Neurodegeneration associated with genetic defects in phospholipase A2

Allison Gregory, Shawn Westaway, I. E. Holm, P. T. Kotzbauer, Penelope (Penny) Hogarth, S. Sonek, J. C. Coryell, T. M. Nguyen, N. Nardocci, G. Zorzi, D. Rodriguez, I. Desguerre, E. Bertini, A. Simonati, B. Levinson, C. Dias, C. Barbot, I. Carrilho, M. Santos, I. MalikJ. Gitschier, Susan Hayflick

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1402-1409
Number of pages8
JournalNeurology
Volume71
Issue number18
DOIs
StatePublished - Oct 28 2008

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Phospholipases A2
Neuroaxonal Dystrophies
Mutation
Phenotype
Group VI Phospholipases A2
Atrophy
Iron
Psychomotor Disorders
Lewy Bodies
Spinal Nerves
Inborn Genetic Diseases
Neurofibrillary Tangles
Globus Pallidus
Brain
Nervous System Diseases
Peripheral Nerves
Parkinson Disease
Spinal Cord
Alzheimer Disease
Genotype

ASJC Scopus subject areas

  • Clinical Neurology

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Neurodegeneration associated with genetic defects in phospholipase A2. / Gregory, Allison; Westaway, Shawn; Holm, I. E.; Kotzbauer, P. T.; Hogarth, Penelope (Penny); Sonek, S.; Coryell, J. C.; Nguyen, T. M.; Nardocci, N.; Zorzi, G.; Rodriguez, D.; Desguerre, I.; Bertini, E.; Simonati, A.; Levinson, B.; Dias, C.; Barbot, C.; Carrilho, I.; Santos, M.; Malik, I.; Gitschier, J.; Hayflick, Susan.

In: Neurology, Vol. 71, No. 18, 28.10.2008, p. 1402-1409.

Research output: Contribution to journalArticle

Gregory, A, Westaway, S, Holm, IE, Kotzbauer, PT, Hogarth, PP, Sonek, S, Coryell, JC, Nguyen, TM, Nardocci, N, Zorzi, G, Rodriguez, D, Desguerre, I, Bertini, E, Simonati, A, Levinson, B, Dias, C, Barbot, C, Carrilho, I, Santos, M, Malik, I, Gitschier, J & Hayflick, S 2008, 'Neurodegeneration associated with genetic defects in phospholipase A2', Neurology, vol. 71, no. 18, pp. 1402-1409. https://doi.org/10.1212/01.wnl.0000327094.67726.28
Gregory, Allison ; Westaway, Shawn ; Holm, I. E. ; Kotzbauer, P. T. ; Hogarth, Penelope (Penny) ; Sonek, S. ; Coryell, J. C. ; Nguyen, T. M. ; Nardocci, N. ; Zorzi, G. ; Rodriguez, D. ; Desguerre, I. ; Bertini, E. ; Simonati, A. ; Levinson, B. ; Dias, C. ; Barbot, C. ; Carrilho, I. ; Santos, M. ; Malik, I. ; Gitschier, J. ; Hayflick, Susan. / Neurodegeneration associated with genetic defects in phospholipase A2. In: Neurology. 2008 ; Vol. 71, No. 18. pp. 1402-1409.
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abstract = "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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T1 - Neurodegeneration associated with genetic defects in phospholipase A2

AU - Gregory, Allison

AU - Westaway, Shawn

AU - Holm, I. E.

AU - Kotzbauer, P. T.

AU - Hogarth, Penelope (Penny)

AU - Sonek, S.

AU - Coryell, J. C.

AU - Nguyen, T. M.

AU - Nardocci, N.

AU - Zorzi, G.

AU - Rodriguez, D.

AU - Desguerre, I.

AU - Bertini, E.

AU - Simonati, A.

AU - Levinson, B.

AU - Dias, C.

AU - Barbot, C.

AU - Carrilho, I.

AU - Santos, M.

AU - Malik, I.

AU - Gitschier, J.

AU - Hayflick, Susan

PY - 2008/10/28

Y1 - 2008/10/28

N2 - 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.

AB - 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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