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Neurodegeneration associated with genetic defects in phospholipase A₂

Address correspondence and reprint requests to Dr. Susan J. Hayflick, Department of Molecular and Medical Genetics, Oregon Health & Science University, L103a, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098 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.

Abbreviations: INAD = infantile neuroaxonal dystrophy; NBIA = idiopathic neurodegeneration with brain iron accumulation; PKAN = pantothenate kinase-associated neurodegeneration.

e-Pub ahead of print on September 17, 2008, at www.neurology.org.

Authors’ affiliations are listed at the end of the article.

Supported by grants from the National Institute of Child Health and Human Development, the National Eye Institute, L’Association Internationale De Dystrophie Neuro Axonale Infantile, and the NBIA Disorders Association. Additional support was provided by the Paolo Zorzi Foundation and the Italian National Ministry of Health. Samples were obtained from the "Cell line and DNA bank from patients affected with genetic diseases" collection at the Giannina Gaslini Institute (http://www.gaslini.org/labdppm.htm) supported by Italian Telethon grants (project #GTF04002) and the Coriell Cell Repositories. This publication was made possible with support from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 01 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research.

Disclosure: The authors report no disclosures.

Received November 27, 2007. Accepted in final form May 29, 2008.

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