DYT16 mimics metabolic disease with fever associated beginning of dystonia and MRI abnormalities

Abstract

Objective: DYT16 (OMIM #612067) is associated with mutations in the PRKRA gene (OMIM *603424), which encodes for an interferon-inducible double stranded RNA-activator of protein kinase PKR. Key features are generalized dystonia with preferred involvement of trunk and oromandibular musculature and Parkinsonism. Only one patient was previously described with early-onset dystonia with bradykinesia, with both abnormal neuroimaging and neurotransmitters after a febrile illness in childhood. Here, we report a second patient with similar signs and clinical course. Methods: The diagnostic work-up is demonstrated and the clinical phenotype described in a male patient with genetically confirmed DYT16. A salient neurological history including a video documentation of the disease course was obtained. Results: After uneventful pregnancy, delivery and normal development in the first year, he suffered from a febrile illness with febrile convulsion at the age of 18 months, loss of motor skills occurred which have not been regained. Development of limb dystonia, bradykinesia and oromandibular dyskinesia followed in the next years. In magnetic resonance imaging (MRI), apparent bilateral symmetric increase of T2 signal in basal ganglia was found. Cerebrospinal fluid (CSF) neurotransmitters revealed a low homovanillin acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels. Treatment with carbidopa-levodopa (3 mg/kg/day) over several years showed only a minimal effect on dystonia. Whole-exome sequencing (trio approach) revealed two variants in PRKRA gene (a paternally derived c.266A>G, p.(His89Arg) in exon 3 and a maternally derived c.904G>A, p.(Ala302Thr) in exon 8) which were confirmed by Sanger sequencing and shown to be present in a compound heterozygous state. In silico analyses considered these variants as disease causing/probably damaging. Conclusion: Onset of dystonia and Parkinsonism after a febrile infection in childhood with neurotransmitter disturbance and MRI abnormalities is a novel phenotype of DYT16. Due to pharmacological treatment difficulties, deep brain stimulation should be considered early.