University of Groningen Eye movement disorders and neurological symptoms in late-onset inborn errors of metabolism Koens, Lisette H.; Tijssen, Marina A. J.; Lange, Fiete; Wolffenbuttel, Bruce H. R.; Rufa, Alessandra; Zee, David S.; de Koning, Tom J. Published in: Movement Disorders DOI: 10.1002/mds.27484 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Koens, L. H., Tijssen, M. A. J., Lange, F., Wolffenbuttel, B. H. R., Rufa, A., Zee, D. S., & de Koning, T. J. (2018). Eye movement disorders and neurological symptoms in late-onset inborn errors of metabolism. Movement Disorders, 33(12), 1844-1856. https://doi.org/10.1002/mds.27484 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 29-04-2019 REVIEW Eye Movement Disorders and Neurological Symptoms in Late-Onset Inborn Errors of Metabolism Lisette H. Koens, MD,1 Marina A.J. Tijssen, MD, PhD,1 Fiete Lange, MD, PhD,2 Bruce H.R. Wolffenbuttel, MD, PhD,3 Alessandra Rufa, MD, PhD,4 David S. Zee, MD5 and Tom J. de Koning, MD, PhD6,7* 1University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, The Netherlands 2University of Groningen, University Medical Center Groningen, Department of Clinical Neurophysiology, Groningen, The Netherlands 3Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4Department of Medicine Surgery and Neurosciences, University of Siena, Eye tracking and Visual Application Lab (EVA Lab)–Neurology and Neurometabolic Unit, Siena, Italy 5Department of Neuroscience, Department of Ophthalmology, The Johns Hopkins University, The Johns Hopkins Hospital, Department of Neurology, Department of Otolaryngology-Head and Neck Surgery, Baltimore, Maryland, USA 6University of Groningen, Division of Metabolic Diseases, University Medical Center Groningen, Groningen, The Netherlands 7University of Groningen, Department of Genetics, University Medical Center Groningen, Groningen, The Netherlands ABSTRACT: Inborn errors of metabolism in adults are can be easily overlooked in a general examination. In still largely unexplored. Despite the fact that adult-onset adults with unexplained psychiatric and neurological phenotypes have been known for many years, little atten- symptoms, a special focus on examination of eye move- tion is given to these disorders in neurological practice. ments can serve as a relatively simple clinical tool to The adult-onset presentation differs from childhood- detect a metabolic disorder. Eye movements can be eas- onset phenotypes, often leading to considerable diag- ily quantified and analyzed with video-oculography, mak- nostic delay. The identification of these patients at the ing them a valuable biomarker for following the natural earliest stage of disease is important, given that early course of disease or the response to therapies. Here, we treatment may prevent or lessen further brain damage. review, for the first time, eye movement disorders that Neurological and psychiatric symptoms occur more fre- can occur in inborn errors of metabolism, with a focus on quently in adult forms. Abnormalities of eye movements late-onset forms. We provide a step-by-step overview are also common and can be the presenting sign. Eye that will help clinicians to examine and interpret eye movement disorders can be classified as central or movement disorders. © 2018 The Authors. Movement peripheral. Central forms are frequently observed in lyso- Disorders published by Wiley Periodicals, Inc. on behalf somal storage disorders, whereas peripheral forms are a of International Parkinson and Movement Disorder key feature of mitochondrial disease. Furthermore, oculo- Society. gyric crisis is an important feature in disorders affecting dopamine syntheses or transport. Ocular motor disorders Key Words: eye movement disorders; inborn errors of are often not reported by the patient, and abnormalities metabolism; movement disorders; adult-onset Inborn errors of metabolism (IEM) are a heteroge- to only present during infancy or early childhood.1 We neous group of genetic disorders that cause dysfunction now know that this prevalence is an underestimate, and of an enzyme or transporter involved in cellular metab- that IEM present in adolescence or adulthood much olism. Historically, inborn errors were thought to be more often than previously thought. Retrospective data rare, occuring in less than 1 per 100,000 live births and from an ethnically diverse population in the United ----------------------------------------------------------------------------------------------------------------------- This is an open access article under the terms of the Creative Full financial disclosures and author roles may be found in the Commons Attribution License, which permits use, distribution and online version of this article. reproduction in any medium, provided the original work is properly cited. Received: 23 March 2018; Revised: 3 August 2018; Accepted: 6 August 2018 *Correspondence to: Dr. Tom J. de Koning, Department of Genetics, University Medical Center Groningen, University of Groningen, Hanze- Published online 28 November 2018 in Wiley Online Library plein 1, P.O. Box 30.001, 9700 RB Groningen, The Netherlands; (wileyonlinelibrary.com). DOI: 10.1002/mds.27484 E-mail: [email protected] Relevant conflicts of interest/financial disclosures: Nothing to report. 1844 Movement Disorders, Vol. 33, No. 12, 2018 EYE MOVEMENT DISORDERS IN LATE-ONSET IEM Kingdom (1999-2003) revealed an overall prevalence Supplementary Appendix I. Only IEMs with at least of metabolic disease of 1 per 784 live births; mitochon- 2 patients with some type of eye movement disorder drial diseases, lysosomal storage diseases, and amino were included in the review. Although we focused on acid disorders were most frequent. Furthermore, more late-onset IEM (adolescent-onset 16-18 years of age, than one quarter of all diagnoses were made after the adult-onset > 18 years of age), it is difficult to discrimi- age of 15 years.2 Adult phenotypes may differ from the nate specifically between early- and late-onset forms, classic childhood-onset phenotypes. In adulthood, given that eye movement disorders are frequently not many IEM patients present with neurological or psychi- described in the literature. For that reason, children were atric symptoms, but considering an IEM in the differen- also included in this review. We included mitochondrial fi tial diagnosis of an adult patient is still uncommon diseases as a combined disease group instead of speci c 3 subtypes. We excluded articles in which nystagmus sec- among neurologists. Missing or delaying diagnosis of ondary to blindness was the only ocular motor finding. an IEM can have important implications. In particular, Supplementary Appendix II presents a list of references patients with a milder phenotype appear to benefit most with videos of eye movement disorders in IEM. from timely treatment, so identifying them is important to prevent further (neurological) damage.4 Whereas the neurological symptoms in patients with Examination of Eye Movements IEM often involve various types of movement disorders,5 eye movement disorders are also frequently Disorders of eye movement can be categorized as observed and can be an important diagnostic clue.6 The peripheral and central (Table 1). Peripheral eye move- type of eye movement disorder can often further delin- ment disorders are particularly frequent in mitochron- eate the type of IEM. drial disorders and commonly affect the two eyes The aim of this article is to review the abnormalities differently, resulting in ocular misalignment and diplo- of eye movements that can be observed in IEM, with pia. Progressive external ophthalmoplegia (PEO) is an an emphasis on those IEMs that can present later in important exception to this rule.7 Because of the insidi- life. Our goal is to increase awareness of eye ous onset and slow progression, patients do not com- movements in adult patients with movement disorders plain of diplopia and may be unaware of any disorder and other neurological or psychiatric disturbances of eye movements.8 Central causes of ocular motor because they can be the key to early diagnosis. abnormalities usually affect both eyes.7,9 Because more types of IEM are being identified that Clinical examination of the eye movements in all can be treated, early recognition of these disorders is patients with a suspected IEM is essential. Patients important. themselves may not report visual symptoms or may only have nonspecific complaints.9,10 Table 2 provides a short step-by-step overview of the clinical examina- Search Strategy