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Published online before print September 17, 2008, doi:10.1212/01.wnl.0000327094.67726.28)
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Received November 27, 2007
Accepted May 29, 2008

Neurodegeneration associated with genetic defects in phospholipase A2

A. Gregory MS, S. K. Westaway PhD, I. E. Holm MD, DMSci, P. T. Kotzbauer MD, PhD, P. Hogarth MD, S. Sonek BS, J. C. Coryell MD, T. M. Nguyen BA, N. Nardocci MD, G. Zorzi MD, D. Rodriguez MD, I. Desguerre MD, E. Bertini MD, A. Simonati MD, B. Levinson MA, C. Dias MD, C. Barbot MD, I. Carrilho MD, M. Santos MD, I. Malik PhD, J. Gitschier PhD, and S. J. Hayflick MD*

From the Departments of Molecular and Medical Genetics, Pediatrics and Neurology (A.G., S.K.W., P.H., S.S., T.M.N., S.J.H.), School of Medicine, Oregon Health and Science University, Portland; the Department of Pathology (I.E.H.), Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark; the Department of Neurology and Hope Center for Neurological Disorders (P.T.K., I.M.), Washington University School of Medicine, St. Louis, MO; the Department of Pediatrics (J.C.C.), School of Medicine, University of Washington, Seattle; the Department of Child Neurology (N.N., G.Z.), Istituto Nazionale Neurologico "Carlo Besta," Milan, Italy; Neuropediatric Service (D.R.), Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau and Université Pierre et Marie Curie, Paris, France; the Department of Pediatric Neurology (I.D.), Hôpital Necker Enfants Malades, Paris, France; the Unit of Molecular Medicine (E.B.), Bambino Gesù Children's Research Hospital, Rome, Italy; the Department of Neurological and Visual Sciences (A.S.), University of Verona School of Medicine, Italy; the Departments of Medicine and Pediatrics (B.L., J.G.), University of California, San Francisco; and Instituto de Genetica Medica (C.D.) and Neuropediatria (C.B., I.C., M.S.), Hospital Maria Pia, Porto, Portugal.


* To whom correspondence should be addressed. E-mail: hayflick{at}ohsu.edu.

Objective: Mutations in the gene encoding phospholipase A2 group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A2.

Methods: We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations.

Results: Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations.

Conclusion: Defects in phospholipase A2 lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A2 suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.




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