Abstract
Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined
by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized
stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal
recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but
the prevalence is uncertain and no clear genotype-phenotype correlation has emerged
yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly
defined. Here we report a new family of patients with a typical HPX phenotype, linked
to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review
of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found
that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including
also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental
issues were reported in a third of the sample; interestingly, we found that these
problems, particularly when severe, were more common in homozygous than in heterozygous
patients. Additional clinical and preclinical studies are needed to define predictors
of adverse neurodevelopmental outcomes and underlying mechanisms.
Keywords
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Article info
Publication history
Published online: May 16, 2022
Accepted:
May 7,
2022
Received:
December 12,
2021
Footnotes
Conflict of interest and source of funding statement: The authors declare no conflict of interest or financial disclosures concerning the materials or methods used in this study or the findings specified in this article.
Consent: Parents of the siblings provided written informed consent for the genetic analysis and the acquisition of multimedia material.
Ethics approval: Ethics approval was not required. Only routine clinical management was made.
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
