Objective: To describe a family with three siblings affected by the combination of dystonia and parkinsonism, as a resulting phenotype of recessive PRKRA mutation.

Background: Dystonias are movement disorders characterized by sustained muscle contractions and abnormal postures. Twenty-five DYT genetic loci have been described, so far. Clinically, the disorder can occur in isolation or in combination with other neurological signs.

Methods: Clinical examination; SNP-arrays; homozygosity mapping, linkage and haplotype analysis; whole exome sequencing (WES); Sanger sequencing.

Results: Here we report three siblings from Southern Italy with childhood-onset generalized dystonia and mild parkinsonism. We performed SNP-arrays genotyping in the whole family, and WES in the proband. The linkage analysis under an autosomal recessive mode of inheritance yielded only one locus with a significant LOD of 3.72. This locus lies on the long arm of chromosome 2 and contains a 4Mb-homozygous region. Within this region, WES uncovered a PRKRA c.665C>T p.Pro222Leu mutation. Sanger sequencing confirmed the mutation which perfectly cosegregates within the family. The same and additional mutations were reported in six independent pedigrees of Polish and Brazilian ancestries providing conclusive evidence for a disease-causing role of PRKRA mutations in DYT16. Our haplotype analysis shows that the Italian patients share a 0.5 Mb identical homozygous region with all the nine p.Pro222Leu carriers.

Conclusions: These results support the contention that c.665C>T is a founder mutation, as already suggested. Mutations in this gene might be more common than earlier thought, and PRKRA screening is warranted in all patients with autosomal-recessive dystonia. Our data contribute to a better delineation of the DYT16 genetic and clinical spectra.

This work has been already presented in October 2015 in Baltimore, during the American Society of Human Genetic congress 2015, and in Decemeber 2015 in Milan, during the International Association of Parkinson and Related Disorders congress.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dyt16prkra-founder-mutation-causes-childhood-onset-generalized-dystonia-in-a-family-from-southern-italy/