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      Abnormal Vertical Eye Movements as a Clue for Diagnosis of Niemann–Pick Type C

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          Abstract

          Background

          Adult-onset Niemann–Pick Type C is a rare neurogenetic lysosomal disorder, whose diagnosis is often delayed and missed because of its heterogeneous clinical presentations and rarity as well as the lack of awareness of characteristic eye findings among neurologists.

          Phenomenology Shown

          Impaired smooth pursuits, saccades, and optokinetic nystagmus in the vertical direction, with relatively normal eye movements in the horizontal direction, and ataxia features on finger chase testing, tandem walking, and gait ataxia.

          Educational Value

          Impairment of vertical eye movements in combination with ataxia, cognitive impairment, and/or psychiatric symptoms in an adult patient should always raise clinical suspicion of Niemann–Pick Type C.

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          Most cited references3

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          Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses.

          Thomas Kirkegaard, James Gray, David Priestman … (2016)
          Lysosomal storage diseases (LSDs) often manifest with severe systemic and central nervous system (CNS) symptoms. The existing treatment options are limited and have no or only modest efficacy against neurological manifestations of disease. We demonstrate that recombinant human heat shock protein 70 (HSP70) improves the binding of several sphingolipid-degrading enzymes to their essential cofactor bis(monoacyl)glycerophosphate in vitro. HSP70 treatment reversed lysosomal pathology in primary fibroblasts from 14 patients with eight different LSDs. HSP70 penetrated effectively into murine tissues including the CNS and inhibited glycosphingolipid accumulation in murine models of Fabry disease (Gla(-/-)), Sandhoff disease (Hexb(-/-)), and Niemann-Pick disease type C (Npc1(-/-)) and attenuated a wide spectrum of disease-associated neurological symptoms in Hexb(-/-) and Npc1(-/-) mice. Oral administration of arimoclomol, a small-molecule coinducer of HSPs that is currently in clinical trials for Niemann-Pick disease type C (NPC), recapitulated the effects of recombinant human HSP70, suggesting that heat shock protein-based therapies merit clinical evaluation for treating LSDs.
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            Miglustat: a review of its use in Niemann-Pick disease type C.

            Katherine Lyseng-Williamson (2014)
            Miglustat (Zavesca®, Brazaves®), a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis, is the only disease-specific drug approved for the treatment of progressive neurological manifestations of Niemann-Pick disease type C (NP-C) in adult and paediatric patients. NP-C is a rare, autosomal-recessive lipid storage disorder characterized by impaired intracellular lipid trafficking and progressive neurological symptoms leading to premature death. In a randomized clinical trial, long-term extension studies and a retrospective observational cohort study, treatment with oral miglustat stabilized key neurological manifestations of NP-C (including horizontal saccadic eye movement peak velocity, ambulation, manipulation, language and swallowing) in paediatric and adult patients with the disease. The therapeutic effects of miglustat in stabilizing or slowing disease progression have been confirmed in other reports in the clinical experience setting. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects (e.g. diarrhoea, flatulence and abdominal pain/discomfort) and weight loss, which usually occur during initial therapy and are generally manageable. In the absence of a cure, miglustat is a valuable agent to reduce the progression of clinically relevant neurological symptoms in paediatric and adult patients with NP-C, which is considered a significant achievement in the treatment of this disease.
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              The Spectrum of Niemann-Pick Type C Disease in Greece

              Irene Mavridou, Evangelia Dimitriou, Marie T Vanier … (2017)
              Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disease caused by mutations in either the NPC1 or the NPC2 gene. It is a cellular lipid trafficking disorder characterized by the accumulation of unesterified cholesterol and various sphingolipids in the lysosomes and late endosomes, and it exhibits a broad clinical spectrum. Today, over 420 disease-causing mutations have been identified in the NPC1 and the NPC2 genes. We present the clinical, biochemical, and molecular findings in 14 cases diagnosed in Greece during the last 28 years. Age at diagnosis ranged from 2.5 months to 48 years. Systemic manifestations were present in 7/14 patients. All developed neurological manifestations (age of onset 5 months to 42 years). Six patients are still alive (age: 5–50 years). Classical filipin staining pattern was observed in all but four patients (3 NPC1, 1 NPC2). The rate of LDL-induced cholesteryl ester formation was severely reduced in 4/7 and significantly reduced in 3/7 patients studied. Increased chitotriosidase activity was observed in 9/12 patients. Mutation analysis in 11 unrelated patients identified 12 different mutations in the NPC1 gene: eight previously described p.E1089K (c.3265G>A), p.F284Lfs*26 (c.852delT), p.A1132P(c.3394G>C), del promoter region and exons 1-10, p.R1186H (c.3557G>A), p.P1007A (c.3019C>G), p.Q92R(c.275A>G),p.S940L (c.2819C>T), and four novel ones: (p.N701K fs*13 (c.2102-2103insA), p.K1057R (c.3170A>G), IVS23+3insT(c.3591+3insT), p.C1119*(c.3357T>C); and the previously described IVS2+5G>A(c.190+5G>A ) mutation in the NPC2 gene. All patients were of Greek origin. Assuming a birth rate of 100,000/year, a rough incidence estimate for NPC disease in Greece would be 0.5/100,000 births.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Tremor Other Hyperkinet Mov (N Y)
                Journal ID (iso-abbrev): Tremor Other Hyperkinet Mov (N Y)
                Journal ID (publisher-id): TOHM
                Title: Tremor and Other Hyperkinetic Movements
                Publisher: Columbia University Libraries/Information Services
                ISSN (Electronic): 2160-8288
                Publication date Collection: 2018
                Publication date (Electronic): 29 May 2018
                Volume: 8
                Electronic Location Identifier: 560
                Affiliations
                [1 ]Department of Neurology, Columbia University, New York, NY, USA
                [2 ]Department of Neurology, Hospital Universitario 12 de Octubre, Madrid, Spain
                [3 ]Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
                Yale University, USA
                Author notes
                *To whom correspondence should be addressed. E-mail: sk3295@ 123456cumc.columbia.edu
                Article
                DOI: 10.7916/D8XS7BGD
                PMC ID: 6026281
                SO-VID: c99f8304-90ea-46f0-ad90-d18be9edcae6
                Copyright © © 2018 Gupta et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommerical–No Derivatives License, which permits the user to copy, distribute, and transmit the work provided that the original author and source are credited; that no commercial use is made of the work; and that the work is not altered or transformed.

                History
                Date received : 13 March 2018
                Date accepted : 4 April 2018
                Page count
                Pages: 2
                Categories
                Subject: Video Abstracts

                Keywords: niemann–pick type c,cerebellar ataxia,eye movements
                Data availability:
                Keywords: niemann–pick type c, cerebellar ataxia, eye movements

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