Cardiac phenotype in ATP1A3 -related syndromes

Figures

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  Figure 1. Study design Diagram illustrating study design with included and excluded cases. AHC = alternating hemiplegia of childhood; CAPOS = cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss; RDP = rapid-onset dystonia-parkinsonism.

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  Figure 2. Holter abnormalities in a young patient with AHC requiring the insertion of an ICD (A) Abnormal Holter ECG showing asymptomatic sinus pauses of up to 4 seconds in duration (red arrows) and (B) polymorphic ventricular ectopics in couplets and bigeminy in a young patient who required insertion of an implantable cardioverter-defibrillator (ICD) at the age of 27 years (patient with alternating hemiplegia of childhood [AHC], c.2401G>A p.D801N mutation).

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  Figure 3. ECG abnormalities in ATP1A3-related syndromes Graphic representation of the ATP1A3-related syndromes (alternating hemiplegia of childhood [AHC] = rectangles, cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss [CAPOS] = triangles, rapid-onset dystonia-parkinsonism [RPD] = hexagons) (n = 110), associated mutations, and prevalence of ECG (12-lead and/or Holter) abnormalities. Each box includes the number of cases with a specific mutation and ECG abnormalities in the upper part or without ECG abnormalities in the lower part. Reference sequences for the corresponding ATP1A3 transcript and protein were NM_152296.4 and Uniprot P13637, respectively. T1 through T10 are transmembrane domains. The position of the mutation across the functional domains was not associated with different prevalence of ECG abnormalities or dynamic changes. In 9 patients with AHC, no mutation was identified in ATP1A3. D = dynamic changes (when serial tests were available).

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  Figure 4. ATP1A3 expression in an adult normal heart Dark brown stripes show strong immunolabeling for ATP1A3 corresponding to intercalated disks in adult myocardium from a 75-year-old man (cause of death at postmortem: bronchopneumonia). Tissue samples were fixed in formalin and embedded in paraffin. A standard immunohistochemistry method was applied to 5-μm-thick sections with primary antibody anti-ATP1A3 (Santa Cruz, polyclonal, goat, sc16052) at a dilution of 1:1,000 with overnight incubation at 4°C in diluent buffer (DAKO REAL, Ab diluent S2022). Immunostaining was qualitatively evaluated.

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  Figure 5. ECG data in the Mashl+/− compared to WT mice Comparison of ECG data acquired from wild-type (WT; n = 15) and Mashl+/− mice (n = 3). (A) Heart rate, (B) QRS interval, (C) PR interval, and (D) QTc interval. Traces are examples of ECG traces in WT and mutant mice. Heart rate, QRS, and PR interval were higher in Mashl+/− mice. ***p ≤ 0.001, **p < 0.01 (Student t test). BPM = beats per minute.

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  Figure 6. ECG abnormalities in the Mashl+/− mice (n = 3) after seizure induction (A) Mashl+/− No. 1 ECG traces. (A.a) Baseline, with normal heart rate, noise present stems from skeletal muscle (breathing) activity. (A.b) Earlier changes started with onset of EEG seizures at 21 minutes after injection: heart rate increase and JT-segment elevation. (A.c) Later changes. Consecutive ECG traces shortly before sinus arrest showing heart rate fluctuation and atrioventricular block (red arrows); premature ventricular contractions are also visible (blue arrows). (A.d) Terminal change. Sinus bradycardia that was followed by sinus arrest. (B) Mashl+/− No. 2 ECG traces. (B.a) Baseline, with normal heart rate. (B.b) Earlier changes started with onset of EEG seizures after 5 minutes of injection and persisted to 1 minute before death (time of B.b. illustration). Increased heart rate with JT-segment depression (red), and JT elevation (blue) widened QRS. (B.c) Later changes. Sequence of events <1 minute before sinus arrest showing atrioventricular block (red arrows) and elevated JT segments (blue arrows). (B.d) Terminal change. Sinus bradycardia that was followed by sinus arrest. Mashl+/− No. 3 had…