PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism

Giri, Anamika; Güven, Gamze; Hanağası, Haşmet; Hauser, Ann‐Kathrin; Erginul-Unaltuna, Nihan; Bılgıç, Başar; Gürvıt, Hakan; Heutink, Peter; Gasser, Thomas; Lohmann, Ebba; Simón‐Sánchez, Javier

doi:10.7916/d81g0m12

Cited by 10 publications

(1 citation statement)

References 16 publications

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“…Instead, frontal and generalized white matter atrophy may be observed. 13 , 14 Moreover, a recent comprehensive article revealed that in some cases, mild to moderated cerebral and cerebellar atrophy was observed with a degree of variability in several newly identified cases. 15 Limb tremor and gait disturbance have favorable responses to dopaminergic agents.…”

Section: Introductionmentioning

confidence: 99%

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

Bakhit

Tesson

Ibrahim

et al. 2023

Ann Clin Transl Neurol

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Introduction The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult‐onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia‐parkinsonism (DP), and autosomal recessive early‐onset parkinsonism (AREP). Few studies in Africa reported PLA2G6‐associated disorders and none with parkinsonism of late adult onset. Material and Methods The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS‐UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom‐made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR‐amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation. Result Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in‐frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic. Conclusion This is the first case in which PLA2G6 is associated with late‐onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β.

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Section: Introductionmentioning

confidence: 99%

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

Bakhit

Tesson

Ibrahim

et al. 2023

Ann Clin Transl Neurol

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PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia

et al. 2017

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PLA2G6-associated neurodegeneration (PLAN) and hereditary spastic paraplegia (HSP) are two groups of heterogeneous neurodegenerative diseases. In this study, we report PLA2G6 gene mutations in three families from Turkey, Morocco, and Romania. Two affected Turkish siblings presenting HSP adds the disease to PLAN phenotypes. They were homozygous for the PLA2G6 missense c.2239C>T, p.Arg747Trp variant and the ages of onset were 9 and 21. Parkinsonism, dystonia or cognitive decline were not the clinical elements in these patients contrary to the cases that has been previously reported with the same variant, however, iron accumulation was evident in their cranial MRI. The Moroccan patient was homozygous for a novel missense c.1786C>T, p.Leu596Phe variant and the Romanian patient had two novel mutations; c.1898C>T, p.Ala633Val and c.1765_1768del, p.Ser589ThrfsTer76. Both of these patients conformed better to childhood onset PLAN with the age of onset at four and seven years, respectively. Interestingly, all identified mutations were affecting the highly conserved patatin-like phospholipase domain of the PLA2G6 protein.

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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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PLA2G6 Mutations Related to Distinct Phenotypes: A New Case with Early-onset Parkinsonism

Cited by 10 publications

References 16 publications

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

PLA2G6‐associated late‐onset parkinsonism in a Sudanese family

PLA2G6 mutations associated with a continuous clinical spectrum from neuroaxonal dystrophy to hereditary spastic paraplegia

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

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