Genetic analysis of mummified remains uncovers the first known case of LOPD

Genetic analysis of mummified remains uncovers the first known case of LOPD

Posted On: 29/10/2021

The DNA of an Italian nobleman, Cangrande della Scala, who died almost 700 years ago, could point toward the first known case of late-onset Pompe disease.

Cangrande della Scala (1219-1329 CE), Lord of Verona from 1311 to 1329, was a great military commander and politician who brought neighbouring cities under his control to form a “kingdom” of the Venetian hinterland spanning from Verona to Treviso.

Most accounts of Cangrande’s childhood describe a child who did not like traditional games or the company of peers but was predisposed to military life. In combat on horseback, he preferred to use the bow in the Parthian manner rather than the spear or sword, allowing his arm more freedom of movement. Cangrande was reportedly ill for some time at the age of 23 but recovered enough for battle after imbibing a small dose of an antidote and a sip of wine. The discomfort to one foot was reported, which prevented him from riding. At the age of 29, he was reportedly pierced by an arrow in the thigh but managed to return to camp, rally his troops and return to fight. His autopsy in 2004 did not reveal any wounded limbs, suggesting that he instead suffered crippling thigh discomfort, possibly a cramp.

At the age of 34, Cangrande fell seriously ill for a long time and was given up for dead. He died at the age of 38 after showing symptoms of malaise for 3 days, identified as fever and a generic fluxum, which can be translated as vomiting or perhaps haemorrhage.

The clinical manifestation of pompe disease is entirely consistent with Cangrande’s three episodes of severe weakness after exercise as reported in the historical records, and his death after 3 days of sickness. No scar was found on his thighs, supporting the hypothesis that the arrow wound reported in 1320 was in fact a severe muscle cramp. Given the finding of digitalis in his body, it is possible that it was administered to counteract tachycardia, a key symptom of cardio-respiratory insufficiency, and would represent the first known clinical use of this drug.

Cangrande della Scala was interred in a marble tomb that promoted mummification. His remains were exhumed in 2004 for scientific analysis by a multidisciplinary team of researchers, revealing the presence of digitalis in his well-preserved organs. This led to several hypotheses, including murder by poisoning and the therapeutic use of digitalis to remedy a cardiac disorder. Samples of bone tissue were used from the mummified remains for the extraction of ancient DNA, followed by clinical whole-genome sequencing and whole-exome sequencing. Two pathogenic variants in the GAA gene encoding α-glucosidase, a genotype associated with late-onset Pompe disease. The clinical phenotype of this disease is consistent with data from the historical records, suggesting that Cangrande della Scala is the earliest known case of this prototypic lysosomal storage disorder.