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Indian-subcontinent NBIA: Unusual phenotypes, novel PANK2 mutations, and undetermined genetic forms

Authors

  • Annu Aggarwal MD,

    1. Center for Brain and Nervous Diseases, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
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    • Annu Aggarwal and Susanne A. Schneider contributed equally and are shared first authors for this article.

  • Susanne A. Schneider MD, PhD,

    1. Schilling Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Luebeck, Luebeck, Germany
    2. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, United Kingdom
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    • Annu Aggarwal and Susanne A. Schneider contributed equally and are shared first authors for this article.

  • Henry Houlden MD, PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Monty Silverdale MD, PhD,

    1. Department of Neurology, Greater Manchester Neurosciences Centre, Hope Hospital, Salford, Manchester, United Kingdom
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  • Reema Paudel MD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Coro Paisan-Ruiz PhD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Shrinivas Desai MD,

    1. Department of Neuroradiology, Jaslok Hospital and Research Center, Mumbai, India
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  • Mihir Munshi MD,

    1. Department of Neuroradiology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
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  • Darshana Sanghvi MD,

    1. Department of Neuroradiology, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
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  • John Hardy PhD, MD,

    1. Department of Molecular Neuroscience and Reta Lila Weston Institute, UCL Institute of Neurology, London, Queen Square, London, United Kingdom
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  • Kailash P. Bhatia MD, FRCP,

    Corresponding author
    1. Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, Queen Square, London, United Kingdom
    2. Clinical Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom
    • Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, England

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  • Mohit Bhatt MD

    1. Center for Brain and Nervous Diseases, Kokilaben Dhirubhai Ambani Hospital and Medical Research Institute, Mumbai, India
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  • Potential conflict of interest: Nothing. to report.

Abstract

Neurodegeneration with brain iron accumulation (NBIA) is etiologically, clinically, and by imaging a heterogeneous group including NBIA types 1 [pantothenate kinase-associated neurodegeneration (PKAN)] and 2 (PLA2G6-associated neurodegeneration), neuroferritinopathy, and aceruloplasminaemia. Data on genetically defined Indian-subcontinent NBIA cases are limited. We report 6 patients from the Indian-subcontinent with a movement disorder and MRI basal ganglia iron deposition, compatible with diagnosis of an NBIA syndrome. All patients were screened for abnormalities in serum ceruloplasmin and ferritin levels and mutations in NBIA-associated genes [pantothenate kinase 2 (PANK2), PLA2G6 and ferritin light chain (exon 4)]. We present clinical, imaging and genetic data correlating phenotype–genotype relations. Four patients carried PANK2 mutations, two of these were novel. The clinical phenotype was mainly dystonic with generalized dystonia and marked orobulbar features in the 4 adolescent-onset cases. One of the four had a late-onset (age 37) unilateral jerky postural tremor. His mutation, c.1379C>T, appears associated with a milder phenotype. Interestingly, he developed the eye-of-the-tiger sign only 10 years after onset. Two of the six presented with adult-onset levodopa (L-dopa)-responsive asymmetric re-emergent rest tremor, developing L-dopa-induced dyskinesias, and good benefit to deep brain stimulation (in one), thus resembling Parkinson's disease (PD). Both had an eye-of-the-tiger sign on MRI but were negative for known NBIA-associated genes, suggesting the existence of further genetic or sporadic forms of NBIA syndromes. In conclusion, genetically determined NBIA cases from the Indian subcontinent suggest presence of unusual phenotypes of PANK2 and novel mutations. The phenotype of NBIA of unknown cause includes a PD-like presentation. © 2010 Movement Disorder Society

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