Novel mutations in siblings with later-onset <i>PLA2G6</i>
-associated neurodegeneration (PLAN)

Bower, Matthew; Bushara, Khalaf; Dempsey, Melissa A; Das, Soma; Tuite, Paul J.

doi:10.1002/mds.23617

Cited by 29 publications

(41 citation statements)

References 4 publications

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“…This kindred exhibits the wide spectrum of manifestations and course of NBIA2 and the difficulties of considering NBIA at early stages, causing delayed diagnosis. Clinical and age at onset discrepancies between siblings has been reported in NBIA2 . This report confirms this fact, which is very important for prognosis and raises issues of other factors influencing onset and severity.…”

Section: Discussionsupporting

confidence: 86%

PLA2G6 ‐Associated Neurodegeneration: Report of a Novel Mutation in Two Siblings with Strikingly Different Clinical Presentation

Pérez-Torre

Villalba

Ulloa

et al. 2016

Movement Disord Clin Pract

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Neurodegeneration with brain iron accumulation (NBIA) comprises a group of hereditary heterogeneous disorders (most of them autosomal recessive) characterized by the presence of an extrapyramidal progressive dysfunction and excess iron accumulation in different locations in the brain. Overall, it remains unclear whether increased brain iron content, documented in many neurodegenerative diseases, is a direct cause of neurodegeneration, a secondary event in a pathophysiologic cascade, or just a nonspecific marker of neurodegeneration. NBIA disorders present a wide spectrum of clinical manifestations such as progressive hypo-and/ or hyperkinetic movement disorders, and a variable degree of pyramidal, cerebellar, peripheral nerve, autonomic, cognitive, and psychiatric involvement, and visual dysfunction. The responsible mutated gene defines each syndrome.1 The second most common types of NBIA after pantothenate kinase-associated neurodegeneration (PKAN), are PLA2G6-related disorders. PLA2G6 encodes iPLA2-VI, a calcium-independent phospholipase. Traditionally mutations on this gene were thought to cause progressive neurodegeneration with miscellaneous manifestations in three phenotypes: classic infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and late-onset dystonia/parkinsonism starting in adolescence or early adulthood. 2 Reports suggest that PLA2G6 mutations cause a phenotypic continuum rather than three discrete phenotypes, further ensuing clinical implications. 3 We report two siblings with NBIA2 with a striking disparity in presentation: one as INAD and the second as atypical neuroaxonal dystrophy. Case ReportThe kindred included two siblings from nonconsanguineous parents. Family history was unremarkable except for the presence of Parkinson's disease (PD) in their grandmother.Case III-1Our index case, a 20-year-old woman had normal development up to the age of 9 when she begun to experience subtle difficulties in school, social withdrawal, and progressive clumsiness. A few years later she began neurological evaluations that included several MRIs, but up to age 16, brain iron accumulation was not sufficiently detected by MRI to raise the suspicion of PLA2G6 mutation. She had a tonic-clonic seizure at the age of 19. At age 20, she had normal height and weight, marked ataxia, intention tremor, and slurring speech (Video S1). Examination showed generalized hyperreflexia, gait disturbance, slight dystonic signs such as mild torticollis, and cognitive impairment. EEG was normal and since she was 16, several MRIs showed hypointensity in the substantia nigra and globus pallidus (Fig. 1). There was also a marked cerebellar atrophy in MRI. Case III-2Patient III-1 had a 32-year-old sister. She had been born after a normal pregnancy with Apgar 10. In her first months she had weak cry and frequently adopted opisthotonus posture so she was evaluated throughout her first year with normal EEG, cranial CT, and CSF. A diagnosis of cerebral palsy had been made shortly after birth. She was ab...

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Section: Discussionsupporting

confidence: 86%

PLA2G6 ‐Associated Neurodegeneration: Report of a Novel Mutation in Two Siblings with Strikingly Different Clinical Presentation

Pérez-Torre

Villalba

Ulloa

et al. 2016

Movement Disord Clin Pract

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“…PARK 14 is characterized by rapidly progressive young-adult onset Parkinsonism associated with dystonia, cognitive decline and cerebral atrophy on MRI [9]. Onset may vary between 4 and 30 years, and abnormal brain iron may not be evident on MRI studies until late in the disease course [10-12]. …”

Section: Introductionmentioning

confidence: 99%

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

et al. 2013

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Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients’ muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

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“…PLA2G6 mutations were detected by gene sequencing in 80–90% of children with INAD . To date, almost 80 different mutations have been reported in PLAN , including point mutations and small insertions/deletions. In our study, PLA2G6 mutations were identified by DNA sequencing in 92.3% of clinically diagnosed INAD cases and in the late‐onset case.…”

Section: Discussionmentioning

confidence: 99%

Follow‐up study of 25 Chinese children with PLA2G6‐associated neurodegeneration

Zhang

Gao

Jiang

et al. 2012

Euro J of Neurology

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Novel mutations in siblings with later-onset PLA2G6 -associated neurodegeneration (PLAN)

Cited by 29 publications

References 4 publications

PLA2G6 ‐Associated Neurodegeneration: Report of a Novel Mutation in Two Siblings with Strikingly Different Clinical Presentation

PLA2G6 ‐Associated Neurodegeneration: Report of a Novel Mutation in Two Siblings with Strikingly Different Clinical Presentation

New Findings in a Global Approach to Dissect the Whole Phenotype of PLA2G6 Gene Mutations

Follow‐up study of 25 Chinese children with PLA2G6‐associated neurodegeneration

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