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

Abstract

Early infantile epileptic encephalopathy 38 (EIEE38, MIM #617020) is caused by biallelic variants in ARV1, encoding a transmembrane protein of the endoplasmic reticulum with a pivotal role in glycosylphosphatidylinositol (GPI) biosynthesis. We ascertained seven new patients from six unrelated families harboring biallelic variants in ARV1, including five novel variants. Affected individuals showed psychomotor delay, hypotonia, early onset refractory seizures followed by regression and specific Smrithi Salian and Marcello Scala contributed equally to this work

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

“…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 ).…”

“…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 ).…”

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

“…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].…”

“…[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].…”

“…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.…”