RESUMO
Cisplatin (CDDP) is a platinum-based drug with anti-cancer activity and is widely used as a standard therapy for bladder cancer. It is well known that CDDP causes cell death by increasing the generation of reactive oxygen species (ROS) and lipid peroxidation, but the mechanism of its anti-cancer effects has not been fully elucidated. There are still some problems such as chemoresistance in CDDP therapy. In the present study, we found the expression of Ca2+-independent phospholipase A2γ (iPLA2γ), which has been reported to regulate cellular redox homeostasis by inhibiting lipid peroxide accumulation, in human bladder cancer tissues. Thus, we investigated the effect of iPLA2γ knockdown on CDDP-induced bladder cancer cell death. As a result, we found that iPLA2γ knockdown significantly enhanced CDDP-induced apoptosis, intracellular and mitochondrial ROS production, cytochrome c release and caspase activation in bladder cancer cells. Moreover, mitochondrial membrane potential was decreased and peroxidation of mitochondrial phospholipids was increased by iPLA2γ knockdown. It was also shown that co-treatment of bromoenol lactone, an iPLA2 inhibitor, increased CDDP-induced apoptosis. These results indicated that iPLA2γ plays an important role in protecting bladder cancer cells from CDDP-induced apoptosis, and that iPLA2γ inhibitors might represent a novel strategy in CDDP-based multi-drug therapy.
Assuntos
Apoptose , Cisplatino , Fosfolipases A2 do Grupo VI , Peroxidação de Lipídeos , Mitocôndrias , Fosfolipídeos , Espécies Reativas de Oxigênio , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Cisplatino/farmacologia , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Fosfolipases A2 do Grupo VI/metabolismo , Fosfolipases A2 do Grupo VI/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Linhagem Celular Tumoral , Fosfolipídeos/metabolismo , Antineoplásicos/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Pironas/farmacologia , NaftalenosRESUMO
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.
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Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Adulto , Doença de Parkinson/patologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Transtornos Parkinsonianos/genética , Mutação/genética , Fosfolipases A2 do Grupo VI/genética , Fosfolipases A2 do Grupo VI/metabolismoRESUMO
BACKGROUND: Phospholipase-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. METHODS: An 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. RESULTS: Eighteen 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. CONCLUSION: PLAN 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.
Assuntos
Distrofias Neuroaxonais , Transtornos Parkinsonianos , Adulto , Criança , Humanos , Genótipo , Fosfolipases A2 do Grupo VI/genética , Mutação/genética , Distrofias Neuroaxonais/genética , Transtornos Parkinsonianos/genética , FenótipoRESUMO
Here we investigated whether antipsychotic treatment was influenced by three polymorphisms: rs10798059 (BanI) in the phospholipase A2 (PLA2)G4A gene, rs4375 in PLA2G6, and rs1549637 in PLA2G4C. A total of 186 antipsychotic-naïve first-episode psychosis patients or nonadherent chronic psychosis individuals (99 males and 87 females) were genotyped by polymerase chain reaction analysis/restriction fragment length polymorphism. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed patients' Positive and Negative Syndrome Scale (PANSS) scores, PANSS factors, and metabolic syndrome-related parameters (fasting plasma lipid and glucose levels, and body mass index). We found that PLA2G4A polymorphism influenced changes in PANSS psychopathology, and PLA2G6 polymorphism influenced changes in PANSS psychopathology and metabolic parameters. PLA2G4C polymorphism did not show any impact on PANSS psychopathology or metabolic parameters. The polymorphisms' effect sizes were estimated as moderate to strong, with contributions ranging from around 6.2-15.7%. Furthermore, the polymorphisms' effects manifested in a gender-specific manner.
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Antipsicóticos , Fosfolipases A2 do Grupo VI , Transtornos Psicóticos , Feminino , Humanos , Masculino , Antipsicóticos/uso terapêutico , Genótipo , Polimorfismo Genético , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Fosfolipases A2 do Grupo VI/genéticaRESUMO
BACKGROUND: PLA2G6-associated neurodegeneration (PLAN) can be categorized into infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (aNAD), neurodegeneration with brain iron accumulation (NBIA), and early-onset parkinsonism (EOP). OBJECTIVES: To determine the genotype-phenotype association in PLAN. METHODS: "PLA2G6" or "PARK14" or "phospholipase A2 group VI" or "iPLA2ß" were searched across MEDLINE from June 23, 1997, to March 1, 2023. A total of 391 patients were identified, and 340 patients of them were finally included in the assessment. RESULTS: The loss of function (LOF) mutation ratios were significantly different (p < 0.001), highest in INAD, followed by NBIA, aNAD, and EOP. Four ensemble scores (i.e., BayesDel, VARITY, ClinPred, and MetaRNN) were assessed to predict the deleteriousness of missense mutations and demonstrated significant differences (p < 0.001). Binary logistic regression analyses demonstrated that LOF mutations were independently associated with brain iron accumulation (p = 0.006) and ataxia (p = 0.025). CONCLUSIONS: LOF or more deleterious missense mutations are more likely to promote the development of serious phenotype of PLAN, and LOF mutations are independently associated with brain iron accumulation and ataxia.
Assuntos
Distrofias Neuroaxonais , Transtornos Parkinsonianos , Humanos , Mutação/genética , Transtornos Parkinsonianos/genética , Estudos de Associação Genética , Distrofias Neuroaxonais/genética , Ferro , Ataxia , Fosfolipases A2 do Grupo VI/genéticaRESUMO
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.
Assuntos
Distrofias Neuroaxonais , Doenças Neurodegenerativas , Transtornos Parkinsonianos , Humanos , Doenças Neurodegenerativas/genética , Transtornos Parkinsonianos/genética , Distrofias Neuroaxonais/genética , Estudos de Associação Genética , Mutação , Fosfolipases A2 do Grupo VI/genéticaRESUMO
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 iPLA2ß.
Assuntos
Distonia , Distúrbios Distônicos , Transtornos Parkinsonianos , Adulto , Humanos , Pessoa de Meia-Idade , Distonia/genética , Distúrbios Distônicos/genética , Testes Genéticos , Fosfolipases A2 do Grupo VI/genética , Mutação , Transtornos Parkinsonianos/genéticaRESUMO
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.
Assuntos
Células-Tronco Pluripotentes Induzidas , Distrofias Neuroaxonais , Doenças Neurodegenerativas , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Doenças Neurodegenerativas/genética , Mutação/genética , Homozigoto , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/patologia , Fosfolipases A2 do Grupo VI/genéticaAssuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Distrofias Neuroaxonais , Humanos , Ferro , Imageamento por Ressonância Magnética/métodos , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Encéfalo/diagnóstico por imagem , Fosfolipases A2 do Grupo VI/genéticaRESUMO
Phospholipase A2 group 6 (PLA2G6, iPLA2ß or PARK14) gene encodes a calcium-independent group 6 phospholipase A2 enzyme and is associated with young-onset autosomal recessive Parkinson's disease (PD). We generated human induced pluripotent stem cell (iPSC) lines from a patient with young-onset PD carrying a homozygous PLA2G6: c.2222G>A (p. Arg741Gln) mutation (NCBSi003-A) and unaffected heterozygous parent (NCBSi004-A). These iPSC lines will be used for investigating the key molecular signatures of young-onset PD (YOPD), and to understand the predictive phenotypes of the disease.
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Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Doença de Parkinson/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos Parkinsonianos/genética , Mutação , Transgenes , Fosfolipases A2 do Grupo VI/genéticaAssuntos
Estimulação Encefálica Profunda , Fosfolipases A2 do Grupo VI , Atividade Motora , Transtornos Parkinsonianos , Núcleo Subtalâmico , Humanos , China , Estimulação Encefálica Profunda/métodos , Fosfolipases A2 do Grupo VI/genética , Mutação/genética , Transtornos Parkinsonianos/fisiopatologia , Transtornos Parkinsonianos/terapia , Núcleo Subtalâmico/fisiopatologiaRESUMO
Polymorphisms of phospholipase A2VIA (iPLA2ß or PLA2G6) are associated with body weights and blood C-reactive protein. The role of iPLA2ß/PLA2G6 in non-alcoholic steatohepatitis (NASH) is still elusive because female iPla2ß-null mice showed attenuated hepatic steatosis but exacerbated hepatic fibrosis after feeding with methionine- and choline-deficient diet (MCDD). Herein, female mice with myeloid- (MPla2g6-/-) and hepatocyte- (LPla2g6-/-) specific PLA2G6 deletion were generated and phenotyped after MCDD feeding. Without any effects on hepatic steatosis, MCDD-fed MPla2g6-/- mice showed further exaggeration of liver inflammation and fibrosis as well as elevation of plasma TNFα, CCL2, and circulating monocytes. Bone-marrow-derived macrophages (BMDMs) from MPla2g6-/- mice displayed upregulation of PPARγ and CEBPα proteins, and elevated release of IL6 and CXCL1 under LPS stimulation. LPS-stimulated BMDMs from MCDD-fed MPla2g6-/- mice showed suppressed expression of M1 Tnfa and Il6, but marked upregulation of M2 Arg1, Chil3, IL10, and IL13 as well as chemokine receptors Ccr2 and Ccr5. This in vitro shift was associated with exaggeration of hepatic M1/M2 cytokines, chemokines/chemokine receptors, and fibrosis genes. Contrarily, MCDD-fed LPla2g6-/- mice showed a complete protection which was associated with upregulation of Ppara/PPARα and attenuated expression of Pparg/PPARγ, fatty-acid uptake, triglyceride synthesis, and de novo lipogenesis genes. Interestingly, LPla2g6-/- mice fed with chow or MCDD displayed an attenuation of blood monocytes and elevation of anti-inflammatory lipoxin A4 in plasma and liver. Thus, PLA2G6 inactivation specifically in myeloid cells and hepatocytes led to opposing phenotypes in female mice undergoing NASH. Hepatocyte-specific PLA2G6 inhibitors may be further developed for treatment of this disease.
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Hepatopatia Gordurosa não Alcoólica , Feminino , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/genética , Fosfolipases A2 Independentes de Cálcio , PPAR gama/genética , Interleucina-6 , Lipopolissacarídeos , Dieta , Hepatócitos , Fenótipo , Metionina , Colina , Racemetionina , PPAR alfa , Receptores de Quimiocinas , Fosfolipases A2 do Grupo VI/genéticaAssuntos
Distúrbios Distônicos , Transtornos Parkinsonianos , Adulto , Humanos , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/genética , Mutação/genética , Fosfolipases A2 do Grupo VI/genéticaRESUMO
BACKGROUND: PLA2G6-Associated Neurodegeneration, PLAN, is subdivided into: Infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and adult-onset dystonia parkinsonism [1]. It is elicited by a biallelic pathogenic variant in phospholipase A2 group VI (PLA2G6) gene. In this study we describe new cases and provide a comprehensive review of previously published cases. METHODS: Eleven patients, from four different institutions and four different countries. All underwent a comprehensive chart review. RESULTS: Ages at onset ranged from 1 to 36 years, with a median of 16 and a mean of 16.18 ± 11.91 years. Phenotypic characteristics were heterogenous and resembled that of patients with infantile neuroaxonal dystrophy (n = 2), atypical neuroaxonal dystrophy (n = 1), adult-onset dystonia parkinsonism (n = 1), complex hereditary spastic paraparesis (n = 3), and early onset Parkinson's disease (n = 2). Parental genetic studies were performed for all patients and confirmed with sanger sequencing in five. Visual evoked potential illustrated optic atrophy in P4. Mineralization was evident in brain magnetic resonance imaging of P1, P2, P4, P5, P7, and P11. Single photon emission computed tomography was conducted for three patients, revealed decreased perfusion in the occipital lobes for P10. DaTscan was performed for P11 and showed decreased uptake in the deep gray matter, bilateral caudate nuclei, and bilateral putamen. Positive response to Apomorphine was noted for P10 and to Baclofen in P2, and P3. CONCLUSIONS: PLAN encompasses a wide clinical spectrum. Age and symptom at onset are crucial when classifying patients. Reporting new variants is critical to draw more attention to this condition and identify biomarkers to arrive at potential therapeutics.
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Distúrbios Distônicos , Distrofias Neuroaxonais , Transtornos Parkinsonianos , Adolescente , Adulto , Criança , Pré-Escolar , Potenciais Evocados Visuais , Fosfolipases A2 do Grupo VI/deficiência , Fosfolipases A2 do Grupo VI/genética , Humanos , Lactente , Distúrbios do Metabolismo do Ferro , Mutação , Distrofias Neuroaxonais/diagnóstico por imagem , Distrofias Neuroaxonais/genética , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/genética , Fenótipo , Adulto JovemRESUMO
NADK2 encodes the mitochondrial form of nicotinamide adenine dinucleotide (NAD) kinase, which phosphorylates NAD. Rare recessive mutations in human NADK2 are associated with a syndromic neurological mitochondrial disease that includes metabolic changes, such as hyperlysinemia and 2,4 dienoyl CoA reductase (DECR) deficiency. However, the full pathophysiology resulting from NADK2 deficiency is not known. Here, we describe two chemically induced mouse mutations in Nadk2-S326L and S330P-which cause severe neuromuscular disease and shorten lifespan. The S330P allele was characterized in detail and shown to have marked denervation of neuromuscular junctions by 5 weeks of age and muscle atrophy by 11 weeks of age. Cerebellar Purkinje cells also showed progressive degeneration in this model. Transcriptome profiling on brain and muscle was performed at early and late disease stages. In addition, metabolomic profiling was performed on the brain, muscle, liver and spinal cord at the same ages and on plasma at 5 weeks. Combined transcriptomic and metabolomic analyses identified hyperlysinemia, DECR deficiency and generalized metabolic dysfunction in Nadk2 mutant mice, indicating relevance to the human disease. We compared findings from the Nadk model to equivalent RNA sequencing and metabolomic datasets from a mouse model of infantile neuroaxonal dystrophy, caused by recessive mutations in Pla2g6. This enabled us to identify disrupted biological processes that are common between these mouse models of neurological disease, as well as those processes that are gene-specific. These findings improve our understanding of the pathophysiology of neuromuscular diseases and describe mouse models that will be useful for future preclinical studies.
Assuntos
Hiperlisinemias , Distrofias Neuroaxonais , Animais , Camundongos , Humanos , NAD/genética , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Mitocondriais/genética , Fosfolipases A2 do Grupo VI/genéticaRESUMO
Neurodegenerative disorders and leukodystrophies are progressive neurologic conditions that can occur following the disruption of intricately coordinated patterns of gene expression. Exome sequencing has been adopted as an effective diagnostic tool for determining the underlying genetic etiology of Mendelian neurologic disorders, however genome sequencing offer advantages in its ability to identify and characterize copy number, structural, and sequence variants in noncoding regions. Genome sequencing from peripheral leukocytes was performed on two patients with progressive neurologic disease of unknown etiology following negative genetic investigations including exome sequencing. RNA sequencing from peripheral blood was performed to determine gene expression patterns in one of the patients. Potential causative variants were matched to the patients' clinical presentation. The first proband was found to be heterozygous for a likely pathogenic missense variant in PLA2G6 (c.386T>C; p.Leu129Pro) and have an additional deep intronic variant in PLA2G6 (c.2035-926G>A). RNA sequencing indicated this latter variant created a splice acceptor site leading to the incorporation of a pseudo-exon introducing a premature termination codon. The second proband was heterozygous for a 261 kb deletion upstream of LMNB1 that included an enhancer region. Previous reports of copy number variants spanning this region of cis-acting regulatory elements corroborated its pathogenicity. When combined with clinical presentations, these findings led to a definitive diagnosis of autosomal recessive infantile neuroaxonal dystrophy and autosomal dominant adult-onset demyelinating leukodystrophy, respectively. In patients with progressive neurologic disease of unknown etiology, genome sequencing with the addition of RNA analysis where appropriate should be considered for the identification of causative noncoding pathogenic variants.
Assuntos
Fosfolipases A2 do Grupo VI , Lamina Tipo B , Distrofias Neuroaxonais , Adulto , Sequência de Bases , Fosfolipases A2 do Grupo VI/genética , Fosfolipases A2 do Grupo VI/metabolismo , Heterozigoto , Humanos , Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Sítios de Splice de RNA , Sequenciamento do ExomaRESUMO
BACKGROUND: Infantile 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. METHODS: The mutation screening was done by whole exome sequencing followed by direct Sanger sequencing. RESULTS: We 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. CONCLUSIONS: Because 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.