstrated that the SCA2 locus is located in an approximately 7-cM interval flanked by D 12S 105 and D12S79. Using thez _max-l method, multipoint analysis further reduced the candidate interval for SCA2 to a region of 5 cM. Two families shared a common haplotype at loci spanning 7 cM, which suggests a founder effect, whereas a different haplotype segregated with the disease in the third family. Finally, a mean anticipation of 12 ± 14 years was found in parent-child couples, with no parental sex effect, suggesting that the disease might be caused by an expanded and unstable triplet repeat.     

Machado Joseph disease is not an allele of the spinocerebellar ataxia 2 locus

Machado Joseph disease (MJD) is a progressive, spinocerebellar ataxia (SCA) with an autosomal dominant mode of inheritance and almost complete penetrance. Clinically, it is difficult to distinguish it from other autosomal dominantly inherited ataxias, and it has been suggested that MJD may be caused by an allelic variant of SCA. Exclusion of MJD from the SCA1 locus on chromosome 6p has previously been demonstrated. However, following the recent assignment of a second locus for spinocerebellar ataxia (SCA2) to chromosome 12q in a large Cuban kindred of Spanish origin, we have investigated linkage in MJD families using the two markers, D12S58 and PLA2, that flank this disease gene. The MJD locus was definitively excluded from an interval spanning approximately 70 cM, which includes these loci. These studies demonstrate that MJD and SCA2 are genetically distinct despite similarities in disease phenotype and ancestral origins of the patients. Thus, the as yet unmapped MJD locus represents a third SCA locus, providing further evidence for genetic heterogeneity within these disorders.     

The Machado-Joseph disease locus is different from the spinocerebellar ataxia locus (SCA1).

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative spinocerebellar ataxia that has been described primarily in families of Azorean or Portuguese descent. MJD and chromosome 6p-linked spinocerebellar ataxia (SCA1) are difficult to differentiate clinically, and it has been suggested that they may be allelic variants of the same disorder. We have tested MJD families for linkage to six DNA sequence polymorphisms located on chromosome 6p, including the highly informative dinucleotide repeat, D6S89. Seventeen centimorgans telomeric to and 41 cM centromeric to D6S89, a region that includes the SCA1 locus reported to be within 3 cM of D6S89, have been excluded. These data provide conclusive evidence that MJD and SCA1 are nonallelic.     

Machado-Joseph Disease in Pedigrees of Azorean descent is Linked to Chromosome 14

A locus for Machado-Joseph disease (MJD) has recently been mapped to a 30-cM region of chromosome 14q in five pedigrees of Japanese descent. MJD is a clinically pleomorphic neurodegenerative disease that was originally described in subjects of Azorean descent. In light of the nonallelic heterogeneity in other inherited spinocere-bellar ataxias, we were interested to determine if the MJD phenotype in Japanese and Azorean pedigrees arose from mutations at the same locus. We provide evidence that MJD in five pedigrees of Azorean descent is also linked to chromosome 14q in an 18-cM region between the markers D14S67 and AACT (multipoint lod score +7.00 near D14S81). We also report molecular evidence for homozy-gosity at the MJD locus in an MJD-affected subject with severe, early-onset symptoms. These observations confirm the initial report of linkage of MJD to chromosome 14; suggest that MJD in Japanese and Azorean subjects may represent allelic or identical mutations at the same locus; and provide one possible explanation (MJD gene dosage) for the observed phenotypic heterogeneity in this disease.     

The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.

Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II.     

Mapping of the Gene for Machado-Joseph Disease within a 3.6-cM Interval Flanked by D14S291/D14S280 and D14S81, on the Basis of Studies of Linkage and Linkage Disequilibrium in 24 Japanese Families

The gene locus of Machado-Joseph disease (MJD) has recently been mapped within a 29-cM subregion of 14q chromosome. We did a linkage study of 24 multigenerational MJD Japanese pedigrees, in an attempt to narrow the candidate region of this gene. Pairwise and multipoint linkage analysis, together with haplotype segregation analysis, led to the conclusion that the MJD gene is located at the 6.8-cM interval between D14S256 and D14S81 (Z_max = 24.78, multipoint linkage analysis). D14S291 and D14S280, located at the center of this interval, showed no obligate recombination with the MJD gene (Z_max = 5.93 for D14S291 and 9.99 for D14S280). A weak, but significant, linkage disequilibrium of MJD gene was noted with D14S81 (P < .05) but not with D14S291 or D14S280. These results suggest that a 3.6-cM interval flanked by D14S291/D14S280 and D14S81 is the most likely location of the MJD gene and that it is closest to D14S81.     

Identification of a New Locus for Autosomal Recessive Charcot–Marie–Tooth Disease with Focally Folded Myelin on Chromosome 11p15

Autosomal recessive Charcot–Marie–Tooth disease type 4B (CMT4B) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. A locus for CMT4B has previously been mapped to chromosome 11q23 in a southern Italian pedigree. We initially excluded linkage in two Tunisian families with CMT4B to chromosome 11q23, demonstrating genetic heterogeneity within the CMT4B phenotype. Subsequently, using homozygosity mapping and linkage analysis in the largest Tunisian pedigree, we mapped a new locus to chromosome 11p15. A maximum two-point lod score of 6.05 was obtained with the marker D11S1329. Recombination events refined the CMT4B locus region to a 5.6-cM interval between markers D11S1331 and D11S4194. The second Tunisian CMT4B family was excluded from linkage to the new locus, demonstrating the existence of at least a third locus for the CMT4B phenotype.     

Expanded CAG repeats in spinocerebellar ataxia (SCA1) segregate with distinct haplotypes in South African families

The autosomal dominant late onset spinocerebellar ataxias (SCAs) are genetically heterogeneous. Three genes, SCA1 on 6p, SCA2 on 12q and MJD1 on 14q, have been isolated for SCA1, SCA2 and Machado-Joseph disease (MJD), respectively. In these three autosomal dominant disorders the mutation is an expanded CAG repeat. Evidence for heterogeneity in families not linked to the SCA1, SCA2 and MJD loci is provided by the mapping of SCA loci to chromosomes 16q, 11cen and 3p. A total of 14 South African kindreds and 22 sporadic individuals with SCA were investigated for the expanded SCA1 and MJD repeats. None of the families nor the sporadic individuals showed expansion of the MJD repeat. Expanded SCA1 and CAG repeats were found to cosegregate with the disorder in six of the families tested and were also observed in one sporadic individual with a negative family history of SCA. The use of the microsatellite markers D6S260, D6S89 and D6S274 provided evidence that the expanded SCA1 repeats segregated with three distinct haplotypes in the six families. Use of the highly polymorphic tightly linked microsatellite markers is still important as this stage, particularly where this coincides with the possibility of a homozygous genotype with the trinucleotide repeat marker. Importantly, our molecular findings indicate: (1) an absence of MJD expanded repeats underlying SCA; (2) the major disease in this group is due to mutations in the SCA1 gene; and (3) the familial disorder in the majority population group (i.e. mixed ancestry) in the Western Cape region of South Africa is most likely to be the result of two distinct founder events. Received: 4 November 1996 / Accepted: 6 February 1997     

Tight linkage of the gene for spinocerebellar ataxia to D6S89 on the short arm of chromosome 6 in a kindred for which close linkage to both HLA and F13A1 is excluded.

A locus for an autosomal dominant form of spinocerebellar ataxia (SCA1) has been assigned to the short arm of chromosome 6 on the basis of linkage to the major histocompatibility system (HLA). In this study of a five-generation American black family, close linkage between the disease locus and both HLA and the coagulation factor XIIIA (F13A1) locus was excluded, and lod scores for all locations of the disease locus between HLA and F13A1 were less than -1.4. These results suggest that the locus causing spinocerebellar ataxia in this family is not in this region. However, the disease locus was found to be closely linked to a microsatellite polymorphism, D6S89, which is between HLA and F13A1. The maximum lod score for SCA1 and D6S89 is 4.90 at a recombination fraction of 0, both in males and in females. These data show that exclusion of close linkage to the HLA complex and F13A1 in a kindred with spinocerebellar ataxia does not rule out the possibility that the disease locus in that family is on 6p. Accordingly, all families segregating a dominantly inherited ataxia should be evaluated for linkage to D6S89, to determine whether the locus causing the disease is SCA1.     

Familial periodic cerebellar ataxia without myokymia maps to a 19-cM region on 19p13.

Familial periodic cerebellar ataxia (FPCA) is a heterogeneous group of rare autosomal dominant disorders characterized by episodic cerebellar disturbance. A potassium-channel gene (KCNA1) has been found to be responsible for one of its subgroups, familial periodic cerebellar ataxia with myokymia (FPCA/+M; MIM 160120). A different subgroup that is not associated with myokymia (FPCA/-M; MIM 108500) was recently mapped to chromosome 19p. Here we have performed linkage analysis in two large families with FPCA/-M that also demonstrated neurodegenerative pathology of the cerebellum. Three markers in 19p13 gave significant lod scores (> 3.0), while linkage to KCNA1 and three known loci for spinocerebellar ataxia (SCA1, SCA2, and SCA3) was excluded. The highest lod score was obtained with the marker D19S413 (4.4 at recombination fraction 0), and identification of meiotic recombinants in affected individuals placed the locus between the flanking markers D19S406 and D19S226, narrowing the interval to 19 cM. A CAG trinucleotide-repeat expansion was detected in one family but did not cosegregate with the disease.     

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations

Type I autosomal dominant cerebellar ataxia (ADCA) is a type of spinocerebellar ataxia (SCA) characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA). Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical examination, genetic molecular testing, and exclusion of other diseases. Differential diagnosis is broad and includes secondary ataxias caused by drug or toxic effects, nutritional deficiencies, endocrinopathies, infections and post-infection states, structural abnormalities, paraneoplastic conditions and certain neurodegenerative disorders. Given the autosomal dominant pattern of inheritance, genetic counseling is essential and best performed in specialized genetic clinics. There are currently no known effective treatments to modify disease progression. Care is therefore supportive. Occupational and physical therapy for gait dysfunction and speech therapy for dysarthria is essential. Prognosis is variable depending on the type of ADCA and even among kindreds.     

Mapping of a new autosomal dominant spinocerebellar ataxia to chromosome 22.

The autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of disorders. The clinical symptoms include cerebellar dysfunction and associated signs from dysfunction in other parts of the nervous system. So far, five spinocerebellar ataxia (SCA) genes have been identified: SCA1, SCA2, SCA3, SCA6, and SCA7. Loci for SCA4 and SCA5 have been mapped. However, approximately one-third of SCAs have remained unassigned. We have identified a Mexican American pedigree that segregates a new form of ataxia clinically characterized by gait and limb ataxia, dysarthria, and nystagmus. Two individuals have seizures. After excluding all known genetic loci for linkage, we performed a genomewide search and identified linkage to a 15-cM region on chromosome 22q13. A maximum LOD score of 4.3 (recombination fraction 0) was obtained for D22S928 and D22S1161. This distinct form of ataxia has been designated "SCA10." Anticipation was observed in the available parent-child pairs, suggesting that trinucleotide-repeat expansion may be the mutagenic mechanism.