Commentary: Atypical, Early-Onset Dystonia-Parkinsonism with Oculogyric Crises and Anterior Horn Cell Disorder due to a Novel DJ-1 Mutation.

Abstract

Clinical phenomenology is the first step to generate a differential diagnosis. In the case presented by Desai et al.,1 the diagnostic reasoning from the phenomenological observations changed after the results from paraclinical investigations. The clinical features included a combination of segmental dystonia, oculogyric crises (OGC),2, 3 jerky movements of the fingers suggesting myoclonus, and muscle atrophy. Since parkinsonism was not particularly evident in the video, the discussant's differential diagnosis centered on the combination of dystonia, OGC and myoclonus. But the results of the investigations changed everything. The EMG revealed evidence of motor neuron disease (MND) and a DAT Scan was abnormal. After these results, the differential diagnosis shifted to disorders that can cause juvenile parkinsonism, dystonia and MND such as variant ataxia-telangiectasia, ATP1A3, SCA2, DJ14 and others. Consanguinity suggested an autosomal recessive disorder and whole exome sequencing (WES) revealed a novel homozygous mutation in the DJ1 gene. This novel case was very humbling and, thus, highly instructive. It emphasizes the value of EMG in jerky movement disorders; the tremulous movements of the fingers represented minipolymyoclonus, an expression of MND.5 It also serves to highlight the limitations of conclusions reached from phenomenological observations alone. Since there was little if any clinical parkinsonism and no benefit from levodopa, juvenile parkinsonism was not considered in the initial differential diagnosis. Yet, it was ultimately the DAT Scan that pointed towards the correct diagnostic category; this case suggests that it might be worth obtaining a DAT Scan in the absence of parkinsonism in selected unusual movement disorders. Although whole exome sequencing can misguide us by revealing variants of unknown significance, in this case, exome sequencing was key. Another curious twist in this case is that oculogyric crises feature prominently in dopa-responsive dystonia, in which a DAT scan is normal and the response to L-dopa is usually marked—the opposite of what was observed in this case. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. S.G.R.: 3B K.D.: 3B S.A.: 3B P.W.: 3B S.H.R.: 3B P.A.A.: 3B A.J.E.: 3A The authors confirm that neither informed patient consent nor the approval of an institutional review board was necessary for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Authors KD, SA, PW, SHR, PAA have nothing to disclose. Dr. Reich has received research support from the NINDS; served as a consultant for the MDS and Best Doctors; served as reviewer for UpToDate; served as the chair of the Data Safety Monitoring Board of Enterin; and has received book royalties from Springer and Oxford. Dr. Espay has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Abbvie, Neuroderm, Neurocrine, Amneal, Acadia, Acorda, Kyowa Kirin, Sunovion, Lundbeck, and USWorldMeds; honoraria from Acadia, Sunovion, Amneal, USWorldMeds; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He cofounded REGAIN Therapeutics, owner of a patent application that covers synthetic soluble non-aggregating peptide analogues as replacement treatment in proteinopathies.