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

ABSTRACT: 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.

SUBMITTER: Chu YT

PROVIDER: S-EPMC7076921 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Chu Yung-Tsai YT Lin Han-Yi HY Chen Pei-Lung PL Lin Chin-Hsien CH

BMC neurology 20200317 1

<h4>Background</h4>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.<h4>Case presentations</h4>The first index patient presented with dystonia-park ...[more]

PMID: 32183746

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Project description:BackgroundPhospholipase-associated neurodegeneration (PLAN) caused by mutations in the PLA2G6 gene is a rare neurodegenerative disorder that presents with four sub-groups. Infantile neuroaxonal dystrophy (INAD) and PLA2G6-related dystonia-parkinsonism are the main two subtypes. In this cohort, we reviewed clinical, imaging, and genetic features of 25 adult and pediatric patients harboring variants in the PLA2G6.MethodsAn extensive review of the patients' data was carried out. Infantile Neuroaxonal Dystrophy Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was used to determine the disease's underlying etiology followed by co-segregation analysis using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was used to assess the pathogenicity of genetic variants. We aimed to survey a genotype-genotype correlation in PLA2G6 considering all reported disease-causing variants in addition to our patients using the HGMD database and the chi-square statistical approach.ResultsEighteen cases of INAD and 7 cases of late-onset PLAN were enrolled. Among 18 patients with INAD, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, the mean rate of progression was 0.58 points per month of symptoms (Standard error 0.22, lower 95% - 1.10, and upper 95% - 0.15). Sixty percent of the maximum potential loss in the INAD-RS had occurred within 60 months of symptom onset in INAD patients. Among seven adult cases of PLAN, hypokinesia, tremor, ataxic gate, and cognitive impairment were the most frequent clinical features. Various brain imaging abnormalities were also observed in 26 imaging series of these patients with cerebellar atrophy being the most common finding in more than 50%. Twenty unique variants in 25 patients with PLAN were detected including nine novel variants. Altogether, 107 distinct disease-causing variants from 87 patient were analyzed to establish a genotype-phenotype correlation. The P value of the chi-square test did not indicate a significant relationship between age of disease onset and the distribution of reported variants on PLA2G6.ConclusionPLAN presents with a wide spectrum of clinical symptoms from infancy to adulthood. PLAN should be considered in adult patients with parkinsonism or cognition decline. Based on the current knowledge, it is not possible to foresee the age of disease onset based on the identified genotype.

Project description:BackgroundGenotype-phenotype correlations of the CACNA1A-related neurodevelopmental disorders such as global developmental delay (GDD)/intellectual disability (ID), epileptic encephalopathy (EE), and autism spectrum disorder (ASD) are unknown. We aimed to summarize genotype-phenotype correlations and potential treatment for CACNA1A-related neurodevelopmental disorders.MethodsSix children diagnosed with CACNA1A-related neurodevelopmental disorders at Xiangya Hospital, Central South University from April 2018 to July 2021 were enrolled. The PubMed database was systematically searched for all reported patients with CACNA1A-related neurodevelopmental disorders until February 2023. Thereafter, we divided patients into several groups for comparison.ResultsSix patients were recruited from our hospital. Three cases presented with epilepsy, five with GDD/ID, five with ataxia, and two with ASD. The variants included p.G701R, p.R279C, p.D1644N, p.Y62C, p.L1422Sfs*8, and p. R1664Q [two gain-of-function (GOF) and four loss-of-function (LOF) variants]. About 187 individuals with GDD/ID harboring 123 variants were found (case series plus data from literature). Of those 123 variants, p.A713T and p.R1664* were recurrent, 37 were LOF, and 7 were GOF. GOF variants were linked with severe-profound GDD/ID while LOF variants were associated with mild-moderate GDD/ID (p = 0.001). The p.A713T variant correlated with severe-profound GDD/ID (p = 0.003). A total of 130 epileptic patients harboring 83 variants were identified. The epileptic manifestations included status epilepticus (n = 64), provoked seizures (n = 49), focal seizures (n = 37), EE (n = 29), absence seizures (n = 26), and myoclonic seizures (n = 10). About 49 (42.20%) patients had controlled seizures while 67 (57.80%) individuals remained with refractory seizures. Status epilepticus correlated with variants located on S4, S5, and S6 (p = 0.000). Among the 83 epilepsy-related variants, 23 were recurrent, 32 were LOF, and 11 were GOF. Status epilepticus was linked with GOF variants (p = 0.000). LOF variants were associated with absence seizures (p = 0.000). Six patients died at an early age (3 months to ≤5 years). We found 18 children with ASD. Thirteen variants including recurrent ones were identified in those 18 cases. GOF changes were more linked to ASD.ConclusionThe p.A713T variant is linked with severe-profound GDD/ID. More than half of CACNA1A-related epilepsy is refractory. The most common epileptic manifestation is status epilepticus, which correlates with variants located on S4, S5, and S6.

Project description:BackgroundBiallelic pathogenic variants in the SCARB2 gene have been associated with action myoclonus-renal failure (AMRF) syndrome. Even though SCARB2 associated phenotype has been reported to include typical neurological characteristics, depending on the localization and the feature of the pathogenic variants, clinical course and the presentations have been shown to differ.Case presentationWhole exome sequencing (WES) analysis revealed a homozygous truncating variant (p.N45MfsX88) in SCARB2 gene in the index case, and subsequent sanger sequencing analysis validated the variant in all affected family members from a Turkish family with the clinical characteristics associated with AMRF and related disorders. Intrafamilial clinical heterogeneity with common features including dysarthria, tremor and proteinuria, and distinct features such as peripheral neuropathy (PNP), myoclonus and seizures between the affected cases, was observed in the family. In-depth literature review enabled the detailed investigation of the reported variants associated with AMRF and suggested that while the type of the variant did not have a major impact on the course of the clinical characteristics, only the C terminal localization of the pathogenic variant significantly affected the clinical presentation, particularly the age at onset (AO) of the disease.ConclusionsIn this study we showed that biallelic SCARB2 pathogenic variants might cause a spectrum of common and distinct features associated with AMRF. Of those features while the common features include myoclonus (100%), ataxia (96%), tonic clonic seizures (82%), dysarthria (68%), tremor (65%), and renal impairment (62%), the uncommon features involve PNP (17%), hearing loss (6.8%), and cognitive impairment (13.7%). AO has been found to be significantly higher in the carriers of the p.G462DfsX34 pathogenic variant. SCARB2 pathogenic variants have not been only implicated in AMRF but also in the pathogenesis of Parkinson's disease (PD) and Gaucher disease (GD), suggesting the importance of genetic and functional studies in the clinical and the diagnostic settings. Given the proven role of SCARB2 gene in the pathogenesis of AMRF, PD and GD with a wide spectrum of clinical symptoms, investigation of the possible modifiers, such as progranulin and HSP7, has a great importance.

Dataset Information

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

Publications

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

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