Brain Advance Access originally published online on December 2, 2006
Brain 2007 130(1):110-119; doi:10.1093/brain/awl319
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Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation
1 Institute of Human Genetics, University of Newcastle upon Tyne UK 2 Department of Neurology, University of Newcastle upon Tyne UK 3 Department of Neuroradiology, Regional Neurosciences Centre Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK 4 Institute of Neurology Queen Square, London 5 Queens Medical Centre Nottingham, UK 6 The Walton Centre for Neurology and Neurosurgery Liverpool, UK 7 Greater Manchester Centre for Clinical Neurosciences Hope Hospital, Salford, UK 8 Department of Medical Imaging, University of Queensland Royal Brisbane and Women's Hospital, Brisbane, Australia 9 Institut National de la Santé et de la Recherche Médicale U582, Paris, France
Correspondence to: Professor Patrick F. Chinnery, The Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK Email: p.f.chinnery{at}ncl.ac.uk
Neuroferritinopathy is a progressive potentially treatable adult-onset movement disorder caused by mutations in the ferritin light chain gene (FTL1). Features overlap with common extrapyramidal disorders: idiopathic torsion dystonia, idiopathic Parkinson's disease and Huntington's disease, but the phenotype and natural history have not been defined. We studied a genetically homogeneous group of 41 subjects with the 460InsA mutation in FTL1, documenting the presentation, clinical course, biochemistry and neuroimaging. The mean age of onset was 39.4 years (SD = 13.3, range 13–63), beginning with chorea in 50%, focal lower limb dystonia in 42.5% and parkinsonism in 7.5%. The majority reported a family history of a movement disorder often misdiagnosed as Huntington's disease. The disease progressed relentlessly, becoming generalized over a 5–10 year period, eventually leading to aphonia, dysphagia and severe motor disability with subcortical/frontal cognitive dysfunction as a late feature. A characteristic action-specific facial dystonia was common (65%), and in 63% there was asymmetry throughout the disease course. Serum ferritin levels were low in the majority of males and post-menopausal females, but within normal limits for pre-menopausal females. MR brain imaging was abnormal on all affected individuals and one presymptomatic carrier. In conclusion, isolated parkinsonism is unusual in neuroferritinopathy, and unlike Huntington's disease, cognitive changes are absent or subtle in the early stages. Depressed serum ferritin is common and provides a useful screening test in routine practice, and gradient echo brain MRI will identify all symptomatic cases.
Key Words: chorea; dystonia; ferritin; iron; movement disorder; neurodegeneration; neuroferritinopathy
Abbreviations: FTL1, ferritin light chain gene; ITD, idiopathic torsion dystonia; PANK2, pantothenate kinase 2
Received August 23, 2006. Accepted October 16, 2006.
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