Sudden cardiac death triggered by minimal alcohol consumption in the context of novel PPA2 mutations in 2 unrelated families.

Biallelic variants in PPA2 gene cause a rare but lethal mitochondrial disorder. We describe the first four cases reported in Spain of PPA2 disease in two unrelated families. We have conducted a revision of the clinical history, necropsies, and postmortem genetic testing from probands, and clinical evaluation, genetic testing and blood transcript analysis in family members. All the cases harbored biallelic PPA2 variants in compound heterozygous status. Two brothers from family 1 suffered sudden death after a small first intake of alcohol in 2013 and 2022. The sister remains alive but affected with cardiomyopathy, extensive scar on cardiac imaging, and high sensitivity to alcohol intake. The three siblings carried PPA2 c.290A > G (p.Glu97Gly) novel missense variant and PPA2 c.513C > T (p.Cys171 = ) altering splicing site variant, both probably leading to mRNA degradation based on in-silico and transcript analyses. A teenager from family 2 suffered sudden death after a small intake of alcohol in 2018 and carried PPA2 c.683C > T (p.Pro228Leu) missense and PPA2 c.980_983del (p.Gln327fs) novel frameshift variant, both probably leading to abnormal protein structure. All cases were asymptomatic until adolescence. Furthermore, the sister in family 1 has survived as an asymptomatic adult. PPA2 disease can manifest as cardiac arrest in the young, especially after alcohol exposure. Our results show that PPA2 deficiency can be related to different pathogenicity mechanisms such as abnormal protein structure but also mRNA decay caused by synonymous or missense variants. Strict avoidance of alcohol consumption and early defibrillator implantation might prevent lethal arrhythmias in patients at risk.

A prospective study among neonates born to mothers with active or past Graves disease.

OBJECTIVE: The aim of this prospective study was to describe demographic and clinical characteristics of neonates born to mothers with active or past Graves disease and to assess compliance since implementation of a new protocol in our center. METHODS: We prospectively followed up neonates born to mothers with active or past Graves disease in a tertiary hospital in Spain between August 2019 and September 2021 according to our protocol. We reviewed maternal and neonatal history of these neonates, and we followed up newborns at risk of neonatal hyperthyroidism. RESULTS: Among 5808 births, 33 neonates were born to mothers with active or past Graves disease (0.57%). Six mothers (18.2%) had positive levels of thyroid-stimulating hormone receptor antibodies during pregnancy and five mothers (15.1%) between weeks 20 and 24 of pregnancy. Two of them had received definitive therapy for Graves disease before pregnancy. Two neonates (7.1%) were at high risk of neonatal hyperthyroidism and were followed-up until two months, without hyperthyroidism signs or abnormal thyroid hormone levels. Compliance of protocol during pregnancy was 84.9% and 75.8% at birth. CONCLUSIONS: Prevalence of Graves disease among pregnant women was 0.57%, with no cases of neonatal hyperthyroidism. Compliance of protocol was adequate during pregnancy (84.9%) and acceptable at birth (75.8%).