Correspondence Address:
Rohan Yesudian
University of Cambridge, Cambridge
UK

Full Text



Sir,

Naxos disease is an autosomal recessive disease characterized by the triad of woolly hair, palmoplantar keratoderma, and arrhythmogenic right ventricular dysplasia (ARVD). It has a prevalence of 1 in 1000 in Naxos, the largest of the Greek Cyclades islands, where up to 5% of the population are heterozygote carriers.^[1]

After serving in the Greek army from 1981 to 1983, Dr. Nikos Protonotarios, a cardiologist, returned to his hometown in Naxos to complete compulsory rural service in Filoti for 2 years. There, he noted the curious familial link between palmoplantar keratoderma, hair defects, and cardiac abnormalities. It was associated with poor prognosis, especially in the young, with an annual disease-related and sudden death mortality estimated at 3% and 2.3%, respectively.^[2] This condition was distinct to the more common Mal de Meleda disease that manifests with palmoplantar keratoderma without associated woolly hair.

Learning that this cardiocutaneous condition was unreported in the literature, Dr. Adalena Tsatsopoulou, a pediatrician and wife of Protonotarios, traveled to the Elsevier library in Amsterdam with her husband. Over a period of a month, they painstakingly pored over manuscripts dating back to 1895 until finally coming across an article describing ARVD,^[3] which was a common complication for many of Protonotarios' patients. Equipped with information on the mysterious cardiac abnormality, the duo published the seminal article establishing the link between familial palmoplantar keratoderma, woolly hair, and ARVD.^[4] The study included four families from the island of Naxos. There were nine cases of palmoplantar keratoderma, where all had scalp hair abnormalities and seven showed signs of heart disease. All patients with heart abnormalities exhibited enlargement of the right ventricle and the septomarginal trabecula. Of the forty family members who did not have keratosis, none displayed signs of heart disease. In 1994, after further epidemiological study, the term “Naxos disease” was coined.

With the genomic revolution, the focus turned to the genetics of the disease. Protonotarios and Tsatsopoulou were once again at the forefront of the research. In 1998, the gene predisposing to Naxos disease was mapped to chromosome 17q21^[5] and in 2000, the target gene was identified. The disease involved a two base pair deletion mutation leading to truncation of the protein plakoglobin,^[6] a key protein in desmosomes (structures that mediate cell-cell adhesion), which relays signals to the nucleus.^[7] There have since been at least 13 genes implicated with ARVD.^[8]

Tissues exposed to greater mechanical stress, such as the heart, palmoplantar skin, and skin appendages, have larger desmosomes with increased protein expression.^[9] Therefore, they are more susceptible to injury. Disruption to desmosome structures impairs the integrity of the cardiac functional syncytium, resulting in arrhythmias. Furthermore, desmosomes play a role in cell signaling. Damage to these structures promotes apoptotic pathways, leading to the fibrofatty replacement of cardiomyocytes.In vitro experiments have confirmed that plakoglobin forms a complex with the Lef-1 transcription factor, which binds to and represses the c-Myc promoter.^[10] Mutations in plakoglobin prevent the formation of the repressor complex, predisposing to palmoplantar keratinocyte hyperproliferation. It also promotes the excess production of soft keratin in the inner root sheath of hair follicles, causing woolly hair.

The current treatments for Naxos disease target cardiac symptoms. This includes automatic cardioverter-defibrillator implantation and administration of antiarrhythmic drugs. However, appreciation of molecular biology could improve the outcomes for patients with different forms of ARVD. For instance, Protonotarios' team developed the drug SB216763, which has shown promise in cell and animal models.^[11] In addition, one can speculate the immense potential for gene-editing technology such as the Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 nuclease for genetic diseases.

Protonotarios and Tsatsopoulou's work on Naxos disease has progressed the understanding of other cell adhesion diseases. For example, Carvajal syndrome, first described by Carvajal-Huerta in Ecuador (1998) is another autosomal recessive genetic disease affecting desmosomes with clinical features similar to Naxos disease but causing left ventricular cardiomyopathy. They have also raised the awareness of rare inherited cardiovascular diseases and pushed for state-run genetic screening of Naxos disease for inhabitants of the Cyclades islands, which was approved in 2018.^[12]

Science has witnessed significant advances through serendipity. However, we should continue in our pursuit of knowledge driven by astute observation, research, and desire to help patients. The study of rare diseases can be valuable in understanding the pathophysiology of different conditions. In the words of William Harvey:

“Nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature, by the careful investigation of cases of rarer forms of disease.”

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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