Corticobasal Degeneration Shares a Common Genetic Background with Progressive Supranuclear Palsy
abstract & commentary
Source: Di Maria E, et al. Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 2000;47:374-377.
Corticobasal ganglionic degeneration (cbgd), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD) are clinically and pathologically similar disorders of the microtubule-associated protein tau. Termed tauopathies, these conditions are related by the finding of insoluble aggregates of tau in neuronal and glial inclusions. The distribution of these deposits differs between the conditions: they are predominantly cortical in FTD, predominantly subcortical in PSP, and either cortical and/or subcortical in CBGD.
FTD is usually autosomal dominant, and recent work has linked the disorder to point mutations in the tau gene (Neuron 1998;21:955-958). The question thus arises whether PSP and CBGD, both sporadic illnesses, are also linked to abnormalities in the biology and cellular processing of tau. For PSP, the question has been answered in the affirmative. Recently it has been shown that patients with PSP have an over-representation of a specific allele, termed A0, in intron 9 of the tau gene (Ann Neurol 1997;41:277-281).
In this paper, Di Maria and colleagues report their results of genotyping of tau in 16 typical cases of CBGD. Because there can be considerable clinical overlap between atypical cases of PSP and CBGD and because pathology was available in only two cases, they only included patients with classic symptoms of CBGD (asymmetric rigidity with an apraxic and dystonic limb). Fifty normal controls were also genotyped. Di Maria et al sequenced the tau gene to look for point mutations, and also searched for the A0 allele and several other polymorphisms. They found that the A0 allele was over-represented in patients with CBGD relative to controls (P < 0.005), thus showing that CBGD and PSP are genetically closely related.
Commentary
PSP and CBGD are two of the most common causes of atypical parkinsonism seen in a university movement disorders clinic. These conditions were initially described as distinct clinical entities. However, recent clinical observations have blurred the boundaries between the two disorders. Limb dystonia and apraxia may occur in patients who otherwise have the classic supranuclear vertical gaze deficit and postural impairment of PSP. Patients with CBGD may have a supranuclear vertical gaze defect late in the course of their illness, and sometimes the characteristic asymmetric rigid dystonic limb is absent. Cases of CBGD have also been reported where the clincal profile fits a pattern of frontal dementia similar to FTD. Thus these three conditions are best viewed as part of a spectrum of disorders of tau, with clinical symptoms reflecting the cortical or subcortical location of pathology.
The importance of Di Maria et al’s observation is that it provides the missing link connecting CBGD to PSP and FTD. By understanding how and why tau accumulates in inclusions, it may be possible to target therapies to interrupt this process. This offers the promise of rational treatment for conditions that otherwise pose a daunting challenge for the neurologist. —sf
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