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Alternating Hemiplegia of Childhood

What is Alternating Hemiplegia of Childhood?

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder often caused by a mutation in ATP1A3,[1][2] though growing evidence strongly supports mutation of the ATP1A3 gene as the primary cause of this disease.[3][4] AHC is named for the transient episodes, often referred to as attacks or episodes, of hemiplegia from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete paralysis on one or both sides of the body, and they can vary greatly in duration. Attacks may also alternate from one side of the body to the other, or alternate between affecting one or both sides during a single attack. AHC is associated with many symptoms besides hemiplegia, and the majority of these become apparent in early infancy. AHC typically presents before the age of 18 months. Normally, hemiplegia and other associated symptoms cease completely with sleep, but they may recur upon waking.[5] 

 

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder often caused by a mutation in ATP1A3,[1][2] though growing evidence strongly supports mutation of the ATP1A3 gene as the primary cause of this disease.[3][4] AHC is named for the transient episodes, often referred to as attacks or episodes, of hemiplegia from which those with the disorder suffer. These hemiplegic attacks can cause anything from mild weakness to complete paralysis on one or both sides of the body, and they can vary greatly in duration. Attacks may also alternate from one side of the body to the other, or alternate between affecting one or both sides during a single attack. AHC is associated with many symptoms besides hemiplegia, and the majority of these become apparent in early infancy. AHC typically presents before the age of 18 months. Normally, hemiplegia and other associated symptoms cease completely with sleep, but they may recur upon waking.[5] 

The disorder was only recently discovered, having first been characterized in 1971.[1][6] Besides hemiplegia, symptoms of the disorder include an extremely broad range of neurological and developmental impairments which are not well understood.

AHC is also extremely rare – approximately 1 in 1,000,000 people have this disorder.

Synonyms for Alternating Hemiplegia of Childhood has not been added yet.

To discover and understand all genetic markers and genes involved in AHC.  Currently the genes thought to have defects are:

ATP1A2

ATP1A3

CACNA1A

CACNA1C

EFHC1

EFHC2

GJB1

KCNA1

PRRT2

SCN1A

SLC1A3

SLC2A1

ADCY5

AHC patients exhibit a wide range of symptoms in addition to hemiplegic attacks.[5] These can be further characterized as paroxysmal and non-paroxysmal symptoms. Paroxysmal symptoms are generally associated with hemiplegic attacks and may occur suddenly with hemiplegia or on their own. Paroxysmal symptoms may last for variable amounts of time. Non-paroxysmal symptoms tend to be side effects of AHC which are present at all times, not just during episodes or attacks. Epilepsy, which is also considered a paroxysmal symptom, plays an important role in the progression and diagnosis of AHC.

Hemiplegic attacks[edit]

Chronologically, hemiplegic attacks are not always the first symptom of AHC, but they are the most prominent symptom, as well as the symptom for which the disorder is named. Hemiplegic attacks may affect one or both sides of the body, and attacks which affect both sides of the body may be referred to as either bilateral or quadriplegic attacks. One of the unique characteristics of AHC is that hemiplegic attacks, as well as other symptoms which may co-occur with hemiplegia, cease immediately upon sleep. During strong attacks, the symptoms may reoccur upon waking.[1][7] Hemiplegic attacks can occur suddenly or gradually, and the severity of an attack can vary over its duration.[7] The attacks may alternate from one side of the body to another, though this is rare.[8] The length of attacks may also vary from minutes to weeks,[1] though length of attacks varies more greatly between people than between attacks for one person.[7] Both bilateral and hemiplegic attacks are associated with pseudobulbar features such as dysphagiadysarthria, and respiratory difficulty.[1][7][8]Paralysis is also often accompanied by changes in skin color and temperature, sweating, restlessness, tremor, screaming, and the appearance of pain.[7] Hemiplegic attacks happen irregularly and can occur with speech, eating, and swallowing impairment. Patients with AHC are frequently underweight due to these side effects.[8] The average age of onset for hemiplegic episodes has been found to be 6–7 months of age.[1] This early onset gives the name of this disorder the slightly misleading ending 'of childhood'. AHC is not exclusively limited to childhood – attacks become milder after the first ten years of life, but they never completely disappear.[8]

Paroxysmal symptoms[edit]

AHC patients have exhibited various paroxysmal symptoms which manifest to different degrees in each person.[7] Paroxysmal symptoms include tonictonic-clonic, or myoclonic limb movements,[9] dystonic posturing, choreoathetosis, occular nystagmus, and various other ocular motor abnormalities.[5][7] Almost half of all people have dystonic symptoms prior to experiencing hemiplegia.[1] These symptoms generally begin before 8 months of age.[9] Ocular motor abnormalities occur early, and these are the most frequent early symptoms of AHC, particularly nystagmus.[1][7] Almost 1/3 of people with this disorder had episodic ocular motor features within 1–2 days of birth. Many also experienced hemiplegia and dystonia before 3 months of age.[1] A final symptom that may be considered paroxysmal is a temporary change in behavior - some patients will become unreasonable, demanding, and aggressive either before or after an attack [10]

Not all patients have all of these symptoms, and it is not known whether they are caused by AHC.[5] Symptoms usually manifest in the first 3 months of the child's life, with an average onset of 2.5 months. Frequently, some of these symptoms will manifest in the neonatal period. These paroxysmal symptoms are often used to help diagnose AHC, since there is no simple test for it.

In some cases, EEGs taken during these paroxysmal events were characterized by a generalized background slowing.[1][9] Overall however, EEG during episodes and other investigative methods such as brain MRI, TACs, angiographic MRIs and CFS have normal results.[11]

Non-paroxysmal symptoms[edit]

In the long term, many paroxysmal symptoms occur along with AHC, and while these symptoms vary in strength depending on the person, they are consistent features of AHC.[12] It is thought that some of these symptoms are brought on or worsened by hemiplegic attacks, though it is not known for certain. Patients suffer persistent motor, movement (ataxia), and cognitive deficits.[1][7][8] These deficits become more apparent over time and include developmental delays, social problems, and retardation.[5] It is rare for someone with AHC not to have cognitive deficits, but a study in Japan did find two patients who met all of the diagnostic criteria for AHC but who were not mentally impaired.[13] It is not known whether AHC is a progressive disease, but severe attacks are suspected to cause damage which result in permanent loss of function.[8] 100% of children studied in the USA have had some form of mental impairment, which is usually described as mild to moderate,[1] but varies greatly among individuals.

Epilepsy[edit]

At least 50% of AHC sufferers also suffer from epilepsy,[1] and AHC is often misdiagnosed as epilepsy because of this.[8] These epileptic events are distinguished from other episodes by an alteration of consciousness, as well as frequent tonic or tonic-clonic activity. Epileptic episodes are generally rare, though they do increase with age. Due to the rarity of epileptic episodes, there are few EEG confirmations of them.

Name Description
Seizures Seizures
Ataxia Loss of the ability to coordinate muscle movement

As of 1993 only approximately 30 people with AHC had been described in scientific literature.[7] Due to the rarity and complexity of AHC, it is not unusual for the initial diagnosis to be incorrect, or for diagnosis to be delayed for several months after the initial symptoms become apparent.[8] The average age of diagnosis is just over 36 months.[1] Diagnosis of AHC is not only difficult because of its rarity, but because there is no diagnostic test, making this a diagnosis of exclusion. There are several generally accepted criteria which define this disorder, however other conditions with a similar presentation, such as HSV encephalitis, must first be ruled out. Due to these diagnostic difficulties, it is possible that the commonness of the disease is underestimated.

The following descriptions are commonly used in the diagnosis of AHC. The initial four criteria for classifying AHC were that it begins before 18 months of age, includes attacks of both hemiplegia on either side of the body, as well as other autonomic problems such as involuntary eye movement (episodic monocular nystagmus), improper eye alignment, choreoathetosis, and sustained muscle contractions (dystonia).[1][7] Finally, patients suffer from intellectual disabilities, delayed development, and other neurological abnormalities.[8][10] These diagnostic criteria were updated in 1993 to include the fact that all of these symptoms dissipate immediately upon sleeping. Diagnostic criteria were also expanded to include episodes of bilateral hemiplegia which shifted from one side of the body to the other.[10]

Recent criteria have been proposed for screening for AHC early, in order to improve the diagnostic timeline. These screening criteria include focal or unilateral paroxysmal dystonia in the first 6 months of life, as well as the possibility of flaccid hemiplegia either with or separate from these symptoms. Paroxysmal ocular movements should also be considered, and these should include both binocular and monocular symptoms which show in the first 3 months of life.[1]

Clinical Testing and Work-up

A diagnosis of AHC is primarily one of exclusion. A wide variety of specialized tests may be used to rule out other conditions. Such tests include magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and magnetic resonance spectroscopy (MRS). An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues such as brain tissue. An MRA, images are produced to evaluate the blood vessels. An MRS is used to detect metabolic changes in the brain and other organs.

Additional tests may include electroencephalogram (EEG), which measures electrical responses in the brain, and is typically used to identify epilepsy; metabolic screening to detect urine organic acids, which is indicative of certain metabolic disorders; studies of cerebrospinal fluid (CSF), which can exclude neurotransmitter deficiency disorders with similar episodic oculomotor abnormalities; erythrocyte sedimentation rates, which measures how long it takes red blood cells to settle in a test tube over a given period to detect inflammatory disorders; and hypercoagulable studies to detect disorders with a predisposition to forming blood clots.

Molecular genetic testing for mutations in the ATP1A3 gene is available on a clinical basis via individual targeted gene sequencing or as part of larger gene panels. Increasingly, ATP1A3 mutations are identified in the context of clinical exome sequencing.

 

Overall outcomes for AHC are generally poor, which is contributed to by AHC's various diagnostic and management challenges. In the long term, AHC is debilitating due to both the hemiplegic attacks and permanent damage associated with AHC. This damage can include cognitive impairment, behavioral and psychiatric disorders, and various motor impairments.[8] There is, however, not yet any conclusive evidence that AHC is fatal or that it shortens life expectancy, but the relatively recent discovery of the disorder makes large data for this type of information unavailable. Treatment for AHC has not been extremely successful, and there is no cure.[5] There are several drugs available for treatment, as well as management strategies for preventing and dealing with hemiplegic attacks.

Management strategies[edit]

Hemiplegic attacks can be brought on by particular triggers, and management of AHC often centers around avoiding common or known triggers. While triggers vary greatly from person to person, there are also some common ones which are prevalent in many patients. Common triggers include temperature changes, water exposure, bright lights, certain foods, emotional stress, and physical activity. While avoiding triggers may help, it cannot prevent all hemiplegic episodes because many occur without being triggered. Because attacks and other associated symptoms end with sleep, various sedatives can be used to help patients sleep.[1][8]

Flunarizine[edit]

The most common drug used to treat AHC is flunarizine. Flunarizine functions by acting as a calcium channel blocker. Other drugs, in order of frequency of use are benzodiazepines, carbamazapine, barbiturates, and valproic acid. Flunarizine is prescribed for the purpose of reducing the severity of AHC attacks and the number of episodes, though it rarely stops attacks altogether.[1] Minimizing the attacks may help reduce damage to the body from hemiplegic attacks and improve long-term outcomes as far as mental and physical disabilities are concerned.[5][13]

Experts differ in their confidence in flunarizine's effectiveness.[7][13] Some studies have found it to be very effective in reducing the duration, severity, and frequency of hemiplegic attacks.[13] It is generally considered the best treatment available, but this drug is thought by some to be of little benefit to AHC patients. Many patients suffer adverse effects without seeing any improvement.[7] Flunarizine also causes problems because it is difficult for patients to obtain, as it is not readily available in the United States.[citation needed]

Sodium oxybate[edit]

Current research at the University of Utah is investigating whether sodium oxybate, also known as Gamma-Hydroxybutyric acid is an effective treatment for AHC.[16] Thus far, only a small number of patients have been sampled, and no conclusive results are yet available. While some success has been had thus far with the drug, AHC patients have been known to respond well initially to other drugs, but then the effectiveness will decline over time. Currently, sodium oxybate is used as a narcolepsy-cataplexy treatment, though in the past it has been used controversially in nutritional supplements. This drug was chosen to test because of a possible link between the causes of narcolepsy-cataplexy and AHC.[citation needed]

 

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.

Every child with AHC is unique, and children can be severely or mildly affected. 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. There is developing evidence that AHC may cause ongoing mental and neurological deficits with a progressive course. Early intervention for such children is extremely important to help maximize their developmental achievements.

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 insuring safe management of secretions may be needed during severe episodes.

Gene editing and gene defect correction will be the ultimate solution for this condition.  The following is a suggested pathway to that solution:

 

 

This plan is designed to develop an eventual gene knockin replacement with the corrected genetic sequence to repair and replace each of the defective base pairs.   The process shall involve developing:

 

  1. Identify genetic (base pair) defects in the ATP1A3 gene along with other defective genes related to AHC.
  2. Apply CRISPR CAS9 to modify mouse model populations through direct mouse embryo transfer to effectively emulate AHC defective genes in the mice.
  3. Apply CRISPR CAS9 with modified synthetic single guide RNA (SynMsgRNA) to knockout the defective gene base pairs to prove concept of gene therapy in ATP1A3 and other AHC genes.
  4. Develop a nano sized vesicle or system to deliver SynMsgRNA across the blood brain barrier (BBB).
  5. Develop a coating or peptide to target and open the tight junctions between adjacent endothelial cells within the BBB.
  6. Apply fluorescent nano particles within the nano vesicle to test for efficacy of the delivery system.
  7. Develop packaging and storage technique to manufacture the nano vesicle around the SynMsgRNA.
  8. Evaluate the system in mice models for efficacy of system and response to therapy - genome mapping before and after of mice.
  9. Collaborate on other possible SynMsgRNA to up regulate (express) to create neuron (axon) epigenetic regeneration-associated genes (RAGs) - acetyltransferases.
  10. Enhance delivery system, neuron RAGS and gene editing of ATP1A3 and other genes should be greater than 85% targeting and less than 5% off targeting.
  11. Conduct a porcine model double arm study with full gene mapping before and after treatment or placebo.
  12. Prepare for Phase 1 clinical human trial.

References

TEXTBOOKS
Dangond F. Alternating hemiplegia of childhood. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:512-513.

JOURNAL ARTICLES
Heinzen EL, Swoboda KJ, Hitomi Y, et al. De novo mutations in ATP1A3 cause alternating hemiplegia of childhood. Nat Genet. 2012;44(9):1030-4. The National Center for Biotechnology Information advances science and healthhttp://www.ncbi.nlm.nih.gov/pubmed/22842232

Rosewich H, Thiele H, Ohlenbusch A, et al. Heterozygous mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study. Lancet Neurol. 2012;11:764-763. http://www.ncbi.nlm.nih.gov/pubmed/22850527

Panagiotakaki E, Gobbi G, Neville B, et al. Evidence of a non-progressive course of alternating hemiplegia of childhood: study of a large cohort of children and adults. Brain. 2010;133:3598-3610. http://www.ncbi.nlm.nih.gov/pubmed/20974617

Tenney JR, Schapiro MB. Child neurology: alternating hemiplegia of childhood. Neurology. 2010;74:e57. http://www.ncbi.nlm.nih.gov/pubmed/20368625

Sweney MT, Silver K, Gerard-Blanluet M, et al. Alternating hemiplegia of childhood: early characteristics and evolution of a neurodevelopmental syndrome. Pediatrics. 2009;123:e534-e541. http://pediatrics.aappublications.org/content/123/3/e534

Neville BG, Ninan M. The treatment and management of alternating hemiplegia of childhood. Dev Med Clin Neurol. 2007;49:777-780. http://www.ncbi.nlm.nih.gov/pubmed/17880649

Jiang W, Chi Z, Du B, et al. Topiramate: a new agent for patients with alternating hemiplegia of childhood. Neuropediatrics. 2006;37:229-233. http://www.ncbi.nlm.nih.gov/pubmed/17177149

Di Rosa G, Spano M, Pustorino G, et al. Alternating hemiplegia of childhood successfully treated with topiramate: 18 months of follow-up. Neurology. 2006;66:146. http://www.ncbi.nlm.nih.gov/pubmed/16401872

Bassi MT, Bresolin N, Tonelli A, et al. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. J Med Genet. 2004;41:621-628. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1735877/?tool=pmcentrez

Swoboda KJ, Kanavakis E, Xaidara A, et al. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Ann Neurol. 2004;55:884-887. http://www.ncbi.nlm.nih.gov/pubmed/15174025

Mikati MA, Maguire H, Barlow CF, et al. A syndrome of autosomal dominant alternating hemiplegia: clinical presentation mimicking intractable epilepsy, chromosomal studies; and physiologic investigations. Neurology. 1992;42:2251-2257. http://www.ncbi.nlm.nih.gov/pubmed/1361034

Verret S, Steele JC. Alternating hemiplegia in childhood: a report of eight patients with complicated migraine beginning in infancy. Pediatrics. 1971;47(4):675-80. http://www.ncbi.nlm.nih.gov/pubmed/5089756

INTERNET
Brashear A, Sweadner KJ, Cook JF, et al. ATP1A3-Related Neurologic Disorders. 2008 Feb 7 [Updated 2014 Nov 6]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016.Available from: http://www.ncbi.nlm.nih.gov/books/NBK1115/ Accessed April 4, 2016.

National Institute of Neurological Disorders and Stroke. Alternating Hemiplegia Information Page. September 16, 2011. Available at: http://www.ninds.nih.gov/disorders/alternatinghemiplegia/alternatinghemiplegia.htm Accessed April 4, 2016.

Schyns T. Alternating hemiplegia of childhood. Orphanet Encyclopedia, June 2009. Available at: http://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=748&Disease_Disease_Search_diseaseGroup=Alternating-hemiplegia-of-childhood&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Alternating-hemiplegia-of-childhood&title=Alternating-hemiplegia-of-childhood&search=Disease_Search_Simple Accessed April 4, 2016.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:104290; Last Update:09/14/2012. Available at: http://omim.org/entry/104290 Accessed April 4, 2016.

Hope for Annabel Created by RareshareTeam
Last updated 7 Aug 2018, 11:53 PM

Posted by RareshareTeam
7 Aug 2018, 11:53 PM

The Washington, D.C. community has rallied around little Annabel, a young girl living with AHC.  Through awareness campaigns and fundraisers, Annabel's parents hope to raise enough money to alter the course of her disease.  What kinds of fundraisers have you found successful?

You can read more about Annabel's story here:  https://www.hopeforannabel.org/

Current Research in AHC Created by ljmackmd
Last updated 5 Jan 2018, 05:35 PM

Community External News Link
Title Date Link
Alternating Hemiplegia of Childhood: DC Lemonade Stand Raises More Than $1K for Toddler With Rare Disease - NBC Washington 07/29/2018
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Researchers can contact CoRDS to determine if the registry contains participants with the rare disease they are researching. If the researcher determines there is a sufficient number of participants or data on the rare disease of interest within the registry, the researcher can apply for access. Upon approval from the CoRDS Scientific Advisory Board, CoRDS staff will reach out to participants on behalf of the researcher. It is then up to the participant to determine if they would like to join the study.

Visit sanfordresearch.org/CoRDS to enroll.

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ljmackmd

Dr. Leigh J. Mack is a member the Board of Directors for CureAHC (Alternating Hemiplegia of Childhood) and has developed a 5 year research plan to get to a Phase 1 clinical trial using gene editing appications to correct faulty genes in the AHC condition. He is a graduate of USAT Montserrat; holding both MD and PhD degrees. Dr. Mack has post graduate training in Nanotechnology (nanomedicine) from University of Oxford. He trained at John Radcliffe Hospital (University of Oxford/NHS) in Trauma Plastics. Dr. Mack is a Certified Principal Investigator (CPI - ACRP); and a Fellow of the Academy of Physicians in Clinical Research. Recently, became a member of the ACRP Academy Standards Setting Committee for the new CPI exam. Dr. Mack served in the US Army National Guard for 7 years.

 

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Hope for Annabel

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Current Research in AHC

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