PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression

Darling, Alejandra; Aguilera-Albesa, Sergio; Tello, Cristina; Serrano, Mercedes; Tomas, Miguel Santaularia; Camino-León, R; Fernández-Ramos, J.A.; Jiménez‐Escrig, Adriano; Póo, Pilar; O’Callaghan, Mar; Ortez, C.; Nascimento, A.; Mesaque, R. Candau Fernández; Madruga, Marcos; Arrabal, Luisa; Roldán, Susana; Gómez-Martín, Hilario; Garrido, Carmen; Temudo, Teresa; Jou‐Muñoz, Cristina; Muchart, Jordi; Huisman, Thierry A.G.M.; Poretti, Andrea; Lupo, Vincenzo; Espinós, Carmen; Pérez‐Dueñas, Belén

doi:10.1016/j.parkreldis.2018.10.013

Cited by 28 publications

(30 citation statements)

References 22 publications

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“…Including our three patients, we analyzed data for 35 patients. The clinical characteristics and genetic findings are summarized in Table 1 [1][2][3]. The mean age of onset was 26.3 ± 8.6 years.…”

Section: Systematic Review Of Previous Reports Of Patients With Planmentioning

confidence: 99%

“…PLA2G6-associated neurodegeneration (PLAN) is a heterogeneous group of neurodegenerative disorders that result from mutations in the phospholipase A2 group VI gene (PLA2G6) [1,2]. The PLA2G6 gene encodes a group of VIA calcium-independent phospholipase A2 proteins.…”

Section: Introductionmentioning

confidence: 99%

“…The PLA2G6 gene encodes a group of VIA calcium-independent phospholipase A2 proteins. Phospholipase A2 is an enzyme involved in phospholipid metabolism, and it is essential for maintaining cell membrane integrity [1,2]. PLAN can be classified into four subtypes, based on onset age, including: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism, and autosomal recessive early-onset parkinsonism (known as PARK14) [3].…”

Section: Introductionmentioning

confidence: 99%

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Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

et al. 2020

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Background: Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations. Case presentations: The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities. Conclusions: We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

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Section: Systematic Review Of Previous Reports Of Patients With Planmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

et al. 2020

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“…It has been seen in up to 95% of patients with PLA2G6 mutations (55). In infantile neuroaxonal dystrophy (NAD) and childhood-onset PLAN (juvenile NAD), cerebellar atrophy is a near universal feature (56,57). Patients with an earlier disease onset showed a more severe cerebellar atrophy, which was assessed using the ratio of the mid-sagittal vermis size over the total posterior cranial fossa size (57).…”

Section: Disproportionate Cerebellar Atrophy In Planmentioning

confidence: 99%

“…In infantile neuroaxonal dystrophy (NAD) and childhood-onset PLAN (juvenile NAD), cerebellar atrophy is a near universal feature (56,57). Patients with an earlier disease onset showed a more severe cerebellar atrophy, which was assessed using the ratio of the mid-sagittal vermis size over the total posterior cranial fossa size (57). T2 or FLAIR hyperintensity in the cerebellar cortex often accompanies cerebellar atrophy (54,58).…”

Section: Disproportionate Cerebellar Atrophy In Planmentioning

confidence: 99%

Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation

et al. 2020

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Most neurodegeneration with brain iron accumulation (NBIA) disorders can be distinguished by identifying characteristic changes on magnetic resonance imaging (MRI) in combination with clinical findings. However, a significant number of patients with an NBIA disorder confirmed by genetic testing have MRI features that are atypical for their specific disease. The appearance of specific MRI patterns depends on the stage of the disease and the patient's age at evaluation. MRI interpretation can be challenging because of heterogeneously acquired MRI datasets, individual interpreter bias, and lack of quantitative data. Therefore, optimal acquisition and interpretation of MRI data are needed to better define MRI phenotypes in NBIA disorders. The stepwise approach outlined here may help to identify NBIA disorders and delineate the natural course of MRI-identified changes.

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Dissecting the Phenotype and Genotype of PLA2G6‐Related Parkinsonism

et al. 2021

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A BS TRACT: Background: Complex parkinsonism is the commonest phenotype in late-onset PLA2G6associated neurodegeneration. Objectives: The aim of this study was to deeply characterize phenogenotypically PLA2G6-related parkinsonism in the largest cohort ever reported. Methods: We report 14 new cases of PLA2G6-related parkinsonism and perform a systematic literature review. Results: PLA2G6-related parkinsonism shows a fairly distinct phenotype based on 86 cases from 68 pedigrees. Young onset (median age, 23.0 years) with parkinsonism/ dystonia, gait/balance, and/or psychiatric/cognitive symptoms were common presenting features. Dystonia occurred in 69.4%, pyramidal signs in 77.2%, myoclonus in 65.2%, and cerebellar signs in 44.6% of cases. Early bladder overactivity was present in 71.9% of cases. Cognitive impairment affected 76.1% of cases and psychiatric features 87.1%, the latter being an isolated presenting feature in 20.1%. Parkinsonism was levodopa responsive but complicated by early, often severe dyskinesias. Five patients benefited from deep brain stimulation. Brain magnetic resonance imaging findings included cerebral (49.3%) and/or cerebellar (43.2%) atrophy, but mineralization was evident in only 28.1%. Presynaptic dopaminergic terminal imaging was abnormal in all where performed. Fifty-four PLA2G6 mutations have hitherto been associated with parkinsonism, including four new variants reported in this article. These are mainly nontruncating,

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PLA2G6-associated neurodegeneration: New insights into brain abnormalities and disease progression

Cited by 28 publications

References 22 publications

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

Genotype-phenotype correlations of adult-onset PLA2G6-associated Neurodegeneration: case series and literature review

Brain MRI Pattern Recognition in Neurodegeneration With Brain Iron Accumulation

Dissecting the Phenotype and Genotype of PLA2G6‐Related Parkinsonism

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