Mutations in PDYN are not responsible for multiple system atrophy.

We read with great interest the work by Fawcett et al. examining the prevalence of variation in the PDYN gene within a large UK cohort of sporadic and familial ataxia patients, demonstrating this to be a rare genetic cause of spinocerebellar ataxia in this group [1] as previously suggested by work from other populations, [2,3] including our own sample of 119 US patients with sporadic ataxia. [4] While PDYN variants do not appear to be a common cause of spinocerebellar ataxia, it remains possible that mutations could play a role in other phenotypes. For example, we identified one patient with a known PDYN mutation (p.R138S) [2] who was originally classified as having possible multiple system atrophy (MSA) using the Gilman et al. criteria. [4,5] As the clinical phenotype of SCA23 overlaps with that of the cerebellar variant of MSA (MSA-C), Fawcett et al. explored this possibility in their UK sample by examining 190 patients diagnosed with MSA-C without finding any pathogenic variants, suggesting that PDYN mutations are also not a significant cause of MSA in this population. [1] Extending the findings reported by Fawcett et al., we examined a group of 60 US patients with MSA for variations in the PDYN gene. Using the criteria of Gilman et al., 52 (87%) of these patients met the definition of probable MSA, [5] 36 (60%) were women, and the average age was 62 ± 7.7 years. Based on initial clinical presentation, 56 (93%) were classified as MSA-C and 4 (7%) as MSA-P. [5] The majority (70%) were white, non-Hispanic. All study protocols were approved by the UCLA Institutional Review Board and all participants gave informed consent to participate. The entire PDYN coding region was sequenced as previously described. [4] Sequences were compared to the human genome GRCh37/hg19 build. We identified no known pathogenic variants in PDYN although we did identify 9 individuals (15%) heterozygous for a common polymorphism (chr20:1,961,134 A>G, p.(=), rs6045819), a frequency consistent with that observed in normal human variation databases. [4] One of these individuals was also heterozygous for a second rarer polymorphism also seen in normal human variation (chr20:1,961,159 T>A, p.Glu192Val, rs45469293). During the course of the study, two patients with possible MSA were found to have alternate genetic diagnoses (see Table). One was found to carry the premutation associated with the Fragile X tremor/ataxia syndrome. [6] The second patient (who also carried rs6045819) was found to harbor a novel frameshift variation in the transglutaminase 6 gene (TGM6) associated with spinocerebellar ataxia type 35 (SCA35), [7] chr20:2,397,971–2,397,981del, c.1430delGGGGTCGCTGT, p.Gly477Ala fs*2. Of note, this patient ultimately developed a phenotype consistent with progressive supranuclear palsy (PSP), an interesting observation given that transglutaminases have been previously suggested to play a role in PSP. [8,9] Table In summary it would appear that multiple lines of evidence suggest that PDYN variants, while important to consider in very rare cases of familial ataxia, are uncommon causes of cerebellar ataxia worldwide, including multiple system atrophy. Our work further illustrates the challenge of diagnosing a patient with MSA and emphasizes the need to consider rare clinically overlapping genetic disorders in cases with atypical features.