Characterization of PLA2G6 as a locus for dystonia‐parkinsonism

Paisán-Ruı́z, Coro; Bhatia, Kailash P.; Li, Abi; Hernandez, Dena G.; Davis, Mary B.; Wood, Nicholas W.; Hardy, John; Houlden, Henry; Singleton, Andrew B.; Schneider, Susanne A.

doi:10.1002/ana.21415

Cited by 424 publications

(399 citation statements)

References 15 publications

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“…The argument against causality may stem from the observation that some patients with known genetic mutations and phenotypic features of NBIA syndromes can have no iron deposition on neuroimaging [16,17], in addition to excess iron which is often seen within the brain and basal ganglia in normal ageing [18,19]. However, with all of the participants in our study showing no clinical features of neuroferritinopathy at the time of MRI imaging, our study supports a causal role of iron in initiating neurodegeneration in neuroferritinopathy and therefore potentially for other neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Neuroferritinopathy: a new inborn error of iron metabolism

Keogh

Jonas

Coulthard³

et al. 2012

Neurogenetics

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Neuroferritinopathy is an autosomal dominant progressive movement disorder which occurs due to mutations in the ferritin light chain gene (FTL1). It presents in mid-adult life and is the only autosomal dominant disease in a group of conditions termed neurodegeneration with brain iron accumulation (NBIA). We performed brain MRI scans on 12 asymptomatic descendants of known mutation carriers. All three harbouring the pathogenic c.460InsA mutation showed iron deposition; these findings show pathological iron accumulation begins in early childhood which is of major importance in understanding and developing treatment for NBIA.

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Section: Discussionmentioning

confidence: 99%

Neuroferritinopathy: a new inborn error of iron metabolism

Keogh

Jonas

Coulthard³

et al. 2012

Neurogenetics

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“…To date (2010), 11 genes and an additional 3 genetic loci have been associated with PD [168][169][170][171][172][173][174][175][176][177][178][179][180][181][182][183][184]; two additional loci await to be confirmed [185,186]. The PD genes and loci are described in Table 4.…”

Section: Genes and Loci In Familial Pdmentioning

confidence: 99%

“…In two unrelated families from Pakistan with autosomal recessive l-dopa-responsive parkinsonism, dystonia and pyramidal tract signs, two different homozygous mutations in the PLA2G6 gene were found [174]. Mutations in the same gene, a phopholipase, causes two childhood neurological diseases, infantile neuroaxonal dystrophy and neurodegeneration with brain iron accumulation [260].…”

Section: Park14mentioning

confidence: 99%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…For example, iron deposition in NAD may occur later in the disease course or not at all, and a recently identified allelic form of parkinsonism-dystonia is caused by mutations in PLA2G6, with onset in adulthood but without iron deposition on neuroimaging. 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.…”

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

187

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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Characterization of PLA2G6 as a locus for dystonia‐parkinsonism

Cited by 424 publications

References 15 publications

Neuroferritinopathy: a new inborn error of iron metabolism

Neuroferritinopathy: a new inborn error of iron metabolism

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Neuroimaging Features of Neurodegeneration with Brain Iron Accumulation

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