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Alternating hemiplegia of childhood
A rare, genetic, neurodevelopmental disorder characterized by early-onset of recurrent, transient episodes of hemiplegia (including quadriplegia), which typically disappear upon sleep.
ORPHA:2131Classification level: Disorder
Alternating hemiplagia of childhood (AHC) prevalence is estimated at 1/100,000 in children under 16 years old, although underdiagnosis is probable.
Patients usually present in infancy with episodic hemiplegia involving one or alternating sides of the body which typically disappear upon sleep. Episodes occur with variable frequency and may last a few minutes to several days. Isolated or associated episodes of bilateral hemiplegia may also be observed. Early signs of the disease are often noted, in some cases shortly after birth, associating paroxysmal involuntary movements (including tonic-dystonic movements) nystagmus, choreoathetosis, dyskinesia and autonomic abnormalities. Various triggers may precipitate symptoms, including exposure to heat or cold, emotional stress, fatigue, excessive light and sound stimuli, trauma, and bathing. Psychomotor delay, ranging from mild to severe, is common. Additional features include cerebellar signs, speech disorders and behavioral disturbances, such as mood changes, aggressiveness, impulsivity and attention deficit. A considerable number of AHC patients develop epilepsy and cardiac conduction abnormalities.
Although the exact pathophysiological mechanism of AHC remains unclear, de novo heterozygous mutations in the ATP1A3 (19q13.2) gene, encoding a subunit of the Na+/K+ ATPase pump, have been implicated as causative for the majority of screened AHC cases. Over 60 different AHC mutations have been identified so far in the ATP1A3 gene as the most frequent mutations are D801N (43%), E815K (16%), and G947R (11%) Some cases with alternating hemiplegia and atypical features have been reported with mutations in the ATP1A2 (1q23.2),CACNA1A,ADCY5, TANGO2 and SLC1A3 genes.
Diagnosis is based on characteristic clinical manifestations using Aicardi's diagnostic criteria. ATP1A3 gene testing would be recommended to support clinical diagnosis of AHC.
Differential diagnoses includes infantile epilepsy syndrome, benign nocturnal alternating hemiplegia of childhood, as well as allelic disorders with overlapping clinical features, such as rapid-onset dystonia-parkinsonism, familial or sporadic hemiplegic migraine and Moyamoya disease. Neurological, metabolic and vascular syndromes with similar clinical features should also be excluded.
Prenatal diagnosis for pregnancies at increased risk is possible if a causative mutation has been previously identified in the family.
AHC is inherited in an autosomal dominant manner as most cases are sporadic. However, parental germline mosaicism has also been reported in couple of cases with familial recurrence. Therefore genetic counseling should be provided to parents with an affected child and should take into account the risk of recurrence in the family.
Management and treatment
There is no regulatory approved treatment for AHC. Flunarizine has been widely prescribed during the past 30 years to reduce the frequency, severity and duration of hemiplegic episodes. Other commonly used drugs are topiramate, benzodiazepines, chloral hydrate. Seizures and ECG abnormalities should be properly treated and monitored while triggers and irregular sleeping patterns should be avoided as much as possible.
Psychomotor outcome is highly variable as some patients may be wheelchair-bound while others are able to live independent lives in adulthood. Frequency and duration of acute manifestations generally decrease with age, however sudden deterioration can occur in the late course of the disease. Status epilepticus in alternating hemiplegia is linked to severe outcome.