Neurodegeneration associated with genetic defects in phospholipase A(2)

Topic: Brain proteins, microglia and lab models

Objective Mutations in the gene encoding phospholipase A(2) 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 A(2). 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 A(2) 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 A(2) suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.

Key findings

• Objective Mutations in the gene encoding phospholipase A(2) group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA).
• Results Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA.
• We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations.
• 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.

Why it matters

This study found that mutations in the PLA2G6 gene cause childhood neurologic disorders and that some affected patients had Lewy bodies and neurofibrillary tangles. It concerns rare genetic childhood disorders, not Alzheimer's disease, and does not test any treatment for Alzheimer's.

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Study details

• Participants56
• Evidence strengthLow

Read the original

• DOI: 10.1212/01.wnl.0000327094.67726.28
• PubMed: 18799783
• Original source →
• Free full text: PubMed Central →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{gregory2008-18799783,
  author  = {Gregory, A. and Westaway, S. K. and Holm, I. E. and Kotzbauer, P. T. and Hogarth, P. and Sonek, S. and Coryell, J. C. and Nguyen, T. M. and others},
  title   = {{Neurodegeneration associated with genetic defects in phospholipase A(2)}},
  journal = {Neurology},
  year    = {2008},
  doi     = {10.1212/01.wnl.0000327094.67726.28},
  pmid    = {18799783},
  url     = {https://doi.org/10.1212/01.wnl.0000327094.67726.28}
}

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