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Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

ABSTRACT: Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a paternally inherited, pathogenic missense variant (c.514G > A; p.Glu172Lys) and a novel, maternally inherited missense variant of uncertain significance (c.442A > T; p.Thr148Ser). This report expands the presenting phenotype of patients with PPA2 variants. It also highlights the utility of dried blood spots for postmortem molecular diagnosis.

SUBMITTER: Sanford E

PROVIDER: S-EPMC7552926 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

Sanford Erica E Jones Marilyn C MC Brigger Matthew M Hammer Monia M Giudugli Lucia L Kingsmore Stephen F SF Dimmock David D Bainbridge Matthew N MN

Cold Spring Harbor molecular case studies 20201007 5

Biallelic variants in inorganic pyrophosphatase 2 (PPA2) are known to cause infantile sudden cardiac failure (OMIM #617222), but relatively little is known about phenotypic variability of these patients prior to their death. We report a 5-wk-old male with bilateral vocal cord paralysis and hypertension who had a sudden unexpected cardiac death. Subsequently, molecular autopsy via whole-genome sequencing from newborn dried blood spot identified compound heterozygous mutations in PPA2, with a pate ...[more]

PMID: 33028643

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Project description:ImportanceUnilateral vocal fold paralysis (UVFP) is a common and life-changing complication of cancer, trauma, and an estimated 500 000 head, neck, and chest surgeries performed annually in the US, among other causes (eg, idiopathic). Consequent disabilities are profound and often permanent and can include severe voice, swallowing, and breathing dysfunction and concomitant anxiety, isolation, and fear. Physiological measures often correlate poorly with patient-reported disability. The measure described herein was designed to be a comprehensive, psychometrically sound UVFP-specific patient-reported outcome measure (PROM) for use in clinical trials or at point of care.ObjectiveTo evaluate the reliability and validity of the CoPE (vocal Cord Paralysis Experience) PROM in a nationally representative sample for both clinical and research use.Design, setting, and participantsThis survey validation study was performed at 34 tertiary care centers across the US and included English-speaking adults with unilateral vocal fold immobility confirmed via laryngoscopy.Main outcomes and measuresReliability (internal consistency, alternate form, and test-retest) and validity (convergent and known-group).ResultsIn total, 613 patients (mean [SD] age, 58 [15.3] years; 394 [64.5%] women) were recruited, and 555 (92.3%) completed surveys for all time points. Internal consistency was high in the overall 22-item PROM and psychosocial, swallow, and voice subscales (Cronbach α > 0.91). Intraclass correlations for individuals between the baseline and 2-week administrations were moderate for the overall score and subscales (intraclass correlations range, 0.66-0.80). There were significant differences between the online and 2-week paper administrations for the overall score and voice and psychosocial subscales (overall scale mean: 54.4 [95% CI, 49.7-59.1] vs 48.9 [95% CI, 43.7-54.0] at 2 weeks). The confirmatory model was found to be suitably fitted based on average r2 values 0.5 or greater for subscale and overall scores. Correlations between subscales and existing PROMs (Voice-Related Quality of Life, Eating Assessment Tool, and Communication Participation Item Bank) were all greater than 0.69, and mean PROM subscale scores were significantly different across known quartiles of existing PROMs.Conclusions and relevanceThe findings of this survey validation study suggest that the CoPE PROM could serve as a psychometrically sound, comprehensive measure of UVFP-attributed disability suitable for use in clinical and research settings to assess within-person changes. The results will inform a user manual to facilitate use in clinical trials comparing the effectiveness and durability of treatments including behavioral (speech therapy), temporary (eg, injection augmentation), and permanent surgical treatments for UVFP.

Dataset Information

Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

Publications

Postmortem diagnosis of PPA2-associated sudden cardiac death from dried blood spot in a neonate presenting with vocal cord paralysis.

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