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Reply to letter: Novel compound heterozygous mutations in PRKRA cause pure dystonia

We thank Dr. de Carvalho Aguiar and colleagues for their insightful letter entitled “Novel compound heterozygous mutations in PRKRA cause pure dystonia,“ which revisits our recent article on recessively transmitted DYT16 dystonia. The authors used Sanger sequencing to uncover novel compound heterozygous PRKRA variants (c.230G>C [p.Cys77Ser]; c.638G>T [p.Cys213Phe]) in 2 female siblings of a nonconsanguineous Brazilian family presenting an earlyonset isolated dystonia phenotype. In our article, we described a consanguineous Polish sibpair affected by adolescence onset dystonia-parkinsonism, who harbored the recurrent homozygous PRKRA c.665C>T (p.Pro222Leu) mutation within a 1.2-Mb spanning disease haplotype shared with three DYT16 families of Brazilian origin. Now, the identification of independent disease-segregating PRKRA mutations in familial dystonia rules out the possibility that the original c.665C>T (p.Pro222Leu) variant only represents an innocuous tag single-nucleotide polymorphism, which is in linkage disequilibrium with the real causative sequence alteration borne on the common haplotype. Hence, the study by de Carvalho Aguiar and colleagues finally proves that PRKRA coding region mutations are indeed the underlying genetic defect in DYT16. Considered with another recent article reporting compound heterozygous PRKRA variants (c.665C>T [p.Pro222Leu]; c.637T>C [p.Cys213Arg]) in a sporadic infant manifesting dystonia-parkinsonism in the setting of a febrile illness, to date, a total of four different PRKRA missense substitutions affecting distinct parts of the encoded protein have been clearly implicated in DYT16. All of these appear to be either extremely rare or private, as evidenced by recently released exome data from the Exome Aggregation Consortium (ExAC), and only the c.665C>T (p.Pro222Leu) variant seems to occur in diverse ethnicities (prevalence according to ExAC: 1:3336 in Europeans, 1:2575 in African Americans, and 1:964 in Latinos). De Carvalho Aguiar and colleagues applied four different bioinformatics algorithms (PolyPhen2, SIFT, Mutation taster, and CADD) to assess the possible damaging nature of the DYT16-associated PRKRA variants and found at least one benign prediction for each variant, indicating the limited accuracy of some of these in silico tools. On the clinical level, the growing number of molecularly confirmed DYT16 cases highlights phenotypic heterogeneity, ranging from severe infantile combined dystonia syndromes to moderate adolescence onset isolated dystonia (Table 1). Also, remarkable intrafamilial variability is observed, suggesting that additional genetic or environmental disease modifiers may exist in DYT16. The most common clinical expression might be one of early-onset generalized dystonia in combination with varying degrees of parkinsonism, mandating comprehensive PRKRA genetic screening in such cases, particularly within a familial context suggestive of recessive disease transmission. Moreover, functional studies should be the logical consequence to provide insight as to how PRKRA gene mutations mediate the phenotypic effect and to develop therapeutic strategies for this debilitating condition. Autosomal-recessively inherited isolated dystonia phenotypes might be more common than previously appreciated.