What is AHC?
Alternating Hemiplegia of Childhood (AHC) is an ultra rare and complex neurological disorder caused by an ion imbalance in the brain that prevents the correct functioning of neurons. It is characterized by recurrent episodes of temporary paralysis, often affecting one side of the body (hemiplegia) or the whole body including the face, that may last for minutes up to weeks. AHC has a diagnosis rate of one in a million, and there are an estimated 1,000 diagnosed cases in the world. There is currently no cure and no effective treatment for AHC.
Due to its rarity and various phenotypes, AHC has often been misdiagnosed, usually as epilepsy. AHC is unpredictable, variable in how it can show itself, and without warning it robs a child of normal bodily function. Speech, motor, and cognitive functions are delayed and are likely to be compromised as children get older. AHC can be associated with devastating outcomes like death, brain atrophy, and sudden and permanent degeneration.
Symptoms of AHC
Children with AHC can exhibit a wide range of symptoms in addition to episodic paralysis. These include tonic attacks (lack of muscle tone), dystonic posturing (stiffening of extremities), ataxia (lack of coordination when performing voluntary movements), intermittent abnormal eye movements and other ocular motor abnormalities (eye disorders), developmental delays, seizures and spells of reduced consciousness. During these episodes, some affected individuals may experience dysfunction of the autonomic nervous system, which regulates certain involuntary body functions such as heart rate, blood pressure, sweating, and bowel and bladder control. Up to 50% of children with AHC develop “true seizures” sometime during the course of their illness. However, not all children suffer from all of these associated symptoms and the severity can vary.
AHC episodes are often associated with triggers that precede or induce the attack. Triggers for AHC episodes can be anything stimulating and may include–but are not limited to–environmental conditions such as temperature extremes or wind, water exposure, physical activities, lights, foods, emotional response such as anxiety or excitement, odours, fatigue, and medications. AHC episodes may also occur with no apparent triggers.
Clinical Diagnosis of AHC
A diagnosis of AHC is primarily one of exclusion and based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Specific diagnostic criteria for AHC are as follows:
Onset of symptoms occurs prior to 18 months of age
Repeated attacks of hemiplegia that alternate in laterality (meaning that the paralysis alternates from one side of the body to the other)
Episodes of bilateral hemiplegia or quadriplegia
Other paroxysmal disturbances, including tonic or dystonic spells, abnormal involuntary eye movements, or autonomic symptoms which may occur in addition to the hemiplegia attacks or independently
Relief from symptoms upon sleeping, which may later resume after waking
Evidence of developmental delay or neurologic findings such as choreoathetosis (a type of involuntary, continuous and flowing movement), dystonia, or ataxia
Genetic Cause of AHC
In 2012 the de novo mutation of the ATP1A3 gene was identified as a leading cause of AHC and represents approximately 80% of those affected. Over 60 variants of the ATP1A3 gene mutation causing AHC have been identified to date. Three of these variants (D801, E815K and G947R) make up approximately 70% of the total number of cases. These three mutations are associated with different clinical phenotypes in terms of symptoms, severity and prognosis.
The ATP1A3 gene is responsible for the production of the protein ATPase, sodium and potassium ions transporting, alpha 3 polypeptide, that is required for normal function of nerve cells in the brain. This protein plays a role in the transport of sodium and potassium ions across a channel that connects nerve cells (neurons), helping regulate brain activity. Consequently, AHC may be classified as a channelopathy, a group of disorders characterized by abnormalities in the flow of electrically charged particles known as ions (commonly calcium, sodium, and potassium) through pores in cell membranes (ion channels). These channels are involved in various functions of the body and, therefore, channelopathies can potentially cause a wide variety of symptoms.
Other genes which cause AHC or a disorder with similar symptoms include the CACNA1A, SLC1A3, and ATP1A2 in less than 1% of patients. Because some individuals with AHC do not have an identifiable mutation of the ATP1A3 gene, it is possible that mutations in other, yet to be discovered, genes may also be associated with AHC. Ongoing research will hopefully provide a genetic identification for the remaining patients and a treatment for all.
Long Term Effects of AHC
AHC is a highly variable and unpredictable disorder and the specific symptoms and severity can vary greatly from one person to another. Some individuals may have mild forms of the disorder with a good prognosis and develop almost normally. However, others may have a severe form with the potential for serious and disabling complications that can disrupt various aspects of life and manifest as persistent neurologic disability.
Although the disorder is named of “childhood” those affected by AHC do not grow out of the disorder. The AHC episodes may change and sometimes even decrease in frequency as a child gets older. However, as children get older, developmental problems between episodes became more apparent. These developmental problems may include difficulties in fine and gross motor function, cognitive function, speech and language, and even social interactions. Some children who experience prolonged, recurrent episodes may develop slowly progressive neurological problems including loss of previously acquired skills (psychomotor regression) and cognitive impairment. Behavioral or psychiatric issues such as impulsivity, short-temperedness, poor communication and poor concentration may also occur. Some affected children may have learning disabilities and issues with skills that require movement and coordination (dyspraxia).
Although there is no proof that the disorder limits life expectancy, these children do appear more susceptible to complications such as aspiration, which can sometimes be life-threatening. In rare cases, children have died suddenly and unexpectedly, in circumstances similar to the sudden death reported in patients with epilepsy (known as SUDEP, or sudden unexplained death in epilepsy). For this reason, careful evaluation to identify problems which could be associated with such episodes is a critical part of the care plan for these patients. Monitoring oxygen levels and ensuring safe management of secretions may be needed during severe episodes.
Treatment of AHC
Currently there is no cure for AHC and medicinal treatment options are extremely limited. Because AHC is highly variable, an individualized treatment program needs to be devised for each child. The effectiveness of current therapies for AHC will vary greatly among affected individuals. What is effective for one person may not be effective for another.
The medication Flunarizine (trade name Sibelium), is a calcium channel blocker and has shown some effectiveness in reducing the severity, intensity, and/or duration of paralytic episodes, but is not an effective treatment in all cases. Anti-seizure medications are also used either alone or in combination to treat individuals with AHC who also have epilepsy and to prevent non-epileptic symptoms such as hemiplegia and dystonia. During the onset of an AHC episode, benzodiazepines are used as a rescue medication to lower brain activity and promote sleep. The effectiveness of these medications is highly variable and they are often minimally or not effective.
The various symptoms of AHC can affect a child’s growth and development and impact their ability to learn and participate. Proactive management and a supportive team approach for children with AHC will help maximize their developmental achievements. This may include special education and speech, physical, and occupational therapies.
Watch the AHC Documentary
The 2014 AHC Documentary Human Timebombs provides excellent insight into the difficulties that AHC kids and families have to endure on a daily basis. From watching this film, you will learn about the disease as explained by doctors, researchers, and families across the world. Learn why AHC is such an important disorder to discover and manage, not only for AHC patients and their families, but also for millions of people all over the world.