CAG REPEAT EXPANSION

DRPLA Joins the growing list of neurodegenerative diseases caused by dynamic mutations of DNA. In particular, there is a group of conditions which have a pathogenic expansion of a CAG repeat within the coding region of the gene (table 5.2). These are Kennedy’s disease or X-linked spinobulbar neuronopathy (XLSBN) (La Spada et al, 1991), HD (The Huntington’s disease collaborative research group, 1993), SCAl (Orr et al, 1993), SCA 2 (Imbert et al, 1996; Pulst et al, 1996) and MJD (Kawaguchi et al, 1994).

Affected individuals in the four families with DRPLA had expansions of 60-74 CAG repeats, whilst in Japan the disease range was 49-74 repeats (Koide et al, 1994; Nagafuchi et al, 1994a). The range of expansions for the other conditions is listed in table 5.2. In the U.K. control population, the range of repeats was 7-26 showing that for DRPLA there is no overlap in size of the repeat between control and disease chromosomes, a feature also seen in XLSBN, SCAl, SCA 2 and MJD. A report of a patient with DRPLA whose asymptomatic 66 year old father had CAG repeats alleles of 59/18 may represent non-penetrance rather than an overlap in the disease and normal range of repeats (Shimizu et al, 1996). For HD there is a region of overlap between 34 and 37 repeats. Analysis of 178 individuals with HD with CAG repeat length in the

TABLE 5.2: GLUTAMINE REPEAT MEDIATED DISEASES

DISEASE DEFECTIVE PROTEIN GLUTAMINE REPEATS NEURONAL REGION AFFECTED

Normal Mutant

Huntington’s Huntingtin 11-34 37-121 Basal ganglia, cerebral cortex

Spinobulbar muscular atrophy Androgen Receptor 11-33 40-62 Spinal cord, brainstem, sensory neurons

DRPLA Atrophin 7-23 49-75 Cerebellum, brainstem, spinal cord, cortex

Spinocerebellar ataxia type 1 Ataxin 1 6-44 40-82 Cerebellum, spinocerebellar tracts, inf. olives

Spinocerebellar ataxia type 2 Ataxin 2 17-29 37-50 Cerebellum, spinocerebellar tracts, inf. olives

Spinocerebellar ataxia type 3 MJD 1 13-40 68-79 Multiple motor control regions of brain and spinal cord

30-40 range (Rubinztein et al, 1996) identified some patients with 36 repeats with HD and some very old people with 36-39 repeats who did not have recognisable HD, implying incomplete penetrance.

There is a strong correlation between the number of repeats and the age of onset of DRPLA providing a molecular explanation for the anticipation seen in these families. This is a consistent feature for the other members of this group of neurodegenerative conditions (Doyu et al, 1992; Snell et al, 1993; Orr et al, 1993; Kawaguchi et al, 1994) and in HD a significant correlation between repeat size and severity of neuronal loss in the striatum has also been demonstrated (Furtado et al, 1996). The repeat size in DRPLA appears to be unstable, particularly when passing through the male germline. In agreement with the reports in Japan (Koide et al, 1994; Nagafuchi et al, 1994a) was the finding of an increase in repeat size when the disease allele was transmitted by an affected father. Komure et al (1995) studied 12 Japanese DRPLA pedigrees and found that in 80% of paternal transmissions there was an increase of > 5 repeats, whereas all the maternal transmissions showed either a decrease or increase of < 5 repeats. This paternal transmission bias is also seen in HD, MJD and SCAl (Snell et al, 1993; Durr et al, 1996; Orr et al, 1993), but not in SCA 2 where no parental bias is seen (Imbert et al, 1996; Pulst et al, 1996). This was confirmed by an analysis of segregation patterns in 211 transmissions in 24 DRPLA pedigrees (Ikeuchi et al, 1996). Significant distortions in favour of transmission of mutant alleles was found in male meiosis, where the mutant alleles were transmitted to 62% of all offspring in DRPLA, providing evidence for meiotic drive. Two Japanese DRPLA families where anticipation by maternal transmission was apparent have also been reported. In one kindred this was associated with an increase in the size of the affected allele from 64 to 67 repeats (Aoki et al, 1994). It thus appears that expansion of the pathogenic allele can occur through both germlines, but is more common through the male.

The range of CAG repeats in U.K. controls was similar to that in Japan, but alleles of 32 to 35 repeats were found in Japanese individuals (Nagafuchi et al, 1994a). In African-American controls, the largest expansion was of 29 repeats (Burke et al, 1994b). It has been proposed that the larger alleles in the Japanese population are the source of the expansion to the pathological DRPLA range, and the difference in trinucleotide repeat size among racial groups explains the difference in disease prevalence. Thus the expansion of these "intermediate alleles", probably through paternal transmission, could lead to apparently sporadic cases of DRPLA. This could explain why no sporadic cases of DRPLA were found in the U.K. series. In addition, in the survey by Hirayama et al (1994), the majority of sporadic cases in Japan had the ataxo- choreoathetoid phenotype. This could also explain why none of the potential sporadic cases

tested as part of this study had an expanded DRPLA allele, as they had either a myoclonic epilepsy or pseudo-huntington phenotype.

To date DRPLA appears genetically homogeneous. A report suggesting that a family with the pathological features of DRPLA showed linkage to chromosome 14q (in the region of the MJD/SCA3 locus) probably indicates that this family actually has MJD and that the pathology of this syndrome overlaps with DRPLA (Cancel et al, 1994). This is supported by the finding of supranuclear ophthalmoplegia in all affected individuals (rare in DRPLA) and severe amyotrophy in two. Subsequent analysis of this family for the expanded MJD GAG repeat proved positive (Durr et al, 1996).