New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

Mustafa A. Salih, Emeline Mundwiller, Arif O. Khan, Abdulmajeed AlDrees, Salah A. Elmalik, Hamdy H. Hassan, Mohammed Al-Owain, Hisham M. S. Alkhalidi, Istvan Katona, Mohammad M. Kabiraj, Roman Chrast, Amal Y. Kentab, Hamad Alzaidan, Richard J. Rodenburg, Thomas M. Bosley, Joachim Weis, Michel Koenig, Giovanni Stevanin, Hamid Azzedine
PLoS ONE. 2013-10-09; 8(10): e76831
DOI: 10.1371/JOURNAL.PONE.0076831

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

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

Salih MA(1), Mundwiller E, Khan AO, AlDrees A, Elmalik SA, Hassan HH, Al-Owain M,
Alkhalidi HM, Katona I, Kabiraj MM, Chrast R, Kentab AY, Alzaidan H, Rodenburg
RJ, Bosley TM, Weis J, Koenig M, Stevanin G, Azzedine H.

Author information:
(1)Division of Pediatric Neurology, College of Medicine, King Saud University,
Riyadh, Saudi Arabia.

Erratum in
PLoS One. 2013;8(11).

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.

DOI: 10.1371/journal.pone.0076831
PMCID: PMC3792983
PMID: 24130795 [Indexed for MEDLINE]

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