Knowledge on rare diseases and orphan drugs

Prevalence is ~1:100,000 in children up to the age of 16 (calculated on Danish population), but is probably underestimated.

Onset is before age of 18 months, initially presenting with dystonic episodes (torticollis, opisthotonos) and abnormal ocular movements (monocular nystagmus) in a hypotonic infant with delayed motor milestones. Initial hemi- or tetraplegic episodes may go unnoticed, appearing as reduced awareness or marked hypotonia. Children progressively develop recurrent hemiplegia lasting minutes to days, occurring monthly to daily. Patients may lose developmental milestones during prolonged attacks, but most regain them slowly over weeks or months. Paroxysmal dyspnea and autonomic dysfunction can also occur. Symptoms resolve with sleep but frequently recur upon awakening. With age, permanent neurologic deficits become prominent and epilepsy may develop. Episodes may be triggered by stress, illness, excitement, bathing, hot or cold weather, noise, and bright lights.

80% of cases present de novoATP1A3 pathogenic variants (PV), coding for the a3 subunit of the sodium-potassium pump, highly expressed in the cortex, basal ganglia, cerebellum, and to some extent in the heart. The three most common PVs are D801N, E815K (more severe), and G947R (milder). Reduced ATPase function, could lead to increased intracellular calcium via N-type voltage-gated calcium channels, increasing neuron excitability. Additionally, as ATP1A3 is primarily expressed in GABAergic inhibitory interneurons, reduced expression can also increase excitability, resulting in spreading depolarization and seizures. Other genes identified include ATP1A2, RHOBTB2, CLDN5, SCN2A, SLC2A1, and TBC1D24.

The Aicardi criteria diagnosis of AHC includes: onset before 18 months, episodes of hemiplegia, tetraplegia, and other paroxysmal disturbances, disappearance upon sleep, and developmental delay. A revision was proposed in 2021 to separate symptoms in Essential, Major and Minor criteria and include the presence of an ATP1A3 PV. Genetic screening should be offered early on clinical suspicion. There is no specific biomarker and MRI is usually normal. Video EEG is valuable for distinguishing epileptic from other attacks.

The differential diagnosis includes hemiplegic migraine, epilepsy and epileptic encephalopathy, Moyamoya disease, pyruvate dehydrogenase deficiency, MELAS, GLUT-1 deficiency syndrome, and neurotransmitter disorders.

Antenatal or preimplantation diagnosis can be proposed to affected individuals and their parents when a PV has been identified in the family.

Transmission is autosomal dominant for most genetic variants except a few TBC1D24-related cases. Penetrance is usually complete for the variants associated with severe forms but can be incomplete for PVs associated with a milder form (ex: D923N). Patients (or unaffected carriers, in the rare cases with incomplete penetrance) can thus transmit the disorder to their offspring with a chance of 50%. The recurrence to siblings of a child with a de novo PV is rare and related to the risk of germline mosaicism (2-3%).

For acute management, avoid triggers and use relaxation or pharmacological sleep induction. Preventive therapies include flunarizine (calcium channel blocker), topiramate, other antiseizure medication, ketogenic diet, or acetazolamide. Epilepsy should be treated with standard procedures. A cardiological workup is mandatory due to the increased risk of cardiac arrhythmias. Sleep studies are recommended. Developmental and psychiatric evaluations should be offered along with occupational, physical, and speech therapy.

AHC was considered a fixed entity, with only a minority of cases displaying regression, mostly with the E815K variant. However, recent research shows that non-paroxysmal symptoms show some progression with age.

Last update: May 2025 - Expert reviewer(s): Dr Carmen FONS | EpiCARE* - Pr Gaëtan LESCA | EpiCARE* - Dr Eleni PANAGIOTAKAKI | EpiCARE* - Dr Tsveta SCHYNS-LIHARSKA | EpiCARE*

* European Reference Network