JLE

Epileptic Disorders

MENU

A de novo GABRB2 variant associated with myoclonic status epilepticus and rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS) Volume 22, numéro 4, August 2020

Vidéo

  • A de novo GABRB2 variant associated with myoclonic status epilepticus and rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS)

Illustrations


  • Figure 1

  • Figure 2

  • Figure 3

Alpers syndrome (AS) is an early-onset neurodegenerative disorder with a poor prognosis, characterized by the triad of developmental regression, intractable epilepsy, and hepatic dysfunction (Sofou et al., 2012; Rose and Al Khalili, 2019). The neuropathological examination demonstrates neuronal loss, status spongiosus, and astrocytosis, affecting the cerebral cortex (Harding et al., 1986). The most common age at onset is between one month and six years of age, although a few prenatal- and adult-onset cases have been reported. As an early symptom, epileptic seizures resistant to antiepileptic drug (AED) treatment develop in the form of focal, multifocal or myoclonic seizures evolving into epilepsia partialis continua (EPC) or myoclonic status epilepticus (MSE), which markedly increase in frequency over months or years (Wolf et al., 2009; Rose and Al Khalili, 2019). Among the laboratory findings, the emergence of rhythmic high-amplitude delta with superimposed (poly) spikes (RHADS) was demonstrated to be specific for this syndrome (Boyd et al., 1986; Wolf et al., 2009; van Westrhenen et al., 2018). In order to make an early diagnosis and avoid the use of sodium valproate (VPA), which may accelerate fatal hepatic failure, the POLG1 (polymerase gamma 1) mutation test is recommended (Saneto et al., 2010). We report a child presenting with daily MSE and RHADS, associated with a de novo missense variant of the β2 subunit of GABA A receptor (GABRB2).

Case study

The patient is currently a 10-year, eight-month-old boy. His family history was unremarkable. He was born by Caesarean section uneventfully due to pelvic position at 38 weeks of gestation. His birth weight, length, and head circumference were 2,880 g (-0.18 SD), 47.6 cm (-0.45 SD), and 33.0 cm (-0.30 SD), respectively, which were appropriate for his gestational age. After birth, he was crying a little and feeding poorly. At the one-month medical check-up, hypertonia, poor feeding, poor weight gain, and ptosis were noted. He maintained a rigid posture with flexion of both arms at the elbow and extension of both legs, and became opisthotonic during the traction manoeuvre. At four months of age, rhythmic myoclonus affecting his face and extremities developed which gradually increased in frequency (see video sequence). At 10 months of age, he was transferred to another hospital for further examination and microcephaly (-3.6 SD), hypotonia and no neck fixation, mild rigidity, and frequent rhythmic myoclonus of the extremities were observed. At the age of one year and seven months, he underwent gastrostomy and Nissen's operation because of disabling gastroesophageal regurgitation.

At three years and two months of age, he was referred to our hospital. He was 95 cm (+ 0.28 SD) tall, weighed 13.9 kg (+ 0 SD) and had a head circumference of 43.5 cm (-4.0 SD). He was unable to hold his head or sit and had marked generalized hypotonia with mild spasticity of the extremities. He had ptosis, no visual fixation or following, and no language ability. Sensory stimulation, such as sudden touch or sudden noise, easily provoked the rhythmic myoclonus of the face and all four extremities synchronously lasting for several minutes to a few hours. Polygraphic analysis demonstrated that the rhythmic myoclonus corresponding to RHADS localized to both midfrontal-central-parietal regions (figure 1A). In addition, the jerked-locked back-averaging revealed that the RHADS-polyspike component was time-locked to myoclonic EMG potentials and preceded their onset by 8 msec. (figure 1B). He had no respiratory compromise nor autonomic symptoms during the attack, and no postictal EEG slowing after the seizures. Thus, the rhythmic myoclonus was considered to be either bilateral EPC or MSE. He also had daily autonomic seizures originating from the left or right temporal region.

The interictal EEG exhibited persistent diffuse slow waves with multifocal spikes, frequently interrupted by RHADS during wakefulness, and an intermittent suppression-burst (SB) pattern during sleep (figure 2). On brain MRI, moderate brain atrophy with diffuse T2 high intensity in the white matter was observed (figure 3).

The protein, lactic acid and pyruvate levels on CSF examination were normal. No abnormalities were found for blood amino acids, urine organic acids, or tandem mass screening tests. Array CGH results were normal. Visual and sensory evoked potential studies showed a normal response and poor separation of N20 component, respectively. Only a mild increase in liver enzymes was found by liver function tests. Based on the clinical and EEG findings, as well as the progressive nature of the disorder, AS was strongly suspected. No pathological or biochemical abnormalities were found on muscle biopsy. At present, he receives artificial respiratory assistance and is cared for at home. MSE has continued, and the suppression-burst EEG pattern has gradually become dominant on EEG during sleep and wakefulness.

Gene analysis

The targeted sequence analysis for POLG1 was performed at four years of age, but no pathogenic POLG1 variants were found. At six years and five months of age, whole-exome sequencing was carried out, as previously described (Nakashima et al., 2019), for the patient and his parents, which revealed a de novo GABRB2 variant (NM_021911.2: c.784G>T, p.[Val262Phe]) in the patient. The variant was not observed in exome data of 575 in-house Japanese controls or gnomAD, another database comprising 125,748 exome sequencing and 15,708 genome sequencing samples (Karczewski et al., 2019). This variant was judged to be likely pathogenic (PS2+PM2+PP3) according to the American College of Medical Genetics and Genomics (ACMG) guidelines (Richards et al., 2015).

Informed consent was received from all participants in accordance with the Japanese regulations. The study was approved by the institutional review boards of the Yokohama City University School of Medicine.

Discussion

In our case, neurological abnormalities were already observed in the neonatal period, and MSE appeared from four months after birth, suggesting neonatal-onset AS. Sofou et al. (2012) examined the phenotype-genotype association in 19 patients meeting the clinical definition of AS. When the phenotypes were compared between the POLG1-positive mutation group (n=6) and POLG1-negative mutation group (n=13), the former group was characterized by a median age at neurological onset of 6.5 months, pharmacoresistant epileptic seizures as the first or second main clinical symptom, and accompanying ataxia and stroke-like episodes. On the other hand, in the POLG-negative mutation group, symptom onset often occurred at the perinatal stage, and microcephaly and spasticity were common. EPC, status epilepticus, and myoclonus were more often observed in the former group, whereas neonatal seizures and infantile spasms were more common in the latter group. Furthermore, liver dysfunction was more severe in the former group. In our patient, the clinical findings were similar to those of the POLG1-negativemutationgroup, such as neonatal onset and absence of POLG1 mutation, but the seizure characteristics were similar to those of the POLG1-positivemutationgroup. A de novo GABRB2 missense variant was identified as an underlying cause.

To date, 18 patients with developmental disorders or developmental and epileptic encephalopathies associated with GABRB2 missense variants have been reported, all exhibiting global developmental delay, intellectual disability and epilepsy (Hamdan et al., 2017). As there have been no case reports of GABRB2 truncating variants or copy number variations, and a loss of receptor function has also been confirmed by functional studies in three patients with different GABRB2 missense variants, it is possible that dominant-negative effects of p.(Val262Phe) caused the developmental and epileptic encephalopathy in this patient (Ishii et al., 2017; May et al., 2018). Detailed clinical information was described for 13 patients; two developed early myoclonic encephalopathy (EME) and three others had myoclonic epileptic encephalopathies (Hamdan et al., 2017; Ishii et al., 2017) presenting with MSE. In addition, the descriptions of EEG findings for two patients were similar to that of RHADS.

EPC is a variant of simple focal motor status epilepticus in which frequent repetitive muscle jerks, usually arrhythmic, continue over a prolonged period of time. The jerks are often stereotyped, affecting single muscles, muscle groups, entire limbs or large parts of a hemibody. Previous clinical and electrophysiological studies suggested that focal cortical myoclonus, EPC and focal motor seizures, bilateral EPC, and MSE comprise a spectrum from a single jerk to repetitive jerks and clonic motor seizures, and from focal jerks to generalized jerks through the intrahemispheric and transcallosal spreading of abnormal sensorimotor cortical discharges (Donaldson et al., 2012). MSE in our patient was easily provoked by sensory stimulation, indicating a neurophysiological characteristic of cortical-reflex myoclonus (Hallett et al., 1979).

According to the polygraphic study, the MSE corresponded to RHADS recorded from both centro-parietal regions. RHADS was first reported be a specific EEG finding for AS in 1986 and has been confirmed by many case series (Boyd et al., 1986; Wolf et al., 2009; van Westrhenen et al., 2018). RHADS was characterized by asymmetry between both hemispheres, intermittent appearance, a large slow wave with an amplitude ranging from 200 to 1,000 μV and a frequency at 1 to 3 Hz preceded by small polyspike discharges. Some mitochondrial diseases, such as myoclonic epilepsy with ragged-red fibres (MERRF), mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) and AS, are widely known to often associate with EPC, presumably affecting primary sensorimotor neurons (Lamperti and Zeviani, 2016). The GABRB2 variants are also suspected to excite primary sensorimotor neurons through reduced GABA inhibitory function (Ishii et al., 2017). In conclusion, the GABRB2 variants are associated with an AS phenotype characterized by treatment-resistant MSE and RHADS. In addition, they may represent an alternative aetiology of neonatal-onset AS without POLG1 mutation (Sofou et al., 2012).

Supplementary data

Summary didactic slides are available on the www.epilepticdisorders.com website.

Acknowledgements and disclosures

We thank Prof. Toshiyuki Yamamoto at the Institute of Medical Genetics, Tokyo Women's Medical University, who underwent the aCGH and targeted sequence analysis for POLG1. We are also grateful to the patients and their families for their participation in this study. This study was supported by Health and Labour Sciences Research Grants on rare and intractable diseases from the Ministry of Health, Labour and Welfare, Japan (H29- nanchitou-ippan-010).

We certify that we have read the journal's position regarding issues pertaining to ethical publications and confirm that this report is consistent with those guidelines.

None of the authors have any conflict of interest to declare.