PLA2G6 Research Articles

An estimation of global genetic prevalence of PLA2G6-associated neurodegeneration

BackgroundPLA2G6-associated neurodegeneration (PLAN) comprises three diseases with overlapping features: infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (atypical NAD), and PLA2G6-related dystonia-parkinsonism. INAD is an early onset disease characterized by progressive loss of vision, muscular control, and mental skills. The prevalence of PLA2G6-associated diseases has not been previously calculated.MethodsTo provide the most accurate prevalence estimate, we utilized two independent approaches: database-based approach which included collecting variants from ClinVar, Human Gene Mutation Database (HGMD) and high confidence predicted loss-of-function (pLoF) from gnomAD (Rare Genomes Project Genetic Prevalence Estimator; GeniE), and literature-based approach which gathered variants through Mastermind Genomic Search Engine (Genomenon, Inc). Genetic prevalence of PLAN was calculated based on allele frequencies from gnomAD, assuming Hardy–Weinberg equilibrium.ResultsIn the PLA2G6 gene, our analysis found 122 pathogenic, 82 VUS, and 15 variants with conflicting interpretations (pathogenic vs VUS) between two approaches. Allele frequency was available for 58 pathogenic, 42 VUS, and 15 conflicting variants in gnomAD database. If pathogenic and/or conflicting variants are included, the overall genetic prevalence was estimated to be between 1 in 987,267 to 1 in 1,570,079 pregnancies, with the highest genetic prevalence in African/African-American (1 in 421,960 to 1 in 365,197) and East-Asian (1 in 683,978 to 1 in 190,771) populations.ConclusionOur estimates highlight the significant underdiagnosis of PLA2G6-associated neurodegeneration and underscores the need for increased awareness and diagnostic efforts. Furthermore, our study revealed a higher carrier frequency of PLA2G6 variants in African and Asian populations, stressing the importance of expanded genetic sequencing in non-European populations to ensure accurate and comprehensive diagnosis. Future research should focus on confirming our findings and implementing expanded sequencing strategies to facilitate maximal and accurate diagnosis, particularly in non-European populations.

Analysis of the causes of neonatal death and genetic variations in congenital anomalies: a multi-center study.

Neonatal deaths often result from preventable conditions that can be addressed with appropriate interventions. This study aims to analyze the distribution of the causes of neonatal death and explore genetic variations that lead to congenital anomalies in Northwest China. This multi-center observational study was conducted across six medical centers in Shaanxi province, Northwest China. Clinical data were retrospectively collected from neonates admitted between 2016 and 2020. Kaplan-Meier analysis was utilized to estimate survival rates, while high-throughput sequencing platforms were employed to detect mutations causing congenital anomalies. Among 73,967 neonates requiring hospital care, 424 neonatal deaths were recorded, leading to a neonatal mortality rate of 0.57%. The primary causes of death included neonatal respiratory distress syndrome (23.8%), birth asphyxia (19.8%), neonatal septicemia (19.3%), and congenital anomalies (13.6%). The leading causes of neonatal deaths due to congenital anomalies were congenital heart defects (38.6%), bronchopulmonary dysplasia (14.0%), and inherited metabolic disorders (10.5%). Genetic analysis identified 83 pathogenic or likely pathogenic variants in 23 genes among the neonates with congenital anomalies, including four novel mutations (c.4198+1G>T, c.1075delG, c.610-1G>A, c.7769C>T) in the ABCC8, CDKL5, PLA2G6, and NIPBL genes. Congenital anomalies represent a significant and preventable cause of neonatal deaths in Northwest China. Early detection of congenital anomalies through genetic testing and comprehensive prenatal care are crucial for reducing neonatal mortality rates and improving pregnancy outcomes.

Generation of induced pluripotent stem cell line LNDWCHi001-A from a patient with early-onset Parkinson’s disease carrying the homozygous c.1898C > T (p. A633V) mutation in the PLA2G6 gene

A variant of the phospholipase A2 group VI gene (PLA2G6, PARK14) has been found to cause early-onset Parkinson’s disease (EOPD). In this study, we reprogrammed peripheral blood mononuclear cells from a 39-year-old patient with EOPD carrying a homozygous PLA2G6 mutation c.1898C > T (p. A633V) to generate the human induced pluripotent stem cell line LNDWCHi001-A. This cell line was identified based on pluripotent markers and displayed differentiation capacity, providing an essential model for studying the pathogenesis of EOPD and drug screening.

The Clinical, Radiological and Genetic Spectrum of PLA2G6-Associated Neurodegeneration: An Experience From a Tertiary Center.

Despite being the second most common type of neurodegeneration with brain iron accumulation, there is limited literature on PLA2G6-associated neurodegeneration (PLAN) within the Asian ethnicity, particularly in the Indian context. We conducted a retrospective observational study on patients with pathogenic/likely pathogenic PLA2G6 variants based on exome sequencing. We identified 26 patients (22 families, 15 males) of genetically-confirmed PLAN with a median age of 22.5 years and age at onset of 13.0 years, encompassing various subtypes: infantile neuroaxonal dystrophy (5/26;19.2%), atypical neuroaxonal dystrophy (3/26;11.5%), dystonia-parkinsonism (5/26;19.2%), dystonia-parkinsonism-myoclonus (n = 4, 15.38%), early-onset Parkinson's disease (2/26;7.7%), complex dystonia (2/26;7.7%), and complicated hereditary spastic paraparesis (cHSP; 5/26;19.2%). The common initial symptoms included walking difficulty (7/26;26.9%), developmental regression (6/26;23.1%), and slowness (4/26;15.4%). Dystonia (14/26;53.8%), followed by parkinsonism (11/26; 42.3%), was the most common motor symptom. Non-motor symptoms included cognitive decline (12/26;46.2%) and behavioral changes (6/26;23.1%). Neuroimaging revealed cerebellar atrophy in 23/26 (88.5%) patients and claval hypertrophy in 80% (4/5) of INAD patients. Levodopa responsiveness was noted in 12 of 14 patients with parkinsonism/dystonia who received levodopa, and dyskinesia was noted in 10/11 patients. Genetic analysis revealed a total of 19 unique variants in PLA2G6 gene, of which 11 were novel. Twelve patients harbored the c.2222G>A variant, which is predominantly seen in Asian subpopulations. The study introduces 26 new patients of PLAN and 12 patients associated with the c.2222G>A variant, potentially forming the most extensive single center series to date. It also expands the phenotypic, neuroimaging, and genotypic spectrum of PLAN.

Dementia associated with early‐onset Parkinson’s disease: Description of a family case in Colombia

AbstractBackgroundParkinson’s Disease (PD) is a motor neurodegenerative disorder of the dopaminergic neurons in the substantia nigra1. One of the frequent complications is dementia and often is a late symptom1,2. Some studies suggest that around 10% of patients with PD develop dementia per year2,3. Mutations in PLA2G6 are responsible of PARK14, an autosomal recessive L‐DOPA responsive dystonia/parkinsonism with early/adult onset4. This phenotype presents a high clinical variability, which consists in the occurrence of cerebral and cerebellar atrophy, iron accumulation in the basal ganglia, and cognitive decline4. In this study, we describe the genotype of two brothers diagnosed with early onset PD and a phenotype with FTD‐like characteristics.MethodA complete clinical evaluation consisting of geriatric, psychyatric, neurologic and neurpsychologic evaluation, was carried out in two affected male individuals, and their family. NGS was performed (PD targeted panel, WES, WGS) and MLPA on the two affected individuals.ResultThe two affected individuals were diagnosed around their thirties, presenting classic motor symptoms of PD. Subsequently, dementia associated to frontotemporal disease was diagnosed. No iron accumulation in the basal ganglia was found in either of the affected siblings. Genetic tests showed the pathogenic variant in heterozygous state c.2132C>G, p.Pro711Arg in PLA2G6 gene in the two affected brothers and their healthy mother.ConclusionAtypical frontotemporal dementia in two siblings with early‐onset PD is described. Additional studies should be performed to identify another variant or another gene in this family. Some studies have risen the hypothesis that even heterozygous PLA2G6 mutations may cause PARK144.

INFANTIL NEUROAXONAL DYSTROPHY: A CASE REPORT

Infantile neuroaxonal dystrophy is a rare, hereditary neurodegenerative disease that begins before the end of the second year of life, after an interval of normal psychomotor development caused by Biallelic mutations in the PLA2G6 gene in the most of cases. It is characterized by progressive motor and cognitive deterioration leading to a bedridden state and death before the end of the first decade. We report the case of a two and a half year patient who showed psychomotor regression with ophthalmological damage, truck hypotonia and impaired visual contact as the main neurological signs. Infantile neuroaxonal dystrophy is a rare and serious disease in children with a risk of generally fatal complications, but it remains a preventable disease thanks to genetic counselling.

Identification and bioinformatics analysis of a novel mutation in PLA2G6 gene in a patient with neurodegenerative disorder

PLA2G6-associated neurodegeneration disorders are a group of conditions that result from mutations in the PLA2G6 gene. These disorders can cause a range of symptoms affecting the brain and nervous system, such as movement problems, cognitive decline, and vision loss. In this case, Whole Exome Sequencing (WES) was conducted on a 9-year-old boy born to consanguineous parents, who have an increased risk of passing on recessive genetic disorders. Although the boy did not exhibit any clinical symptoms until he was seven months old, his condition deteriorated severely by the age of two, rendering him unable to sit or move around, and he did not develop the ability to speak. DNAs were extracted from the blood samples of the proband (the 9-year-old boy) and his parents. The proband's DNA was sequenced using WES to identify potential disease-causing mutations. To confirm the WES findings, PCR-Sanger sequencing analysis was performed on the DNAs obtained from the proband (the 9-year-old boy) and his parents. The effect of the mutation on the protein structure was studied using the I-TASSER web-tool, which uses computational methods to predict protein structure and function based on amino acid sequences.The analysis of WES data revealed a homozygous dinucleotide TG insertion at position c.1362–1363 in exon 10 of the PLA2G6 gene (NC_000022.11(NM_003560.4):c.1362_1363insTG). This insertion introduced a premature stop codon at position 455 (p.Met455Ter) in the protein sequence. The validation of the WES results using PCR-Sanger sequencing confirmed the presence of the mutation in the proband and revealed that both parents were carriers of the mutation. The premature stop codon, located 65 nucleotides before the exon-junction complex, is likely to be detected by the nonsense-mediated mRNA decay (NMD) pathway, leading to the degradation of the mRNA. The use of the I-TASSER web-tool further supported the findings by demonstrating significant structural and functional changes in the mutant protein. Observing a very severe phenotype in our case supports the idea that the mutation was highly deleterious.

The role of the PLA2G6 gene in neurodegenerative diseases.

PLA2G6-associated neurodegeneration (PLAN) represents a continuum of clinically and genetically heterogeneous neurodegenerative disorders with overlapping features. Usually, it encompasses three autosomal recessive diseases, including infantile neuroaxonal dystrophy or neurodegeneration with brain iron accumulation (NBIA) 2A, atypical neuronal dystrophy with childhood-onset or NBIA2B, and adult-onset dystonia-parkinsonism form named PARK14, and possibly a certain subtype of hereditary spastic paraplegia. PLAN is caused by variants in the phospholipase A2 group VI gene (PLA2G6), which encodes an enzyme involved in membrane homeostasis, signal transduction, mitochondrial dysfunction, and α-synuclein aggregation. In this review, we discuss PLA2G6 gene structure and protein, functional findings, genetic deficiency models, various PLAN disease phenotypes, and study strategies in the future. Our primary aim is to provide an overview of genotype-phenotype correlations of PLAN subtypes and speculate on the role of PLA2G6 in potential mechanisms underlying these conditions.

Diagnosis, treatment and genetic analysis of a child with infantile neuroaxonal dystrophy.

Infantile neuroaxonal dystrophy (INAD) is a rare autosomal recessive neurodegenerative disease characterized by early hypotonia, and rapid progression to psychomotor development regression, pyramidal tract positivity, and spastic quadriplegia. In this report, we describe a Chinese patient with INAD who presented with hypotonia, delayed motor and language development, and subsequently improved with rehabilitation training. Genetic testing revealed that the patient had compound heterozygous PLA2G6 gene variants, with the heterozygous c.496dupG (p.Glu166fsTer32) variant inherited from her father and the heterozygous c.2189T>G (p.Met730Arg) variant inherited from her mother. The p.Met730Arg was a novel variant. The protein structure predicts that the structural stability of the mutant protein may change, and the in vivo experimental results show that the expression of the mutant protein decrease. This study enriches the PLA2G6 gene mutation spectrum, and improves the clinicians' diagnostic awareness of INAD.

Phenotype and genotype heterogeneity of PLA2G6-associated neurodegeneration in a cohort of pediatric and adult patients

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.

Human induced pluripotent stem cell line (ONHi001-A) generated from a patient with infantile neuroaxonal dystrophy having PLA2G6 c.517C > T (p.Q173X) and c.1634A > G (p.K545R) compound heterozygous mutations

Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disease caused mainly by homozygous or compound heterozygous mutations in the PLA2G6 gene. We generated a human induced pluripotent stem cell (hiPSC) line (ONHi001-A) using fibroblasts derived from a patient with INAD. The patient exhibited c.517C > T (p.Q173X) and c.1634A > G (p.K545R) compound heterozygous mutations in the PLA2G6 gene. This hiPSC line may be useful for studying the pathogenic mechanism underlying INAD.

Phenotype and Genotype Heterogeneity of PLA2G6-associated Neurodegeneration (S2.009)

<h3>Objective:</h3> We reviewed the clinical, imaging, and genetic features of 25 adult and pediatric patients with Phospholipase-associated neurodegeneration (PLAN), and validated a genotype-phenotype correlation in this disorder. <h3>Background:</h3> PLAN is a rare neurodegenerative disorder caused by mutations in <i>PLA2G6</i> and can present four phenotypes including infantile neuroaxonal dystrophy (INAD), atypical NAD, PLA2G6-related dystonia-parkinsonism, and autosomal recessive early-onset parkinsonism (AREP). <h3>Design/Methods:</h3> An extensive chart review of enrolled patients was carried out. INAD Rating Scale (INAD-RS) was used for evaluating the severity and progression of INAD patients. Whole-exome sequencing was performed to determine the disease’s underlying etiology, and co-segregation analysis was examined using Sanger sequencing. In silico prediction analysis based on the ACMG recommendation was utilized to assess the pathogenicity of detected variants. The HGMD professional database and the chi-square statistical approach were utilized considering all reported disease-causing variants in 17 exons of the PLA2G6 gene in addition to our patient. <h3>Results:</h3> 18 cases of INAD and 7 cases of adult-onset NAD with a mean age of disease onset of 22.4 months and 25 years old, respectively, were enrolled. Among 18 INAD patients, gross motor regression was the most common presenting symptom. Considering the INAD-RS total score, 60% percent of the maximum potential loss occurred within 60 months of symptom onset. Among seven adult cases, movement disorders i.e., hypokinesia, tremor, ataxic gait, and cognitive impairment were the most frequent clinical features. Cerebellar atrophy was the most common imaging finding.. We found twenty unique variants in 25 patients including nine novel variants. Based on the retrieved p-value on the chi-Square, no significant phenotype-genotype correlation was obtained in PLAN. <h3>Conclusions:</h3> PLAN presents with a wide spectrum of clinical symptoms spanning from infancy through adulthood. PLAN should be considered in adult patients presenting with parkinsonism or cognitive decline. Genotype of the disease cannot predict the age of disease onset. <b>Disclosure:</b> Dr. Tavasoli has nothing to disclose. Ali Zare Dehnavi has nothing to disclose. Maryam Bemanalizadeh has nothing to disclose. Mohammad Kahani has nothing to disclose. Dr. Rohani has nothing to disclose. Mehran Beriraghi Toosi has nothing to disclose. Prof. Ashrafi has nothing to disclose. Morteza Heidari has nothing to disclose. Mr. Amanat has nothing to disclose. Sareh Hosseinpour has nothing to disclose.

Spectrum of Neurodegeneration with Brain Iron Accumulation with PLA2G6 Variation: A Report of Three Cases from Two Families

AbstractNeurodegeneration with brain iron accumulation consists of disorders characterized by progressive neuronal degeneration, cognitive decline, brain iron accumulation in extrapyramidal system, dentate nucleus, and gray and white matters boundary. We present a case series of PLA2G6-associated neurodegeneration (PLAN), with definite PLA2G6 gene mutations in two cases and suspected in one case. Diagnosis was based on clinical presentations, brain magnetic resonance imaging (MRI) findings, and detection of PLA2G6 mutations. Case 1: An 8-year-old boy presented with weakness of lower limbs, subnormal intelligence, scanning speech, spasticity, dysdiadochokinesia, pendular knee jerk, and extensor plantar reflex. MRI of the brain showed diffuse cerebellar atrophy and white matter T2 hyperintensity with iron deposition in bilateral globus pallidi. Case 2: Elder sister of Case 1, who developed ataxia at the age of 6 years and became bedridden at 14 years. She had nocturnal enuresis, seizures, cervical dystonia, dysphagia, and died at 23 years of age. MRI showed cerebral and cerebellar atrophies and iron deposition in basal ganglia and substantia nigra. Case 3 had infantile onset with quadriparesis, optic atrophy, developmental delay, cerebral and cerebellar atrophies, and brain iron accumulation in basal ganglia. Case 1 revealed two heterozygous mutations of PLA2G6 gene in exons 16 (c.2264G &gt; A, p. Arg755Gln) and 12 (c.1637G &gt; A, p. Arg546Gln), classified as likely pathogenic. Elder sister (Case 2) could not be tested for this mutation. Case 3 showed homozygous silent splice site point variation in exon 7 (c.1077 G &gt; A; p. Ser 359 Ser) of PLA2G6 gene. Thus, in patients presenting with neurodegeneration and imaging findings of brain iron accumulation, diagnosis can be established by PLA2G6 gene mutation analysis.

A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson’s disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study.

Frequency of Parkinson's Disease Genes and Role of PARK2 in Amyotrophic Lateral Sclerosis: An NGS Study.

Amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD) patients show a higher prevalence of Lewy body disease than the general population. Additionally, parkinsonian features were found in about 30% of ALS patients. We aimed to explore the frequency of Parkinson’s disease (PD)-causative genes in ALS patients, compared to AD and healthy controls (HCs). We used next-generation sequencing multigene panels by analyzing SNCA, LRRK2, PINK1, PARK2, PARK7, SYNJ1, CHCHD2, PLA2G6, GCH1, ATP13A2, DNAJC6 and FBXO genes. GBA gene, a risk factor for PD, was also analyzed. In total, 130 ALS and 100 AD patients were investigated. PD-related genes were found to be altered in 26.2% of ALS, 20% of AD patients and 19.2% of HCs. Autosomal recessive genes were significantly more involved in ALS as compared to AD and HCs (p = 0.021). PARK2 variants were more frequent in ALS than in AD and HCs, although not significantly. However, the p.Arg402Cys variant was increased in ALS than in HCs (p = 0.025). This finding is consistent with current literature, as parkin levels were found to be decreased in ALS animal models and patients. Our results confirm the possible role of PD-related genes as risk modifier in ALS pathogenesis.

Novel PLA2G6 Pathogenic Variants in Chinese Patients With PLA2G6-Associated Neurodegeneration.

BackgroundPLA2G6-associated neurodegeneration (PLAN) is a heterogeneous group of neurodegenerative diseases caused by biallelic PLA2G6 mutations, covering diseases such as infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). The study aims to report the clinical and genetic features of a series of PLAN patients.MethodsThe clinical and radiological findings of five Chinese patients from three families were collected. Whole-exome next generation sequencing (NGS) was applied to identify the genetic causes. Co-segregation analysis of the detected candidate variants were performed in their families. The pathogenicity of identified novel variants was predicted by in silico analysis.ResultsNGS revealed compound heterozygous variants of PLA2G6 gene in all five patients. There were six PLA2G6 variants identified, including two known variants (c.116G>A, c.238G>A) and four novel variants (c.2120dupA, c.2071C>G, c.967G>A, c1534T>A). ACMG predicts c.2120dupA to be pathogenic, c.2071C>G and c.1534T>A to be likely pathogenic, and c1534T>A to be of uncertain significance. Clinically, four patients fell into the diagnosis of ANAD, and 1 into the diagnosis of AREP. Brain imaging revealed cerebellar atrophy, iron deposition in bilateral globus pallidus, and substantia nigra in three cases.ConclusionsFour novel pathogenic variants were discovered and the pathogenic variant spectrum of the PLA2G6 gene was expanded.

Phosphatidylglycerol Supplementation Alters Mitochondrial Morphology and Cardiolipin Composition.

The pathogenic variant of the TAZ gene is directly associated with Barth syndrome. Because tafazzin in the mitochondria is responsible for cardiolipin (CL) remodeling, all molecules related to the metabolism of CL can affect or be affected by TAZ mutation. In this study, we intend to recover the distortion of the mitochondrial lipid composition, especially CL, for Barth syndrome treatment. The genetically edited TAZ knockout HAP1 cells were demonstrated to be a suitable cellular model, where CL desaturation occurred and monolyso-CL (MLCL) was accumulated. From the species analysis by mass spectrometry, phosphatidylethanolamine showed changed species content after TAZ knockout. TAZ knockout also caused genetic down-regulation of PGS gene and up-regulation of PNPLA8 gene, which may decrease the biosynthesis of CLs and increase the hydrolysis product MLCL. Supplemented phosphatidylglycerol(18:1)2 (PG(18:1)2) was successfully biosynthesized to mature symmetrical CL and drastically decrease the concentration of MLCL to recover the morphology of mitochondria and the cristae shape of inner mitochondria. Newly synthesized mature CL may induce the down-regulation of PLA2G6 and PNPLA8 genes to potentially decrease MLCL production. The excess supplemented PG was further metabolized into phosphatidylcholine and phosphatidylethanolamine.

Novel insertion mutation in the PLA2G6 gene in an Iranian family with infantile neuroaxonal dystrophy

BackgroundInfantile neuroaxonal dystrophy is an autosomal recessive neurological disorder. Individuals with infantile neuroaxonal dystrophy experience progressive loss of vision, mental skills and muscular control, and other variable clinical signs. Pathogenic variants in the PLA2G6 gene, encoding phospholipase A2, are recognized to be the fundamental reason for infantile neuroaxonal dystrophy. This study aimed to detect pathogenic variant in a consanguine Iranian family with infantile neuroaxonal dystrophy.MethodsThe mutation screening was done by whole exome sequencing followed by direct Sanger sequencing.ResultsWe identified a homozygous insertion mutation, NM_003560: c.1548_1549insCG (p.G517Rfs*29) in exon 10 of PLA2G6 in the patient. The parents were heterozygous for variant.ConclusionsBecause of the clinical heterogeneity and rarity of infantile neuroaxonal dystrophy, whole exome sequencing is critical to confirm the diagnosis and is an excellent tool for INAD management.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

Unusual Presentation of PLA2G6-Related Neurodegeneration with Retinal Vasculitis.

PLA2G6 gene mutation and infantile neuroaxonal degeneration; report of three cases from Iran.

Objective(s):Infantile neuroaxonal degeneration (INAD) is a rare subgroup of neurodegeneration with brain iron accumulation (NBIA) disorders. This progressive disorder may develop during the early years of life. Affected individuals mostly manifest developmental delay and/or psychomotor regression as well as other neurological deficits. In the present study, we discussed 3 INAD patients diagnosed before the age of 10 by using Whole-Exome Sequencing (WES).Materials and Methods: We evaluated 3 pediatric patients with clinical phenotypes of INAD who underwent WES. Sanger sequencing was performed for co-segregation analysis of the variants in the families. An in-silico study was conducted for identification of the molecular function of the identified genetic variants in the PLA2G6 gene.Results:We detected three novel genetic variants in the PLA2G6 gene including a homozygous missense (NM_003560.2; c.1949T>C; p.Phe650Ser), a splicing (NM_001349864; c.1266-1G>A) and a frameshift variant (NM_003560.4; c.1547_1548dupCG; p.Gly517ArgfsTer29). Since the variants were not previously reported in literature or population databases, we performed in-silico studies for these variants and demonstrated their potential pathogenicity.Conclusion:The current study reports novel genetic variants in the PLA2G6 gene in the Iranian population, emphasizing the importance of high-throughput genetic testing in rare diseases.