The AOPEP (C9ORF3) gene encodes aminopeptidase-O, a proteolytic processing enzyme preferentially expressed in glial cells. Pathogenic AOPEP gene mutations manifest in various forms from generalized dystonia to dystonia-parkinsonism phenotypes. AOPEP-related dystonia 31 has been identified as a biallelic autosomal recessive subtype of dystonia, especially in populations with increased rates of consanguinity. We report a novel phenotype in dystonia-31 (with a unilateral wing-beating component) in a patient with a unique biallelic autosomal recessive AOPEP-related dystonia.

 A 45-year-old active duty right-hand-dominant Army male, without family history of neurologic problems who denies consanguinity, was evaluated for adult-onset right arm action tremor starting in 2018. This progressively worsened resulting in use of his left hand for normal daily activities. A physical exam revealed an immediate right arm high amplitude postural tremor with dystonic posturing at the wrist, worse in the wing-beating position that was not distractible, without parkinsonism features. He had a negligible rest tremor that attenuated with pronation of his arm. Finger-to-nose and complex motor exams were normal. Brain and cervical spine MRIs, labs (including copper), and DaT scan were unremarkable. Genetic testing revealed two different autosomal recessive heterozygous biallelic mutations in the AOPEP gene: one a known pathogenic variant c.2041-1G>A (p.?), and the other a likely pathogenic variant, c.1201C>T (p.Arg410Trp). His tremor was refractory to trihexyphenidyl, propranolol, topiramate, primidone, and a carbidopa/levodopa challenge.

AOPEP variants rarely cause parkinsonism and dystonia. Biallelic mutations are known to cause dystonia 31 which we suspect has manifested with a novel combination of heterozygous autosomal recessive variants, with one allele likely inherited and the other arising de novo. Additionally, the dystonic tremor seen in this case expands the phenotype of dystonia 31 which has not been described yet.