PLA2G6 Mutation Underlies Infantile Neuroaxonal Dystrophy

Abstract

Infantile neuroaxonal dystrophy (INAD) is an autosomal recessive progressive neurodegenerative disease that presents within the first 2 years of life and culminates in death by age 10 years. Affected individuals from two unrelated Bedouin Israeli kindreds were studied. Brain imaging demonstrated diffuse cerebellar atrophy and abnormal iron deposition in the medial and lateral globus pallidum. Progressive white-matter disease and reduction of the N-acetyl aspartate : chromium ratio were evident on magnetic resonance spectroscopy, suggesting loss of myelination. The clinical and radiological diagnosis of INAD was verified by sural nerve biopsy. The disease gene was mapped to a 1.17-Mb locus on chromosome 22q13.1 (LOD score 4.7 at recombination fraction 0 for SNP rs139897), and an underlying mutation common to both affected families was identified in PLA2G6, the gene encoding phospholipase A2 group VI (cytosolic, calcium-independent). These findings highlight a role of phospholipase in neurodegenerative disorders.

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

“…3 Genomic DNA (250 ng) from each subject was processed and labeled with reagents and protocols supplied by the manufacturer. Homozygosity by descent analysis was carried out using an in house tool for homozygosity mapping (Marcus et al, in preparation).…”

“…3 EBV transformation of lymphocytes of affected individuals was carried out as previously described. 5 RNA was extracted from cultured cells of EBV-transformed lymphoblastoid cell lines using the RNeasy Mini Kit (Qiagen, Petach Tikva, Israel) and cDNA was reverse transcribed by the Verso RT-PCR Kits (TAMAR, Mevaseret Zion, Israel) according to the protocol of the manufacturer.…”

“…We then proceeded to perform genome-wide linkage analysis of four patients, four obligatory carriers (parents of affected individuals) and one healthy sibling (IV1, IV2, V1, V2, IV3, III5, V4, V7 and IV5, depicted in Figure 1), using 250K SNP Arrays (GeneChip Human Mapping 500K Array Set (Affymetrix)) as previously described. 3,5 A single region of homozygosity on chromosome 1p33-1p32.3 was identified, that was common to all affected individuals. Fine mapping 2,6 testing the 18 available DNA samples with polymorphic markers narrowed down the locus to 6.75 cM (7.25 Mb) between D1S2824 and D1S200, with a maximum multipoint LOD score of six calculated using SUPERLINK 4 (data not shown).…”

Neuroaxonal Dystrophy in Calcium-Independent Phospholipase A2β Deficiency Results from Insufficient Remodeling and Degeneration of Mitochondrial and Presynaptic Membranes

“…Widespread formation of axonal swellings, referred to as spheroids, and tubulovesicular structures are observed in the CNS and PNS (Cowen and Olmstead, 1963;Khateeb et al, 2006). Gene abnormality in the PLA2G6 [calcium-independent phospholipase A 2 ␤ (iPLA 2 ␤)] gene is associated with 80% of INAD cases (Morgan et al, 2006) and is sometimes found in patients with dystonia-parkinsonism (Paisan-Ruiz et al, 2009).…”

Establishment of an Improved Mouse Model for Infantile Neuroaxonal Dystrophy That Shows Early Disease Onset and Bears a Point Mutation in Pla2g6

“…In fact, mutations in the PLA2G6 gene were identified in patients with a rare neurodegenerative disorder of humans, infantile neuroaxonal dystrophy (INAD). 3,4 INAD usually begins within the first few years of life and leads to progressive impairment of movement and cognition. The pathological hallmark of the disease is the presence of large spheroids containing accumulated material primarily located in distal axons and nerve terminals.…”