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Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

ABSTRACT: Alternative hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder with an extensive phenotypic variability, resulting in a challenging clinical diagnosis. About 75% of AHC cases are caused by pathogenic variants mapping in the ATP1A3, ATP1A2 or GLUT1 gene, leaving many AHC patients clinically and genetically undiagnosed. In this study, we report the case of a 9-year old proband clinically diagnosed with an atypical form of AHC presenting a suspected mitochondrial etiology and an obscure genetic diagnosis. Long-range PCR followed by next generation sequencing of the proband's mitochondrial genome identified a novel mitochondrial variant, m.12302C > A, mapping in the MT-TL2 gene with a low heteroplasmic level in blood and fibroblasts. Whole exome sequencing revealed three known and novel pathogenic variants with different parental inheritance, all involved in the mitochondrial energy metabolism and thus far not associated with AHC. Live-cell mitochondrial metabolic study showed dysregulated mitochondrial oxidative phosphorylation pathway and metabolic plasticity preventing an efficient switch to glycolysis to sustain ATP homeostasis, congruent with the suspected mitochondrial etiology. In conclusion, our comprehensive genetic and metabolic analyses suggest an oligogenic inheritance among the nuclear and mitochondrial variants for the mitochondrial etiology of proband's atypical form of AHC, thereby providing critical insight in terms of genetic clues and bioenergetic deficit. This approach also improves the diagnostic process of atypical form of AHC with an unclear genotype-phenotype correlation to personalize therapeutic interventions.

SUBMITTER: Gropman A

PROVIDER: S-EPMC7262444 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

Gropman Andrea A Uittenbogaard Martine M Brantner Christine A CA Wang Yue Y Wong Lee-Jun LJ Chiaramello Anne A

Molecular genetics and metabolism reports 20200528

Alternative hemiplegia of childhood (AHC) is a rare neurodevelopmental disorder with an extensive phenotypic variability, resulting in a challenging clinical diagnosis. About 75% of AHC cases are caused by pathogenic variants mapping in the ATP1A3, ATP1A2 or GLUT1 gene, leaving many AHC patients clinically and genetically undiagnosed. In this study, we report the case of a 9-year old proband clinically diagnosed with an atypical form of AHC presenting a suspected mitochondri ...[more]

PMID: 32489883

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Project description:Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score (P = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score (P = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial (P = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score (P = 0.001) and first and last non-paroxysmal disability index score scores significantly differed (P = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration.

Project description: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.

Dataset Information

Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

Publications

Molecular genetic and mitochondrial metabolic analyses confirm the suspected mitochondrial etiology in a pediatric patient with an atypical form of alternating hemiplegia of childhood.

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