Alternating Hemiplegia

What Causes Alternating Hemiplegia?

In most cases, AHC is caused by an abnormal change (mutation) in the ATP1A3 gene. In a small number of cases, it results from a mutation in the ATP1A2 gene. The two genes are responsible for the production of two similar proteins. These two proteins play a vital role in the function of nerve cells in different parts of the brain. Scientists are not sure precisely what biochemical mechanism causes the symptoms of AHC, but, likely, a deficiency of these critical proteins caused by the gene mutations is to blame.

Mutations of the ATP1A3 gene are also associated with other disorders, including rapid-onset dystonia-parkinsonism (RDP).

Is Alternating Hemiplegia Hereditary?

In most cases, the gene mutations that cause AHC are not passed from parent to child. Most of the time, the mutations appear to happen spontaneously in an egg or sperm cell or in the embryo early in its development. In these cases, the child develops the disorder even though there is no family history of the condition.

In a small number of cases, the mutation does appear to be inherited by a child from their parent. In these cases, the disorder follows an autosomal dominant pattern, meaning the child needs only to inherit the mutation from one parent for the condition to develop.

How Is Alternating Hemiplegia Detected?

In many cases, early symptoms of AHC may be mild, and diagnosis may be delayed. However, early intervention may help lessen the severity of future neurological and developmental complications, making early detection vital.

Early signs of AHC include:

• Involuntary limb movements
• Involuntary eye movements
• Disruption of automatic body functions

AHC episodes may be triggered by external events or stimuli such as:

• Heat or cold
• Stress
• Fatigue
• Bright light
• Loud sounds
• Exposure to water

How Is Alternating Hemiplegia Diagnosed?

AHC can be challenging to diagnose directly. The diagnostic process typically involves tests and exams to rule out other possible causes for the symptoms.

Diagnostic steps often include:

• Evaluation of the child’s medical history
• Electroencephalogram (EEG) to rule out epilepsy
• Echocardiogram and/or electrocardiogram to rule out heart abnormalities
• Magnetic resonance imaging (MRI) or other imaging exams to rule out brain abnormalities
• Sleep studies to rule out obstructive sleep apnea
• Genetic testing to look for ATP1A3 gene mutations and to rule out other genetic conditions

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Alternating Hemiplegia Treated?

AHC has no cure. Alternating hemiplegia of childhood treatments usually have the goal of preventing or shortening the disorder’s paralytic episodes. Successful management of the episodes may lessen the severity of developmental impairments and other complications. Other alternating hemiplegia of childhood treatments may focus on managing complications.

Common treatment options include:

• Anti-seizure medications. These medications may prevent AHC episodes in some children, and they may be used to treat seizures in the significant number of AHC patients who develop epilepsy.
• Buccal midazolam, chloral hydrate, melatonin, niaprazine, or rectal diazepam to induce sleep
• Vagus nerve stimulation
• Ketogenic diet
• Physical therapy
• Occupational therapy
• Speech therapy
• Flunarizine to prevent AHC episodes. This drug is considered experimental and is only available in exceptional circumstances in the United States.

How Does Alternating Hemiplegia Progress?

The severity of AHC varies widely from case to case, and the long-term prognosis varies with the severity of the condition. In some cases, symptoms are mild and may cause little or no neurological or developmental complications over the long term. However, in more severe cases, intellectual impairments and neurological symptoms often worsen over time and cause life-long disabilities.

Ongoing and progressive symptoms can include:

• Difficulty walking
• Loss of other motor skills
• Loss of cognitive abilities
• Problems with coordination
• Problems with concentration
• Behavioral problems (impulsivity, aggression)

In some cases, the disorder can produce a severe, prolonged seizure (status epilepticus) that can be life-threatening.

How Is Alternating Hemiplegia Prevented?

There is no known way to prevent AHC when the disorder-causing gene mutations are present. Scientists have not identified any risk factors that seem to increase the possibility of the mutations occurring.

In some cases, avoidance of triggers may help to prevent the onset of AHC  episodes. The specific stimuli that trigger episodes vary from case to case, and sometimes episodes begin without a trigger.

Common triggers include:

• Extreme temperatures
• Physical exertion
• Bright lights
• Loud sounds
• Crowds
• Baths or swimming
• Sleep disruptions
• Anxiety or stress
• Fear
• Specific foods or food additives

Alternating Hemiplegia Caregiver Tips

• Learn about AHC. Every child with AHC experiences the disorder differently and faces different challenges. The more you know about AHC and how it affects your child, the better you will be able to help your child live their best life.
• Be ready to be an advocate for your child. After you’ve educated yourself about AHC, you’ll likely have to educate your child’s teachers, medical team, and other important people in their lives about the reality of living with the disorder. But don’t think you have to do it alone. There are resources to help you make sure your child gets what they need.
• Be a part of a community of people like you. The Alternating Hemiplegia of Childhood Foundation maintains a collection of resources for families, including links to news, education, research updates, support groups, and other resources.  

Some people with AHC also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the issues commonly associated with AHC:

• Many people with AHC suffer from seizures.
• AHC is sometimes associated with autism and behavioral disorders.

Alternating Hemiplegia Brain Science

Scientists don’t yet fully understand AHC affects the brain biochemically. The proteins produced using instructions in the ATP1A3 and ATP1A2 genes are part of a complex chemical compound that plays a crucial role in brain function. The compound, called Na+/K+ ATPase, helps transport charged potassium and sodium atoms (ions) from one nerve cell to another. This transport mechanism, called a channel, is an essential part of passing signals from one part of the brain to another and from the brain to other parts of the body.

Although it is not clear how, it’s likely that mutations in the ATP1A3 or other genes inhibit the production of Na+/K+ ATPase, thereby interfering with communication between nerve cells and causing the symptoms of AHC.

Alternating Hemiplegia Research

Title:  Studies of the Variable Phenotypic Presentations of Rapid-Onset Dystonia Parkinsonism and Other Movement Disorders

Stage: Active

Principal investigator: Allison Brashear, MD

University of California, Davis

Sacramento, CA

The purposes of this study are to identify persons with rapid-onset dystonia-parkinsonism (RDP) or mutations of the RDP gene, document the prevalence of the disease, and map its natural history.

Rapid-onset dystonia-parkinsonism (RDP) is a rare movement disorder with variable characteristics ranging from sudden onset (hours to days) of severe dystonic spasms to gradual onset of writer’s cramp. RDP has elements of both dystonia and Parkinson’s disease-two neurological diseases with motor and neuropsychological symptoms that hinder the quality of life. An internal trigger associated with extreme physiological stress has been reported before abrupt symptom onset of RDP.

This study, which is a continuation of an earlier study begun by Dr. Allison Brashear, aims to identify the characteristics associated with RDP more clearly and to explore whether mutations in the RDP gene are associated with atypical dystonias, Parkinson’s disease, and other movement disorders.

The study involves in-person or remote (telemedicine) neurological assessments and blood samples for genetic analysis.

Title: Dystonia Genotype-Phenotype Correlation

Stage: Recruiting

Contact: Deanna M. Myer, BS

University of Texas Southwestern Medical Center

Dallas, TX

The purpose of this study is to (1) investigate the effect of known dystonia-causing mutations on brain structure and function, to (2) identify structural brain changes that differ between clinical phenotypes of dystonia, and to (3) collect DNA, detailed family history, and clinical phenotypes from patients with idiopathic dystonia to identify new dystonia-related genes. Investigators will be recruiting both healthy control subjects and subjects with any form of dystonia. For this study, there will be a maximum of two study visits involving a clinical assessment, collection of medical and family history, task training session, an MRI using the learned tasks, and a blood draw for genetic analysis. In total, these visits will take 3-5 hours. If the dystonia subjects receive botulinum toxin injections for treatment, the participants and their matched controls will be asked to come for a second visit.

Title: Natural History Study of ATP1A3-related Disease

Stage: Recruiting

Contact: Helen Cross, PhD

Great Ormond Street Hospital

London, UK

Alternating hemiplegia of childhood (AHC) is a rare, very disabling neurodevelopmental syndrome caused by mutations in the gene ATP1A3. AHC is characterized by paroxysmal events, including attacks of hemiplegia (weakness), dystonia (painful stiffening), oculomotor abnormalities, and epileptic seizures. As the condition progresses, permanent neurological symptoms, including unsteadiness and learning problems, emerge. Mutations in ATP1A3 also cause other related syndromes: rapid-onset dystonia-parkinsonism (RDP), less severe and usually presenting in adulthood, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome, a severe syndrome of early childhood.

Currently, therapeutic options are very limited, aiming at symptomatic relief with limited success. As ATP1A3-related syndromes are very rare diseases, with an estimated prevalence of about 1/1000000, randomized clinical trials of available therapies are not possible due to the lack of a large enough patient cohort. However, the revolution in genetic diagnostics has identified these patients and the correlation between their phenotypes possible. At the same time, further novel technologies in neuromonitoring and neuroimaging, as well as videography and sleep monitoring, have become available that could help us further examine and understand the underlying mechanisms especially of the paroxysmal episodes that characterize all ATP1A3-related syndromes. The investigators believe that based on these scientific advances, they will be able to recruit a UK-wide patient cohort to conduct an in-depth study of the progression of this disease.

This is particularly relevant at the moment, as rapid progress in genetic therapies and other novel therapeutics makes the availability of new treatment options in the near future a realistic prospect. Even though we will most probably still not be able to identify a large enough cohort for randomized clinical trials, our natural history study will act as a much-needed benchmark to which the success of novel treatments can be evaluated.