In this monozygotic twin pair, there was general concordance in symptoms, age at onset, low plasma progranulin level, neuropsychological profile, and topography of findings on neuroimaging. Although there were some cognitive differences at the time of evaluation, these might reflect the differences between the time of onset and testing. The role of environmental influences is limited in some degree by the fact that both had pursued very similar occupational and cognitive pursuits in adulthood. This unique twin pair highlights the role of genetic determinism, even in the face of environmental differences, particularly in relation to the cortical asymmetry.
The findings in these twins also have intriguing implications for understanding the pathophysiology of PGRN
mutations. The presumed mechanism for PGRN
mutations is that haploinsufficiency results in a markedly reduced level of progranulin, yet how does a chronic low level of an important protein, which is presumably being produced and circulating in a generalized systemic manner including throughout the whole brain over decades, result in only a particular region in one side of the brain being affected? Interestingly, available studies with PGRN
mutations suggest a greater asymmetry in atrophy and brain perfusion compared with sporadic behavioral variant FTD.5,7
Other affected members of a kindred with the same PGRN
mutation typically exhibit various phenotypes ranging from Alzheimer-like dementia, FTD, and primary progressive aphasia, and therefore one could surmise that both genetic (the multitude of dissimilar polymorphisms across the genome) and environmental factors affect the topography of degeneration and hence the phenotype. As for the monozygotic twins with strikingly similar features, one could hypothesize that one or more of the identical non-PGRN
genetic determinants could be driving the topography of degeneration, perhaps by making a particular set of neuronal networks more susceptible to neurodegeneration.3,5,7,10
Perhaps a similar genetic mechanism could explain the rare kindreds that have PGRN
mutations with very similar phenotypes.3,7,10
The hemispheric homology in our case of monozygotic twins may represent an endophenotype that reflects a cortical network susceptibility in combination with additional genetic contributions beyond the PGRN
null mutation; this hypothesis warrants further investigation.