Neurodegeneration associated with genetic defects in phospholipase A ₂

Abstract

Objective: Mutations in the gene encoding phospholipase A 2 group VI (PLA2G6) are associated with two childhood neurologic disorders: infantile neuroaxonal dystrophy (INAD) and idiopathic neurodegeneration with brain iron accumulation (NBIA). INAD is a severe progressive psychomotor disorder in which axonal spheroids are found in brain, spinal cord, and peripheral nerves. High globus pallidus iron is an inconsistent feature of INAD; however, it is a diagnostic criterion of NBIA, which describes a clinically and genetically heterogeneous group of disorders that share this hallmark feature. We sought to delineate the clinical, radiographic, pathologic, and genetic features of disease resulting from defective phospholipase A 2 . Methods:We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations. Results:Eighty percent of patients with INAD had mutations in PLA2G6, whereas mutations were found in only 20% of those with idiopathic NBIA. All patients with two null mutations had a more severe phenotype. On MRI, nearly all mutation-positive patients had cerebellar atrophy, and half showed brain iron accumulation. We observed Lewy bodies and neurofibrillary tangles in association with PLA2G6 mutations. The neuroaxonal dystrophies are degenerative disorders that share the pathologic feature of axonal spheroids in brain. Spheroids are poorly understood axonal swellings that occur in infantile neuroaxonal dystrophy (INAD), pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome), idiopathic neurodegeneration with brain iron accumulation (NBIA), and Schindler disease. INAD is a severe psychomotor disorder with early onset and rapid progression of hypotonia, hyperreflexia, and tetraparesis. Conclusion:1 Spheroids are found in both the central and peripheral nervous systems in INAD, and iron accumulates in brain in a subset of these patients. 2,3 The term "neurodegeneration with brain iron accumulation" is used both as a descriptor

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

“…Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease with various neurological symptoms (Gregory et al, 2008b). 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).…”

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

“…13 In contrast, children with INAD may develop iron deposition later in their disease course or not at all. 14 The observation that the degree of iron deposition correlates incompletely with clinical symptoms suggests that though iron is a useful neuroimaging feature in NBIA, it likely is neither necessary nor sufficient to produce the disease phenotype. This has important clinical implications because clinical trials are currently underway for deferiprone, a chelating agent known to traverse the blood-brain barrier.…”

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

“…These findings might explain non-neurological features of progressive chest deformities (kyphosis/pectus carinatum) present in affected individuals. Complex phospholipid defects involving CNS have received much attention of late (Lamari et al, 2013), providing insights into late-onset neurodegenerative disease pathophysiology, such as gene PLA2G6 encoding PLA 2 , underlying autosomal-recessive infantile neuroaxonal dystrophy, neurodegeneration associated with brain iron accumulation, and early-onset dystonia/parkinsonism (Khateeb et al, 2006;Gregory et al, 2008).…”

“…Different binding affinities, varying cellular expression profiles, and attenuation of secondary messengers of these receptors lead to intricate, and sometimes opposing, signal transduction. While in Alzheimer's disease and amyotrophic lateral sclerosis, it plays a neurotoxic role (Bazan et al, 2002), in excitotoxicity and cerebral ischaemia scenarios, PGE 2 is neuroprotective (Gregory et al, 2008). Thus, modulation of PGE 2 appears critical for neurological function.…”