Hyperekplexia is a rare non-epileptic paroxysmal disorder characterized by a marked startle response and hypertonia to auditory, tactile, or visual sudden external stimuli. GLRA1, SLC6A5, GLRB, and ATAD1 gene pathogenic variants have been identified in these patients. The girl was born 39+1 weeks and admitted to the neonatal intensive care unit with spasm-like contractions and followed by breath holding. Except for transient hyperammonemia, neurologic and metabolic tests were normal, and there was no seizure-like movement during hospitalization. In the 4th month of her life, the patient had spasm-like findings with stimulation, and the symptoms were controlled with clonazepam, considering hyperekplexia. Clinical exome sequencing revealed a previously undescribed homozygous variant [c.748T>C; p.(Ser250Pro) in exon 4] in the SLC6A5 (NM_004211.5) gene. Sanger sequencing confirmed the c.748T>C variant in the family: both parents were heterozygous carriers, while the brother was homozygous. Her sibling also had stimulus-induced crying and stiffness in infancy, but these resolved within months without treatment, and his developmental milestones have been age-appropriate. This case highlights the importance of recognizing hereditary hyperekplexia in the differential diagnosis of neonatal seizures and supports the potential pathogenic relevance of the SLC6A5 c.748T>C (p.Ser250Pro) variant, particularly in benign, nonrecurrent cases with transient hyperammonemia from catabolic stress and glycine transporter dysfunction.

Hereditary hyperekplexia (HKPX) is a rare neurogenetic disorder caused by mutations in glycine signaling genes, such as GLRB. We report two neonates with autosomal recessive HKPX2 due to a novel GLRB mutation (c.1414C>T, p.Arg472*). Case 1, a 1-month-old female, presented with severe startle responses and tonic episodes, normal EEG, and no developmental delays. Case 2, a 2-week-old male, showed similar symptoms but with generalized rhythmic ictal fast activity on EEG. Both had consanguineous parents and unremarkable brain MRIs. Whole exome sequencing identified the same homozygous GLRB mutation in both cases. Treatment with Clonazepam and Levetiracetam significantly improved symptoms. This is the first report of the c.1414C>T (p.Arg472*) mutation in GLRB, expanding the genetic spectrum of HKPX2. The differing EEG findings highlight the disorder's phenotypic variability. Early diagnosis and treatment are crucial to prevent complications like hypoxia and SIDS. This article reports a novel GLRB mutation in two neonates with autosomal recessive HKPX2, presenting with divergent EEG findings.

To report two pediatric cases of hyperekplexia in a small city of São Paulo state, Brazil. Two female patients, one aged three years and six months and one aged five months, receiving care from an APAE (Association of Parents and Friends of People with Disabilities) unit, were diagnosed with hyperekplexia 1, a neurological disorder characterized by an excessive startle response. Hyperekplexia cases can be divided into three subgroups: hereditary, sporadic, and symptomatic. Several specialists have examined patient 1 since she was three weeks old, leading to two initial diagnostic hypotheses (childhood chronic non-progressive encephalopathy and spastic cerebral palsy). She was diagnosed with hyperekplexia 1 at eleven months when a genetic test revealed changes in the GLRA1 gene. Patient 2, at birth, presented hyperextension of both legs, low-set ears, cranial asymmetry, prominent occiput, and tremors in the lower limbs. After several tests and evaluations, the final diagnosis was confirmed at three months old. Her family history indicates the possibility of hereditary hyperekplexia. The cases were compared with information obtained through a bibliographical review. Both patients presented several symptoms associated with hyperekplexia, including neurological symptoms such as increased startle response, convulsions, and hypertonia, which were alleviated with appropriate treatment. So far, combining multidisciplinary assistance with drug treatment, particularly anxiolytics and anticonvulsants, with clonazepam being the most used, has significantly contributed to both patients' improved quality of life. However, physical symptoms, such as hip dislocation and clubfoot, require future surgical intervention. Relatar dois casos de pacientes pediátricos com hiperecplexia do interior de São Paulo, Brasil. Duas pacientes, uma com três anos e seis meses e outra com cinco meses, são atendidas por uma unidade da APAE (Associação de Pais e Amigos dos Excepcionais) e foram diagnosticadas com hiperecplexia 1, um transtorno neurológico caracterizado por uma desordem de sobressalto excessivo. Casos de hiperecplexia podem ser divididos em três subgrupos: hereditário, esporádico e sintomático. Diversos especialistas examinaram a paciente 1 desde que tinha três semanas de vida, levando a duas hipóteses diagnósticas iniciais (encefalopatia crônica não progressiva infantil e paralisia cerebral espástica). Ela foi diagnosticada com hiperecplexia 1 aos onze meses, quando constatada uma mutação no gene GLRA1. A paciente 2, após o nascimento, apresentou hiperextensão de ambas as pernas, orelhas de implantação baixa, assimetria craniana, occipital proeminente e tremores nos membros inferiores. Aos três meses, após testes e avaliações, chegou-se ao diagnóstico final. O histórico familiar da paciente 2 indica a possibilidade de hiperecplexia hereditária. Os casos foram comparados com informações obtidas por revisão bibliográfica. Ambas pacientes apresentaram vários sintomas associados à hiperecplexia, incluindo sintomas neurológicos, como resposta de sobressalto aumentada, convulsões e hipertonia, que foram amenizados com tratamento adequado. Até o momento, a combinação de assistência multidisciplinar com tratamento medicamentoso feito com ansiolíticos e anticonvulsivantes, sendo o clonazepam o medicamento mais utilizado, contribui significativamente para uma melhor qualidade de vida das pacientes. No entanto, sintomas físicos, como luxação de quadril e pé torto, requerem intervenção cirúrgica futura.