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Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
An autosomal recessive disorder, Naxos disease, is caused by mutations in the junctional plakoglobin gene (JUP) and causes palmoplantar keratoderma and woolly hair as well as a biventricular cardiomyopathy resembling ACMP.
Hair dysplasias
Published in Pierre Bouhanna, Eric Bouhanna, The Alopecias, 2015
Juan Ferrando, L. Alheli Niebla, Gerardo A. Moreno-Arias
Genetics. Autosomal dominant variants are due to a mutation of KTR75 (12q13, 20.91 MB between D12S1301 and D12S1610).89 Autosomal recessive variants are caused by mutations in P2RY5 (13q14.2-q14.3), LIPH (3q27-q28), and LAH2 (3q27-q28).90 In Naxos disease, woolly hair is associated with cardiomyopathy and keratoderma of the palms and soles and is caused by the mutation of the plakoglobin gene (17q.21).91,92
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
ACM results from mutations in at least 13 desmosomal genes. Desmosomes are highly specialized cell adhesion junctions which confer resistance to mechanical stress and preserve cellular integrity in cardiac tissue and epidermis. Without normal desmosomes, myocytes detach from one another and die, particularly when the heart muscle is placed under stress (such as during vigorous exercise). Inheritance is usually autosomal dominant but the recessive form called Naxos disease shows severe cardiac disease from an early age. This provided the first genetic evidence for the cause of this disease in the desmosome and fascia adherens. Proteins from three separate families assemble to form desmosomal cadherins (desmoglein and desmocollin), armadillo proteins (plakoglobin and plakophilin) and plakins (desmoplakin). A plakoglobin deletion was first found in Naxos disease, followed by mutations in desmoplakin, plakophilin-2, desmoglein-2, desmocollin-2 and plakoglobin in the dominant forms. Thus, ACM is mainly a disease of the cardiomyocyte junction, and plakophilin-2 (PKP2) mutations are the most common. Convincing evidence is emerging that, particularly for DSG2 and DSC2, many carriers have a second variant. Variants in genes associated with other cardiomyopathies and arrhythmia syndromes have been reported in ACM patients, including in the sarcomere genes, DES (desmin), TTN (titin), LMNA (lamin A/C), PLN (phospholamban), SCN5A (Nav1.5) and FLNC (filamin C). Other non-desmosomal genes implicated in ACM include the cardiac ryanodine-2 receptor, the transforming growth factor β3 and the TMEM43 genes. These findings highlight the genetic heterogeneity and complexity of cardiomyopathies and arrhythmia syndromes. Genotype only occasionally informs management of affected patients. Individuals with multiple pathogenic variants do have earlier-onset disease and a higher risk for malignant ventricular arrhythmias and sudden death. Another genotype/phenotype association that may guide management is a very high risk of sudden death among male carriers of the founder TMEM43 variant p. (Ser358Leu). The likelihood of left ventricular involvement varies among carriers of different mutations with biventricular disease common among patients with PLN or DSP variants. The clinical utility of genetic sequencing for ACM is primarily to inform cascade screening for at-risk family members. Up to 20% have no known mutation so other factors are involved in the ACM phenotype.
Naxos disease – a narrative review
Published in Expert Review of Cardiovascular Therapy, 2020
Marianna Leopoulou, Gustav Mattsson, Jo Ann LeQuang, Joseph V Pergolizzi, Giustino Varrassi, Marita Wallhagen, Peter Magnusson
Unfortunately, the cardiac abnormalities may cause life-threatening arrhythmias and eventually sudden cardiac death (SCD). This review covers diverse aspects of Naxos disease, its clinical characteristics, historic background, genetics, therapeutic management, and future perspectives.