Authors: Luis F. Escobar, Caroline Estes, Francis J Reynoso, Hunter R. Underhill, Audrey Samuelson.
Hereditary hyperekplexia (HPX) is an inherited neuronal disorder characterized by exaggerated startle responses and stiffness to unexpected stimuli. In the newborn period, the phenotype may present as decreased range of motion of all joints, neonatal arthrogryposis or generalized neonatal hypertonia [1]. HPX is associated with three main genes: GLRA1, GLRB, and SLC6A5 [2]. We report three unrelated families with variants in the GLRA1 gene that expand the understanding of the clinical presentation of affected individuals with GLRA1 variants. No variants observed have been previously reported, two of them are familial and one a de-novo change. One of the families presents three generations of affected individuals with neonatal joint contractures. All three probands in this report present with significant developmental delay, speech delay, feeding difficulties, and motor delay. Hearing loss was seen in one of the patients. All patients appear to present with central hypotonia and two of them present with central hypotonia and peripheral hypertonia with hyperreflexia.
Currently it has been suggested that GLRA1 dysfunction results in failure of inhibition of potent neurotransmitters in the central nervous system [3]. This may explain the intrauterine signs and perinatal presentation of neuromuscular dysfunction in the reported patients. We believe that the information presented here helps to understand the natural history of hyperekplexia. Early recognition of this rare disorder is important due to the high risk of sudden infant death in children due to apnea and the potential to implement rescue treatments. Based on these cases, patients with genetic variants in the GLRA1 gene may present with congenital arthrogryposis that improves with time and results in a milder form of distal joint contractures in adulthood. Patients with hyperekplexia may have a better prognosis than other forms of arthrogryposis and we suggest that GLRA1 gene testing should be included in neonatal arthrogryposis panels.
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