Alternating Hemiplegia of Childhood (AHC) is a rare and complex neurological disorder. It is characterized by recurrent, temporary episodes of paralysis beginning in infancy or early childhood, usually before 18 months of age. This condition affects approximately one in one million people. AHC was first characterized as a distinct syndrome in 1971.
Clinical Manifestations of AHC
The hallmark symptom of AHC involves transient episodes of weakness or paralysis, known as hemiplegia, which often alternate from one side of the body to the other. Episodes range from mild weakness to complete paralysis, affecting one limb, multiple limbs, or both sides (quadriplegia). These episodes and other symptoms resolve during sleep but can reappear after waking.
Beyond the hemiplegic episodes, individuals with AHC experience other paroxysmal events. These include dystonia (abnormal muscle tone or sustained contractions). Involuntary eye movements, like nystagmus or improper alignment, are also common, often appearing in infancy. Some individuals may also experience autonomic disturbances, such as changes in breathing or skin color.
Between these episodic attacks, children with AHC often face persistent neurological challenges. These include developmental delays, cognitive impairment, and ataxia (problems with balance and coordination). Chorea (continuous dance-like movements of limbs or facial muscles) can also occur independently.
Various factors can trigger episodes, and identifying them is important for management. Common triggers include:
Exposure to water (e.g., bathing)
Changes in temperature (hot and cold)
Emotional stress
Excitement
Loud noises
Bright lights
Certain foods
The Genetic Basis of AHC
The primary cause of AHC in about 80% of cases is a spontaneous mutation in the ATP1A3 gene. This gene provides instructions for the alpha-3 subunit of the sodium-potassium pump, a protein complex in brain cell membranes. This pump is fundamental for nerve cell function, transporting sodium and potassium ions across membranes to maintain electrical signaling.
Mutations in ATP1A3 disrupt this pump’s function, leading to ion imbalances in brain cells. This disruption underlies AHC’s neurological symptoms. While several different mutations in ATP1A3 can cause AHC, three specific variants (p.Asp801Asn, p.Glu815Lys, and p.Gly947Arg) account for about 60% of all cases.
Most ATP1A3 mutations are de novo, meaning they are new genetic changes occurring spontaneously in the child, not inherited. However, in rare instances, the condition can be inherited in an autosomal dominant pattern, though symptoms tend to be milder in such familial cases. While ATP1A3 is the most common cause, a small number of AHC cases link to ATP1A2 or RHOBTB2 mutations.
The Path to Diagnosis
Diagnosis of AHC often begins with a clinical evaluation based on specific criteria. Criteria include the onset of paroxysmal events, like hemiplegic episodes, before 18 months of age. Repeated bouts of paralysis alternating sides or affecting both (quadriplegia) are also key indicators.
AHC is often a diagnosis of exclusion, requiring doctors to rule out other conditions with similar symptoms. This process involves a comprehensive assessment to differentiate AHC from disorders like epilepsy, mitochondrial disorders, or childhood stroke.
Tests like electroencephalograms (EEGs) measure brain electrical activity to distinguish epileptic seizures from other events. MRI scans exclude structural brain abnormalities. Genetic testing confirms AHC diagnosis. Identifying a pathogenic ATP1A3 mutation confirms diagnosis in about 80% of affected individuals and helps rule out other genetic neurological disorders.
Therapeutic and Management Strategies
Current AHC management focuses on reducing episode frequency and severity, and improving quality of life. Preventative medications are a primary approach; flunarizine, a calcium channel blocker, is a common first-line treatment. Studies show flunarizine can reduce the duration, severity, and frequency of attacks in up to 80% of patients.
During severe or prolonged episodes, rescue treatments resolve paralysis or other symptoms. Benzodiazepines are often used orally, rectally, or nasally. Inducing sleep, sometimes with medications like chloral hydrate or phenobarbital, is also effective, as sleep often resolves AHC symptoms immediately.
Identifying and avoiding individual triggers is a significant management aspect. Caregivers observe and document triggers like temperature changes, emotional stress, certain foods, or environmental stimuli. Minimizing exposure reduces episode occurrence.
Supportive therapies are a cornerstone of comprehensive AHC care. Physical therapy maintains motor function, improves coordination, and addresses ataxia or dystonia. Occupational therapy assists with daily living and fine motor skills. Speech therapy addresses communication and swallowing difficulties.
Prognosis and Developmental Trajectory
AHC is a lifelong condition with a variable long-term outlook. Hemiplegic episodes may change with age but typically persist throughout life. Some studies suggest hemiplegic episodes might decrease in frequency with age, though other paroxysmal events like tonic or dystonic attacks can continue intensely.
Individuals with AHC commonly experience long-term neurological challenges, including global developmental delays and intellectual disability. Persistent motor challenges, such as ataxia (poor coordination) and dystonia (involuntary muscle contractions), are frequent. These deficits can become more apparent over time, impacting learning, movement, and psychological development.
Despite the challenges, ongoing research aims to better understand the natural history of AHC and develop more effective treatments. The complex and variable nature of AHC underscores the importance of a comprehensive care team, including neurology, neurodevelopment, and various therapies, to address diverse needs. While AHC does not definitively shorten life expectancy, complications like aspiration can occur and may be life-threatening.