Phenotypic spectrum of neurodegeneration associated with mutations in the
            <i>PLA2G6</i>
            gene (PLAN)

Kurian, Manju A.; Morgan, Neil V.; MacPherson, Lesley; Foster, Katharine; Peake, Deirdre; Gupta, Rajat Das; Philip, Sunny; Hendriksz, Christian J.; Morton, Jenny; Kingston, Helen; Rosser, Elisabeth; Wassmer, Evangeline; Gissen, Paul; Maher, E.R.

doi:10.1212/01.wnl.0000310986.48286.8e

Cited by 223 publications

(250 citation statements)

References 21 publications

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“…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).…”

Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

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

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

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The Ca 2+ -independent phospholipases A 2 (iPLA 2 s) are part of a diverse family of PLA 2 s that hydrolyze the sn -2 substituent from membrane phospholipids to release a free fatty acid and a lysolipid ( 1, 2 ). These enzymes are ubiquitously expressed, and in contrast to secretory PLA 2 s (sPLA 2 s) and cytosolic PLA 2 s (cPLA 2 s), do not require Ca 2+ for either translocation or activity. Some of the fi rst descriptions of iPLA 2 activity were in the mid-to late-1980s with the identifi cation of a plasmalogen-selective PLA 2 in Abstract Among the family of phospholipases A 2 (PLA 2 s) are the Ca 2+ -independent PLA 2 s (iPLA 2 s) and they are designated group VI iPLA 2 s. In relation to secretory and cytosolic PLA 2 s, the iPLA 2 s are more recently described and details of their expression and roles in biological functions are rapidly emerging. The iPLA 2 s or patatin-like phospholipases (PNPLAs) are intracellular enzymes that do not require Ca 2+ for activity, and contain lipase (GXSXG) and nucleotide-binding (GXGXXG) consensus sequences. Though nine PNPLAs have been recognized, PNPLA8 (membraneassociated iPLA 2 ␥ ) and PNPLA9 (cytosol-associated iPLA 2 ␤ ) are the most widely studied and understood. The iPLA 2 s manifest a variety of activities in addition to phospholipase, are ubiquitously expressed, and participate in a multitude of biological processes, including fat catabolism, cell differentiation, maintenance of mitochondrial integrity, phospholipid remodeling, cell proliferation, signal transduction, and cell death. As might be expected, increased or decreased expression of iPLA 2 s can have profound effects on the metabolic state, CNS function, cardiovascular performance, and cell survival; therefore, dysregulation of iPLA 2 s can be a critical factor in the development of many diseases. This review is aimed at providing a general framework of the current understanding of the iPLA 2 s and discussion of the potential mechanisms of action of the iPLA 2 s and related involved lipid mediators. -Ramanadham, S

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Section: Ipla 2 ␤ and Diseasesmentioning

confidence: 99%

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

Ramanadham

Ali

Ashley

et al. 2015

Journal of Lipid Research

169

190

View full text Add to dashboard Cite

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“…36 The recognition that mutations in PLA2G6 do not always lead to a clear NAD phenotype has led investigators to propose the name PLAN to describe the general class of neurodegenerative disorders caused by mutations in this gene. 37 Although recognizing the phenotypic heterogeneity of NBIA disorders is important, converging evidence implicates several subtypes of NBIA in a shared pathway linking abnormalities of lipid metabolism with fundamental mechanisms underlying neurodegeneration. 29 Given the overlap with other neurodegenerative disorders, improved understanding of NBIA may lead to parallel insights into related synucleinopathies and tauopathies.…”

Section: Nbia Disorders Without Iron Depositionmentioning

confidence: 99%

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Kruer¹,

Boddaert²,

Schneider³

et al. 2011

AJNR Am J Neuroradiol

191

161

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SUMMARY: NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.ABBREVIATIONS: ACP ϭ aceruloplasminemia; CNS ϭ central nervous system; FAHN ϭ fatty acid hydroxylase-associated neurodegeneration; INAD ϭ infantile neuroaxonal dystrophy; KRS ϭ KuforRakeb syndrome; NAD ϭ neuroaxonal dystrophy; NBIA ϭ neurodegeneration with brain iron accumulation; NFT ϭ neuroferritinopathy; PKAN ϭ pantothenate kinase-associated neurodegeneration; PLAN ϭ phospholipase-associated neurodegeneration; SENDA ϭ static encephalopathy of childhood with neurodegeneration in adulthood; WSS ϭ Woodhouse-Sakati syndrome B efore the widespread availability of MR imaging, a diagnosis of NBIA could be made only at the time of autopsy. In contrast, current diagnosis is facilitated by evaluation by using both T1-and T2-weighted sequences. As a paramagnetic substance, Fe 3ϩ catalyzes the nuclear spin relaxation of neighboring water protons. With standard clinical parameters, areas rich in iron appear hypointense on T2-weighted sequences, and isointense on T1 sequences. T2*-weighted acquisitions (gradient-echo sequences) may accentuate this degree of hypointensity ("blooming") and may be helpful in identifying NBIA disorders as may susceptibility-weighted images.1 In biologic iron-oxides, Fe 2ϩ typically has fewer unpaired electrons than Fe 3ϩ and is less effective in quenching T2-weighted signal intensity.2 Calcium may also appear isointense on T1 and hypointense on T2-weighted sequences, mimicking the appearance of iron. The 2 minerals are readily distinguished by CT, however, because Ca 2ϩ characteristically appears hyperintense to the surrounding brain parenchyma, while iron is isointense. In addition, iron typically appears markedly hypointense on both standard clinical diffusionweighted and apparent diffusion coefficient sequences. Other metals that may be deposited in neurodegenerative disorders, such as manganese and copper, have a distinct appearance on T1-and T2-weighted sequences, enabling a heuristic approach to diagnosis based on MR imaging parameters. The characteristics of these metals are summarized in Table 1. Despite the utility of MR imaging in this setting, it does not preclude the need for elemental analysis of neuropathologic specimens; rather, it enables putative diagnosis to be made during life.The radiographic appearance of the lesions themselves is of prime importance. Iron deposition occurs in mul...

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“…The list of NBIAs is continuously expanding. Besides PKAN caused by mutations in the PANK2 gene, [1,2] the best characterized subtypes include MPAN with mutations/deletions in the c19orf12 gene, [7][8][9] the PLA2G6 Associated Neurodegeneration (PLAN) with mutations in the PLA2G6 gene, [10] the Coasy Protein Associated Neurodegeneration (CoPAN) with mutations in the Coasy gene, [11] and the Beta-Propeller Protein Associated Neurodegeneration (BPAN) with mutations in the WDR45 gene. [12] A shared feature of these diseases is brain iron accumulation that is likely secondary to abnormalities in lipid metabolism and autophagy.…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick’s disease type B and brain iron accumulation

Garzuly

Szabó

Bencsik

et al. 2017

CRCP

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Background: Niemann-Pick's type B (NP-B) disease is a rare, autosomal recessive visceral storage disorder related to a lysosomal accumulation of sphingomyelin, which is caused by mutations in the sphingomyelinase gene, SMPD1. Case report: We present a boy who had normal early development, but from one year of age, he showed progressive manifestations of hepatosplenomegaly, somatomotor retardation and cardiopulmonary dysfunction. The activity of the sphingomyelinase enzyme was very low in his fibroblasts. He died at 17 years of age from cardio-respiratory insufficiency. Gross pathology and histology of the internal organs were compatible with Niemann-Pick's disease. His brain and spinal cord displayed no signs of storage disease, confirming the subtype of NP-B. Unexpectedly, however, significant accumulation of iron was seen in the substantia nigra, subthalamic nuclei, putamen, globus pallidus and some cortical regions accompanied by axonal spheroids. Brain iron accumulation is the hallmark of a disease group termed neurodegeneration with brain iron accumulation (NBIA). Sequencing of the known NBIA disease genes was unsuccessful in the proband's DNA isolated from formalin-fixed, paraffin-embedded blocks, but both asymptomatic parents were heterozygous carriers of the same c19orf12 deletion. Conclusions: This case initially raised the question as to whether two rare autosomal recessive disorders, NP-B and a subtype of NBIA could have co-occurred in our patient, or the lipid dysmetabolism due to sphingomyelinase deficiency caused secondary brain iron accumulation. Genetic analyses in the parents suggested the former possibility by identifying a c19orf12 gene deletion known to underlie in homozygous state Mitochondrial Membrane Protein Associated Neurodegeneration.

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Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN)

Cited by 223 publications

References 21 publications

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

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

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

Niemann-Pick’s disease type B and brain iron accumulation

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