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Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN)

From the Department of Pediatric Neurology (M.A.K., D.P., R.G., S.G.P., E.W.), Radiology Department (L.M., K.F.), and Department of Metabolic Medicine (C.H.), Birmingham Children’s Hospital; Department of Medical and Molecular Genetics (M.A.K., N.V.M., P.G., E.R.M.), University of Birmingham School of Medicine; West Midlands Regional Genetics Service (J.E.V.M., E.R.M.), Birmingham Women’s Hospital; Academic Unit of Medical Genetics and Regional Genetic Service (H.M.K.), CMMC NHS Trust; and Department of Clinical Genetics (E.M.R.), Great Ormond Street Hospital, London, UK.

Address correspondence and reprint requests to Professor Eamonn R. Maher, Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Edgbaston, Birmingham, B15 2TT, UK E.R.MAHER{at}bham.ac.uk

Background: Neurodegeneration associated with brain iron accumulation (NBIA) comprises a heterogeneous group of disorders in which disruption of cellular mechanisms leads to accumulation of iron in the basal ganglia. This group includes patients with recently discovered mutations in the PLA2G6 gene encoding a calcium-independent phospholipase A2 enzyme that catalyzes the hydrolysis of glycerophospholipids. Previously, children with PLA2G6 mutations have been diagnosed with several different disorders and we wished to better define the phenotype of PLA2G6- associated neurodegeneration.

Methods: Detailed review of the clinical and genetic features of 14 and radiologic features of 13 of these patients with PLA2G6 mutations was undertaken.

Results: Median age of symptom presentation was 14 months. One third of the cohort presented following an intercurrent illness. The children had progressive cognitive and motor skill regression, with evidence of axial hypotonia, four limb spasticity, bulbar dysfunction, and strabismus. All patients developed cerebellar ataxia and dystonia. Most patients had optic atrophy. Brain imaging demonstrated cerebellar cortical atrophy and gliosis in all patients. Changes consistent with increased iron deposition were identified in the globus pallidus and substantia nigra. Novel corpus callosum changes are also reported.

Conclusion: We describe a cohort of patients with PLA2G6-associated neurodegeneration (PLAN). Although patients with PLAN have previously been diagnosed with infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and Karak syndrome, they display a characteristic clinical and radiologic phenotype. PLA2G6 mutational analysis will negate the need for more invasive diagnostic procedures such as tissue biopsy.

Abbreviations: FLAIR = fluid-attenuated inversion recovery; INAD = infantile neuroaxonal dystrophy; NBIA = neurodegeneration associated with brain iron accumulation; PKAN = pantothenate kinase-associated neurodegeneration; PLAN = PLA2G6-associated neurodegeneration.

Supplemental data at www.neurology.org

Disclosure: The authors report no conflicts of interest.

Received September 11, 2007. Accepted in final form January 8, 2008.