Alternating Hemiplegia of Childhood
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Alternating Hemiplegia of Childhood
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Author: Mohamad A. Mikati, MD; Lyndsey Prange MSN, CPNP, Duke University, Durham, North Carolina

Reviewed: November 2021

SUMMARY

Alternating hemiplegia of childhood (AHC) is a brain disorder involving paralysis and muscle stiffness. It starts in early infancy. AHC causes long-term problems. These problems can include:

  • Developmental issues. AHC can affect learning, movement, and psychological development. These problems are often severe.
  • Motor control spells. Spells are most commonly episodes of paralysis and stiffening. They tend to occur frequently. However, sometimes they are intermittent.
  • Differences in other systems. Other systems in the body can be affect. Examples include:
    • The heart
    • The gastrointestinal tract
    • Sleep patterns

AHC is rare. It seems to occur in only one in a million people. However, it can mimic other conditions. For instance, it can look like epilepsy. Most patients are initially misdiagnosed with epilepsy. The stiffening of AHC spells resembles epileptic seizures. Paralysis in AHC resembles the weakness that often follows epileptic seizures.

There is currently increasing awareness of AHC. This has made early diagnosis more common than before. An early diagnosis is essential because it can:

  • Avoid misdiagnosis and unhelpful medications, which may have negative side effects
  • Get children the help and medications they need more quickly

AHC requires lifelong care. Problems may increase with time. However, there are many treatments that can make a big difference in patients’ lives. The cornerstone of care is the use of multidisciplinary approaches. These can address a variety of needs.

While currently there is no cure for AHC, there is active research on new kinds of therapies. These new therapies could potentially have major impacts on the symptoms and quality of life of these patients.

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Disorder Overview

DESCRIPTION 

Children with AHC always have:

  • Alternating paralysis. Episodes of paralysis that alternate between one side of the body and the other.
  • Paralysis of extremities. Occasional total paralysis of all arms and legs.
  • Delayed neurological development. Developmental delays affecting learning, movement, and behavior.

AHC is usually caused by a genetic mutation. The mutation causes cells in the brain to function differently than normal. They become unable to move sodium and potassium across the wall of the cell as usual. This leads to the AHC symptoms.

SIGNS AND SYMPTOMS 

Symptoms of AHC can last for minutes or for days. Most children with AHC will develop symptoms before 18 months of age.

All children with AHC experience alternating paralysis, occasional paralysis of all arms and legs together, and developmental delays.

Most patients will also have:

  • Episodes of painful muscle stiffness
  • Episodes of abnormal, jerky eye movements
  • Trouble with balance or walking
  • Gastrointestinal issues, such as constipation
  • ADHD

About half of patients will have:

  • Epileptic seizures
  • Episodes of reduced awareness of surroundings
  • Behavioral issues, such as aggression
  • Sleep disorders

Fewer than half of patients will have:

  • Episodes of flushing, sweating, and color change
  • Swallowing disorders
  • Autism spectrum disorder
  • Involuntary jerky or worm-like movements of the arms and legs

The Importance of Sleep in AHC

Symptoms usually do not take place during sleep. In fact, they are relieved by sleep.

Epilepsy in AHC

Up to half of children with AHC eventually develop epilepsy. Seizures can be triggered by:

  • Psychological stress or excitement
  • Exposure to water, heat, or cold

Heart Problems in AHC

People with AHC have a higher risk of developing heart problems later in life.

Special precautions need to be taken if AHC patients undergo sedation or anesthesia. They have a higher risk of respiratory or heart problems during these procedures.

CAUSES

AHC is usually caused by a genetic mutation. About 80% of those with AHC have a mutation in a specific gene called ATP1A3. The ATP1A3 mutation is usually a new mutation. This means it only the affected child has the gene mutation. It rarely runs in families.

Other genes, including ATP1A2 and RhoBTB2, can also cause AHC. However, this is much less frequent.

Genetic mutations cause AHC they can affect the function of brain cells. Brain cells that are not working properly can lead to various symptoms. The brain controls many bodily systems. That’s why these brain functioning can impact:

  • Learning
  • Mood
  • Movements
  • Breathing
  • Swallowing
  • Gastrointestinal function

ATP1A3 is also affects the heart. Thus, heart rhythm problems can be part of AHC.

Sometimes, no gene mutation can be found as the cause of AHC. In these cases, the cause is unknown.

Most of the time, other family members do not have AHC. This is usually true even when the cause of AHC is a genetic mutation. Still, some familial cases do occur.

DIAGNOSIS AND LABORATORY INVESTIGATIONS

Diagnosis

The sooner AHC can be diagnosed, the sooner it can be managed. An early diagnosis can help patients maximize their developmental potential. This is because an early diagnosis means that children get the right kinds of treatments and therapies.

The diagnosis of AHC takes place during a clinical exam. A thorough medical history is key to diagnosing AHC. The diagnosis will be based on the presence of several important symptoms of AHC. Other diseases must also be ruled out for a diagnosis.

Genetic Testing

The diagnosis is often confirmed by genetic testing. Genetic testing can help with:

  • Looking at the ATP1A3 Genetic tests often show an ATP1A3 mutation. This mutation is responsible for 80% of cases. However, not all patients will have this.

Ruling out other disorders. Genetic tests can also rule out mutations associated with other disorders.

Families should get genetic counseling. A counselor can discuss the risk that future siblings might also have AHC.

Other Testing

Other testing is also often used in AHC.

  • Electroencephalogram (EEG). An EEG measures electrical activity in the brain. It can help confirm or rule out epilepsy.
  • Echocardiogram (ECG). An ECG looks for structural abnormalities of the heart. It may also look for issues with the heart’s rhythm.
  • Sleep studies. Sleep studies can identify sleep problems associated with AHC. For instance, they can look for:
    • Sleep apnea
    • Restless legs syndrome

Magnetic resonance imaging (MRI). MRI and other brain scans can detect or rule out other causes of paralysis or muscle stiffness. For instance, they can look for differences in brain structure.

TREATMENT AND THERAPIES

AHC affects many aspects of a child’s development. Therefore, children with AHC can benefit from working with a team of specialists who deeply understand the disorder.

Currently, there is no cure for AHC. However, certain treatments can help control symptoms and address physical or mental challenges. They can make a big difference for many patients.

Some treatments that can help with AHC include:

Medication

There are several medicines used in those with AHC:

  • This drug can help with the spells of paralysis and muscle stiffness. It can reduce their frequency, severity, and duration. This drug is not FDA approved. It cannot be marketed in the United States. Still, doctors are able to offer it with special permission from the FDA.
  • Sleeping medication. Medication to induce sleep may be given during a spell. This can relieve symptoms.

Antiseizure medication. Children who also have epilepsy may need medication to manage seizures.

Vagus nerve stimulator (VNS)

People with AHC are prone to epilepsy. Sometimes, seizures are hard to control. A VNS provides electrical stimulation along the vagus nerve. This can be helpful in when epilepsy does not respond to medication.

Diet

Diet can sometimes help control seizures in a child with AHC. A ketogenic diet is low in carbohydrates and very high in fat. Studies have shown that this diet can reduce seizures in children with epilepsy. However, families should not adopt this diet without support from a medical team. A medical team can help ensure that:

  • Dietary requirements are met

The diet includes the right amounts of fat, carbohydrates, and protein.

Some therapies that can help with AHC include:

Physical or occupational therapy

This can:

  • Strengthen muscles
  • Improve balance
  • Increase mobility

Teach more efficient ways of performing everyday tasks

Speech therapy

This can help children with:

  • Speaking
  • Eating
  • Swallowing

OUTLOOK

AHC is a lifelong disease.

In January 2012, researchers discovered that ATP1A3 mutations are the most common cause of AHC. Since that time, some important changes have taken place. We now have:

  • More awareness of the disease
  • Better tools for diagnosis
  • New approaches to treatment that bring many disciplines together

Future Treatments

Researchers are now working to develop new treatments for AHC. This research holds great promise for better future AHC treatment:

  • Gene therapy
  • New drugs

Researchers are also continuing to look at how to improve the quality of life for those with AHC.

Resources 

Organizations

Cure AHC
The mission of Cure AHC is to financially support research and therapies, improve quality of life and strengthen connections to the global alternating hemiplegia of childhood community. Cure AHC works closely with the Duke Alternating Hemiplegia program at Duke Children’s Hospital. Family support and information can be accessed through the Families page, which includes a link to a documentary, Human Timebombs. Cure AHC aims to be the voice to raise awareness among neurologists, the general public, and researchers so that someday a cure for AHC will be found.

Alternating Hemiplegia of Childhood Foundation
Through research, education, and family support, Alternating Hemiplegia of Childhood Foundation (AHCF) has one mission – END AHC. AHCF’s primary goal is to fund and direct cutting edge research that will lead to clinical trials and a cure for AHC. They also provide advocacy, support, education, and awareness to improve the activities of daily living for AHC patients.  AHCF has an active board whose members are primarily passionately driven parents. AHCF also maintains the largest directory of AHC families in the U.S., and holds a signature biennial conference the “Family Meeting”, a combination of professional, medical and family oriented presentations. AHCF’S Medical Advisory Board is comprised of recognized authorities of the Alternating Hemiplegia of Childhood disorder. They provide strategic advice and counsel to the AHCF Board, in addition to consulting with and teaching other medical professionals to improve the care of AHC patients. There is also a dedicated AHCF coordinator who acts as a triage person for the Foundation.

The IAHCRC International Consortium for the Research on Alternating Hemiplegia of Childhood

The IAHCRC International Consortium for the Research on Alternating Hemiplegia of Childhood (AHC) was formed in 2012 to carry out collaborative research that led to the identification of the ATP1A3 gene as the main cause of AHC. The Consortium involves clinicians, geneticists and researchers working at university centers in Europe, USA and Australia; it operates in close collaboration with health professionals and patient organizations.

Child Neurology Foundation (CNF) solicits resources from the community to be included on this webpage through an application process. CNF reserves the right to remove entities at any time if information is deemed inappropriate or inconsistent with the mission, vision, and values of CNF. 

Research 

ClinicalTrials.gov for Alternation Hemiplegia of Childhood (birth to 17 years)

These are clinical trials that are recruiting or will be recruiting. Updates are made daily, so you are encouraged to check back frequently.

ClinicalTrials.gov is a database of privately and publicly funded clinical studies conducted around the world. This is a resource provided by the U.S. National Library of Medicine (NLM), which is an institute within the National Institutes of Health (NIH). Listing a study does not mean it has been evaluated by the U.S. Federal Government. Please read the NLM disclaimer for details.  

Before participating in a study, you are encouraged to talk to your health care provider and learn about the risks and potential benefits. 

Family Stories

The Alternating Hemiplegia of Childhood Foundation shares stories of children with AHC — the journey from strange symptoms through the relief and pain of diagnosis, as well as how families adapt to a life with AHC.

The information in the CNF Child Neurology Disorder Directory is not intended to provide diagnosis, treatment, or medical advice and should not be considered a substitute for advice from a healthcare professional. Content provided is for informational purposes only.  CNF is not responsible for actions taken based on the information included on this webpage. Please consult with a physician or other healthcare professional regarding any medical or health related diagnosis or treatment options. 

References

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Helseth AR, Hunanyan AS, Adil S, Linabarger M, Sachdev M, Abdelnour E, et al. Novel E815K knock-in mouse model of alternating hemiplegia of childhood. Neurobiol Dis. 2018 Nov;119:100-112. https://doi.org/10.1016/j.nbd.2018.07.028. Epub 2018 Jul 30. PMID: 30071271.

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Rodriguez-Navarro MA, Mikati MA. Anaesthesia recommendations for alternating hemiplegia of childhood syndrome. OrphaNet. 2020 Sept. https://www.orpha.net/data/patho/Ans/en/Alternating-hemiplegia-of-childhood-syndrome.pdf.

Balestrini S, Mikati MA, Álvarez-García-Rovés HYPERLINK ” R, Carboni M, Hunanyan AS, Kherallah B, et al. Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study. Neurology. 2020 Nov 24;95(21):e2866-e2879. https://doi.org/10.1212/WNL.0000000000010794. Epub 2020 Sep 10. PMID: 32913013; PMCID: PMC7734736.

Uchitel J, Helseth A, Prange L, McLean M, Ghusayni R, Sachdev M, Hunanyan A, Mikati MA. The epileptology of alternating hemiplegia of childhood. Neurology. 2019 Sep 24;93(13):e1248-e1259. https://doi.org/10.1212/WNL.0000000000008159. Epub 2019 Sep 4. Erratum in: Neurology. 2020 Oct 13;95(15):708. PMID: 31484714.

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Wallace K, Uchitel J, Prange L, Jasien J, Bonner M, D’Alli R, Maslow G, Mikati MA. Characterization of severe and extreme behavioral problems in patients with alternating hemiplegia of childhood. Pediatr Neurol. 2020 Oct;111:5-12. https://doi.org/10.1016/j.pediatrneurol.2020.06.012. Epub 2020 Jun 27. PMID: 32951661.

Uchitel J, Abdelnour E, Boggs A, Prange L, Pratt M, Bonner M, Jasien J, Dawson G, Abrahamsen T, Mikati MA. Social impairments in alternating hemiplegia of childhood. Dev Med Child Neurol. 2020 Jul;62(7):820-826. https://doi.org/10.1111/dmcn.14473. Epub 2020 Feb 7. PMID: 32031250.

Kansagra S, Ghusayni R, Kherallah B, Gunduz T, McLean M, Prange L, Kravitz RM, Mikati MA. Polysomnography findings and sleep disorders in children with alternating hemiplegia of childhood. J Clin Sleep Med. 2019 Jan 15;15(1):65-70. https://doi.org/10.5664/jcsm.7572. PMID: 30621840; PMCID: PMC6329557.

Pratt M, Uchitel J, McGreal N, Gordon K, Prange L, McLean M, Noel RJ, Rikard B, Rogers Boruta MK, Mikati MA. Alternating hemiplegia of childhood: Gastrointestinal manifestations and correlation with neurological impairments. Orphanet J Rare Dis. 2020 Sep 3;15(1):231. https://doi.org/10.1186/s13023-020-01474-w. PMID: 32883312; PMCID: PMC7469407.

Wallace K, Greene E, Moya-Mendez M, Freemark M, Prange L, Mikati MA. Hypothalamic-pituitary dysfunction in alternating hemiplegia of childhood. Eur J Paediatr Neurol. 2021 May;32:1-7. https://doi.org/10.1016/j.ejpn.2021.03.007. Epub 2021 Mar 11. PMID: 33756210.

Uchitel J, Wallace K, Tran L, Abrahamsen T, Hunanyan A, Prange L,  HYPERLINK “https://doi.org/et al. Alternating hemiplegia of childhood: https://doi.org/Evolution over time and mouse model corroboration. Brain Commun. 2021 Jun 4;3(3):fcab128. https://doi.org/10.1093/braincomms/fcab128. PMID: 34396101; PMCID: PMC8361420.

Hunanyan AS, Kantor B, Puranam RS, Elliott C, McCall A, Dhindsa J, et al. Adeno-associated virus-mediated gene therapy in the mashlool, Atp1a3Mashl/+, mouse model of alternating hemiplegia of childhood. Hum Gene Ther. 2021 Apr;32(7-8):405-419. https://doi.org/10.1089/hum.2020.191. Epub 2021 Feb 12. PMID: 33577387; PMCID: PMC8182483.

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