Objective: We describe the clinical presentation, diagnosis, and treatment of a case of dystonia-parkinsonism associated with a heterozygous mutation in the initiator methionine of the PRKRA gene.

Background: Dystonia has a broad range of etiologies and clinical manifestations. The genetic understanding of dystonia is still being expanded. Recently, a novel form of recessively inherited dystonia (DYT16) was described, characterized by early onset generalized dystonia-parkinsonism caused by a homozygous mutation in the PRKRA gene. There has also been preliminary evidence of heterozygous PRKRA mutations correlating with DYT16 symptomatology.

Method: Clinical evaluation and genetic testing of the patient was completed. A literature review of PRKRA mutations was performed.

Results: A 35-year-old female presented with 2-3 years of progressive left calf and foot cramping, with intorsion and upgoing toes of the left foot. Symptoms were triggered and exacerbated by activity. Patient also experienced onset of left hand rest tremor several months before presentation. MRI brain and cervical spine were normal. Examination showed left foot dystonia elicited by several minutes of ambulation and left upper extremity rest tremor with reduced left arm swing. There was no rigidity, bradykinesia, or postural instability. Smell test revealed moderate microsmia. Laboratory investigations including routine chemistries, serum and urine copper level, ceruloplasmin, cyroglobulin, and thyroid antibodies were unremarkable. Genetic testing using a hereditary parkinson’s disease and parkinsonism panel revealed a heterozygous c.1A>G affecting the initiator methionine of the PRKRA mRNA, previously unreported in literature. Patient was started on carbidopa-levodopa, and at initial follow-up reported >90% reduction in episodes of left foot dystonia.

Conclusion: While the majority of DYT16 cases previously described have been autosomal recessively inherited homozygous mutations, here we have described a novel heterozygous mutation of PRKRA leading to a focal dystonia with parkinsonism. While the c.1A>G mutation is currently considered a variant of uncertain significance, its alteration of the initiator methionine of PRKRA mRNA could potentially lead to a truncated PRKRA protein that explains its suspected pathogenic nature.

References: https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.25981 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(08)70075-9/fulltext https://pubmed.ncbi.nlm.nih.gov/18243799/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749865/

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-case-of-dystonia-parkinsonism-associated-with-a-heterozygous-prkra-dyt16-gene-mutation/