A patient with pontocerebellar hypoplasia type 6: Novel RARS2 mutations, comparison to previously published patients and clinical distinction from PEHO syndrome

Abstract

21 Pontocerebellar hypoplasia type 6 (PCH6) is a rare infantile-onset progressive encephalopathy 22 caused by biallelic mutations in RARS2 that encodes the mitochondrial arginine-tRNA synthetase 23 enzyme (mtArgRS). The clinical presentation overlaps that of PEHO syndrome (Progressive Encephalopathy with oedema, Hypsarrhythmia and Optic atrophy). The proband presented with 25 severe intellectual disability, epilepsy with varying seizure types, optic atrophy, axial hypotonia, 26 acquired microcephaly, dysmorphic features and progressive cerebral and cerebellar atrophy and 27 delayed myelination on MRI. The presentation had resemblance to PEHO syndrome but 28 sequencing of ZNHIT3 did not identify pathogenic variants. Subsequent whole genome sequencing 29 revealed novel compound heterozygous variants in RARS2, a missense variant affecting a highly 30 conserved amino acid and a frameshift variant with consequent degradation of the transcript 31 resulting in decreased mtArgRS protein level confirming the diagnosis of PCH6. Features 32 distinguishing the proband's phenotype from PEHO syndrome were later appearance of hypotonia 33 and elevated lactate levels in blood and cerebrospinal fluid. On MRI the proband presented with 34 more severe supratentorial atrophy and lesser degree of abnormal myelination than PEHO 35 syndrome patients. The study highlights the challenges in clinical diagnosis of patients with 36 neonatal and early infantile encephalopathies with overlapping clinical features and brain MRI 37 findings. 38 39 Keywords 40 Pontocerebellar hypoplasia type 6, RARS2, PEHO syndrome, progressive cerebellar and cerebral 41 atrophy 3 42 Introduction 43 Pontocerebellar hypoplasia (PCH) is a group of neurodegenerative disorders with autosomal 44 recessive inheritance. Up to date 11 different subtypes have been described, with 17 causative 45 genes identified (van Dijk et al., 2018). Most of the subtypes are characterized by prenatal or 46 neonatal onset, global developmental delay and intellectual disability, microcephaly, hypoplasia and variable atrophy of cerebellar cortex and/or brainstem. The specific neurological symptoms 48 and the severity of symptoms and brain loss vary between the subtypes (van Dijk et al., 2018).49 Pontocerebellar hypoplasia type 6 (PCH6; MIM 611523) is a rare form of PCH first described in 50 2007 in three patients of a consanguineous Sephardic Jewish family (Edvardson et al., 2007). Since 51 then, altogether 32 patients in 18 families have been reported in the literature (for a detailed 52 summary of the patients and phenotypes, see Supplementary Table;Edvardson et al., 2007;

Infantile‐onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype

“…There are ten recurrent variant positions (p.Met1(Val/Leu) 15,18,29 ; p.Gln12Arg 4,6,13,28 ; c.110+5A>G 1,8,13 ; p.Lys158del 3,7,28 ; p.Gln208* 20,26 ; p.Arg258His 5,26 ; p.Leu283Gln 7,23,25 ; p.Met342Ile 12,20 ; p.Asp515Gly 9,22 ; p.Val522Ile 28,29 ); however no clear genotype-phenotype correlation has been identified. 2 We describe a new RARS2 phenotype of infantile-onset myoclonic developmental and epileptic encephalopathy in two unrelated children and compare this to the epileptology in the previously reported cases. We reanalyze the published variants and suggest there is enrichment for variants that disrupt splicing in this gene.…”

“…Here we describe two children with a new RARS2 phenotype that is quite distinct from the previously described early infantile developmental and epileptic encephalopathy RARS2 phenotype. In the 15 published cases that describe the RARS2 epilepsy phenotype in detail, [2][3][4][5][6][7][8][9][10][11][12] seizure onset occurred by 3 months in the setting of abnormal development. In contrast, our children presented with a progressive movement disorder at 8 and 9 months on a background of normal development.…”

“…We compared our cases with the epileptology reported for RARS2 encephalopathy; adequate information was only available for 15/52 reported cases (Table 1). [2][3][4][5][6][7][8][9][10][11] 3 | RESULTS…”

“…While RARS2 was first identified as a recessive gene for pontocerebellar hypoplasia (PCH), 1 a 2020 review of 25 cases with reported imaging found PCH in only 48%. 2 There are now 52 published cases with RARS2 variants with clinical information available for 43. Seizures are reported in 40 (93%) individuals with onset prior to age 3 months in 37 (93%).…”

No, it is not mutually exclusive! A case report of a girl with two genetic diagnoses: Craniofrontonasal dysplasia and pontocerebellar hypoplasia type 1B

“…At least six types of pontocerebellar hypoplasia type 1 is characterized by central and peripheral motor dysfunction from birth. 9 , 10 …”