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.

Calcium-independent phospholipases A2 and their roles in biological processes and diseases

“…From the collection of related studies, it can be ascertained that iPLA 2 ␤ activation in the heart may be benefi cial and also detrimental ( 265,385,386 ). For instance, increases in membrane-iPLA 2 ( 387 ) and mitochondrial-iPLA 2 ( 388 ) activities were associated with irreversible cell damage mutations and combination of mutations in PLA2G6 -associated neurodegeneration may be associated with Parkinson's and Alzheimer's diseases in the absence or presence of iron accumulations ( 316,(339)(340)(341)(342)(343)(344)(345)(346)(347).…”

Ophthalmic features ofPLA2G6-related paediatric neurodegeneration with brain iron accumulation

“…Details regarding their neurological findings are described in a companion publication 5. Age at examination ranged from 4–26 years.…”

“…A cohort of known Saudi Arabian patients from consanguineous families and affected by PLA2G6- related NBIA5 underwent prospective ophthalmic examination. Their genetic diagnosis was established by homozygosity analysis guided candidate gene testing, which revealed homozygous PLA2G6 mutations to segregate with their phenotypes 5. At the time of ophthalmic examination, their mutation status was unknown.…”

Genetic landscape remodelling in spinocerebellar ataxias: the influence of next-generation sequencing

“…ARCA3, caused by ANO10 mutations, almost always presents as cerebellar atrophy with lack of neuropathy [44]. All PLA2G6 carriers of biallelic mutations show a childhood-onset cerebellar atrophy preceding brain iron accumulation, with some correlation between the genotype and age at onset [45].…”

“…PNPLA6, which encodes a bifunctional enzyme with a role in fatty acids and glycerophosphocholine synthesis, and in 2-arachidonoyl lysophosphatidylinositol catalyzation, has been mentioned above [42,93]. Mutations in PLA2G6, encoding phospholipase A2, account for a large phenotypic spectrum, but childhood-onset cerebellar ataxia is a core element [45]. Finally, ELOVL4 and ELOVL5, which code for elongases of very long chain fatty acids were, respectively, implicated in SCA34 and SCA38 [10,94].…”