Famous Musician Cause of Death Revealed - Through DNA

Unlocking a mystery.

I’m going to open this week with a case.

In addition to the jaundice, this acute illness was accompanied by fever as well as diffuse edema, and the patient underwent several abdominal paracenteses to drain excess fluid. One consulting physician administered alcohol to relieve pain to little avail.

The patient succumbed to his illness. An autopsy showed liver injury, as well as papillary necrosis of the kidneys. Notably, the nerves of his auditory canal were noted to be thickened along with the bony part of the skull, consistent with Paget’s disease of the bone and explaining, potentially, why the talented musician had gone deaf at such a young age.

An interesting note on social history. The patient had apparently developed some feelings for the niece of that doctor who prescribed alcohol. Her name was Therese – perhaps mistranscribed as Elise - and it seems he may have written this song for her.

This week, we unravel the curious case of Ludwig Van Beethoven thanks to modern DNA extraction techniques, genome-wide association studies, and 8 locks of hair.

We’re talking about this paper in Current Biology, by Tristan Begg and Colleagues, which gives us a look into the very genome of what some would argue is the world’s greatest composer.

The ability to extract DNA from older specimens has transformed the fields of anthropology, archaeology, and history and perhaps, now, musicology as well.

The researchers identified 8 locks of hair in private and public collections, all attributed to the Maestro.

Four of the samples had an intact chain of custody from the time the hair was cut. DNA sequencing on these four and an additional one of the 8 locks came from the same individual – a male of European heritage.

The three locks with less documentation came from three other unrelated individuals. Interestingly, analysis of one of those hair samples – the so-called Hiller Lock - had shown high levels of lead – leading historians to speculate that lead poisoning could account for some of Beethoven’s symptoms.

DNA analysis of that hair reveals it to have come from a woman – likely of North African, middle eastern, or Jewish ancestry. We can no longer presume that plumbism was involved in Beethoven’s death.

Beethoven’s ancestry turns out to be less exotic, and maps quite well to ethnic German populations today.

SOURCE: CURRENT BIOLOGY

In fact, there are Van Beethoven’s alive as we speak, primarily in Belgium. Genealogic records suggest these Van Beethoven’s share a common ancestor with the virtuoso composer, a man by the name of Aert Van Beethoven.

But the DNA reveals a scandal.

The Y-chromosome Beethoven inherited was not Aert Van Beethoven’s. Questions of Beethoven’s paternity have been raised before, but this evidence strongly suggests an extra-marital paternity event, at least in the generations preceding his birth. That’s right. Beethoven may not have been a Beethoven.

SOURCE: CURRENT BIOLOGY

With 5 locks now essentially certain to have come from Beethoven himself, the authors could use DNA analysis to try to explain three significant health problems he experienced throughout his life and death: his hearing loss, his terrible gastrointestinal issues, and his liver failure.

Let’s start with the most disappointing results – explanations for his hearing loss. No genetic cause was forthcoming, though the authors note that they have little to go on with regard to the genetic risk of otosclerosis, to which his hearing loss has often been attributed. Lead poisoning is of course possible here, though this report focuses only on genetics – there was no testing for lead – and as I mentioned the lock that was strongly lead-positive in prior studies is almost certainly inauthentic.

What about his life-long GI complaints?  Some have suggested celiac disease or lactose intolerance as explanations. These can essentially be ruled out by the genetic analysis, which shows no risk alleles for celiac disease and the presence of the lactase-persistence gene which confers the ability to metabolize lactose throughout one’s life. IBS is harder to assess genetically, but for what it’s worth he scored quite low on a polygenic risk score for the condition – in just the 9th percentile of risk. We should probably be looking elsewhere to explain the GI distress.

The genetic information bore much more fruit with regards to his liver disease – remember Beethoven’s autopsy showed cirrhosis. His polygenic risk score for liver cirrhosis puts him in the 96th percentile of risk. He was also heterozygous for two variants that can cause hereditary hemochromatosis. The risk of cirrhosis among those with these variants is increased by the use of alcohol. And historical accounts are quite clear that Beethoven consumed more than his share.

But it wasn’t just Beethoven’s DNA in these hair follicles. Analysis of a follicle from later in his life revealed the unmistakable presence of hepatitis B virus. Endemic in Europe at the time, this was a common cause of liver failure, and is likely to have contributed, if not directly caused Beethoven’s demise.

It’s hard to read these results and not marvel at the fact that, two centuries after his death, our fascination with Beethoven has led us to probe every corner of his life. His letters, his writings, his medical records, and now his very DNA. What are we actually looking for? Is it relevant to us today what caused his hearing loss? His stomach troubles? Even his death? Will it help any patients in the future? I propose that what we are actually trying to understand is something ineffable – genius of magnitude that is rarely seen in one or many lifetimes. And our scientific tools, as sharp as they may have become, are still far too blunt to probe the depths of that transcendence.

In any case friends, no more of these sounds. Let us sing more cheerful songs. More full of joy.

A version of this commentary first appeared on Medscape.com.