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Neurodegeneration associated with genetic defects in phospholipase A(2)

A Gregory1, S K Westaway, I E Holm

  • 1Department of Molecular and Medical Genetics, Oregon Health & Science University, L103a, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA.

Neurology
|September 19, 2008
PubMed

Insights

Mutations in phospholipase A(2) group VI (PLA2G6) cause infantile neuroaxonal dystrophy (INAD) and some neurodegeneration with brain iron accumulation (NBIA) cases. Genotype correlates with phenotype, with cerebellar atrophy predicting PLA2G6 mutations.

Area of Science:

  • Neurogenetics
  • Molecular Neurology
  • Biochemistry

Background:

  • Mutations in phospholipase A(2) group VI (PLA2G6) are linked to infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA).
  • INAD is a severe neurodegenerative disorder characterized by axonal spheroids.
  • NBIA is a heterogeneous group of disorders defined by brain iron accumulation, particularly in the globus pallidus.

Purpose of the Study:

  • To delineate the clinical, radiographic, pathological, and genetic features of neurodegenerative diseases caused by defective phospholipase A(2).
  • To investigate the role of PLA2G6 mutations in INAD and NBIA.

Main Methods:

  • Genetic screening of PLA2G6 mutations in 56 patients with INAD and 23 with idiopathic NBIA.
  • Clinical, radiographic (MRI), and pathological assessments of affected individuals.

Main Results:

  • PLA2G6 mutations were identified in 80% of INAD patients and 20% of idiopathic NBIA patients.
  • Patients with two null mutations exhibited a more severe phenotype.
  • Cerebellar atrophy was observed in nearly all mutation-positive patients; half showed brain iron accumulation.
  • Neuropathology revealed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations.

Conclusions:

  • Defects in phospholipase A(2) result in a spectrum of neurological phenotypes.
  • PLA2G6 mutations account for most INAD cases but only a subset of NBIA cases.
  • Genotype-phenotype correlation exists, and cerebellar atrophy is a predictor of PLA2G6 mutation positivity.
  • Pathological findings suggest shared mechanisms with Parkinson and Alzheimer diseases.
Abstract

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