A term neonate with early myoclonic encephalopathy caused by RARS2 gene variants: a case report

Abstract

The RARS2 gene encodes mitochondrial arginine-tRNA synthetase. Patients with variants of the RARS2 gene have pontocerebellar hypoplasia type 6 (PCH6), which is characterized by early onset seizures, progressive microcephaly, and developmental delay. PCH6 is a rare mitochondrial encephalopathy.To the best of our knowledge, the onset seizure type which the ictal video-electroencephalogram (VEEG) was compatible with early myoclonic encephalopathy (EME) has not been reported. Here we reported a term female neonate with EME caused by heterozygous variants of the RARS2 gene [NM_020320: exon10: c.773G>A (p. R258H) Maternal, NM_020320: exon4: c.282_285delAGAG Paternal]. Groan was the first symptom manifested, followed by metabolic disorders, and early marked cerebral atrophy. Metabolic disorders were corrected after feeding with extensively hydrolyzed protein formula. Seizures started at the 19th day of life. Interictal VEEG showed a suppression-burst (SB) pattern and ictal VEEG revealed myoclonic seizures that were compatible with early myoclonic encephalopathy (EME). She had frequent myoclonic seizures resistant to multi-antiepileptic drugs including phenobarbital, levetiracetam and oxcarbazepine, and soon developed into convulsive status epilepticus. At 7 months of age, she had severe developmental delay, and developed infantile spasms. Our case report expands the phenotypic spectrum of the PCH6, meanwhile, RARS2 should be considered be a causative gene in patients with EME.

Clinical and genetic analysis of infants with pontocerebellar hypoplasia type 6 caused by RARS2 variations

“…Since it was first reported by Edvardson et al 6 . in 2007, around 30 cases have been reported, 7 few of which were from China 8,9 …”

“…5 Since it was first reported by Edvardson et al 6 in 2007, around 30 cases have been reported, 7 few of which were from China. 8,9 Patients with RARS2 mutations are more likely to develop symptoms within 3 months of birth. Initial symptoms include seizures, hypotonia, difficulty feeding, dyspnea, and hypoglycemia.…”

“…10 Some authors even consider that the diagnosis of PCH6 cannot be used to generalize all phenotypes of RARS2 mutations, and suggest that "early onset mitochondrial encephalopathy" or "RARS2 mutations" should be used instead. 11,13 In two recent domestic studies, Xu et al 8 reported early myoclonic encephalopathy, suggesting that the RARS2 gene be included in the detection of early myoclonic encephalopathy. Jiang et al suggested that PCH6, a RARS2 mutation, was no longer suitable for clinical diagnosis.…”

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

“…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…”