Alternating Hemiplegia of Childhood (AHC) is a rare and complex neurological disorder that typically manifests in infancy. It is defined by recurrent episodes of hemiplegia, temporary paralysis that often affects one side of the body. AHC is ultra-rare, affecting about one in a million children. It is a lifelong condition, though the name suggests childhood limitation, and involves a broad spectrum of neurological symptoms. The onset of the first symptoms generally occurs before 18 months of age, frequently presenting with subtle signs before the characteristic paralysis begins.
Defining the Core Symptoms
AHC symptoms are paroxysmal, meaning they have a sudden onset, vary in duration, and resolve spontaneously, often with sleep. The most recognizable symptom is the alternating hemiplegia, where weakness or complete paralysis affects one side of the body and then frequently switches to the other side. A single episode may also affect both sides, known as quadriplegia. These attacks of paralysis can last from a few minutes to several days and may range from mild weakness to complete immobility.
Patients also experience other paroxysmal events, which may occur alone or alongside the paralytic attacks. These include dystonia (muscle stiffness), choreoathetosis (involuntary, jerky movements), and nystagmus (abnormal eye movements). Autonomic disturbances, such as sudden flushing or abnormal breathing, can also occur. A characteristic feature is that all paroxysmal symptoms temporarily disappear completely when the child falls asleep, only to potentially return shortly after waking.
AHC is also associated with permanent, non-paroxysmal neurological impairments. Almost all individuals experience some degree of global developmental delay and intellectual disability. These persistent issues often include problems with movement control, such as ataxia (lack of voluntary coordination) and balance, in addition to behavioral and learning difficulties. Approximately half of children with AHC also develop epileptic seizures.
The Genetic Basis
The underlying cause of AHC is primarily genetic, with the vast majority of cases being linked to mutations in the $ATP1A3$ gene. This gene provides the instructions for making the alpha-3 subunit of the Na+/K+-ATPase, a protein pump located in the membranes of cells. The Na+/K+-ATPase is highly expressed in the brain, particularly in neurons.
The pump maintains the electrochemical gradient across the cell membrane by actively transporting sodium ions (Na+) out of the cell and potassium ions (K+) into the cell. Powered by the breakdown of adenosine triphosphate (ATP), this ion exchange is necessary for neurons to generate and transmit electrical signals. This process is the basis of all communication in the nervous system.
When a mutation occurs in the $ATP1A3$ gene, it results in a defective alpha-3 subunit, which disrupts the normal activity of the sodium-potassium pump. This dysfunction compromises the neuron’s ability to maintain the correct balance of ions, leading to hyperexcitability or instability in the brain’s electrical activity. This inability to regulate ion concentration predisposes the patient to the sudden, transient neurological episodes that characterize AHC.
The mutations are typically spontaneous, meaning they arise newly in the affected child and are not inherited from the parents. Specific mutations, such as D801N and E815K, are commonly observed in AHC patients, with the E815K variant often being associated with a more severe presentation. However, about 20% of AHC cases do not show a mutation in $ATP1A3$, suggesting that other genes may also be responsible for the condition.
Diagnosis and Ongoing Care
The diagnosis of AHC is initially based on clinical observation, specifically by identifying the characteristic pattern of paroxysmal episodes and developmental impairment. Given the rarity of the condition and the similarity of its early symptoms to other neurological disorders, a comprehensive evaluation is needed to rule out other potential causes.
Definitive confirmation of the diagnosis is typically achieved through genetic testing. Genetic sequencing of the $ATP1A3$ gene can identify the specific mutation in the majority of patients, which helps to solidify the diagnosis and distinguish AHC from other conditions. Other tests, such as an electroencephalogram (EEG) or imaging studies, may be used to assess for co-occurring epilepsy and to evaluate the overall brain structure.
Management of AHC is primarily supportive, as there is currently no cure for the underlying disorder. Treatment focuses on minimizing the frequency, severity, and duration of the episodes. The medication Flunarizine, a calcium channel blocker, is widely used as a prophylactic treatment and has been reported to reduce the severity and frequency of attacks in a significant percentage of patients. Management also involves non-pharmacological strategies, such as identifying and avoiding specific triggers like stress, fatigue, or temperature changes. Inducing sleep is a common tactic used during an attack, as it is known to temporarily stop the symptoms. Patients benefit most from a multidisciplinary team of specialists, including neurologists, geneticists, physical therapists, and occupational therapists.