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Debrisoquine hydroxylase gene polymorphism (CYP2D6*4) in dementia with Lewy bodies
  1. C Huckvale1,
  2. A M T Richardson1,
  3. D M A Mann1,
  4. S M Pickering-Brown2
  1. 1Clinical Neuroscience Research Group and Department of Neurology, Greater Manchester Neurosciences Centre, University of Manchester, Hope Hospital, Salford M6 8HD, UK
  2. 2Department of Old Age Psychiatry, Institute of Psychiatry, University of London, UK
  1. Correspondence to:
 Professor D M A Mann;

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After Alzheimer’s disease, dementia with Lewy bodies (DLB) is probably the second most common cause of dementia among the elderly, having been shown to account for around 20% of cases at necropsy.1 Pathologically, DLB is characterised by the presence of Lewy bodies within the cerebral cortex, especially the parahippocampal gyrus, cingulate gyrus and temporal neocortex, amygdala, and within brain stem nuclei, principally the substantia nigra and locus caeruleus.1 Nonetheless, histopathological changes classically associated with Alzheimer’s disease (amyloid plaques and neurofibrillary tangles) are frequently widespread within the cerebral cortex of patients with DLB.1,2

Although most cases of DLB appear to arise sporadically, cases with a previous family history of similar disorder are known, suggesting that genetic factors may contribute to the risk of developing disease. It is well recognised that cases of DLB, especially male, show an increased frequency of APO E ε4 allele,2,3 though possession of this is generally associated with an accompanying Alzheimer’s disease type pathology,2 with DLB cases without Alzheimer’s disease type pathology having a normal APO E ε4 allele frequency (Huckvale C et al, unpublished data). Hence, possession of APO E ε4 allele per se is unlikely to contribute to the generation of the Lewy body component of the pathological spectrum.

Some genetic association studies in idiopathic Parkinson’s disease4,5 have reported an increased frequency of the CYP2D6*4 allele of the debrisoquine hydroxylase gene (involving a G/A transition at the intron 3-exon 4 junction) which results in an inactive copy of the enzyme and a “poor metaboliser” phenotype. Other work has suggested that this same allelic variation may also occur more frequently in DLB,6,7 but not all studies agree.5,8

We have examined the frequency of the CYP2D6*4 allele of the debrisoquine hydroxylase (DBH) gene in 53 patients with DLB. The clinical diagnosis of DLB was made in accordance with the consensus criteria of McKeith et al.9 Twenty five of the patients have died, and pathological examination of their brains (DMAM) confirmed the clinical diagnosis in every instance. Genomic DNA was extracted from blood (in living patients) or frozen brain tissue (in necropsy cases) by standard methods. DBH and APO E and genotyping were performed according to standard methods.4,10 Differences in APO E ε4 allele and DBH CYP2D6*4 allele frequency between patient and control groups were analysed by Fisher’s exact test. As previously reported,2,3 the APO E ε4 allele frequency was significantly increased (compared to controls) in both clinic and pathological DLB groups, separately or combined (table 1). However, in agreement with previous reports,5,8 there were no significant differences in frequency of CYP2D6*4 allele of DBH gene between DLB cases (clinic or pathological groups (separately or combined) and control subjects. Neither were there any differences in age at onset of disease or (in the pathological cases) duration of illness between DLB cases with and without mutant CYP2D6*4 allele. Cases with CYP2D6*4 allele were no more likely to show any, or more severe, Alzheimer’s disease type pathological changes than those without. Hence, in this present series of cases of DLB we have not been able to confirm possession of CYP2D6*4 allele in the pathogenesis of the disorder, either in terms of generating Alzheimer’s disease or Lewy body type pathology or in influencing the age at onset or duration of the illness. We therefore conclude that possession of CYP2D6*4 allele of DBH gene does not act as a risk factor for DLB.

Table 1

Frequency of APO E alleles and DBH alleles and genotypes in different DLB groups and controls


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  • Competing interests: none declared

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