Parkinson Disease in Twins

To the Editor: Dr Tanner and colleagues¹ investigated potential genetic contributions to the cause of sporadic Parkinson disease (PD) through the ascertainment of PD in monozygotic (MZ) and dizygotic (DZ) twin pairs and found that concordance for PD was low and was equivalent in MZ and DZ pairs. They concluded that heredity is not a major causal component in most cases of PD.

While this study argues strongly against a role for conventional Mendelian (chromosomal) genetic mechanisms in PD, it does not argue against all genetic mechanisms since it fails to evaluate mitochondrial genetics. Mitochondrial genes are inherited cytoplasmically and maternally and do not follow the rules of Mendelian inheritance upon which the study by Tanner et al is predicated. Mutations in mitochondrial genes are known to cause human diseases that do not follow Mendelian patterns.² Unlike the case with nuclear genes, there is no a priori basis for assuming exactly equivalent portioning of cytoplasm (and thus mitochondrial genes) during the fissioning process that produces MZ twins; MZ twins need not be genetically identical with respect to mitochondrial genes. Monozygotic twins may be discordant for many years for disorders arising via mitochondrial genetic mechanisms.^{3 - 4}

Mitochondrial genes are of critical importance in any evaluation of genetic mechanisms in PD because a considerable body of experimental evidence has directly implicated mitochondrial genetics in the pathogenesis of PD.⁵ The evidence was generated primarily by expressing the mitochondrial genome from sporadic PD patients in cultured human cell lines that had been depleted of endogenous mitochondrial DNA (mtDNA knockout systems).⁶ Three groups of investigators using different techniques found that such human cell lines expressing PD mitochondrial genes lost activity of complex I, the target enzyme of the parkinsonism-inducing neurotoxin 1-methyl,4-phenyl,1,2,3,6-tetrahydropyridine (MPTP) discussed by Tanner et al. In addition to loss of activity of complex I, these genetically transformed cells also displayed numerous other pathological changes, including sensitization toward apoptotic cell death, increased production of oxygen radicals and up-regulation of free radical defense enzymes, disordered calcium homeostasis. In addition, there are mitochondrial ultrastructural changes typical of PD (unpublished data, September 1999).

The study by Tanner et al does not address all known genetic mechanisms and careful consideration of mitochondrial genes is required before genetic mechanisms are excluded as a cause of PD.