POLG mutation

Prince Frederik of Luxembourg, the son of Prince Robert of Luxembourg and Princess Julie of Nassau, has died at the age of 22.

Prince Robert shared the news in a statement on the website for the POLG Foundation, an organization started by Frederik to help with treatments and a cure for the illness.

Frederik was born with PolG mitochondrial disease, a rare genetic condition.

"It is with a very heavy heart that my wife and I would like to inform you of the passing of our son," Prince Robert wrote in the statement, sharing that Frederik had died on March 1.

The day before on "Rare Disease Day," Prince Robert shared that Frederik spoke with his family, including his brother Alexander and sister Charlotte, as well as cousins and other extended family, "one last time."

"After gifting each of us with our farewells – some kind, some wise, some instructive – in true Frederik fashion, he left us collectively with a final long-standing family joke. Even in his last moments, his humor, and his boundless compassion, compelled him to leave us with one last laugh… to cheer us all up."

He also wrote that Frederik asked, "Papa, are you proud of me?"

"He had barely been able to speak for several days, so the clarity of these words was as surprising as the weight of the moment was profound. The answer was very easy, and he had heard it oh so many times, but at this time, he needed reassurance that he had contributed all that he possibly could in his short and beautiful existence and that he could now finally move on," his father wrote.

The statement continued, "Frederik knows that he is my Superhero, as he is to all of our family, and to so very many good friends and now in great part thanks to his POLG Foundation, to so very many people the world over. Part of his superpower was his ability to inspire and to lead by example."

Prince Robert explained that Frederik was born with PolG mitochondrial disease.

Frederik wasn’t diagnosed until he was 14, "when his symptoms were showing more clearly and when the progression of his disease had become more acute."

The disease causes "such a wide range of symptoms and affects so many different organ systems, it is very difficult to diagnose and has no treatments much less a cure. POLG disease is a genetic mitochondrial disorder that robs the body’s cells of energy, in turn causing progressive multiple organ (brain, nerves, liver, intestines, muscles, swallowing and ocular function, etc.) dysfunction and failure. One might compare it to having a faulty battery that never fully recharges, is in a constant state of depletion and eventually loses power."

Prince Robert said Frederik "jumped" at the opportunity to create a foundation to find a cure.

"Though he always made it very clear that he did not want this dreadful disease to define him, he nonetheless immediately identified with and helped define the mission of The POLG Foundation."

According to his father’s statement, Frederik created the look for the charity in the United States, and launched a MITO clothing line, encouraged by Donna Karan.

He also "actively and literally gave of himself to develop multiple mouse models and cell lines in Switzerland, the United States, and Europe and to make these available to further facilitate research into POLG."

Prince Robert concluded, "On behalf of Frederik, Julie, Charlotte, Alexander, Mansour and the entire global POLG community, we thank you for helping this worthy cause that will honor our son. We will be resolutely focused on alleviating suffering for the POLG community and other diseases and conditions far beyond, associated with mitochondrial diseases."

https://www.foxnews.com/entertainment/prince-frederik-luxembourg-dead-22-from-rare-genetic-condition

Rahman S, Copeland WC. POLG-related disorders and their neurological manifestations. Nat Rev Neurol. 2019 Jan;15(1):40-52. doi: 10.1038/s41582-018-0101-0. PMID: 30451971; PMCID: PMC8796686.

Abstract

The POLG gene encodes the mitochondrial DNA polymerase that is responsible for replication of the mitochondrial genome. Mutations in POLG can cause early childhood mitochondrial DNA (mtDNA) depletion syndromes or later-onset syndromes arising from mtDNA deletions. POLG mutations are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations. POLG-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. The six leading disorders caused by POLG mutations are Alpers-Huttenlocher syndrome, which is one of the most severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathy sensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia. This Review describes the clinical features, pathophysiology, natural history and treatment of POLG-related disorders, focusing particularly on the neurological manifestations of these conditions.