Different missense-, nonsense- and frameshift-variants have been identified in patients with a KCNC1-related disorder. A clear genotype-phenotype correlation exist for two recurrent missense variants (p.Arg320His and p.Ala421Val). For all other reported variants, a larger patient collective and further investigation are needed to elucidate the genotype-phenotype correlation.
Myoclonus and Ataxia due to Potassium channel mutation; MEAK-Syndrome (c.959G>A, p.Arg320His)
• Age at onset: 3 – 15 years of age (mean ~10 years)
• de novo, familial and germline mosaicism cases reported
• Progressive myoclonus (in all patients)
• Seizures (generalized, tonic-clonic, myoclonic)
• Ataxia
• Cerebellar atrophy
• cognitive decline (some patients)
• wheelchair dependency by adulthood (some patients)
• developmental delay (very rare)
Developmental and Epileptic Encephalopathy with Ataxia (c.1262C>T, p.Ala421Val)
• de novo
• Global developmental delay
• Seizures (absence, generalized, tonic-clonic, myoclonic)
• Ataxia
• Muscular hypotonia (some patients)
Intellectual disability without seizures (c.1015C>T, p.Arg339Ter; c.1196C>T, p.Thr399Met; c.1474C>T, p.Gln492Ter; c.950G>A, p.Arg317His)
• de novo and familial cases
• Global developmental delay
• Mild to moderate intellectual disability
Others:
Mild non-progressive myoclonus or “tremor” (c.623G>A, p.Cys208Tyr)
• Age at onset: 2 years
• de novo
• Mild non-progressive myoclonus or “tremor”
• Mild cognitive decline
• 1 patient
Epilepsy of infancy with focal migrating seizures (c.1538C>T, p.Ala513Val)
• Infancy onset
• de novo
• Severe intellectual disability
• Intractable early-onset epilepsy (focal migrating seizures)
Developmental and Epileptic Encephalopathy with MRI Abnormalities (c.1538C>T, p.Arg317Ser)
• Mild developmental delay
• Inherited from mother (mother showed ataxia)
• Seizure onset 14 years (myoclonic jerking, gaze deviation followed by secondary generalization)
• MRI: “multiple T2/fluid attenuated inversion recovery (FLAIR) cortical signal abnormalities in bilateral frontal, temporal, parietal and occipital lobes, without gadolinium contrast enhancement or restricted diffusion”
KCNC1