The Genetic Mutation That Plagued Beethoven

Posted on Categories Discover Magazine

Did a tiny amino acid, a cluster of carbon, hydrogen, nitrogen, oxygen and sulfur atoms, kill Beethoven, and not syphilis or lead poisoning, as previously proposed?

A new genetic analysis of his hair, borrowed from collectors, suggests that the acid, called methionine, may have greatly accelerated his death from liver disease.

Genetics of Beethoven

Perhaps the greatest composer of all time, Beethoven had a simple but serious genetic mutation that affected the PNPLA3 protein – found in fat and liver cells. Out of 481 amino acids, he had a dangerous quirk: he had methionine at one important linkage instead of isoleucine.

PNPLA3 Mutation

This meant the protein fumbled to do its job, breaking down fat in the liver, thereby causing levels of it to rise. And with fat, may have come fatty liver disease and a predisposition to liver scarring and cirrhosis.

Previous to this new Beethoven study, researchers had investigated the PNPLA3 mutation for links to fatty liver disease in all its forms, and in some cases, liver cancer. In 2008, a landmark study found fattier livers in people with the mutation, setting off a wave of other studies.

PNPLA3 Damage

Researchers commonly found that the genetic quirk made people more vulnerable to fatty buildup or fibrosis (scarring) when exposed to alcohol, viral diseases like hepatitis or metabolic factors such as obesity.

The link in people with alcohol-related liver disease is especially strong. Heavy drinking quickly leads to fat buildup, and having the wrong PNPLA3 protein raises the risk of lasting damage. It also increases the risk of liver cancer in cirrhotic patients by a factor of two, according to one paper.

Beethoven and Alcohol

Leading up to his death, Beethoven suffered from attacks of jaundice, potentially a sign of liver damage, and he drank heavily, according to one close friend. Alcohol consumption could have worsened his condition by raising fat levels further in the organ, to unhealthy levels.

At lunch, he routinely downed about a liter of wine, the study says, which comes to about seven standard glasses. Given his small stature, 5-foot-3-inches, his blood alcohol content may have soared to about .20, taxing his liver further. What’s more, he likely suffered from hepatitis B during the later months of life, an illness that damages the organ.

The gene also affects non-alcoholic fatty liver disease, which does much the same damage as the alcoholic variety. While the non-alcoholic variety is wildly common (about 24 percent of the U.S. population), no medication yet exists to treat it directly.

Read More: How Much Alcohol is Too Much

Other Genetic Impacts

The Beethoven study also probed the cause of the composer’s longtime gastro-intestinal problems, namely abdominal pain and bouts of diarrhea. While other researchers have attempted to chalk them up to irritable bowel syndrome, the new study found a very low (although still possible) genetic predisposition for the condition. The authors also ruled out celiac disease and lactose intolerance, while ulcerative colitis and Crohn’s disease emerged as more likely.

Beethoven Hearing Loss

Beethoven’s DNA revealed little about his hearing condition, which started early in his life and progressed to complete deafness.

In 1802, in his Heiligenstadt Testament, he writes despairingly to his brothers of his hearing problems and other afflictions, which would only worsen by the time of his death in 1827.

He notes his reluctance to say, “‘Speak louder, shout, for I am deaf’ […] How could I possibly admit an infirmity in the one sense which ought to be more perfect in me than others, a sense which I once possessed in the highest perfection, a perfection such as few in my profession enjoy or ever have enjoyed.”

In the letter, he asks his doctor to describe his “malady” to the public, after his passing, so “at least the world may become reconciled to me after my death.”

Read More: Navigating Hearing Loss and New Over-the-Counter Solutions

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