Generalized Dystonia as a Prominent Feature in a Case of NUS1 Gene Mutation

An autosomal dominant mutation of the nuclear undecaprenyl pyrophosphate synthase 1 (NUS1) gene, located on chromosome 6q22.1,causes a syndrome of medication-responsive absence and/or generalized tonic-clonic (GTC) epilepsy, tremors and myoclonus, intellectual disability, and cerebellar ataxia.1,2 Parkinson's disease has also been reported in NUS1 mutation.2 Aside from one prior adult patient with NUS1 mutation who was noted to have nonprogressive childhood onset arm dystonia in the setting of tremor, myoclonus, and intellectual disability, there has been no other report to our knowledge of dystonia in NUS1 mutation.3 Here, we present a case of NUS1 mutation with a prominent and progressive generalized dystonia.This 34-year-old female of mixed European ancestry developed a slight head tremor at 18 months of age.Intellectual disability was diagnosed by second grade.She developed a mild but progressive gait ataxia, dysarthria, and dyscoordination of the hands.By age 10, she had a GTC seizure followed by absence type seizures which resolved on lamotrigine and clonazepam.She experienced progressive clonazepam-responsive myoclonus beginning at the age of 13, action tremors, irritability, and mild dysphagia.Aside from an uncle with tremor, she has no other family history.Prominent and disabling slowly progressive cervical and limb dystonia responded partially to trihexyphenidyl, clonazepam, and onabotulinumtoxinA.On examination, there was intention tremor and diffuse moderate amplitude action myoclonus.There were mildly elevated knee-jerk reflexes but no frank spasticity.Prominent cervical and limb dystonia was present, with a Fahn-Marsden score of 46 out of 120, 7 months after her last onabotulinum-toxinA injections.Cervical dystonia was characterized by a 30-degree right tilt, minimal left turn, anterior shift, right shoulder elevation, and a coarse head tremor.There was dystonic posturing of the limbs with wrist and finger hyperextension, knee hyperextension, and asymmetric equinovarus posturing of the feet, with a mildly wide-based ataxic gait.She had oromandibular dystonia and a strained dystonic as well as dysarthric speech pattern.With written informed consent, pertinent examination findings including components of the Dystonia Study Group videotape examination protocol are presented 4 (see Video).Brain MRI was normal except for mild atrophy, and EEG showed generalized spike and wave complexes with bursts of generalized discharges up to 10 s in duration.Laboratory testing was normal including metabolic testing in blood and urine (plasma amino acids, plasma acylcarnitine profile, ammonia, lactate, pyruvate, copper, ceruloplasmin, urine orotic acid, CoQ10 in blood and leukocytes, transferrin, biotinidase level, lysosomal studies in leukocytes, activity of palmitoyl-protein

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