Neurological features
- Epilepsy
Generalized epileptic seizures including absences, eyelid myoclonic, tonic and afebrile tonic-clonic seizures are the main clinical features of patients with HCN1 mutations. Some patients have focal seizures with a variable combination of symptoms including hypotonia, hypomotor behaviour, apnoea and cyanosis, tonic posturing, clonic jerking with or without secondary generalization. Median age at seizure onset is around 7 months (range: 30 hours to 72 months). In about 30-50% of patients seizures are triggered by febrile illness. The frequency is variable from rare, yearly episodes to monthly and multiple per day attacks. Overall nearly 60% of patients have drug-resistant epilepsy non-responsive to combinations of several conventional antiepileptic drugs.
- Intellectual disability
Approximately 70% of patients have a variable degree of intellectual disability ranging from mild to moderate or severe intellectual disability whereas autistic traits are more rare. Patients with mild phenotypes and fever-related seizures usually have a normal or borderline development and their epilepsy is usually drug-responsive. Patients with epileptic encephalopathies have severe impairment of motor and cognitive functions, have multiple per day seizures not responding to conventional antiepileptic drugs.
- EEG and neuroimaging findings
EEG recordings shows either focal, multifocal or generalized paroxysmal activity. Brain MRI is normal or shows non-specific brain abnormalities including parietal, occipital or fronto-temporal atrophy, thin corpus callosum and mild diffuse white matter hyperintensity. Only a minority of patients has acquired microcephaly.
Clinical variability
The severity of HCN1 epilepsy and associated comorbidities is highly variable. Some patients will be severely impaired while other will have a milder handicap. The age at onset and severity have been correlated to certain mutations or mutations located in particular domains of the channels. However, the type of genetic change and other factors than the mutation itself that are still unidentified likely contribute to modulate the phenotype.
Differential diagnosis
It can be difficult to differentiate patients with HCN1-epileptic encephalopathies or HCN1-genetic generalized epilepsy from similar disorders caused by mutations in others ion channel genes, including for example SCN1A. Genetic testing confirming the identification of a mutation in HCN1 is therefore the only reliable test confirming the diagnosis.
Atypical clinical presentation
In two cases, patients had a de novo HCN1 mutation associated with intellectual disability without epilepsy. The relationship between the mutation and the isolated intellectual disability phenotype in these patients has to be confirmed.