title: New findings in a global approach to dissect the whole phenotype of PLA2G6 gene mutations.
abstract: 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.
authors.affiliation: Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Salih
authors.forename: Emeline
authors.initials: E
authors.lastname: Mundwiller
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.forename: Abdulmajeed
authors.initials: A
authors.lastname: AlDrees
authors.forename: Salah A
authors.initials: SA
authors.lastname: Elmalik
authors.forename: Hamdy H
authors.initials: HH
authors.lastname: Hassan
authors.forename: Mohammed
authors.initials: M
authors.lastname: Al-Owain
authors.forename: Hisham M S
authors.initials: HM
authors.lastname: Alkhalidi
authors.forename: Istvan
authors.initials: I
authors.lastname: Katona
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Kabiraj
authors.forename: Roman
authors.initials: R
authors.lastname: Chrast
authors.forename: Amal Y
authors.initials: AY
authors.lastname: Kentab
authors.forename: Hamad
authors.initials: H
authors.lastname: Alzaidan
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bosley
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Michel
authors.initials: M
authors.lastname: Koenig
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stevanin
authors.forename: Hamid
authors.initials: H
authors.lastname: Azzedine
mesh_terms: D000293:Adolescent; D000328:Adult; D018912:Arabs; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D004569:Electroencephalography; D005074:Evoked Potentials, Visual / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D054522:Group VI Phospholipases A2 / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D009132:Muscles / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D009431:Neural Conduction / Q000235:genetics; D019150:Neuroaxonal Dystrophies / Q000208:ethnology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D059906:Neuroimaging; D010375:Pedigree; D010641:Phenotype; D055815:Young Adult
chemical_list: D054522:Group VI Phospholipases A2; C516475:PLA2G6 protein, human