Response to Steroids in IQSEC2-Related Encephalopathy Presenting with Rett-Like Phenotype and Infantile Spasms

Abstract

Introduction  IQSEC2-related encephalopathy is an X-linked childhood neurodevelopmental disorder with intellectual disability, epilepsy, and autism. This disorder is caused by a mutation in the IQSEC2 gene, the product of which plays an important role in the development of the central nervous system.

Case Report  We describe the symptomatology, clinical course, and management of a 17-month-old male child with a novel IQSEC2 mutation. He presented with an atypical Rett syndrome phenotype with developmental delay, autistic features, midline stereotypies, microcephaly, hypotonia and epilepsy with multiple seizure types including late-onset infantile spasms. Spasms were followed by worsening of behavior and cognition, and regression of acquired milestones. Treatment with steroids led to control of spasms and improved attention, behavior and recovery of lost motor milestone. In the past 10 months following steroid therapy, child lags in development, remains autistic with no further seizure recurrence.

Conclusion  IQSEC2-related encephalopathy may present with Rett atypical phenotypes and childhood spasms. In resource-limited settings, steroids may be considered for spasm remission in IQSEC2-related epileptic encephalopathy.

Introduction

IQSEC2-related encephalopathy is a newly recognized neurodevelopmental genetic disorder with intellectual disability (ID), autistic spectrum disorder (ASD), and childhood epilepsy. ¹ IQSEC2 gene protein, also known as BRAG1, is expressed early in the development of the central nervous system, and mutations of this gene have been described earlier with nonsyndromic X-linked intellectuology. ²

However, recent data point to the occurrence of syndrome with ID, epilepsy, ASD, hypotonia, speech delay, microcephaly, and facial dysmorphism, which is now recognized as part of the phenotypic spectrum of IQSEC2 variants. ^{3 4 5} Here is the case summary of a child whose clinical features add to the growing spectrum of IQSEC2-related encephalopathy and highlight the role of steroids in IQSEC2. To the best of our knowledge, this is the first case reported from India.

Case Presentation

A 17-month-old male child was referred to the neurology clinic with a history of severe developmental delay, poor social skills, and seizures. He had history of ventricular septal defect (VSD) detected at the age of 1 month with recurrent hospitalizations for lower respiratory infections. The device closure of the VSD was completed at 15 months. Born to a nonconsanguineous married couple with a healthy older female sibling, he had an uneventful birth following a cesarean extraction with a birthweight of 3.6 kg. There was no family history of ID, epilepsy, autism, or behavioral disorders.

At 3 months of age, he had one episode of seizure with uprolling of eyes and unresponsiveness lasting for 2 minutes, without any associated fever; for which no medical attention was sought. Parents noted that all milestones had been delayed by the age of 6 months. He was able to sit with support at the age of 1 year. He did not reach out to grasp objects, and he did not have any purposeful hand movements. He had a persistent abnormal hand clasping in the midline, mimicking wringing, and washing movements. Other abnormal movements noted were repetitive shaking of the head from side to side. Language development was severely delayed, with only cooing sounds even at the age of 17 months. He had poor eye contact and a lack of social reciprocity. At 13 months of age, he had left focal clonic seizures during fever with lower respiratory infection and anticonvulsant phenytoin was started. He was free from seizure for a few months after which he developed flexor spasms occurring in clusters at 16 months of age. Parents noted behavioral changes, irritability, exaggerated crying and disturbed sleep cycle with delayed sleep onset, and intermittent awakening after spasm onset. Subsequently, he had a regression of the motor milestones and lost the ability to sit.

Upon examination, he had a microcephaly with an occipitofrontal circumference of 44 cm falling below the third percentile. Facial features were normal except for deep eyes. He was dull, apathetic, and nonverbal, with minimal eye contact. Complex persistent midline stereotypies such as hand wringing and clasping were observed ( Video 1 ). Motor examination revealed truncal hypotonia with decreased tone in the upper limbs. The tone of the lower limbs was moderately increased with brisk deep tendon reflexes. The plantar reflex were bilateral extensor. The brain MRI performed at the age of 13 months was normal. The electroencephalogram (EEG) performed at this age was normal.

Following a change in seizure semiology, phenytoin was discontinued and sodium valproate was started and dose titrated. EEG at 17 months of age revealed modified hypsarrhythmia with episodes of generalized or regional voltage attenuation and absence of normal sleep structures. Epileptiform discharges in the form of repetitive bursts of generalized polyspike wave discharges and intermittent multifocal spikes were noted ( Fig. 1A ). Additional investigations to exclude metabolic etiology such as arterial lactate, ammonia, creatinine, liver function test, tandem mass spectrometry, serum vitamin B12, serum folic acid, and serum homocysteine were normal. After electroclinical characterization of seizures with video EEG recording, injectable ACTH was advised. However, a trial of steroid therapy was finally considered due to financial constraints. Intravenous pulse of methyl prednisolone at a dose of 30 mg/kg/day for 5 days was administered, followed by oral prednisolone initiated at 2 mg/kg for 2 weeks and tapered over next 2 weeks. During this period, he was continued on 20 mg/kg/day of valproate. He was regularly followed up with clinical evaluation and EEG. Spasms decreased in frequency by the end of first week and stopped by second week. He had improvement in eye contact and visual tracking. Response to sound and alertness improved. He recovered the lost motor milestone and was able to sit with support.

Fig. 1.

( A ) EEG prior to steroid therapy: sleep record with multifocal high amplitude independent epileptiform abnormalities over bilateral frontocentroparietal, and temporal regions, and left posterior head, with episodes of generalized and regional voltage attenuation (arrows) and paucity of normal sleep transients. Sensitivity: 14 μV/mm, high frequency filter: 70 Hz, low frequency filter: 0.5 Hz, paper speed: 3 cm/s, sampling rate 256 Hz, average reference. ( B ) EEG performed 6 months post pulse steroid, showing well-formed sleep spindles (arrow) with bilaterally independent left temporal and right posterior head spike wave discharges, which were less frequent compared with pretreatment. Sensitivity: 14 μV/mm, high frequency filter: 70 Hz, low frequency filter: 0.5 Hz, paper speed: 3 cm/s, sampling rate 256 Hz, average reference. EEG, electroencephalogram.

His repeat EEG with sleep record at 6 months showed improvement in the background with reappearance of sleep spindles and intermittent left frontotemporal sharps and spikes ( Fig. 1B ). Spike-wave index showed a decrease of more than 50% from 167 spike-wave discharges to 55 spike-wave discharges during a 10-minute period of sustained sleep at 6 months post steroid initiation compared with baseline EEG. In addition to medical management, physiotherapy, sensory stimulation, and speech therapy have begun. The maintenance dose of valproate has been continued. He has been free of seizures for 10 months since steroid therapy was completed and has been on regular follow-up for the past 1 year since spasms began. However, he continues to have significant speech and motor delay with autism. Next generation sequencing (NGS) was planned to look for pathogenic mutations in view of early onset epileptic encephalopathy, global delay, microcephaly, hypotonia, and autism. Written consent for clinical testing was provided by the parents. Clinical exome sequencing revealed a novel variant in the IQSEC2 gene. A hemizygous duplication of 14 bases in exon 5 of the IQSEC2 gene at position chrX: 53251127_53251128dupGGGTGGCAGTTCAG [NC_000023.10:g.53251127_53251128dupGGGTGGCAGTTCAG; GRCh38.p13 build; Sequencing depth: 47x] that leads to shifting of reading frame ultimately resulting in a premature stop codon (p.Ser484Ter; ENST00000642864.1) and theoretically many more stop codons downstream. Various in silico analyses like mutation taster predicted this variant to be disease causing. The variant has never been reported in 1,000 genomes, genome aggregation database (gnomAD) and internal databases. Phenotype caused by pathogenic variants in this gene matches the phenotype in our proband. Collating all evidence, this novel variant was considered to be likely pathogenic pending a segregation analysis. To determine whether this was a de novo or an inherited variant, the parents' genetic testing was recommended and parental consent is awaited.

Discussion

The emergence of NGS in the field of molecular genetics has enabled pediatric neurologists to gradually employ it for establishing the etiology in the erstwhile idiopathic syndromes of epilepsy. ⁶ Searching for the etiology of this 17-month-old male child with overall developmental delay, autism, epileptic encephalopathy with infantile spasms, microcephaly, and hand wringing stereotyped movements led to the identification of an X-linked genetic disorder with IQSEC2 gene mutation. IQSEC2 gene mutations were previously reported in families with X-linked ID. ^{2 3} Recent literature has shown that IQSEC2 mutations cause a neurodevelopmental disorder with many features starting early in life. ^{3 4 5 7} The IQSEC2 gene is placed on chromosome Xp11.22 and its product, the BRAG1 protein, is located on the excitatory synapse as a part of the N-methyl- D-aspartic acid receptor complex, and plays a role in synaptic plasticity and dendritic spine formation. ⁸ These proteins are required for trafficking of α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid receptors from the surface of hippocampal neurons, thus playing an important role in learning and memory processes. ⁸

Mutations in IQSEC2 gene account for nearly 2% of patients with ID and epilepsy referred for exome sequencing. ⁹ Epilepsy and even epileptic encephalopathy, such as infantile spasms and Lennox–Gastaut syndrome (LGS), have been noted as part of spectrum. Previously reported cases had onset of seizures ranging from age of 7 months to 4 years of age; the child presented here had an early onset at 3 months of age. ¹⁰ Male children tend to have an earlier onset of seizures with more severe epilepsy compared with females. Varied semiologies including infantile spasms, complex partial seizures, atonic, myoclonic, tonic, absence, focal motor seizures, and generalized tonic-clonic seizures have been reported in this syndrome. ¹¹

The striking feature in this child was the presence of continuous complex midline stereotypies in the form of bilateral hand wringing and hand washing movements. Such stereotypical hand movements have been classically described and studied in children with Rett syndrome. Recently, there have been various genetic disorders apart from FOXG1 , CDKL5 , and MEF2C added to the list of Rett-like disorders, among which IQSEC2 mutations have also been mentioned. ¹² Rett-like phenotype has also been noted in female children with IQSEC2-related encephalopathy. ^{13 14} Midline stereotypies may be a useful clue for diagnosing this condition when seen in a child with developmental delay, regression, autism, microcephaly, and seizures. De novo truncating mutations, causing loss of function, may be responsible for the severe phenotypes with Rett-like symptoms and epileptic encephalopathy in either males or females, whereas inherited missense variants lead to milder phenotypes. ^{4 7 14} Apart from this, the severity of the phenotype may also depend on the domain of gene involved in the mutation, thereby affecting function variably. Our patient had a truncating mutation, which led to a severe Rett-like phenotype.

Other reported clinical features include strabismus, hypotonia, scoliosis, feeding difficulties, drooling, paroxysms of laughter, and facial dysmorphism such as deep-set eyes, full lips, and frontal upsweep of hair. ^{3 5 11} Our case also had VSD that has so far not been described in other series. Other uncommon associations reported are posterior urethral valve and precocious puberty. ³ Females generally have milder symptoms in comparison to males with this disorder. ^{3 4} Imaging of the brain may be normal or show delayed myelination, thin corpus callosum, and cortical atrophy. ^{5 11} Management of these children requires a multidisciplinary approach and seizures may be pharmaco-resistant needing multiple antiepileptic drugs. Hormonal therapy such as ACTH/steroids and vigabatrin are indicated as first line in the treatment of infantile spasms. ¹⁵ Other alternatives are antiepileptic drugs such as valproate, nitrazepam, pyridoxine, topiramate, zonisamide, and lamotrigine. Good response to intravenous methyl prednisolone pulse followed by oral steroids has been noted in several studies with remission in 50 to 64% of treated infants. ^{16 17} This regime is worth considering in resource limited settings as it is less expensive, easily available, and easy to administer. The noteworthy point in our case was the remarkable response to steroids, with the child being rendered seizure free, recovering the lost milestones and exhibiting cognitive improvement. We postulate an underlying immune-mediated mechanism in epileptogenesis, even in genetic epileptic encephalopathies. Further studies are warranted to better understand the pathogenesis and response to immunotherapy in large cohort.

Conclusion

Video 1 Videoclip of the male child demonstrating complex midline hand wringing, clasping, and washing stereotypies. Video keywords: epileptic encephalopathy; IQSEC2; midline stereotypies.

Download video file ^{(755.9KB, mp4)}

IQSEC2 variants may present in childhood with Rett-like phenotype, late-onset infantile spasms with epileptic encephalopathy, developmental regression, microcephaly, ASD, and midline stereotypies. The syndrome may have a more severe phenotype in males, and trial of pulse steroids is worth considering in IQSEC2-related encephalopathy with infantile spasms.