Elsevier

The Lancet Neurology

Volume 11, Issue 9, September 2012, Pages 764-773
The Lancet Neurology

Articles
Heterozygous de-novo mutations in ATP1A3 in patients with alternating hemiplegia of childhood: a whole-exome sequencing gene-identification study

https://doi.org/10.1016/S1474-4422(12)70182-5Get rights and content

Summary

Background

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by early-onset episodes of hemiplegia, dystonia, various paroxysmal symptoms, and developmental impairment. Almost all cases of AHC are sporadic but AHC concordance in monozygotic twins and dominant transmission in a family with a milder phenotype have been reported. Thus, we aimed to identify de-novo mutations associated with this disease.

Methods

We recruited patients with clinically characterised AHC from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. We used whole-exome sequencing of three proband-parent trios to identify a disease-associated gene and then tested whether mutations in the gene were also present in the remaining patients and their healthy parents. We analysed genotypes and characterised their associations with the phenotypic spectrum of the disease.

Findings

We studied 15 female and nine male patients with AHC who were aged 8–35 years. ATP1A3 emerged as the disease-associated gene in AHC. Whole-exome sequencing showed three heterozygous de-novo missense mutations. Sequencing of the 21 remaining affected individuals identified disease-associated mutations in ATP1A3 in all patients, including six de-novo missense mutations and one de-novo splice-site mutation. Because ATP1A3 is also the gene associated with rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) we compared the genotypes and phenotypes of patients with AHC in our cohort with those of patients with rapid-onset dystonia-parkinsonism reported in the scientific literature. We noted overlapping clinical features, such as abrupt onset of dystonic episodes often triggered by emotional stress, a rostrocaudal (face to arm to leg) gradient of involvement, and signs of brainstem dysfunction, as well as clearly differentiating clinical characteristics, such as episodic hemiplegia and quadriplegia.

Interpretation

Mutation analysis of the ATP1A3 gene in patients who met clinical criteria for AHC allows for definite genetic diagnosis and sound genetic counselling. AHC and rapid-onset dystonia-parkinsonism are allelic diseases related to mutations in ATP1A3 and form a phenotypical continuum of a dystonic movement disorder.

Funding

Eva Luise and Horst Köhler Foundation for Humans with Rare Diseases.

Introduction

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder characterised by transient episodes of hemiplegia combined with other paroxysmal symptoms, including dystonia, nystagmus, autonomic disturbances, and seizures.1, 2, 3 Hemiplegic attacks can shift from one side of the body to the other, resulting in episodes of quadriplegia that can be accompanied by mutism, amimia, dysphagia, hypersalivation, and disturbed consciousness.4, 5 Prominent bulbar symptoms affecting speech, feeding, and swallowing can pose a key problem in the care of patients with long-lasting severe attacks.6

Onset of these paroxysmal manifestations usually occurs in the first 6 months of life, and frequency ranges from several times a month to several times a day, with a duration of a few minutes to several days. A typical feature of AHC is that paroxysmal symptoms can be triggered by certain factors and events, including emotional stress, bathing, cold, fatigue, hypothermia, hyperthermia, and upper respiratory tract infection.1, 6 Another unique feature is that of disappearance of all symptoms on falling asleep, so induction of sleep has become an important management tactic for parents and doctors when severe attacks occur. However, symptoms can return within 30 min after waking up in prolonged paroxysms.

Non-paroxysmal manifestations occur after a few months or years, comprising developmental delay, intellectual disability of variable degree, ataxia, dysarthria, choreoathetosis, and, in some patients, pyramidal tract signs. The course of the disease is very variable and unpredictable for each patient. Hemiplegic episodes persist throughout life, although tend to decrease in number and duration as the patient gets older.1 In a subset of patients, the non-paroxysmal manifestations follow a progressive course.7 AHC is probably not intrinsically a progressive disease, but it can show stepwise deterioration with severe episodes.6

Familial cases of AHC with late onset, mild phenotypes, and autosomal dominant inheritance8 and concordant occurrence in monozygotic twins9 have been reported, but almost all cases are sporadic. Therefore, the elucidation of the genetic causes of AHC has been refractory to linkage mapping approaches.

Numerous laboratory and neuroradiological investigations were unable to provide any clues about the pathogenesis of this disease.10 In individual patients with clinical phenotypes mostly consistent with AHC, mutations in the ATP1A2 gene encoding the Na+/K+-ATPase α2 subunit, which is also associated with familial hemiplegic migraine,11, 12 or in the SLC2A1 gene, encoding the glucose transport protein type 1,13 have been reported, but have not been confirmed in larger cohorts of patients with definite AHC.14, 15 Thus, no biochemical or radiological disease markers exist for AHC and the diagnosis has so far been made entirely based on clinical criteria (panel 1).

Because of the sporadic occurrence in almost all cases and reports of concordant AHC in monozygotic twins and of dominant transmission in a family with mild phenotype, we hypothesized that heterozygous dominant de-novo mutations were the cause of AHC. Therefore, we aimed to identify the disease-causing gene by use of whole-exome sequencing of proband-parent trios.

Section snippets

Participants and study design

We recruited patients from paediatric neurology departments in Germany and with the aid of a parental support group between Sept, 2004, and May 18, 2012. All participating patients fulfilled the established diagnostic criteria for AHC.2, 7

In a first step, we undertook a whole-exome sequencing of three proband-parent trios to identify the causal gene. The three chosen patients with AHC fulfilled the diagnostic criteria and their parents agreed to provide blood samples for whole-exome sequencing.

Results

We recruited 15 female and nine male patients with AHC, aged 8–35 years (Table 1, Table 2). Whole-exome sequencing based on the proband-parent trios identified three missense mutations in ATP1A3 in three patients with AHC (965T>A [Val322Asp], 2401G>A [Asp801Asn], and 2443G>A [Glu815Lys]; table 1, appendix) that were confirmed by Sanger sequencing. To confirm that ATP1A3 was associated with AHC, we sequenced this gene in the 21 other patients meeting diagnostic criteria for AHC; we detected two

Discussion

We report mutations in a gene associated with disease in patients with AHC; by whole-exome sequencing of three proband-parent trios and consecutive molecular analyses of 21 additional patients with AHC, we identified heterozygous de-novo mutations in ATP1A3, the gene encoding the α3-subunit of the sodium–potassium ATPase (panel 2).

As transmembrane ion pumps, Na+/K+-ATPases generate chemical and electrical gradients of Na+ and K+ across the plasma membrane. These gradients have a key role not

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