Pathogenic Variants in the PRKRA Gene Can Result in a Rapid‐Onset Dystonia‐Parkinsonism‐like Phenotype

DYT-PRKRA (previously dystonia 16/DYT16) is a rare autosomal recessive dystonia caused by biallelic variants in PRKRA.1 The classical phenotype is a slowly progressive childhood-onset generalized dystonia with prominent oromandibular involvement. Parkinsonism can occur but is typically milder, and the brain magnetic resonance imaging (MRI) is normal in most patients.1 In four reported cases, DYT-PRKRA has presented acutely with encephalopathy, axial hypotonia, pyramidal signs, and developmental regression associated with a febrile illness. These patients all had bilateral striatal T2-weighted hyperintensities on brain MRI.2-4 We describe a video-documented case of DYT-PRKRA with an acute encephalopathic onset with striking similarities to those reported previously, including characteristic striatal MRI findings. Our patient is a 22-year-old man whose mother had an uncomplicated delivery after a normal, full-term pregnancy. He achieved appropriate milestones developmentally and was a healthy young boy. At age 3 years, he developed a febrile illness from a viral infection. He became increasingly somnolent and confused, unable to walk, and eventually unable to sit unsupported. He was admitted to the hospital for evaluation. Examination at that time showed axial hypotonia, slurred speech, severe ataxia, and limb spasticity. Initial cerebrospinal fluid analysis, metabolic screening, and infectious screening were normal. His brain MRI demonstrated T2-weighted hyperintensities in the putamen, suggestive of a mitochondrial disorder. Subsequent MRIs showed progressive putaminal atrophy (Fig. 1A). Mitochondrial genetics were negative, and muscle biopsy was normal without ragged red fibers. He regained some developmental skills but did not return to his premorbid baseline. He subsequently developed a progressive generalized dystonia. He was treated with levodopa and a mitochondrial cocktail including biotin and thiamine with no improvement. During adolescence, he developed more prominent oromandibular dystonia causing dysarthria and dysphagia (Video 1). At age 16, whole-exome sequencing identified homozygous likely pathogenic variants in PRKRA [c.665C>Tp. (Pro222Leu)], confirming the diagnosis of DYT-PRKRA dystonia-parkinsonism. He was retrialed on high-dose biotin and thiamine with no improvement. This observation adds to growing evidence that DYT-PRKRA can manifest with an acute, encephalopathic presentation triggered by febrile illness, clinically mimicking classic rapid-onset dystonia-parkinsonism (RDP; DYT-ATP1A3), but distinguished by MRI evidence of striatal necrosis, a feature also characteristic of biotin-thiamine–responsive basal ganglia disease (BTBGD, SLC19A3).5 DYT-PRKRA patients with normal brain MRIs have been reported to have bilateral loss of presynaptic dopamine transporters by dopamine transporter single-photon emission computed tomography with clear putaminal involvement.6 Interestingly, two of the previous reports have described improvement with biotin.2, 4 There have also been reports of the insidious-onset phenotype of DYT-PRKRA responding to high-dose thiamine.7 SLC19A3-related BTBGD can also have overlapping features with a subacute encephalopathy with dystonia and other brainstem features. Early diagnosis of this condition is important given its documented response to high-dose biotin. Our patient supports the concept of a shared clinicopathological spectrum among PRKRA-, ATP1A3-, and SLC19A3-related disorders that impact neuronal energy metabolism, mitochondrial function, and basal ganglia vulnerability to metabolic or stress-related injury. We further suggest adding PRKRA and SCL19A3 to ATP1A3 as genes associated with RDP-like presentations (Fig. 1B). Written informed consent for publication was gained from the patient. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the first draft, B. Review and Critique. M.B.: 1A, 1B, 1C, 3A. S.M.: 1B, 1C, 3B. C.E.-V.: 1B, 1C, 3B. K.G.: 1B, 3B. T.L.: 1B, 3B. R.A.W.: 1B, 3B. A.J.E.: 1A, 1B, 1C, 3B. C.F.: 1A, 1B, 1C, 3B. We sincerely thank the patient for consenting to participate in this study.