Getting Started

AHC is a complex neurodevelopmental syndrome most frequently manifesting in infancy or early childhood with paroxysmal episodic neurologic dysfunction including alternating hemiparesis or dystonia, quadriparesis, seizure-like episodes, and oculomotor abnormalities. Episodes can last for minutes, hours, days, or even weeks. The remission of symptoms occurs with sleep and immediately after awakening. Over time, persistent neurologic deficits including oculomotor apraxia, ataxia, choreoathetosis, dystonia, parkinsonism, and cognitive and behavioral dysfunction develop in the majority of those affected; more than 50% develop epilepsy in addition to their episodic movement disorder phenotype. [1]

AHC affects males and females in equal numbers. It is estimated to occur in approximately 1 in 1,000,000 births. However, since cases may go unrecognized or misdiagnosed, it is difficult to determine the true frequency of AHC in the general population.

In 1993, specific diagnostic criteria for AHC were introduced as the Aicardi Criteria and then periodically updated. Aicardi’s criteria for AHC are:

1. the onset of paroxysmal events before 18 months of age;
2. repeated bouts of hemiplegia involving the right and left sides of the body during some attacks;
3. episodes of bilateral hemiplegia or quadriplegia starting either as a generalization of a hemiplegic episode or as bilateral from the start;
4. other paroxysmal disturbances including tonic/dystonic attacks, nystagmus, strabismus, dyspnea, and other autonomic phenomena occurring during hemiplegic bouts or in isolation;
5. immediate disappearance of all symptoms upon sleep, with probable recurrence of long-lasting bouts, 10–20 min after awakening;
6. evidence of developmental delay, intellectual disability, neurological abnormalities, choreoathetosis, and dystonia or ataxia; and
7. not attributable to other disorders. [2]

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.

ATP1A3-related neurologic disorders are inherited in an autosomal dominant manner. ATP1A3 pathogenic variants may be inherited or occur de novo. In AHC, pathogenic variants are more commonly de novo than inherited. Each child of an individual with an ATP1A3-related neurologic disorder has a 50% chance of inheriting the ATP1A3 pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the ATP1A3 pathogenic variant in the family is known. The variability of presentation within a family with a known ATP1A3 pathogenic variant further complicates genetic counseling. [3]

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.

AHC includes characteristic episodic neurological symptoms and signs that vary in severity, duration, and frequency of occurrence. Affected patients typically present in the context of an acute onset of paroxysmal, episodic neurological symptoms ranging from oculomotor abnormalities, hypotonia, paralysis, dystonia, ataxia, seizure-like episodes, or encephalopathy. Neurodevelopmental delays or persistence of dystonia, chorea, or ataxia after resolution of an initial episode are common, providing important clues for diagnosis. [4]

It is well known that AHC patients harboring ATP1A3 mutations exhibit various forms of hyperkinetic non-paroxysmal movement disorders as chorea, dystonia, myoclonus, and ataxia, with a heterogeneous degree of severity. Since 2020, studies are reporting conflicting results. A 2021 Italian study differed from a French study that found choreoathetosis and ataxia were described in all cases. And, in a US study, ataxia was reported in 68% of cases. In another study, a lower rate of non-paroxysmal movement disorders has been reported. It is reasonable to hypothesize that these differences between studies are partly due to the complexity of assessing movement disorders and that more research is needed. [5]

Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. Deficits may include language, psychomotor abilities, psychosocial functioning, reduced attention, reduced speed of information processing, and difficulties in understanding, speaking, and working memory. In addition, parents and teachers reported behavioral disturbances, difficulties in inhibition capability, self-control, and in regulating emotions.

Patients with AHC have significantly more repolarization abnormalities as well as a shorter mean QT interval, specifically in patients with the ATP1A3-D801N variant. This suggests a possible predisposition to lethal ventricular arrhythmias preceded by bradycardia among patients with AHC. This finding may suggest a high-risk genotype among patients with AHC and underscores a critical role for ATP1A3 in maintaining the timing of cardiac repolarization. [6]

Most AHC patients have gastrointestinal problems. These are usually severe and are most commonly indicative of dysmotility. Gastrointestinal motility refers to the movement of food from the mouth through the pharynx (throat), esophagus, stomach, small and large intestines and out of the body. The pathophysiology of AHC and gastrointestinal dysmotility, both involve autonomic and GABAergic dysfunction. Surgical therapies may be required. [7]

Autonomic disturbances affect the autonomic neurons of the nervous system. Since the autonomic nervous system supplies almost every organ in the body, autonomic diseases influence localized organ function as well as integrated processes that control vital functions in the body such as arterial blood pressure and body temperature.

A 2020 study indicates impaired control of the muscles producing plantar and dorsal flexion of the foot, stabilizing muscles of the foot, as well as muscles straightening the knee and hip joints, which are active during hopping, walking and running. Additionally, the test results suggest impaired coordination and fluidity of movement, with a narrow base of support. Tests performed in a lying position did not reveal any dysfunction of trunk muscles. However, significantly impaired function of the upper limbs was observed during catching and throwing. Such a pattern of muscle function abnormalities is consistent with disturbances in consecutive phases of development and indicates generally delayed development. Interestingly, the inability to perform alternate movements of the trunk and extremities was observed in all study patients. The study findings may indicate the need to introduce individualized physiotherapy management of patients with AHC, tailored to their motor development. [8]

Many central nervous system disorders result in hypothalamic-pituitary (HP) axis dysfunction. GABAergic interneurons and the ATP1A3 subunit are both critical for the function of the hypothalamus. A 2021 study found that AHC was associated with HP dysfunction in about 12% of patients. Awareness of such dysfunction is important for anticipatory guidance and management, particularly in the case of fever with unknown origin (FUO) which often presents a diagnostic dilemma.[9]

Alternating hemiplegia of childhood often manifests severe or extreme behavioral problems, the nature of which remains to be fully characterized. A 2020 study found 5% of patients had mild behavioral problems, 13% have moderate, 25% had severe, 15% had extreme, and 41% had none. Extreme cases exhibited disruptive behaviors escalating to assaults. Triggers, when present, included peer provocation, low frustration tolerance, limits set by others, and sleep disruption. Of the patients with severe or extreme symptoms, 80% had concurrent neuropsychiatric diagnoses. Occurrence of severe or extreme symptoms did not correlate with age, puberty, the severity of an intellectual disability, or mutation status. [10]

Disease course and progression in AHC are now a matter of debate. A non‐progressive course has been described in the past. In contrast, in a more recent case series, seven patients, aged 12 years and below, were reported to have experienced abrupt and irreversible regression along with significant acquired cortical and cerebellar atrophy. Slow and mild progression of non‐paroxysmal disability was recently observed in a multicentric cohort of 94 children and young adults. A 2022 retrospective single-center study’s cohort suggests that individuals with AHC may experience either abrupt or slowly progressive worsening of their neurological function and for most adults, the hemiplegic episodes may no longer be the main clinical issue. [11]

Patients with AHC have an increased risk of mortality of 3.2 deaths per 1000 people per year, which increases to 4.5% by 29 years of age. [12] The increased mortality observed in patients with AHC is attributable to sudden death.

AHC patients are at increased risk for SUDEP; however, the underlying cause of the susceptibility to sudden death is not fully understood. The increased mortality observed in patients with AHC is attributable to sudden death. Sudden unexpected death in epilepsy (SUDEP) has been observed in association with seizure activity in patients with AHC with concurrent epilepsy. SUDEP has also been observed in mouse models of AHC hosting the D801N and E815K variants of the ATP1A3 gene; however, the mechanism remains unknown.

A recent study focusing on ATP1A3-related syndromes identified cardiac repolarization abnormalities, but the genetic underpinning of this finding remains unknown. One potential explanation for sudden unexplained death in patients with AHC are cardiac arrhythmias, which may be fatal and have been associated with SUDEP in overlapping phenotypes. Although the neurologic impacts of ATP1A3 variants are well described, the role of ATP1A3 in the heart is not well described, and the cardiac manifestations of disease-associated variants are not well delineated. [13]

Besides the classic AHC phenotype, several atypical features have been described. With regard to age at onset, a delayed occurrence of hemiplegic attacks up to 4 years of age has been described. Regarding cognitive impairment, mild cases with normal development have been reported. Other uncommon features include a predominantly dystonic phenotype, the absence of quadriplegic attacks, or the occurrence of alternating upper limb monoplegia. [14]