The heart in <scp>RASopathies</scp>

Delogu, Angelica Bibiana; Limongelli, Giuseppe; Versacci, Paolo; Adorisio, Rachele; Kaski, Juan Pablo; Blandino, Rita; Maiolo, Stella; Monda, Emanuele; Putotto, Carolina; Rosa, Gabriella De; Chatfield, Kathryn C.; Gelb, Bruce D.; Calcagni, Giulio

doi:10.1002/ajmg.c.32014

Cited by 11 publications

(7 citation statements)

References 106 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently these drugs have been proposed as potential therapies in NS and related syndromes. 26,27 Marin et al 28 showed that the treatment of NSML mice with rapamycin could prevent the onset of disease or reverse HCM. Recently, an infant with NSML and severe obstructive HCM was treated with everolimus, showing a significant improvement in symptoms and b-type natriuretic peptide levels.…”

Section: Discussionmentioning

confidence: 99%

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

Monda

Prosnitz

Aiello

et al. 2023

Circ: Genomic and Precision Medicine

Self Cite

View full text Add to dashboard Cite

BACKGROUND: We aimed to examine clinical features, and outcomes of consecutive molecularly characterized patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy. METHODS: A retrospective, longitudinal multicenter cohort of consecutive children and adults with a genetic diagnosis of Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy between 2002 and 2019 was assembled. We defined a priori 3 different patterns of left ventricular remodeling during follow-up: (1) an increase in ≥15% of the maximal left ventricular wall thickness (MLVWT), both in mm and z -score (progression); (2) a reduction ≥15% of the MLVWT, both in mm and z -score (absolute regression); (3) a reduction ≥15% of the MLVWT z -score with a stable MLVWT in mm (relative regression). The primary study end point was a composite of cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator-shock. RESULTS: The cohort comprised 42 patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy, with a median age at diagnosis of 3.5 (interquartile range, 0.2–12.3) years. Freedom from primary end point was 92.7% (95% CI, 84.7%–100%) 1 year after presentation and 80.9% (95% CI, 70.1%–90.7%) at 5 years. Patients with MLVWT z -score >13.7 showed reduced survival compared with those with <13.7. During a median follow-up of 3.7 years (interquartile range, 2.6–7.9), absolute regression was the most common type of left ventricular remodeling (n=9, 31%), followed by progression (n=6, 21%), and relative regression (n=6, 21%). CONCLUSIONS: These findings provide insights into the natural history of left ventricular hypertrophy, and can help inform clinicians regarding risk stratification and clinical outcomes in patients with Noonan syndrome with multiple lentigines and hypertrophic cardiomyopathy.

show abstract

Section: Discussionmentioning

confidence: 99%

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

Monda

Prosnitz

Aiello

et al. 2023

Circ: Genomic and Precision Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mutations in genes associated with RAS signalling are associated with CHD in humans and mice (Araki et al, 2004;Delogu et al, 2022). Consistent with this, according to Bgee multispecies' expression database (version 15.0; accessed 26 October 2023; https:// www.…”

Section: Introductionmentioning

confidence: 61%

“…Mutations in RAS/MAPK cell signalling pathway, or ‘RASopathies’, are associated with PS; these include Noonan and Leopard syndromes (Delogu et al., 2022 ; Tartaglia et al., 2011 ). PRKD1 is also associated with the regulation of RAS signalling (Su et al., 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…PRKD1 (Protein kinase D1, also known as PKCμ) encodes a serine/threonine protein kinase, which is involved in a variety of fundamental cellular functions including cell survival, migration, differentiation, proliferation and adhesion (Barrio‐Hernandez et al., 2020 ; Bollag et al., 2018 ; Eiseler et al., 2009 ; Spasojevic et al., 2018 ; Sroka et al., 2016 ), Golgi transport (Baron & Malhotra, 2002 ; Maeda et al., 2001 ) and the regulation of RAS signalling (Su et al., 2018 ). Mutations in genes associated with RAS signalling are associated with CHD in humans and mice (Araki et al., 2004 ; Delogu et al., 2022 ). Consistent with this, according to Bgee multispecies' expression database (version 15.0; accessed 26 October 2023; https://www.bgee.org/search/genes ) (Bastian et al., 2021 ), Prkd1 in mouse is highly expressed in the cardiovascular system, including the adult atria, ventricles, aorta and valves.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Waheed‐Ullah,

Wilsdon,

Abbad

et al. 2024

Journal of Anatomy

View full text Add to dashboard Cite

Congenital heart disease (CHD) is the most common congenital anomaly, with an overall incidence of approximately 1% in the United Kingdom. Exome sequencing in large CHD cohorts has been performed to provide insights into the genetic aetiology of CHD. This includes a study of 1891 probands by our group in collaboration with others, which identified three novel genes—CDK13, PRKD1, and CHD4, in patients with syndromic CHD. PRKD1 encodes a serine/threonine protein kinase, which is important in a variety of fundamental cellular functions. Individuals with a heterozygous mutation in PRKD1 may have facial dysmorphism, ectodermal dysplasia and may have CHDs such as pulmonary stenosis, atrioventricular septal defects, coarctation of the aorta and bicuspid aortic valve. To obtain a greater appreciation for the role that this essential protein kinase plays in cardiogenesis and CHD, we have analysed a Prkd1 transgenic mouse model (Prkd1em1) carrying deletion of exon 2, causing loss of function. High‐resolution episcopic microscopy affords detailed morphological 3D analysis of the developing heart and provides evidence for an essential role of Prkd1 in both normal cardiac development and CHD. We show that homozygous deletion of Prkd1 is associated with complex forms of CHD such as atrioventricular septal defects, and bicuspid aortic and pulmonary valves, and is lethal. Even in heterozygotes, cardiac differences occur. However, given that 97% of Prkd1 heterozygous mice display normal heart development, it is likely that one normal allele is sufficient, with the defects seen most likely to represent sporadic events. Moreover, mRNA and protein expression levels were investigated by RT‐qPCR and western immunoblotting, respectively. A significant reduction in Prkd1 mRNA levels was seen in homozygotes, but not heterozygotes, compared to WT littermates. While a trend towards lower PRKD1 protein expression was seen in the heterozygotes, the difference was only significant in the homozygotes. There was no compensation by the related Prkd2 and Prkd3 at transcript level, as evidenced by RT‐qPCR. Overall, we demonstrate a vital role of Prkd1 in heart development and the aetiology of CHD.

show abstract

“…From a cardiac perspective, RASopathies present with hypertrophic heart disease in childhood, commonly characterized by biventricular involvement, end-stage remodeling, frequent heart failure-related hospitalizations, and increased mortality. 11,12 Mitogen-Activated Protein Kinase 1 Inhibitors…”

Section: Rasopathiesmentioning

confidence: 99%

Targeted Therapies in Pediatric and Adult Patients With Hypertrophic Heart Disease: From Molecular Pathophysiology to Personalized Medicine

Monda

Bakalakos

Rubino

et al. 2023

Circ: Heart Failure

Self Cite

View full text Add to dashboard Cite

Hypertrophic cardiomyopathy is a myocardial disease defined by an increased left ventricular wall thickness not solely explained by abnormal loading conditions. It is often genetically determined, with sarcomeric gene mutations accounting for around 50% of cases. Several conditions, including syndromic, metabolic, infiltrative, and neuromuscular diseases, may present with left ventricular hypertrophy, mimicking the hypertrophic cardiomyopathy phenotype but showing a different pathophysiology, clinical course, and outcome. Despite being rare, they are collectively responsible for a large proportion of patients presenting with hypertrophic heart disease, and their timely diagnosis can significantly impact patients’ management. The understanding of disease pathophysiology has advanced over the last few years, and several therapeutic targets have been identified, leading to a new era of tailored treatments applying to different etiologies associated with left ventricular hypertrophy. This review aims to provide an overview of the existing and emerging therapies for the principal causes of hypertrophic heart disease, discussing the potential impact on patients’ management and clinical outcome.

show abstract

The heart in RASopathies

Cited by 11 publications

References 106 publications

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines

Effect of deletion of the protein kinase PRKD1 on development of the mouse embryonic heart

Targeted Therapies in Pediatric and Adult Patients With Hypertrophic Heart Disease: From Molecular Pathophysiology to Personalized Medicine

Contact Info

Product

Resources

About