PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Heterotaxy: fluctuat nec mergitur.

The International Pediatric and Congenital Cardiac Code (IPCCC) states that visceral heterotaxy is defined as "a congenital malformation in which the internal thoraco-abdominal organs demonstrate abnormal arrangement across the left-right axis of the body. By convention, in congenital cardiology, heterotaxy syndrome does not include patients with complete mirror-imaged arrangement of the internal organs along the left-right axis also known as "total mirror imagery" or "situs inversus totalis"." [www.ipccc.net]In patients with heterotaxy, it is important to describe both the cardiac relations and the junctional connections of the cardiac segments, with documentation of the arrangement of the atrial appendages, the ventricular topology, the nature of the unions of the segments across the atrioventricular and the ventriculoarterial junctions, the infundibular morphologies, and the relationships of the arterial trunks in space. Particular attention is required for the venoatrial connections, since these are so often abnormal. The relationship and arrangement of the remaining thoraco-abdominal organs, including the lungs, the spleen, the liver, and the intestines, also must be described separately, because, although common patterns of association have been identified, there are frequent exceptions to these common patterns. Therefore, in patients with heterotaxy, it is important to describe each thoracic and abdominal organ independently.

Abnormal origin of the left pulmonary artery from the descending aorta and heterotaxy syndrome: an undescribed phenotypic association.

Extensive screening in a newborn with prenatal suspicion of VACTERL syndrome identified an anomalous origin of the left pulmonary artery from the descending aorta with an arterial duct and left aortic arch, and normal intra-cardiac anatomy. Other anatomical anomalies suggested heterotaxy syndrome. At one-month-old, re-implantation of the 3.5 mm left pulmonary artery was performed by direct tension-low anastomosis. Post-operative course was complicated by severe left pulmonary atelectasis, and the patient died 20 days later.

Perinatal intracardiac teratoma: unusual presentation and review of the literature.

Intracardiac teratomas are rare primary tumours. We report the case of an infant prenatally diagnosed with an isolated multi-cystic mass developed in the right ventricle causing neonatal refractory ventricular arrhythmia. Despite rescue extracorporeal support and partial surgical resection, he died as almost all the previous reported perinatal intracardiac teratomas whatever the prenatal tolerance and the size of the tumour. The common poor outcome of fetal intracardiac teratomas should be known when counselling parents during pregnancy.

Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates.

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.

Genetic resiliency associated with dominant lethal TPM1 mutation causing atrial septal defect with high heritability.

Analysis of large-scale human genomic data has yielded unexplained mutations known to cause severe disease in healthy individuals. Here, we report the unexpected recovery of a rare dominant lethal mutation in TPM1, a sarcomeric actin-binding protein, in eight individuals with large atrial septal defect (ASD) in a five-generation pedigree. Mice with Tpm1 mutation exhibit early embryonic lethality with disrupted myofibril assembly and no heartbeat. However, patient-induced pluripotent-stem-cell-derived cardiomyocytes show normal beating with mild myofilament defect, indicating disease suppression. A variant in TLN2, another myofilament actin-binding protein, is identified as a candidate suppressor. Mouse CRISPR knock-in (KI) of both the TLN2 and TPM1 variants rescues heart beating, with near-term fetuses exhibiting large ASD. Thus, the role of TPM1 in ASD pathogenesis unfolds with suppression of its embryonic lethality by protective TLN2 variant. These findings provide evidence that genetic resiliency can arise with genetic suppression of a deleterious mutation.

Late Pediatric Mechanical Thrombectomy for Embolic Stroke as Bridge Reinforcement From LVAD to Heart Transplantation.

Although the left ventricular assist device is an important bridge to heart transplantation for patients with end-stage heart failure, it can also be a source of embolic stroke. We present a case of late intracranial mechanical thrombectomy performed for embolic stroke beyond the recommended 6 h, thus allowing for heart transplantation 4 days after intracranial mechanical thrombectomy. (Level of Difficulty: Advanced.).

Common deletion variants causing protocadherin-α deficiency contribute to the complex genetics of BAV and left-sided congenital heart disease.

Bicuspid aortic valve (BAV) with ~1%-2% prevalence is the most common congenital heart defect (CHD). It frequently results in valve disease and aorta dilation and is a major cause of adult cardiac surgery. BAV is genetically linked to rare left-heart obstructions (left ventricular outflow tract obstructions [LVOTOs]), including hypoplastic left heart syndrome (HLHS) and coarctation of the aorta (CoA). Mouse and human studies indicate LVOTO is genetically heterogeneous with a complex genetic etiology. Homozygous mutation in the Pcdha protocadherin gene cluster in mice can cause BAV, and also HLHS and other LVOTO phenotypes when accompanied by a second mutation. Here we show two common deletion copy number variants (delCNVs) within the PCDHA gene cluster are associated with LVOTO. Analysis of 1,218 white individuals with LVOTO versus 463 disease-free local control individuals yielded odds ratios (ORs) at 1.47 (95% confidence interval [CI], 1.13-1.92; p = 4.2 × 10-3) for LVOTO, 1.47 (95% CI, 1.10-1.97; p = 0.01) for BAV, 6.13 (95% CI, 2.75-13.7; p = 9.7 × 10-6) for CoA, and 1.49 (95% CI, 1.07-2.08; p = 0.019) for HLHS. Increased OR was observed for all LVOTO phenotypes in homozygous or compound heterozygous PCDHA delCNV genotype comparison versus wild type. Analysis of an independent white cohort (381 affected individuals, 1,352 control individuals) replicated the PCDHA delCNV association with LVOTO. Generalizability of these findings is suggested by similar observations in Black and Chinese individuals with LVOTO. Analysis of Pcdha mutant mice showed reduced PCDHA expression at regions of cell-cell contact in aortic smooth muscle and cushion mesenchyme, suggesting potential mechanisms for BAV pathogenesis and aortopathy. Together, these findings indicate common variants causing PCDHA deficiency play a significant role in the genetic etiology of common and rare LVOTO-CHD.

Ascending aorta and aortic root replacement (with or without valve sparing) in early childhood: surgical strategies and long-term outcomes.

OBJECTIVES: Aortic root and ascending aorta replacements (AARs) are rarely required in the paediatric population. We report here a series of AAR performed in young children using different surgical techniques. METHODS: Between 1995 and 2017, 32 children under the age of 10 years (median age 5.4 years) underwent AAR procedures at our institution. Twenty-two (69%) had a connective tissue disease (infantile Marfan syndrome or Loeys-Dietz syndrome). We performed 11 AAR using a composite graft with a mechanical prosthesis and 21 valve-sparing procedures (10 Yacoub operations and 11 David operations). Median follow-up for operative survivors was 7.7 years (interquartile range 4.2-12.8 years). RESULTS: The cardiac-related early mortality rate was 6%. Patient survival was 91% at both 1 and 10 years. Eleven survivors (38%), all with a status of post-valve-sparing procedure, required an aortic root reintervention with an aortic valve replacement after a median interval of 4.2 years. Interestingly, only patients with infantile Marfan syndrome tended to be associated with risk of reoperation. CONCLUSIONS: Aortic root and AARs are safe in young children whatever the surgical procedure. Aortic valve-sparing procedures show good long-term results except in children with infantile Marfan syndrome whose ineluctable aortic annulus dilatation or aortic valve regurgitation requires reintervention after a short period.

Prenatal Diagnosis of Aorto-Left Ventricular Tunnel With Dysplastic Bicuspid Aortic Valve: From Fetal Cardiac Failure to Favorable Outcome.

Aorto-left ventricular tunnel (ALVT) is a rare congenital heart defect. Surgery has to be performed early to avoid life-threatening complications. Prenatal diagnosis of this defect is challenging. We report a case of ALVT diagnosed in a fetus showing premature severe cardiac failure at 24 GA. The new born was operated at day 3 of life with good results. Two years later, he is still doing well recovering a complete normal cardiac function. ALVT should be suggested in front of any fetal cardiac failure. Thanks to early diagnosis, prompt neonatal management can be organized and allows positive outcome.

Anomalous aortic origin of coronary arteries: an alternative to the unroofing strategy.

OBJECTIVES: Anomalous aortic origin of a coronary artery (AAOCA) is the second leading cause of sudden death in children and young adults. The most threatening anatomy is an interarterial and an intramural course, both probably involved in ischaemic phenomena and sudden death. The treatment of interarterial AAOCA remains controversial. Most of the published studies describe the results of the unroofing technique. Our study aims to evaluate the results of a different surgical approach. METHODS: From 2005 to 2019, 61 patients were operated on for an interarterial AAOCA (median age 14.7 years). Forty patients had a right AAOCA, and 21 patients had a left AAOCA including 5 patients with intraseptal course. Seventy percent of patients were symptomatic. Five patients had an aborted sudden cardiac death. Two surgical techniques were used: an 'anatomical' repair for 35 patients (15 left and 22 right AAOCA) or a coronary translocation with creation of a neo-ostia in 19 patients (1 left and 18 right AAOCA). The 5 left AAOCA patients with an intra-septal course required a complete release of the coronary artery from the septum. RESULTS: There was no early or late postoperative death. Three patients had an acute postoperative ischaemic event. Two patients required immediate angioplasty and stenting: 1 patient (7 years) with a hypoplastic right AAOCA and 1 patient (66 years) for inadequate tailoring after septal release. The third patient required an immediate surgical revision (H-2) for left AAOCA thrombosis at the level of the pericardial patch with full myocardial recovery at discharge. During follow-up, 1 patient with right AAOCA translocation and chronic chest pain required subsequent stenting and finally a coronary artery bypass grafting 2 years after initial surgery. One patient who had an asymptomatic mild right coronary stenosis 1 year after anatomical repair was successfully treated by angioplasty alone. All patients but 1 who underwent coronary translocation are totally asymptomatic. All patients with anatomical repair or septal release are free from ischaemic symptoms. CONCLUSIONS: Anatomical repair might provide a better protective option for these patients. Unlike unroofing, it treats the entire intramural segment, relocates the ostium at the appropriate sinus level and corrects any acute take-off angle.

A Membrane-Tethered Ubiquitination Pathway Regulates Hedgehog Signaling and Heart Development.

The etiology of congenital heart defects (CHDs), which are among the most common human birth defects, is poorly understood because of its complex genetic architecture. Here, we show that two genes implicated in CHDs, Megf8 and Mgrn1, interact genetically and biochemically to regulate the strength of Hedgehog signaling in target cells. MEGF8, a transmembrane protein, and MGRN1, a RING superfamily E3 ligase, assemble to form a receptor-like ubiquitin ligase complex that catalyzes the ubiquitination and degradation of the Hedgehog pathway transducer Smoothened. Homozygous Megf8 and Mgrn1 mutations increased Smoothened abundance and elevated sensitivity to Hedgehog ligands. While mice heterozygous for loss-of-function Megf8 or Mgrn1 mutations were normal, double heterozygous embryos exhibited an incompletely penetrant syndrome of CHDs with heterotaxy. Thus, genetic interactions can arise from biochemical mechanisms that calibrate morphogen signaling strength, a conclusion broadly relevant for the many human diseases in which oligogenic inheritance is emerging as a mechanism for heritability.

Mitral valve replacement with a pulmonary autograft: long-term follow-up in an infant.

A 7-month-old boy with a complete atrioventricular septal defect presented with severe left atrioventricular valve regurgitation 4 months after complete repair. As the valve was unsuitable for the repair and the annulus was too small to accommodate a mechanical prosthesis, the modified mitral Ross operation was performed. The long-term outcome was uneventful for 12 years. The mitral Ross procedure is an old-described technique in which classically the pulmonary autograft is encased in a prosthetic conduit preventing any growth potential. On the contrary, the modified technique used in this case shows that the long-term function can be obtained. This procedure may be a valuable option when mitral valve replacement is necessary in infants.

Tetralogy of Fallot and abnormal coronary artery: use of a prosthetic conduit is outdated.

OBJECTIVES: Repair of tetralogy of Fallot (ToF) can be challenging in the presence of an abnormal coronary artery (CA) in 5-12% of cases. The aim of this study was to report our experience with ToF repair without the systematic use of a right ventricle-to-pulmonary artery (RV-PA) conduit. METHODS: We conducted a monocentric retrospective study from 2000 to 2016, including 943 patients with ToF who underwent biventricular repair, of whom 8% (n = 76) presented with an abnormal CA. Mean follow-up time was 50 months (1 month-18 years). RESULTS: The most frequent CA anomaly was the left descending artery arising from the right CA (n = 47, 61.8%). The median age at repair was 7.7 months (1.8 months-16 years). Thirteen patients (17%) required prior palliation, mostly systemic pulmonary shunts for anoxic spells in the neonatal period. Surgical repair allowed us to preserve the annulus in 40 patients (53%) by combining PA trunk plasty, commissurotomy and infundibulotomy under the abnormal CA. If the annulus had to be opened (n = 35, 46%), a transannular patch was inserted after a vertical incision of the PA trunk and extended obliquely on the RV over the anomalous crossing CA (with an infundibulotomy under the abnormal CA). Three patients (4%) required the insertion of an RV-PA conduit (1 valved tube and 2 RV-PA GORE-TEX tubes with annulus conservation). The early mortality rate was 4% (n = 3); none of the deaths was coronary related. Four patients (5%) required reoperation (2 early and 2 late reoperations) for residual pulmonary stenosis, 3 of whom had annulus preservation during the initial repair. The mean RV/left ventricle (LV) pressure ratio and an RV/LV pressure ratio >2/3 were identified as risk factors for right ventricular outflow tract (RVOT) reinterventions (P = 0.0026, P = 0.0085, respectively), RVOT reoperations (P = 0.0002 for both) and reoperation for RVOT residual stenosis (P = 0.0002, P = 0.0014, respectively). Two patients underwent pulmonary valve replacement. Freedom from late reoperation was 100% at 1 year, 97% at 5 years and 84% at 10 and 15 years. CONCLUSIONS: Repair of ToF and abnormal CA can be performed without an RV-PA conduit, with an acceptable low reintervention rate. The high early mortality rate in this series remains a concern. If any doubt remains about the surgical relief of the RVOT obstruction, the RV/LV pressure ratio should always be measured in the operating room.

Double orifice and atrioventricular septal defect: dealing with the zone of apposition†.

OBJECTIVES: A double orifice of the left atrioventricular valve (LAVV) associated with atrioventricular septal defects (AVSD) can significantly complicate surgical repair. This study reports our experience of AVSD repair over 3 decades, with special attention to the zone of apposition (ZoA) of the main orifice, and presents a technique of hemivalve pericardial extension in specific situations. METHODS: We performed a retrospective study from 1987 to 2016 on 1067 patients with AVSD of whom 43 (4%) had a double orifice, plus 2 additional patients who required LAVV pericardial enlargement. Median age at repair was 1.3 years. Mean follow-up was 8.2 years (1 month-32 years). RESULTS: Associated abnormalities of the LAVV subvalvular apparatus were found in 7 patients (5 parachute LAVV and 2 absence of LAVV subvalvular apparatus). ZoA was noted in 4 patients (9%): partially closed in 15 (35%) and completely closed in 24 (56%). Four patients required, either at first repair or secondarily, a hemivalve enlargement using a pericardial patch without closure of the ZoA. The early mortality rate was 7% (n = 3), all before 2000. Two patients had unbalanced ventricles and the third had a single papillary muscle. There were no late deaths. Six patients (14%) required 7 reoperations (3 early and 4 late reoperations) for LAVV regurgitation and/or dysfunction, of whom 4 (9%) required mechanical LAVV replacement (all before 2000). Freedom from late LAVV reoperation was 97% at 1 year, 94% at 5 years and 87% at 10, 20 and 30 years. Unbalanced ventricles (P = 0.045), subvalvular abnormalities (P = 0.0037) and grade >2 LAVV postoperative regurgitation (P = 0.017) were identified as risk factors for LAVV reoperations. Freedom from LAVV mechanical valve replacement was 95% at 1 year, 90% at 5 years and 85% at 10, 20 and 30 years. An anomalous LAVV subvalvular apparatus was identified as a risk factor for mechanical valve replacement (P = 0.010). None of the patients who underwent LAVV pericardial extension had significant LAVV regurgitation at the last follow-up examination. CONCLUSIONS: Repair of AVSD and double orifice can be tricky. Preoperative LAVV regurgitation was not identified as an independent predictor of surgical outcome. LAVV hemivalve extension appears to be a useful and effective alternate surgical strategy when the ZoA cannot be closed.

Functional Benefits of Bilateral Emphysema Reduction Surgery in an Adolescent.

Acquired emphysema is a rare pathology in pediatrics. We report the case of a patient born at term with a neonatal respiratory distress, which had required mechanical ventilation. She developed gradually chronic obstructive pulmonary disease with severe emphysematous lesions, respiratory failure and functional impairments. Bilateral emphysema resection, performed at 16 years old, allowed major functional benefits at rest and during exercise. We present the results of respiratory functional evaluations, walk tests and maximal exercise tests (including measure of dynamic hyperinflation) before and after surgery, which highlights that surgery is a successful option in the treatment of compressive emphysema in childhood.

MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates.

Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates.