Abnormal neurodevelopment outcome in case of neonatal hyperekplexia secondary to missense mutation in GLRB gene

Abstract

Hyperekplexia is an exaggerated startle to external stimuli associated with a generalised increase in tone seen in neonates with both sporadic and genetic predisposition. This is an uncommon neurological entity that is misdiagnosed as seizure. A 28-days-old infant was admitted to us with characteristic intermittent generalised tonic spasm being treated as a seizure disorder. The infant had characteristic stiffening episode, exaggerated startle and non-habituation on tapping the nose. Hyperekplexia was suspected and confirmed by genetic testing (mutation in the β subunit of glycine was found). Initial improvement was seen with the use of clonazepam, which was not sustained. At the age of 4.5 years, the child is still having neurobehavioural issues like hyperactivity and sensory hyper-responsiveness. Usually, hyperekplexia is benign in nature. We report a case of hyperekplexia with non-sense mutation in the β subunit of GlyR gene having abnormal neurodevelopmental findings at 4.5 years.

Background

Hyperekplexia, also called startle disease, is a rare genetic disorder seen in neonates characterised by generalised muscle rigidity, excessive startle reaction to sudden unexpected auditory, tactile and somatosensory stimuli, and sometimes tonic spasms. In most cases, the mutation is found in the α1 and β subunits of the presynaptic glycine receptor gene GLRA1. Startle response to nose tapping or any other stimulus is present in most cases. Electroencephalogram (EEG) is usually normal. Clonazepam is the first-line drug. Although stiffness resolves by 2–3 years of age, an exaggerated startle persists. The disease is usually benign with normal development between 2 and 7 years in most of the affected babies.¹ We report a case of neonatal hyperekplexia presented to us on day 28 of life with exaggerated startle response to tactile and auditory stimuli. On clinical suspicion, clonazepam was started. Next-generation sequencing revealed mutation in the β subunit of GLRA1 gene. At 4.5 years of age, the baby is having significant neurological issues in the form of hyperactivity and sensory processing.

Case presentation

A male baby was admitted at 28 days of life with a history of abnormal movements present since birth. The baby was born at 39 weeks gestation by normal vaginal delivery to non-consanguineous marriage. The antenatal period was uncomplicated. On the first day of life, the baby developed abnormal movements noticed while feeding. He was treated with antibiotics and anticonvulsants. Because of the persistence of abnormal movements, the baby was brought to us on day 28 of life for further evaluation. The mother noticed stiffness of the body during feeding and startle response to the lightest of auditory or tactile stimuli. The stiffness decreased during sleep. There was no history of feeding difficulties or any clonic movements. There is no family history of any neurological or seizure disorder or any neonatal death.

At admission, the baby was haemodynamically stable, alert, awake, interested in surroundings with normal tone and reflexes. On examination, while doing glabellar tap or trying to elicit moro reflex, the baby had generalised hypertonia with opisthotonus posturing lasting for approximately 30 s not associated with autonomic disturbance. He also had an exaggerated startle response. There were tonic spasms mimicking titanic spasms but trismus was not significant (videos 1 and 2, figure 1). On careful evaluation, the mother has received 2 doses of tetanus toxoid during pregnancy and cord care was appropriate. There was a history of increased movements felt during pregnancy.

Video 1.

Download video file ^{(7.2MB, mp4)}

DOI: 10.1136/bcr-2020-236152.video01

Video 2.

Download video file ^{(2.6MB, mp4)}

DOI: 10.1136/bcr-2020-236152.video02

Figure 1.

Generalised stiffness with hypertonia.

Investigations

The baby was investigated to find out the cause of seizures. Electrolytes including ionised calcium and magnesium was normal. Blood sugars were normal. Ammonia and lactate levels were also within normal limits. Tandem mass spectrometry was normal. The sepsis screen and cerebrospinal fluid examination were normal.

Electroencephalogram (EEG) and cerebral MRI were normal.

Hyperekplexia gene panel analysis by next-generation sequencing revealed homozygous base substitution of cytosine to thymine (Chr4: 158059984; C>T) resulting in a premature stop codon at position 212 (p.R212Ter) in exon 7 of GLRB gene. This mutation results in a defective GLRB which will produce a truncated protein with only the first 211 amino acids out of 497 residues present in the wild-type GLRB.

Differential diagnosis

The baby had generalised tonic seizures with opisthotonos posturing starting from day 1 of life in the absence of a history of asphyxia or any drug intake of the mother. The tone was normal during sleep. In between tonic episodes, the child was completely normal. On examination, tonic spasms could be induced with a glabellar tap. That is why the history of retanus toxoid intake was evaluated in the antenatal period to rule out tetanus neonatorum.

Generalised tonic seizures may represent posturing only and are frequently associated with severe intraventricular haemorrhage. Approximately 85% of generalised tonic seizures are not accompanied by electrographic activity and autonomic phenomenon. Fifteen per cent of generalised tonic seizures accompanied by electrographic changes do have autonomic phenomenon. Thus, these generalised tonic events may represent ‘brain stem release’ phenomena and uninhibited extensor posturing that appears similar to tonic stiffening in patients with severe brain injury.

A normal cranial ultrasound in our case ruled out intraventricular haemorrhage as cause.

Neonatal epilepsy syndromes like early infantile epileptic encephalopathy are accompanied by tonic spasms. EEG shows burst suppression pattern and child is in encephalopathy. In our case, EEG was normal and child was well between spasms.

With a characteristic pattern of generalised stiffness in response to tactile and auditory stimuli, hyperekplexia was thought off.

Issac’s syndrome and Schwartz-Jampel syndrome were the other differentials owing to generalised stiffness. Babies with Issac’s syndrome usually do not respond to benzodiazepines. In our baby, episodes of stiffness reduced after starting clonazepam. Babies with Schwartz-Jampel syndrome usually have facial dysmorphism which was absent in our case.

Tandem mass spectrometry was done to rule out inborn errors of metabolism.

Underlying brain malformation was kept as differential owing to seizure episodes starting on the first day of life, which was ruled out by normal cerebral MRI.

Treatment

The baby was started on clonazepam at a dose of 0.1 mg/kg/day in two divided doses. Spasm frequency decreased initially, but after 3 days, the baby started having more spasms. So levitaracetam was added in a dose of 10 mg/kg/dose two times per day. He responded and was discharged on day 40 of life on both clonazepam and levitaracetam. The baby was advised to be in constant follow-up to paediatric neurologist.

Outcome and follow-up

The child was under regular follow-up and the dose of anticonvulsants was titrated. At present, the child is 4.5 years old and is still having intermittent bouts of tonic spasms that need temporary escalation of clonazepam doses. The present baseline requirement of clonazepam is 0.5 mg per day in divided doses and any attempt to wean this further precipitates flurry of tonic spasms. Significant neurodevelopmental issues in the form of hyperactivity and sensory processing are ongoing. He remains restless and on the go and has faced significant challenges for adjustment into school. Whether some of these neurobehavioural issues are secondary to benzodiazepines or inherent is difficult to ascertain but plausibly a combination of both these factors.

Discussion

Hyperekplexia or startle disease or congenital stiff-man syndrome is a movement disorder that usually presents in infancy and is misdiagnosed as seizures. It is characterised by generalised muscle rigidity, excessive startle and stiffness in response to auditory, tactile or visual stimuli.²

Mutations in several inhibitory glycinergic genes have been found in patients with hyperekplexia. These genes encode either postsynaptic inhibitory glycine receptor (GlyR; GLRA1&GLRB) or presynaptic glycine transport (GlyT2; SLC6A5).³ In our case, mutation in β subunit was found. Initially thought to follow autosomal dominant inheritance, recent literature reveals autosomal recessive as the main mode of inheritance with autosomal dominant present in only 16% of cases.⁴ Approximately 200 genetically proven cases of hyperekplexia have been reported in the literature.⁴

Age at presentation varied between 1 week and 6 months with a mean of 3.3 months.¹ Early manifestations include abnormal responses to unexpected auditory, visual and somaesthetic stimuli such as sustained tonic spasm, exaggerated startle response, and posture with flexion of forearm and legs, clenched fists and vacant stare. Consistent generalised flexor spasm in response to the tapping of the nasal bridge (non-habituation) is the clinical hallmark of hyperekplexia which was present in our case.⁵ The increased tone is apparent only when the infant is awake. The EEG during spasms is not accompanied by epileptic discharges. Nerve conduction studies are also normal. Electromyography shows a characteristic pattern in the form of permanent muscular activity with periods of electrical quietness.⁶

Common differentials include neonatal tetanus, phenothiazine toxicity, neonatal drug withdrawal syndrome, Issac’s syndrome and Schwartz-Jampel syndrome. These seizures are often therapy-resistant and the prognosis is generally poor.

Hyperekplexia is considered to be benign in nature. A case series of 39 children with hyperekplexia reported development assessment at 2 years within normal range.¹ However, recent case series of 16 children in Jordan with hyperekplexia reported abnormal neurodevelopmental outcomes in the form of motor delay (43.8%), speech delay (25%), global developmental delay (6.3%) and autism spectrum disorder (6.3%).⁷ Of note, all children in this case series have autosomal recessive disease. The index child in our case is facing problems at 4.5 years of age in the form of hyperactivity and sensory issues.

These babies are also at increased risk of sudden infant death syndrome in the first 2 years of life due to central apnoea secondary to brainstem dysfunction. Although the stiffness resolves by approximately 3 years of age, exaggerated startle remains resulting in frequent falls and injury.⁸

Clonazepam (0.05–0.1 mg/kg/day), a gamma-aminobutyric acid receptor agonist, is the treatment of choice. The degree of stiffness, however, may not be significantly influenced by clonazepam.⁹ No definite guideline for the duration of therapy but the drug can be tapered slowly once the symptoms subside. A simple manoeuvre like forced flexion of the head and legs towards the trunk is known to be lifesaving when prolonged stiffness impedes respiration.¹⁰

Patient’s perspective.

I am happy with my son’s treatment. My child is having delayed milestones and seizures for which he is getting drugs and is under regular follow-up of doctor.

Learning points.

• In any infant presenting with hyperalert gaze and constant interest in surroundings combined with exaggerated startle and generalised stiffness in response to auditory, visual or tactile stimulus, hyperekplexia should be suspected.

• Consistent generalised flexor spasm in response to tapping of the nasal bridge (non-habituation) is the clinical hallmark of hyperekplexia.

• Electroencephalogram is usually normal. Genetic analysis is usually required to confirm the diagnosis.

• Clonazepam in dose of 0.05–0.1 mg/kg/day is the treatment of choice.

• Usually hyperekplexia carries a favourable development outcome.