Neurodegeneration associated with genetic defects in phospholipase A(2)

Department of Molecular and Medical Genetics, Oregon Health & Science University, L103a, 3181 SW Sam Jackson Park Rd., Portland, OR 97239-3098, USA.
Neurology (Impact Factor: 8.29). 10/2008; 71(18):1402-9. DOI: 10.1212/01.wnl.0000327094.67726.28
Source: PubMed


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).
We identified 56 patients clinically diagnosed with INAD and 23 with idiopathic NBIA and screened their DNA for PLA2G6 mutations.
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.
Defects in phospholipase A(2) lead to a range of phenotypes. PLA2G6 mutations are associated with nearly all cases of classic infantile neuroaxonal dystrophy but a minority of cases of idiopathic neurodegeneration with brain iron accumulation, and genotype correlates with phenotype. Cerebellar atrophy predicts which patients are likely to be mutation-positive. The neuropathologic changes that are caused by defective phospholipase A(2) suggest a shared pathogenesis with both Parkinson and Alzheimer diseases.

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Available from: Cristina Dias
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    • "'Neurodegeneration with Brain Iron Accumulation' (NBIA) encompasses a group of disorders characterised by progressive motor symptoms , neurological regression and radiologically discernible brain iron accumulation [1] [2] [3] [4]. The major childhood NBIA syndromes include pantothenate kinase associated neurodegeneration (PKAN; MIM#234200) [5], fatty acid hydroxylase associated neurodegeneration (FAHN; MIM#612319) [6], mitochondrial membrane protein associated neurodegeneration (MPAN; MIM#614298) [7], beta-propeller protein associated neurodegeneration (BPAN; MIM#300894) [8], and phospholipase A 2 associated neurodegeneration (PLAN; MIM#256600). "
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    ABSTRACT: Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of the classical PLAN features as well as ‘apparent claval hypertrophy’ is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.
    Full-text · Article · Jun 2014 · Molecular Genetics and Metabolism
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    • "The hallmark of this disease is the eyeof-the-tiger signal in the globus pallidus on T 2 -weighted MRI (Hayflick et al., 2003; Gregory et al., 2009) To date, the mechanistic connection linking PANK2 dysfunction, neurodegeneration and alteration of iron homeostasis has not been understood, thus preventing our comprehension of the pathogenesis of the disease and the design of efficient therapeutic strategies. It has been proposed that reduced PANK2 enzymatic activity determines the accumulation of cysteine, which may chelate iron thus promoting the formation of free radicals (Gregory et al., 2008); alternatively, defects in co-enzyme A and, as a consequence, in phospholipid metabolism may damage the membranes and lead to increased oxidative stress, which may alter iron homeostasis (Leonardi et al., 2007). "
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    ABSTRACT: Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration.
    Full-text · Article · Dec 2013 · Brain
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    • "Neurodegeneration with brain iron accumulation (NBIA) describes a group of progressive neurodegenerative disorders that are pathologically characterized by the presence of axonal spheroids and iron deposition in the brain [1-3]. These neurodegenerative diseases consist of a clinically and genetically heterogeneous group of disorders, including pantothenate kinase-associated neurodegeneration (PKAN, formerly known as Hallervorden-Spatz disease), infantile neuroaxonal dystrophy (INAD), and an unknown gene mutation-linked idiopathic neuroaxonal dystrophy [1,2,4]. "
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    ABSTRACT: Background Infantile neuroaxonal dystrophy (INAD) is a rare autosomal-recessive neurodegenerative disorder. Patients with INAD usually show neurological symptoms with infant onset and die in childhood. Recently, it was reported that mutations in the PLA2G6 gene cause INAD, but neuropathological analysis of genetically confirmed individuals with neuroaxonal dystrophy has been limited. Results Here, we report a Japanese individual with neuroaxonal dystrophy associated with compound heterozygous mutations in the PLA2G6 gene. A novel splice-site mutation resulting in skipping and missense mutations (p.R538C) in exon 9 was identified in the patient. This patient initially presented with cerebellar ataxia at the age of 3 years, which was followed by symptoms of mental retardation, extrapyramidal signs, and epileptic seizure. The patient survived until 20 years of age. Neuropathological findings were characterized by numerous axonal spheroids, brain iron deposition, cerebellar neuronal loss, phosphorylated alpha-synuclein-positive Lewy bodies (LBs), and phosphorylated-tau-positive neurofibrillary tangles. In particular, LB pathology exhibited a unique distribution with extremely severe cortical involvement. Conclusions Our results support a genetic clinical view that compound heterozygous mutations with potential residual protein function are associated with a relatively mild phenotype. Moreover, the severe LB pathology suggests that dysfunction of the PLA2G6 gene primarily contributes to LB formation.
    Full-text · Article · May 2013
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