Genetic penetrance, the frequency with which obligate HSP gene carriers exhibit the disorder, is age-dependent and nearly complete. The age by which symptoms develop is variable between and within families. This is an important consideration when counseling subjects who are at risk of inheriting mutant HSP genes. Segregation ratios in large, autosomal dominant HSP kindreds approach 0.5, as predicted for completely penetrant, autosomal dominant disorders. In the review reported by Fink et al (Fink et al., 1996) with at least three generations of affected subjects, there was not one instance of incomplete penetrance (an asymptomatic subject, older than the maximal age of symptom onset in the family who had one affected parent and at least one affected child). In contrast, Cooley et al reported (Cooley et al., 1990) a kindred that included one subject (IV-9) who was an apparently asymptomatic carrier of autosomal dominant, uncomplicated HSP. HSP's apparently high degree of genetic penetrance may include an ascertainment bias. Autosomal dominant HSP is more readily diagnosed in large kindreds for whom the disorder is highly penetrant. This could contribute to over-representation of highly penetrant HSP kindreds in published studies. Fink et al (Fink et al., 1996) state that genetic penetrance could not be determined in approximately 30% of their HSP kindreds. For example, it is not possible to estimate genetic penetrance from kindreds consisting of affected siblings (with unaffected parents) since this could represent an autosomal recessive disorder or an autosomal dominant disorder with incomplete penetrance. Similarly, it is not possible to estimate penetrance from kindreds consisting of an affected child, an affected parent, and unaffected grandparents since this could represent either incomplete penetrance (in a grandparent) or a new mutation (in a parent).
Genetic linkage analysis is making important contributions to our understanding of HSP. Hentati et al (Hentati et al., 1993) showed that uncomplicated, autosomal recessive HSP is mapped to chromosome 8q12-13. They showed that uncomplicated autosomal recessive HSP is genetically heterogeneous by excluding this locus in other autosomal recessive HSP families (Hentati et al., 1993). Non-allelic genetic heterogeneity indicates that the syndrome of HSP can be caused by mutations in different genes. Three loci for autosomal dominant HSP have been discovered. Hazan et al (Hazan et al., 1993) found the first locus for uncomplicated autosomal dominant HSP on chromosome 14q in a large French kindred. Subsequently, independent investigators identified linkage to this locus in an unrelated German (Gispert et al., 1995), North American, (Lennon et al., 1995) Turkish and Australian HSP kindreds (Fink et al unpublished observation) HSP kindreds. Two additional loci for autosomal dominant HSP have been discovered thus far. Several groups working independently identified a locus on chromosome 2p that is linked to HSP in unrelated North American, French-Canadian, and Belgian kindreds (Hazan et al., 1994; Hentati et al., 1994; Figlewicz et al., 1994). Finally, Fink et al (Fink et al., 1995) identified tight linkage between a locus on chromosome 15q and autosomal dominant HSP in a large North American HSP kindred (Fink et al., 1995). The observation by the HSP Working Group (Fink et al., 1996) that known HSP loci are excluded in approximately 45% of autosomal dominant HSP kindreds indicates the existence of other, as yet unidentified, loci for autosomal dominant HSP.
Occasionally, HSP kindreds exhibit progressively younger age of symptom onset or increased disease severity in succeeding generations. Examples of such genetic anticipation has been reported in German (Gispert et al., 1995) and Dutch (Bruyn et al., 1993) HSP kindreds. The possibility that ascertainment bias may contribute to apparent anticipation must also be considered. The occurrence of genetic anticipation in some HSP kindreds suggests that trinucleotide repeat mutations probably could be involved in a proportion of HSP kindreds. Disorders due to such mutations, including Huntington's chorea, Machado-Joseph's disease, Fragile X syndrome, myotonic dystrophy, Kennedy syndrome, spinocerebellar ataxia type I, and dentato-rubro-palidoluysian atrophy often exhibit genetic anticipation (see review (Plassart et al., 1994)). Recently, an expanded trinucleotide repeat was identified that segregated with the disorder in six unrelated Danish HSP kindreds that were linked to chromosome 2p (Nielsen et al., 1997). Cloning and analyzing this expanded repeat may identify an important candidate gene for chromosome 2p linked HSP.
X-linked uncomplicated HSP is rare and genetically heterogeneous (Thurmon et al., 1971; Zastz et al., 1976; Keppen et al., 1987; Cambi et al., 1995). The disorder in two kindreds studied by genetic linkage analysis was shown to map to a locus (Keppen et al., 1987; Cambi et al., 1995). on Xq22. Cambi et al found a missense mutation in the proteolipoprotein (PLP) gene coding sequence in affected males of one family (K313), but not in the other family (K101) (Cambi et al., 1995). Affected members of an unrelated X-linked HSP kindred were also shown to have PLP gene mutations (Dube et al., 1997). Thus in these families uncomplicated X-linked HSP was allelic to complicated X-linked HSP (Zastz et al., 1976; Kobayashi et al., 1994) and Pelizaeus-Merzbacher disease, as they result from PLP gene mutations. The basis for clinico-pathologic differences between PLP mutations that result in Pelizeaus Merzbacher and X-linked HSP are not known although one factor could be differences in the nature of the specific gene mutations associated with each disorder.
Preliminary genotype-phenotype correlations. With identification of HSP loci on chromosomes X, 2p, 8q, 14q, and 15q, it is possible to compare phenotypes in families for whom the disorder is linked to one of these loci as well as HSP families for whom these loci are excluded. Thus far, genetically diverse types of autosomal dominant HSP (those linked to chromosomes 2p, 14q, and 15q) are clinically and electrophysiologically extremely similar. This suggests that the different abnormal gene products may interact in a common biochemical cascade that results in similar patterns of neuronal degeneration. The disorder may be more severe in the chromosome 15q-linked kindred compared to kindreds linked to chromosome 14q. Only one subject required a wheelchair in the chromosome 14q linked kindred reported by Hazan et al (Hazan et al., 1993). In contrast, nine of the affected subjects in a chromosome 15q linked HSP kindred required a wheel chair (beginning for some in their 40's) (Fink et al., 1995). Autosomal dominant HSP kindreds linked to chromosome 2p have exhibited both the prototypical adolescent/adult-onset, progressive form and the less common childhood-onset, relatively nonprogressive form of HSP. These significant variations in age of symptom onset and degree of progression in HSP kindreds linked to chromosome 2p indicate that the complete phenotype is influenced either by different mutations in the same gene or by the effects of modifying genes.
Adapted with permission from (Fink et al., 1996) and (Fink, 1997).