Alternating hemiplegia of childhood (AHC) is a rare neurodevelopmental transient episode of hemiplegia alternating in the laterality or quadriparesis, nystagmus, and other paroxysmal attacks tonic and dystonic spells disorder characterized by repeated episodes of weakness or paralysis that may affect one side of the body or the other (hemiplegia) or both sides of the body at once (quadriplegia). Paroxysmal manifestations include tonic or dystonic spells (either of one limb, one hemibody, or generalized), oculomotor abnormalities, and dysautonomic phenomena (uni- or bilateral mydriasis, flushing, pallor) that may occur alone or in association with hemiplegic attacks
Additional episodic symptoms usually include intermittent abnormal eye movements, episodes of muscle stiffness or posturing (dystonia), and in a substantial percentage of cases, seizures. Delays in attaining developmental milestones (developmental delays), cognitive impairment, persistent issues with balance, and the presence of continuous dance-like movements of limbs or facial muscles (chorea) may occur independently of episodes of paralysis, weakness, or stiffness and persist between episodes. The severity of AHC and the specific types of episodes that occur can vary dramatically from one individual to another. First symptoms usually begin before the age of 18 months. AHC is caused by mutations in the ATP1A3 gene in the majority of those affected. AHC is a rare disorder that was first reported in the medical literature in 1971 by doctors Simon Verret and John C. Steele. They described an unusual disorder in eight children who demonstrated intermittent episodes of weakness, affecting first one side of the body, then the other, with onset in early childhood, including one child who manifested symptoms as early as 3 months of age. However, the disorder remained poorly understood for many years, in part, because of its rarity and complex and highly variable symptoms. More research is necessary to improve early diagnosis, understand the full range of symptoms, and develop more effective treatments. The identification of a causative gene for AHC should lead to a better understanding of the disorder and open new avenues for treatment. The spectrum of related disorders with overlapping symptoms continues to expand, and has led to the increasingly common use of the term “ATP1A3-related neurologic disorders”. This umbrella includes patients with rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome. However, an increasing number of patients with overlapping symptoms that further expand the phenotypes even beyond these well-described disorders initially thought to be completely distinct continues to expand.
Symptoms
AHC is a highly variable and unpredictable disorder and the specific symptoms and severity of the disorder 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 a persistent neurologic disability such as cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.
It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms, and overall prognosis. Symptoms usually develop before 18 months of age.
The most prominent symptom is repeated episodes of weakness or paralysis affecting one side of the body at a time in an alternating fashion (alternating hemiplegia or hemiparesis). Weakness or paralysis may also sometimes affect both sides of the body (quadriplegia) or rapidly transition from one side to the other. These episodes typically last for minutes to hours, but in some children under certain circumstances can persist for several days or even weeks in some cases. They may occur daily, weekly, or once every few months. In some individuals, one side of the body is affected more than the other. In episodes when both sides are involved, one side may recover more quickly than the other. The face may be spared during an episode, but the weakness of facial muscles (facial paresis) can occur with mouth deviation, slurred speech, and difficulty swallowing. The intensity of individual episodes varies as well and can range from numbness to a complete loss of feeling and movement. Episodes often begin to appear in early infancy, and sometimes even in the first few days of life.
During an episode, affected individuals usually remain alert and may be able to communicate verbally. A unique aspect of these episodes is that they cease when sleeping and may not resume for approximately 15-20 minutes upon waking. In severe, prolonged cases, this window of time may allow affected individuals to eat and drink. Episodes can become worse over time and, in severe cases, can make walking unassisted difficult. Some affected individuals may feel tired or unwell shortly before a hemiplegic episode occurs.
Some individuals with AHC may also have additional neurologic symptoms that may occur isolated from or during hemiplegic episodes. These symptoms include sudden, dance-like, involuntary movements of the limbs and facial muscles (choreoathetosis), difficulty breathing (dyspnea), difficulty coordinating muscles (ataxia) causing walking and balance problems, and dystonia. Dystonia is a general term for a group of muscle disorders generally characterized by involuntary muscle contractions that force the body into abnormal, sometimes painful, movements and positions (postures). Dystonic attacks can involve the tongue potentially causing breathing and swallowing difficulties.
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. Symptoms associated with autonomic dysfunction can vary greatly but may include excessive or lack of sweating, changes in body temperature, skin discoloration, altered pain perception, and gastrointestinal problems. Cardiorespiratory problems such as a slow heartbeat (bradycardia), a high-pitched wheezing (stridor), sudden constriction of the walls of the tiny airway branches called bronchioles (bronchospasm), and difficulty breathing or gasping for breath may also develop.
The characteristic episodes that define AHC are not epileptic, although are frequently mistaken for epileptic seizures early in life. However, 50% or more of affected individuals develop epilepsy as they get older. Epileptic seizures typically occur much less frequently than hemiplegic episodes, but when they do, may result in status epilepticus, or persistent seizure activity requiring medical intervention. Epilepsy in children with AHC is often treated with standard antiepileptic medications, but may sometimes prove resistant to traditional epilepsy treatments (intractable epilepsy).
Some infants and children with AHC exhibit developmental delays. In addition, 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).
A common, frequent type of spell in infants with AHC results in irregular eye movements including rapid, involuntary, “jerking” eye movements that may be side to side, up and down, or rotary (episodic nystagmus). Nystagmus often affects only one eye (monocular). In some patients, these irregular eye movements are the first noticeable symptom of AHC, but they often go unrecognized or are considered most likely to represent seizure activity. Some affected individuals may intermittently appear crossed-eyed, where the eyes are misaligned either outward (exotropia) or inward (esotropia). With exotropia, one eye drifts outward toward the ear, while the other eye faces straight ahead. With esotropia, one eye drifts inward toward the nose, while the other eye faces straight ahead.
Causes
In at least 2/3 of individuals, AHC is caused by a mutation in the ATP1A3 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.
Paroxysmal abnormal ocular movements (including monocular and binocular nystagmus, strabismus, disconjugate gaze, ocular bobbing, ocular flutter) are often the first neurological manifestations, occurring in isolation before the onset of other paroxysmal spells.[rx]
Paroxysmal events typically recognize emotional or environmental trigger factors (exercise, exposure to light, sounds or hot water, specific foods), while symptoms are relieved by sleep and post-awakening periods.[rx] A high variability in duration and frequency of paroxysms has been reported, even in the same patient, lasting from minutes to entire days and occurring up to several times per day.[rx]
Beyond paroxysmal manifestations, AHC is also characterized by persistent, interictal neurological abnormalities, whose prevalence increases with age. Developmental issues (speech and language delay, cognitive deficits, behavioral problems) with various degrees of severity are the most common finding, followed by dysarthria, ataxia, chorea, dystonia, and, less frequently, pyramidal tract signs.[rx] Neurological deterioration may show a stepwise progression, with discrete motor or cognitive decline following a prolonged paroxysmal episode. Fixed neurological deficits often show a rostrocaudal gradient of severity, with severity of oro-mandibular dystonia and dysarthria overcoming upper and lower limbs dystonia severity.[rx]
In cases where a mutation in ATP1a3 is disease-causing, AHC almost always occurs as a new (sporadic or de novo) mutation, which means that in nearly all cases the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent, and in AHC, de novo mutations are more common than inherited mutations. However, dominant inheritance (where a trait is transmitted from either an affected mother or father to their child) has been documented in at least one affected family with classic AHC, and in several patients with rapid-onset dystonia-parkinsonism, also due to mutations in ATP1A3.
The ATP1A3 gene is responsible for the production of the protein, ATPase, Na+K+ transporting, and alpha 3 polypeptides, that is required for the 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 to 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.
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. Other genes which cause AHC or a disorder with similar symptoms include the CACNA1A, SLC1A3, and ATP1A2 in less than 1% of patients.
In rare cases where AHC runs in families, it is thought that the disorder is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that is on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. The spectrum of ATP1A3-related neurologic disorders includes rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) syndrome.
Families have noted that individuals may have “triggers” that precede a hemiplegic episode. Identified triggers for AHC include certain environmental situations such as extreme temperatures, crowds, irregular sleep habits, or specific odors; certain physical activities such as exercise: water exposure including bathing, swimming, or showering; bright sunlight or fluorescent bulbs; certain foods such as chocolate or food dyes; certain medications; childhood illnesses and infections: and certain emotional situations such as stress, anxiety or fright. Although many different triggers have been reported, many episodes occur with no identifiable trigger.
Alternating hemiplegia of childhood is primarily caused by mutations in the ATP1A3 gene. Very rarely, a mutation in the ATP1A2 gene is involved in the condition. These genes provide instructions for making very similar proteins. They function as different forms of one piece, the alpha subunit, of a larger protein complex called Na+/K+ ATPase; the two versions of the complex are found in different parts of the brain. Both versions play a critical role in the normal function of nerve cells (neurons). Na+/K+ ATPase transports charged atoms (ions) into and out of neurons, which is an essential part of the signaling process that controls muscle movement. Mutations in the ATP1A3 or ATP1A2 gene reduce the activity of the Na+/K+ ATPase, impairing its ability to transport ions normally. It is unclear how a malfunctioning Na+/K+ ATPase causes the episodes of paralysis or uncontrollable movements characteristic of alternating hemiplegia of childhood.
Diagnosis
A diagnosis of AHC is based upon the identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests. Specific diagnostic criteria have been proposed for AHC. The seven criteria are: (1) onset of symptoms before 18 months; (2) repeated episodes of hemiplegia that sometimes involve both sides of the body; (3) quadriplegia that occurs as an isolated incident or as part of a hemiplegic attack; (4) relief from symptoms upon sleeping; (5) additional paroxysmal attacks such as dystonia, tonic episodes, abnormal eye movements or autonomic dysfunction; (6) evidence of developmental delay or neurological abnormalities such as choreoathetosis, ataxia or cognitive disability; (7) cannot be attributed to another cause.
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. In 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 individually targeted gene sequencing or as part of larger gene panels. Increasingly, ATP1A3 mutations are identified in the context of clinical exome sequencing.
Treatment
No specific therapy exists for individuals with AHC. Treatment is directed toward the specific symptoms apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, neurologists, ophthalmologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. 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.
Treatment is generally focused on trying to reduce the frequency and severity of the characteristic episodes and the management of episodes when they occur. Triggers include psychological stress/excitement; environmental stressors (e.g., bright light, excessive heat or cold, excessive sound, crowds); water exposure (e.g., bathing, swimming); certain foods or odors (e.g., chocolate, food dyes, missed meals); excessive or atypically strenuous exercise; illness; irregular sleep (missing a nap, delayed bedtime. Avoiding triggers to the extent possible is recommended for individuals with AHC. In addition, long-term drug therapy may be recommended to help lessen the frequency of episodes.
A medication that has proved effective in reducing the frequency or severity of episodes in some individuals is a drug called flunarizine, a drug with calcium channel blocking properties. Flunarizine is given as a preventive (prophylactic) agent and has lessened the frequency, duration, and severity of non-epileptic episodes in some individuals with AHC. Flunarizine is not readily available in the US. However, flunarizine is available in other countries for the treatment of migraine and other neurological symptoms.
Anti-seizure medications (anti-convulsants) 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. The effectiveness of these medications is highly variable and they are often minimally effective or ineffective. Benzodiazepines such as diazepam have been used to reduce the duration of dystonic episodes.
Because some hemiplegic episodes have an early phase where individuals feel unwell, some researchers have recommended using certain medications to prematurely induce sleep. This can lessen the duration and severity of an episode. Such medications include buccal midazolam, chloral hydrate, melatonin, niaprazine, or rectal diazepam.
Severe episodes of AHC can require hospitalization. In some cases, epileptic seizures can necessitate urgent medical intervention including intravenous to halt seizures or induce sleep in the setting of severe prolonged dystonia.
The various symptoms of AHC can affect a child’s growth and development. Episodes can disrupt daily life and impact a child’s ability to learn and participate in various activities. Proactive management of potential complications is required. A supportive team approach for children with AHC is of benefit and may include special education, physical therapy, and additional social, medical, or vocational services. Genetic counseling may be of benefit for affected individuals and their families.
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