Epileptic encephalopathy caused by <scp>ARV1</scp> deficiency: Refinement of the genotype–phenotype spectrum and functional impact on <scp>GPI</scp>‐anchored proteins

Salian, Smrithi; Scala, Marcello; Nguyen, Thi Tuyet Mai; Severino, Mariasavina; Accogli, Andrea; Amadori, Elisabetta; Torella, Annalaura; Pinelli, Michele; Hudson, Beth; Boothe, Megan; Hurst, Anna; Ben‐Omran, Tawfeg; Larsen, Martin Jakob; Fagerberg, Christina; Sperling, L.; Miceikaitė, Ieva; Hérissant, Lucas; Doco‐Fenzy, Martine; Nigro, Vincenzo; Striano, Pasquale; Minetti, Carlo; Sachdev, Rani; Palmer, Emma Elizabeth; Capra, Valeria; Campeau, Philippe M.

doi:10.1111/cge.14033

Cited by 7 publications

(6 citation statements)

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“…Early detection of the causative gene will enable the development of new drugs specifically targeting mutated proteins and selectively addressing pathogenic mechanisms, and therefore open new scenarios for personalized therapeutic approaches ( 36 ). Other metabolic disorders can exhibit similar clinical characteristics to the ACADM gene variant, responsible for the medium-chain acyl-CoA dehydrogenase deficiency ( 37 , 38 ). Early infantile epileptic encephalopathy, caused by biallelic variants in ARV1 , encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis, showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features ( 37 ).…”

Section: Discussionmentioning

confidence: 99%

“…Other metabolic disorders can exhibit similar clinical characteristics to the ACADM gene variant, responsible for the medium-chain acyl-CoA dehydrogenase deficiency ( 37 , 38 ). Early infantile epileptic encephalopathy, caused by biallelic variants in ARV1 , encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis, showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific neuroimaging features ( 37 ). Similarly, developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

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Case report: Diagnosis of a patient with Sifrim–Hitz–Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency

Zeka,

Zhubi

et al. 2023

Front. Pediatr.

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BackgroundIt is generally recognized that genetic metabolic disorders can result in neurological symptoms such as seizures, developmental delay, and intellectual disability. Heterogeneous clinical presentations make the diagnosis challenging.Case presentationIn this case report, we present a unique and complex genetic disorder observed in a female patient who exhibited three pathogenic gene variants in the KCNT1, ACADM, and CHD4 genes. The convergence of these variants resulted in a multifaceted clinical presentation characterized by severe seizures of combined focal and generalized onset, metabolic dysfunction, and neurodevelopmental abnormalities. The identification and functional characterization of these gene variants shed light on the intricate interplay between these genes and the patient's phenotype. EEG revealed an epileptiform abnormality which presented in the inter-ictal period from the left frontal-central area and in the ictal period from the left mid-temporal area. The brain MRI revealed volume loss in the posterior periventricular area and parietal parenchyma, myelin destruction with no sign of hypoxic involvement, and left dominant enlargement of the lateral ventricles secondary to loss of central parenchyma. The patient was diagnosed through exome sequencing with Sifrim–Hitz–Weiss syndrome, development and epileptic encephalopathy-14, and medium-chain acyl-CoA dehydrogenase deficiency. An antiseizure medication regimen with valproic acid, levetiracetam, phenobarbital, and clonazepam was initiated. However, this led to only partial control of the seizures.ConclusionClinical follow-up of the patient will further define the clinical spectrum of KCNT1, ACADM, and CHD4 gene variants. It will also determine the long-term efficacy of the treatment of seizures and the development of precision medicine for epilepsy syndromes due to gain-of-function variants. Special emphasis should be put on the role and importance of large-scale genomic testing in understanding and diagnosing complex phenotypes and atypical epileptic syndromes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Case report: Diagnosis of a patient with Sifrim–Hitz–Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency

Zeka,

Zhubi

et al. 2023

Front. Pediatr.

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“…Those with missense type of mutation, have a milder form of epilepsy that has onset in the rst year of life and can go into remission and present with ataxia like in our case. [4] These cases are also noticed to have a longer lifespan compared to the premature death seen in the splice site mutation involving c.294 + 1 G > A [2,4,7,8]. Of the reported cases, 10 have succumbed to death before 5 years of age, of which 8 are due to splice site mutation involving c.294 + 1 G > A and two other cases are sisters with compound heterozygous loss of function mutation in c.363_364del and c.489 G > A [2,4,7,8,10].…”

Section: Discussionmentioning

confidence: 99%

“…[4] These cases are also noticed to have a longer lifespan compared to the premature death seen in the splice site mutation involving c.294 + 1 G > A [2,4,7,8]. Of the reported cases, 10 have succumbed to death before 5 years of age, of which 8 are due to splice site mutation involving c.294 + 1 G > A and two other cases are sisters with compound heterozygous loss of function mutation in c.363_364del and c.489 G > A [2,4,7,8,10]. Movement disorder in the form of dystonia and ataxia can be present along with ocular abnormalities [1,2,[4][5][6][7][8][9][10][11].…”

Section: Discussionmentioning

confidence: 99%

“…Of the reported cases, 10 have succumbed to death before 5 years of age, of which 8 are due to splice site mutation involving c.294 + 1 G > A and two other cases are sisters with compound heterozygous loss of function mutation in c.363_364del and c.489 G > A [2,4,7,8,10]. Movement disorder in the form of dystonia and ataxia can be present along with ocular abnormalities [1,2,[4][5][6][7][8][9][10][11]. Thus, a genotype-phenotype correlation is possible in ARV1 gene.…”

Section: Discussionmentioning

confidence: 99%

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ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein

Kamate,

Basavanagowda

2023

Cerebellum

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Comprehensive prenatal diagnostics: Exome versus genome sequencing

et al. 2023

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ObjectiveThis study aimed to assess the diagnostic yield of prenatal genetic testing using trio whole exome sequencing (WES) and trio whole genome sequencing (WGS) in pregnancies with fetal anomalies by comparing the results with conventional chromosomal microarray (CMA) analysis.MethodsA total of 40 pregnancies with fetal anomalies or increased nuchal translucency (NT ≥ 5 mm) were included between the 12th and 21st week of gestation. Trio WES/WGS and CMA were performed in all cases.ResultsThe trio WES/WGS analysis increased the diagnostic yield by 25% in cases with negative CMA results. Furthermore, all six chromosomal aberrations identified by CMA were independently detected by WES/WGS analysis. In total, 16 out of 40 cases obtained a genetic sequence variant, copy number variant, or aneuploidy explaining the phenotype, resulting in an overall WES/WGS diagnostic yield of 40%. WES analysis provided a more reliable identification of mosaic sequence variants than WGS because of its higher sequencing depth.ConclusionsPrenatal WES/WGS proved to be powerful diagnostic tools for fetal anomalies, surpassing the diagnostic yield of CMA. They have the potential to serve as standalone methods for prenatal diagnosis. The study highlighted the limitations of WGS in accurately detecting mosaic variants, which is particularly relevant when analyzing chorionic villus samples.

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Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype–phenotype spectrum and functional impact on GPI‐anchored proteins

Cited by 7 publications

References 13 publications

Case report: Diagnosis of a patient with Sifrim–Hitz–Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency

Case report: Diagnosis of a patient with Sifrim–Hitz–Weiss syndrome, development and epileptic encephalopathy-14, and medium chain acyl-CoA dehydrogenase deficiency

ARV1 Gene: A Novel Cause of Autosomal Recessive Cerebellar Ataxia with Elevated Alpha Fetoprotein

Comprehensive prenatal diagnostics: Exome versus genome sequencing

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