Case Report: Hyperekplexia & Encephalopathy

We describe 2 cases of a syndrome of hyperekplexia and encephalopathy in children of Puerto Rican descent (SHEEPR), caused by homozygosity for the same mutation. In both cases, there was no known consanguinity of the parents.

Baby GR

Baby boy GR was born at 36 weeks’ gestation by cesarean section, and hypertonia and apnea were noted at birth, prompting admission to the neonatal intensive care unit. Flexion body movements were triggered by sensory stimulation, sometimes associated with apnea and clonus.

GR’s initial EEG showed multifocal sharp waves (Figure 1). Initial evaluations were otherwise unremarkable (Table).

At presentation, GR was treated with multiple antiseizure medications (ASMs) that failed to ameliorate apneic episodes of stiffening until clonazepam was initiated. At age 3 weeks, based on clinical presentation and response to clonazepam, GR was diagnosed with hyperekplexia by a neurology consultant. Treatment with valproic acid was continued because of the EEG findings of multifocal sharp waves.

GR’s Course and Follow-up Care

GR’s development has been notable for spastic quadriparesis and severe but nonprogressive delays in motor and cognitive milestones. He sat independently at age 3 years and stood without support at age 4 years, at which time he also had surgical correction of bilateral pes cavus. At age 7 years, he walks with a walker and has severe difficulties grasping and holding objects. He can name 4 family members but has no other vocabulary. GR has mild sensorineural hearing loss and visual impairment, poor eye contact, and aggressive behavior.

GR continues treatment with valproic acid and clonazepam, and his last seizure was more than 2 years ago. His caregivers note episodes of exaggerated startle, and his physical exam is remarkable for startle on nose tapping, rotatory nystagmus, appendicular spasticity, and hyperreflexia (Table).

Baby LB

Baby girl LB was born full-term and admitted to the neonatal intensive care unit soon after because of seizure episodes triggered by loud noises or febrile illness. Seizure episodes were characterized by limb stiffening with twitching and eyes rolling back.

Although LB had a routine EEG without findings, long-term videoEEG showed generalized bursts of spike and polyspike wave epileptiform activity during sleep. LB’s brain MRI also showed nonspecific focal T2-weighted fluid-attenuated inversion recovery (T2 FLAIR) signal abnormality in her subcortical white matter (Figure 2).

LB was treated with phenobarbital for epilepsy with continued daily seizures until she was approximately age 1 year, at which time seizures occurred only during sleep. Later, these seizures were associated with unresponsiveness, urinary incontinence, and emesis.

LB’s Course and Follow-up Care

LB had gross motor delay, sitting at age 9 months and walking at age 21 months with toe walking. She had speech delay with a vocabulary of 4 to 5 words at age 22 months. Her clinical examinations are remarkable for esotropia, hypertonic diplegia, and hyperreflexia of her lower extremities. At her most recent evaluation at age 13 years, LB’s seizure episodes continue to occur 3 to 4 times per week, even with clonazepam treatment

Genetic Evaluations of GR and LB

Both GR and LB have putatively nonconsanguineous parents, and the families are reported to be unrelated as well. GR’s mother has a psychiatric disease and intellectual disability. Their parents are from Hatillo and Vega Alta, 2 towns on the northern coast of Puerto Rico.

For both GR and LB, a hyperekplexia gene panel found homozygosity for the c.1431_1452dup (p.Phe485Lysfs*53) variant in the glycine receptor β (GLRB) gene, located on chromosome 4q32.1. Chromosomal microarray for GR reported 1 region of homozygosity larger than 5 million base pairs (Mb), likely due to common ancestry, but this was a 15 Mb stretch at chromosome 5q14.1q15.

Summary of Cases

We have presented 2 cases of hyperekplexia in children of Puerto Rican descent who both have a novel homozygous frameshift variant in GLRB c.1431_1452dup (p.Phe485Lysfs*53) causing a complex hyperekplexia phenotype that includes developmental delay, spasticity, and epilepsy. Hyperekplexia manifested during the neonatal period and responded to clonazepam. Global developmental delays in both cases include delay in reaching motor milestones, speech delay, and learning disabilities. Both also have abnormal physical exam findings consisting of eye movement abnormalities, as previously described in the literature in a large family with hyperekplexia resulting from homozygous mutation c.596T>G in GLRB with eye misalignment disorder, spasticity, and hyperreflexia.¹

The ClinVar database reports F485KfsX53 as a variant of uncertain significance (VCV000970188.2). This entry may represent 1 of our patients. In the dbSNP database this variant (rs948239172) derives from its presence in the admixed American and other populations of the GnomAD study, with global frequency of 5 in 140,204. Neither database entry mentions homozygosity. Most reported pathogenic GLRB variants are predicted to lead to loss of function and include premature terminations, intragenic deletions, and splice site alterations. The SHEEPR variant presented here causes a frameshift at amino acid 485, replacing the last 13 amino acids with 53 novel residues. This c-terminal substitution replaces a highly conserved phenylalanine and tyrosine stretch (Figure 3), and thus would be predicted to be deleterious to GLRB function. In addition, tyrosine-485 of GLRB, changes into a hydrophilic lysine, likely to disrupt the predicted hydrophobic transmembrane domain in this region.

Discussion

Hyperekplexia is attributed to a dysfunction of the inhibitory glycine receptors (GlyR) found predominantly in the brainstem, retina, and spinal cord. The inhibitory GlyR is comprised of 3 ligand-binding α subunits (GLRA1) and 2 Β subunits (GLRB) that together form a heteropentameric ligand-activated ion channel found clustered in the postsynaptic membrane. Pathogenic variants in GLRA1 account for approximately 80% of hyperekplexia cases, whereas pathogenic GLRB variants account for 12% to 14% of cases.³ Nearly 80% of familial hyperekplexia is inherited in an autosomal recessive fashion, with autosomal dominant cases having milder symptoms. In addition, as is true in the cases presented here, GLRB variants cause greater neurologic impairments with moderate-to-severe developmental delay reported in up to 92% of individuals with such variants.⁴

Clinically, hyperekplexia is characterized by sudden generalized muscular rigidity with an exaggerated neuromotor response to a sudden external acoustic, tactile (eg, nose tapping), or visual stimuli that does not habituate and typically subsides during the first month of life.⁵ In the neonatal period, muscle stiffening often causes respiratory impairment and apnea that may be fatal. Later in life, the startle response causes frequent falls without loss of consciousness.

Epilepsy has been reported in 7% to 12% of hyperekplexia cases independent of genotype.⁴ A previous case report described hyperekplexia caused by a compound heterozygous mutation in the GLRB gene in a child who presented in the newborn period with normal testing and was initially diagnosed with epilepsy. Mild developmental delay occurred, but the individual was able to attend regular classes. Later, there were EEG findings of focal spikes; however, because seizure episodes had resolved with clonazepam and did not recur with discontinuation of ASMs, the diagnosis of epilepsy was revoked.⁶

Homozygous deleterious variations in GLRB are associated with phenotypes characterized by severe apnea attacks, and generally moderate-to-severe developmental delays.⁷ In contrast, persons with recessive pathogenic variants in the GLRA1 gene generally have mild cognitive delays. Routine blood tests, urinalysis, brain imaging studies, and EEG results are also normal.²

The mainstay of hyperekplexia treatment is clonazepam, a GABA-receptor agonist that enhances GABA-gated chloride-ion channel function and presumably compensates for the dysfunction of the glycine-gated chloride channel in hyperekplexia.⁸ As would be predicted by pathophysiology and clonazepam mechanism of action, efficacy is similar regardless of genotype. Both individuals reported here had a significant response to clonazepam.

Conclusions

Pathogenic GLRB variations are known to lead to more severe encephalopathy relative to pathogenic GLRA variations. We describe the severe phenotype caused by homozygosity for a frameshift GLRB variant in 2 reportedly unrelated persons with ancestry from a region of Puerto Rico. There are at least 3 other severe infantile encephalopathies with autosomal recessive inheritance described among Puerto Ricans, each with a variant specific to the island population, including TBC1-domain-containing kinase (TBCK)-related infantile hypotonia with psychomotor retardation and characteristic facies-3 (IHPRF3),⁹ferric chelate reductase 1 like (FRRS1L)-related developmental epileptic encephalopathy type 37 (DEE37),¹⁰ and charged multivesicular body protein 1A (CHMP1A)-related pontocerebellar hypoplasia type 8 (PCH8).¹¹ We suggest the SHEEPR phenotype is another recessive encephalopathy due to an ancestral mutation in this population.