Migrating Focal Seizures and Myoclonic Status in ARV1- Related Encephalopathy

Abstract

ObjectiveTo report longitudinal clinical, EEG, and MRI findings in 2 sisters carrying compound heterozygous ARV1 mutations and exhibiting a peculiar form of developmental and epileptic encephalopathy (DEE). Neuropathologic features are also described in one of the sisters.MethodsClinical course description, video-EEG polygraphic recordings, brain MRI, skin and muscle biopsies, whole-exome sequencing (WES), and brain neuropathology.ResultsSince their first months of life, both girls exhibited severe axial hypotonia, visual inattention, dyskinetic movements, severe developmental delay, and slow background EEG activity. Intractable nonmotor seizures started in both at the eighth month of life, exhibiting the electroclinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS). In the second year of life, continuous epileptiform EEG activity of extremely high amplitude appeared in association with myoclonic status, leading to severely impaired alertness and responsiveness. Repeated brain MRI revealed progressive atrophic changes and severe hypomyelination. WES identified a compound heterozygous in the ARV1 gene [(p.Ser122Glnfs*7) and (p.Trp163*)] in one patient and was subsequently confirmed in the other. Both sisters died prematurely during respiratory infections. Postmortem neuropathologic examination of the brain, performed in one, revealed atrophic brain changes, mainly involving the cerebellum.ConclusionsThis report confirms that biallelic ARV1 mutations cause a severe form of DEE and adds epilepsy with migrating focal seizures and myoclonic status to the spectrum of epilepsy phenotypes. Considering the potential role of human ARV1 in glycosylphosphatidylinositol (GPI) anchor biosynthesis, this severe syndrome can be assigned to the group of inherited GPI deficiency disorders, with which it shares remarkably similar clinical and neuroimaging features. ARV1 should be considered in the genetic screening of individuals with EIMFS.

Severe Epilepsy and Movement Disorder May Be Early Symptoms of TMEM106B -Related Hypomyelinating Leukodystrophy

“…Our report underscores that early-onset severe epilepsy may be among the major symptoms of HLD. As already suggested in other rare forms of HLD ( ARV1 and UFM1 -related HLD 7 , 8 ), we think that TMEM106B -HLD should be included in the differential diagnosis of genetic early-onset encephalopathies with epilepsy.…”

Spectrum of Neurological Symptoms in Glycosylphosphatidylinositol Biosynthesis Defects: Systematic Review

“…She also experienced status epilepticus, which turned into multifocal seizure disorder. Mutation of ARV1 gene caused symptomatic disorder resembling early infantile epileptic encephalopathy, as further proved in cases of two sisters with biallelic mutation of ARV1, who also presented with encephalopathy and migrating focal seizures (4,5). Another known case of ARV1 was a 5-year-old (at the time of the study) boy, who presented with a very similar phenotype of DD, epilepsy of unknown onset, and motor and speech developmental delay (6).…”

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

“…[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.…”