LAUSR

Recently, de novo and bi-allelic mutations in PDE10A, encoding a cyclic nucleotide phosphodiesterase selectively expressed in striatal medium spiny neurons, have been recognized as a cause of childhood-onset chorea. Brain MRI consistently showed striking bilateral striatal lesions in the 3 patients with de novo mutations identified to date. Interestingly, these radiological features were not observed in any of the patients with recessive mutations despite a more severe clinical presentation. Herein, we describe a patient carrying a de novo PDE10A mutation presenting with bilateral striatal MRI abnormalities and a yet unreported circadian pattern of nonprogressive chorea. The patient is an Italian 5-year-old boy born full term after an uneventful pregnancy and delivery. Motor and language milestones were normally achieved. At age 2.5 he presented with subacute onset of chorea involving the lower limbs causing frequent falls. No febrile illness preceded the onset of movement disorder. During the following 3 months, chorea slowly progressed and became generalized with sparing of the oro-mandibular and facial muscles and he developed mild dystonic posturing of upper limbs. At this stage, diurnal fluctuations of chorea became evident, with increased severity lasting about 2 hours after waking up in the morning (Video 1). Chorea slowly improved during the day, showed no worsening before falling asleep, and was absent at night. Cognitive assessment was normal (total IQ 5 114). Brain MRI performed 2 months after onset of symptoms revealed bilateral symmetrical hyper-intense lesions on T2weighted, FLAIR and diffusion weighted images involving the putamen and caudate nuclei (Fig. 1). An extensive diagnostic workup, including CSF analysis (neurotransmitters, folates), plasma lactate/pyruvate, activity of the respiratory chain enzymes in muscle, basic metabolic panel, and a screening for autoimmune and infectious conditions, was unremarkable. Targeted sequencing of striatal necrosis-related genes yielded negative results. Whole-exome sequencing was performed as previously described and revealed a heterozygous known pathogenic PDE10A missense variant (c.1000T>C, p.Phe334Leu; transcript ENST00000539869). Sanger sequencing confirmed the presence of the variant and segregation analysis in the parents demonstrated it arose de novo in the proband. The patient was started on trihexyphenidyl (1 mg daily), which was discontinued because of behavioral changes. Tetrabenazine was not administered because of the patient’s young age and overall mild severity of chorea. After 2 years of follow-up, chorea showed no progression, but diurnal fluctuations consistently persisted (Video 1) and brain MRI was unchanged. No additional therapies were started. This report confirms the homogeneous phenotype related to dominant PDE10A mutations. The unique clinical presentation of childhood-onset chorea with a scarcely progressive course associated with bilateral striatal lesions is highly suggestive of dominant PDE10A mutations. To date, only 2 recurrent dominant pathogenic variants have been identified (p.Phe300Leu and p.Phe334Leu, each detected in 2 unrelated patients), suggesting that these residues are mutational hotspots. Unlike previously reported PDE10A mutation carriers, our case showed marked diurnal fluctuations with chorea being more severe upon awakening in the morning. Differently from our case, patients with ADCY5-related chorea often show characteristic exacerbations lasting up to hours both upon awakening and falling asleep. Cases with DOPA-responsive dystonia as a result of GCH1 mutations present with marked worsening of symptoms during the day. The pattern of motor fluctuation observed in this case of PDE10A-related chorea may represent an additional clue for the identification of this rare movement disorder.