In Reply We appreciate the comments by Schottlaender and colleagues concerning our article1 published in JAMA Neurology. We agree that the importance of our article was to highlight the variable phenotypes that are associated with C9orf72 expansions. To date, the reported C9orf72 expansion– associated phenotypes have been frontotemporal dementia, amyotrophic lateral sclerosis (ALS), frontotemporal dementia/ ALS, Huntington disease–like disorders,2 psychiatric disorders, dementia of Lewy bodies,3 parkinsonism,4 and multiple system atrophy (MSA).1
The case presented in our article met clinical, not pathological, criteria for MSA, which included dysautonomia (neurogenic bladder and orthostatic hypotension), cerebellar syndrome (dysarthria, imbalance, and ataxic gait), parkinsonism,5 and the hot-cross-bun sign in the brain imaging. Especially early in disease progression, the symptoms of MSA may overlap with certain inherited conditions such as Fragile X–associated tremor and ataxia syndrome and spinocerebellar ataxias. In fact, we reported a case with ataxia and spinocerebellar ataxia type 2 repeat expansions, who also had a family history of ALS.6 These disorders differ pathologically from MSA yet may involve the same brain areas, leading to similar clinical presentations.
We agree that autopsy will be very helpful to delineate the ultimate pathological diagnosis in this case. To our knowledge, all pathology of C9orf72 expansions showed the characteristic ubiquitin, p62-positive, TDP-43–negative neuronal cytoplasmic and intranuclear inclusions. Therefore, it is reasonable to expect that both the patient and her brother could have typical C9orf72 pathology. Another possibility is the coexistence of synucleinopathy with C9orf72 expansions because MSA synucleinopathy has been reported to occur with other neurodegenerative changes such as tau pathology.5
Until we can confirm the pathology of MSA with C9orf72 expansions, clinicians should be aware that many possible clinical phenotypes are associated with C9orf72 expansions and should consider genetic testing in the presence of family history of a related neurologic disease.
Footnotes
Conflict of Interest Disclosures: None reported.
References
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