When Is Ataxia Not Ataxia?

Genetic evidence now firmly supports the "out of Africa" hypothesis for human migration, with people dispersing from Africa toward Europe and, largely separately, toward Asia. These 3 major populations are genetically distinct, with those of African descent having the greatest genetic diversity and those of Asian and European descent having less diversity, with origins from smaller groups.¹ Nearly all diseases have been clinicopathologically defined in white populations, and yet this group has the least genetic diversity, limiting such definitions.¹ We have functioned with the implicit assumption that diseases will be clinically similar in all populations. However, the article by Lu and colleagues² in this issue of the ARCHIVES offers further evidence that this pervasive but unlikely supposition is not correct, by confirming previous studies that spinocerebellar ataxia type 2 (SCA2) is a cause of familial parkinsonism and can be identical to typical Parkinson disease (PD) symptomatically.^{1 - 7} Their work also reveals that, in their series of ethnic Chinese, SCA2 is responsible for almost 10% of familial parkinsonism cases. Thus, while SCA2 might be a rare cause of PD in whites, it causes a considerable minority of cases in Taiwan. This article, along with prior literature,^{3 - 7} emphasizes how genetic diseases have a spectrum of phenotypes ranging beyond the classically defined forms.

The gene for SCA2 was discovered on chromosome 12q in 1996^{8 - 9} and is classically associated with slow saccades and/or ophthalmoplegia, ataxia, and peripheral neuropathy; this phenotype is variable not only across ethnic groups but also across, and even within, families (Online Mendelian Inheritance in Man 183090). Pathological studies show degeneration of the olivopontocerebellar regions and neuronal loss in the substantia nigra, striatum, and even neocortex.¹⁰ Thus, one would not be surprised to find parkinsonism as a phenotypic manifestation in addition to, or even instead of, ataxia. Such is indeed the case. This range varies across ethnic groups: in white populations the phenotype of SCA2 mutations is, as the name suggests, usually spinocerebellar ataxia, although it can rarely cause typical PD^{5 - 6} ; in contrast, in Asians, parkinsonism may be a much more prevalent fraction of the phenotype, although clearly, parkinsonism still manifests with ataxia in most patients in that population as well.^{1 ,7} This is a quantitative rather than qualitative difference, because nigral loss probably occurs in all SCA2 cases, but in white patients this nigral loss may not typically be enough to be clinically relevant.

In a case series of ethnic Chinese in Taiwan, Shan et al⁷ noted that a small number of their patients with PD had causal SCA2 expansions, and, using fluorodopa F 18 positron emission tomography studies, noted that those with apparent "typical" PD had a reduction of activity in the striatum, confirming that the nigrostriatal dopaminergic system is involved in parkinsonian patients with the SCA2 mutation. In commenting on these findings, Kock et al¹¹ stated that in a study of 270 unrelated patients of non–East Asian ancestry, they found no expanded SCA2 alleles, confirming that genetic contributions to a given clinical diagnostic entity differs across ethnic populations.

Related observations have been made in SCA3 mutation carriers, described by Rosenberg and Fowler.¹² Spinocerebellar ataxia type 3 (Machado-Joseph disease) in white families typically presents as an ataxia syndrome, although ataxia with parkinsonism is at the edge of the phenotypic range^{12 - 13} ; in contrast, in people of African origin with SCA3, ataxia overlapped by parkinsonism in a given patient is apparently common.^{14 - 16} It is noteworthy that the PD phenotype may be more common in those patients with intermediate-range repeated numbers; this narrow range requires precise determination of repeat size, which is not performed by all diagnostic laboratories.¹⁷ Therefore, when ruling out SCA2 as a cause of PD, it is important that methods which accurately assess the repeated numbers in this intermediate (ie, borderline) range be used. Patients of ethnic Chinese and African origin with mutations in the SCA2 and SCA3 genes had a similar age of onset as those from the European population who carried mutations.^{3 ,14 - 15} Thus, although the burden of disease may be similar in the different ethnic populations, the epidemiological conclusions may differ if not based on molecular diagnoses.

Why is this important? First, it is important genetically: it suggests that there are modifier genes that subtly alter disease phenotypes, and as we understand the pathogeneses of these diseases more clearly, we should expect to find that some of the genes in the pathogenic pathways have different allele frequencies in different racial groups. Second, it is important diagnostically: neurologists should consider the ethnic background of a patient in terms of diagnostic evaluation and genetic epidemiology. Additional studies of neurological disease in populations of non-European origin are warranted. Finally, and perhaps most important, this work has implications for future clinical trials in and treatment strategies for ataxia, PD, and other neurodegenerative disorders. Future treatments for neurodegenerative diseases are likely to be based on molecular pathogenesis and not merely palliative measures, as they are currently. Patients with similar clinical phenotypes might need very different treatments, depending on genetic cause or risk factors. Treatment decisions in ataxia will be relevant to a subset of patients with PD, and the size of this subset will vary in differing populations. Conversely, when treating PD, we might sometimes be treating an SCA expansion. This must be taken into account so that biologically appropriate treatment is ultimately prescribed for all.