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Ahead of print publication

RHOBTB2 gene-related developmental and epileptic encephalopathy

 Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India

Date of Submission17-Mar-2021
Date of Acceptance06-Jul-2021
Date of Web Publication07-Jan-2022

Correspondence Address:
Indar K Sharawat,
Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh 249203, Uttarakhand.
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_66_21


How to cite this URL:
Panda PK, Pandey BK, Pradhan AK, Banu R, Sharawat IK. RHOBTB2 gene-related developmental and epileptic encephalopathy. J Pediatr Neurosci [Epub ahead of print] [cited 2023 Sep 29]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=335209

To the Editor,

A two-year-old boy with an uneventful birth history presented with developmental delay and multiple, unprovoked, focal, as well as generalized seizures since four months of age. The seizures lasted from few seconds to two minutes, with a frequency of three to five per month, and required two antiseizure medications (ASMs) (levetiracetam and phenytoin) for achieving seizure control. At two years of age, the boy was able to sit without support, had bisyllabic babbles, and recently learned to wave bye-bye. The development quotient of the child was 38. On physical examination, his weight was 9 kg (less than −2 SD), length was 73 cm (less than −2 SD), and head circumference was 41 cm (less than −3 SD). He also had central hypotonia, more affecting the trunk with preserved exaggerated muscle stretch reflexes and intermittent mild dystonia. There was no evidence of facial dysmorphism or other congenital anomalies. His vision, fundus examination, and hearing assessment were normal. Magnetic resonance imaging of the brain did not reveal any abnormality. Sleep electroencephalogram showed bilateral frontocentral predominant epileptiform discharges. Blood tandem mass spectrometry, urine gas chromatography mass spectrometry, and plasma amino acid profile did not show any elevated abnormal metabolites.

Whole-exome sequencing detected a novel heterozygous missense variant in exon 4 of the RHOBTB2 gene (chr8:g.23004468G>A; Depth: 130×) that resulted in the amino acid substitution of isoleucine for valine at codon 34 (p.Val34Ile), consistent with the diagnosis of developmental and epileptic encephalopathy 64. The in-silico predictions of the variant were probably damaging by PolyPhen-2 (HumDiv), damaging by likelihood ratio test and MutationTaster2. According to American College of Medical Genetics classification, the variant (c.100G>A [p.Val34Ile]) was classified as class 5 (pathogenic). Parental screening did not show the variant.

At the last follow-up, the child is still having developmental delay with development quotient of 44 at six months after the first neuropsychological testing (some improvement in development quotient is probably due to multimodal rehabilitation including physiotherapy and occupational therapy) and continues to be seizure-free.

The role of Rho-linked proteins, including typical Rho GTPases, in cognitive function and dysfunction, as well as synaptic plasticity, is widely acknowledged.[1] Even recently, atypical Rho GTPases like the Rho-related BTB domain containing 2 (RHOBTB2) has been shown to have an important role in neurodevelopment in human and animal models.[2] The knockdown of this gene in the Drosophila dendritic arborization neurons led to a reduced number of dendrites, thereby suggesting its indispensable role in dendritic development.[3] In total, 14 cases have been reported with developmental and epileptic encephalopathy 64 (OMIM#618004) to date from three publications. For the first time, Straub et al.[3] in 2018 described 10 individuals with de novo missense mutations in RHOBTB2 gene clustering in the BTB-domain-encoding region resulted in a relatively identical phenotype, similar to our case with infantile or early childhood-onset epilepsy, postnatal microcephaly, severe intellectual disability, and movement disorders.[3] The seizure semiology was pleomorphic, ranging from febrile seizures to focal nonmotor onset seizures, with behavioral arrest and generalized tonic-clonic seizures, although in most cases responded favorably to ASMs. Those with late-onset seizures and febrile seizures had relatively less affected development and cognition, whereas most of the other individuals also had developmental stagnation or regression after the onset of epilepsy.[3] Around half of the affected patients had status epilepticus. The movement disorders also varied in these patients, including dystonia, chorea, and other paroxysmal dyskinesias. Although the majority of individuals had truncal hypotonia in early life, a substantial proportion later developed spasticity in lower limbs, even requiring botulinum toxin injection.[3] Subtle dysmorphism and postnatal growth retardation were also common in the original cohort, although our case did not have any dysmorphism. Original neuroimaging was either normal or showed nonspecific findings in all cases such as delayed myelination, ventricular enlargement, and thinning of the corpus callosum. But following status epilepticus, some patients developed hemiparesis with acute diffusion abnormalities or infarction, hippocampal atrophy in neuroimaging.[3] Recently, Knijnenburg et al.[4] have described acute encephalopathy after a head injury in a five-year-old boy with RHOBTB2 mutation, who also had diffuse slowing and discontinuous patterns in the electroencephalogram. In another case series of three cases caused by RHOBTB2 mutation by Belal et al., all cases had febrile status epilepticus.[5] Our case is the first from the Indian subcontinent with a novel pathogenic de novo missense RHOBTB2 mutation. This novel epileptic encephalopathy should be suspected in cases with early childhood epilepsy, developmental delay, microcephaly, and movement disorders.

With the kind of presentation seen in our case as well as previously reported cases with pleomorphic seizure onset from infancy with developmental delay, central hypotonia, and movement disorder, a large number of developmental and epileptic encephalopathies need to be considered clinically. While some of the genes such as SCN1A have a relatively predictable phenotype with fever-triggered hemiclonic seizures initially and later myoclonic and atypical absence, as well as other seizure semiologies. However, its not true for recently discovered genes as they often have a variable clinical presentation. Among various genes responsible for epileptic encephalopathy in infants, KCNQ2, STXBP1, ARX, SLC25A22, and GRIN2A are some of the genes commonly reported.[6],[7] Although many of these genes have some peculiar feature in seizure semiology or clinical feature, often it is difficult to pinpoint based on an electroclinical presentation to a particular developmental epileptic encephalopathy. As the number of developmental and epileptic encephalopathy genes reported now crosses 80 in number, often next-generation sequencing helps clinicians in ascertaining the true underlying genetic etiology. However, no specific medication has been explored to be particularly effective in animal models, preclinical and clinical trials in patients with RHOBTB mutation. But as recently, a number of new medications such as radiprodil and almorexant have been found to be effective in infantile spasms and KCNA1 mutations. Probably in the near future, there will be a discovery of targeted medications for these rare disorders.

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There are no conflicts of interest.

   References Top

Berthold J, Schenkova K, Rivero F Rho GTPases of the RhoBTB subfamily and tumorigenesis. Acta Pharmacol Sin 2008;29:285-95.  Back to cited text no. 1
Ji W, Rivero F Atypical Rho GTPases of the RhoBTB subfamily: Roles in vesicle trafficking and tumorigenesis. Cells 2016;5:28.  Back to cited text no. 2
Straub J, Konrad EDH, Grüner J, Toutain A, Bok LA, Cho MT, et al; Deciphering Developmental Disorders Study. Missense variants in RHOBTB2 cause a developmental and epileptic encephalopathy in humans, and altered levels cause neurological defects in drosophila. Am J Hum Genet 2018;102:44-57.  Back to cited text no. 3
Knijnenburg ACS, Nicolai J, Bok LA, Bay A, Stegmann APA, Sinnema M, et al. Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation. Neurol Genet 2020;6:e418.  Back to cited text no. 4
Belal H, Nakashima M, Matsumoto H, Yokochi K, Taniguchi-Ikeda M, Aoto K, et al. De novo variants in RHOBTB2, an atypical Rho GTPase gene, cause epileptic encephalopathy. Hum Mutat 2018;39:1070-5.  Back to cited text no. 5
Sharawat IK, Kasinathan A, Sahu JK, Sankhyan N Response to carbamazepine in KCNQ2 related early infantile epileptic encephalopathy. Indian J Pediatr 2019;86:301-2.  Back to cited text no. 6
Sharawat IK, Yadav J, Saini L Novel GRIN2B mutation: A rare cause of severe epileptic encephalopathy. Neurol India 2019;67:562-3.  Back to cited text no. 7


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