A De Novo HECW2 Variant in a Patient with Acetazolamide-Responsive Episodic Ataxia.

Abstract

To the best of our knowledge, this is the first case to address episodic ataxia (EA) as a possible phenotypic feature of HECW2-related disorder. This single case study describes a 26-year-old female born at term with mild intellectual disability, neonatal hypotonia, and a history of febrile seizures who presented with paroxysmal events since the age of 2. These episodes include frequent falls due to imbalance, dilated pupils, vertigo, diaphoresis, nausea, vomiting, and nystagmus. Brain imaging was normal. A prolonged electroencephalogram (EEG) revealed interictal epileptiform discharges but failed to capture her clinical events. For several years, she was treated for presumed focal seizures with preserved awareness and trialed on adequate dosing of several antiepileptic medications without improvement. After 25 years, given the more prolonged nature of her episodes and the mild interictal cerebellar signs, empiric treatment with acetazolamide was initiated for a presumed diagnosis of EA. Acetazolamide treatment led to a dramatic reduction in event frequency and severity. The initial EA genetic panel was negative. Clinical exome sequence analysis revealed a novel pathogenic de novo missense variant in the HECW2 gene [c.3829 T > C;(p.Tyr1277His)], located in the HECT domain. HECW2 variants are associated with neurodevelopmental delay, hypotonia, and epilepsy. This study expands the genetic and clinical spectrum of HECW2-related disorder and adds EA to the phenotypic spectrum in affected individuals.

• Authors: Leticia Maria Tedesco Silva, Sonali Sharma, Isabelle Schrauwen, Jason Margolesky, Kamil Detyniecki
• Journal: Cerebellum (London, England) (Cerebellum) Vol. 22 Issue 5 Pg. 1029-1033 (Oct 2023) ISSN: 1473-4230 [Electronic] United States
• PMID: 35987951 (Publication Type: Case Reports, Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Acetazolamide
• Anticonvulsants
• HECW2 protein, human
• Ubiquitin-Protein Ligases

Topics

• Adult
• Female
• Humans
• Infant, Newborn
• Acetazolamide (therapeutic use)
• Anticonvulsants (therapeutic use)
• Ataxia (diagnostic imaging, drug therapy, genetics)
• Epilepsy
• Muscle Hypotonia (genetics)
• Ubiquitin-Protein Ligases (genetics)