Case Report: Compound heterozygous KCTD7 variants in two siblings presenting with myoclonic epilepsy and ataxia

Biallelic variants in KCTD7 have been associated with progressive myoclonic epilepsy (PME), a rare autosomal recessive disorder characterized by early-onset epilepsy, cognitive decline, myoclonus, and ataxia.

Whole-exome sequencing was first performed in the elder sister to identify candidate variants, followed by in silico pathogenicity prediction. Sanger sequencing was then used to validate the variants in both parents and the younger brother.

We report two siblings with progressive myoclonic epilepsy (PME) carrying compound heterozygous KCTD7 variants: c.334C > T (p.Arg112Cys), a paternally inherited variant previously reported in homozygous form and currently classified as likely pathogenic, and c.640C > T (p.Arg214Trp), a novel maternally inherited variant currently classified as of uncertain significance. Both patients presented between 2 and 3 years of age with gait instability, myoclonic seizures, and developmental regression. EEG revealed background slowing, multifocal spike-slow wave discharges, and electrical status epilepticus during sleep. Brain MRI findings were initially unremarkable despite progressive neurological deterioration. Whole-exome sequencing and Sanger validation confirmed the variants and their segregation. In silico tools predicted both variants to be deleterious, and structural modeling using PyMOL and I-Mutant 3.0 demonstrated that both variants likely disrupt local residue interactions and reduce protein stability. Both patients received antiepileptic therapy and immunomodulatory treatment, including intravenous methylprednisolone and immunoglobulin. The proband achieved seizure control and improved gait following immunotherapy, though cognitive deficits persisted. The younger sibling exhibited a more severe disease course, with progressive cognitive decline, speech and visual impairment, and loss of independent ambulation, despite partial seizure control. These findings expand the genetic and phenotypic spectrum of KCTD7-related PME and suggest that immunotherapy may confer partial clinical benefit in selected cases.

This case expands the variant spectrum of KCTD7-related disorders and emphasizes the utility of comprehensive genetic testing in early-onset neurodegenerative epileptic syndromes. Functional studies are needed to clarify the clinical significance of the novel KCTD7 variant.