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.