New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations

PLoS One. 2013 Oct 9;8(10):e76831. doi: 10.1371/journal.pone.0076831. eCollection 2013.


Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Arabs
  • Child
  • Child, Preschool
  • Consanguinity
  • Electroencephalography
  • Evoked Potentials, Visual / genetics
  • Female
  • Follow-Up Studies
  • Genotype
  • Group VI Phospholipases A2 / genetics*
  • Humans
  • Infant
  • Male
  • Muscles / pathology
  • Muscles / physiopathology
  • Mutation*
  • Neural Conduction / genetics
  • Neuroaxonal Dystrophies / ethnology
  • Neuroaxonal Dystrophies / genetics
  • Neuroaxonal Dystrophies / pathology
  • Neuroaxonal Dystrophies / physiopathology
  • Neuroimaging
  • Pedigree
  • Phenotype*
  • Young Adult


  • Group VI Phospholipases A2
  • PLA2G6 protein, human

Supplementary concepts

  • Karak Syndrome

Grants and funding

MAM and co-authors are thankful to the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, for supporting the work through the research group project number RGP-VPP. RC was supported by the Gebert Rüf Foundation (grant number GRS-046/09). GS was supported by the French National Agency for Research(ANR), Association Contre les Syndromes Cérébelleux, France, The Verum Foundation, the European Union (Omics call, "Neuromics"), The Fondation Roger de Spoelberch and the program "Investissements d'avenir" ANR-10-IAIHU-06 (to the Brain and Spine Institute). HA was supported by Association Française contre les Myopathies (AFM), France. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.