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. 2015 Oct;138(Pt 10):2859-74.
doi: 10.1093/brain/awv243. Epub 2015 Aug 21.

Faulty Cardiac Repolarization Reserve in Alternating Hemiplegia of Childhood Broadens the Phenotype

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Free PMC article

Faulty Cardiac Repolarization Reserve in Alternating Hemiplegia of Childhood Broadens the Phenotype

Fatima Jaffer et al. Brain. .
Free PMC article

Abstract

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Keywords: ATP1A3; Na+/K+-ATPase; SUDEP; alternating hemiplegia of childhood; electrocardiogram.

Figures

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Alternating hemiplegia of childhood is rare and usually results from mutations in cardiac- and brain-expressed ATP1A3. In an ECG study of 52 cases, Jaffer et al. reveal dynamic cardiac repolarisation or conduction abnormalities in over 50%. Abnormalities are more common in those ≥16 years, and suggest impaired cardiac repolarisation reserve.
Figure 1
Figure 1
Study profile of patients recruited into study of ECG characteristics in patients with alternating hemiplegia. AH = alternating hemiplegia; AHC = alternating hemiplegia of childhood.
Figure 2
Figure 2
Repolarization abnormalities. Examples of ECG recordings showing widespread repolarization abnormalities in Patient 5 (A), isolated inferior repolarization abnormalities in Patient 23 (B), inferior and anterior repolarization abnormalities in Patient 24 (C), and isolated anterior repolarization abnormalities in Patient 47 (D).
Figure 3
Figure 3
Intraventricular conduction delay. Examples of ECG recordings showing incomplete right bundle branch block (RBBB) and anterior repolarization abnormalities in Patient 8 (A), incomplete right bundle branch block in Patient 52 (B), IVCD and anterior repolarization abnormalities in Patient 29 (inferior and lateral repolarization abnormalities not shown) (C), and minor IVCD in Patient 31 (D).
Figure 4
Figure 4
J-point changes. Leads V1 and V2 of the normal baseline 12-lead ECG in Patient 44 (A). The same patient had a single lead (modified V1) ECG recording during video-telemetry, showing dynamic features of Brugada syndrome. While the top tracing is normal, the bottom tracing, recorded at a different time during the same recording, shows mild prolongation of QRS and J-point elevation (arrowheads) (B). Marked early repolarization in inferior leads (arrowheads) in Patient 12 (C). Lateral early repolarization (arrowheads) in Patient 9 (inferior and anterior repolarization abnormalities not shown) (D). Dynamic J-point elevation in V1 (arrowheads) in Patient 21 (E). Notching of the terminal portion of QRS in V1 in Patient 18 (F).
Figure 5
Figure 5
Age-related changes and dynamic changes. The baseline ECG performed in Patient 15 at the age of 3 years shows minor IVCD (A). The ECG performed at the age of 9 years in the same subject shows incomplete right bundle branch block [inferior repolarization abnormalities not shown (B)]. Dynamic anterior repolarization abnormalities in Patient 9: biphasic T-waves (arrowheads) in baseline ECG (C) and inverted T-waves (arrowheads) in the ECG recorded a week later than the baseline ECG (D). The baseline ECG performed at the age of 18 years in Patient 7 shows incomplete right bundle branch block, anterior repolarization abnormalities and right axis deviation [inferior repolarization abnormalities not shown (E)]. The ECG performed at the age of 19 years in the same case shows IVCD and no anterior repolarization abnormalities [arrowheads (F)]. Inferior and lateral dynamic repolarization abnormalities with subtle beat-to-beat variation (arrowheads) in T-waves in Patient 10 (G).

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