Theoretical genetic disorder found in 2012 now confirmed in first humans

8 Jan 2018

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The pace at which the human genome can be sequenced is leading to discoveries that are becoming increasingly more theoretical.

In our efforts to better understand some of the most crippling and damaging genetic conditions, the mapping of the human genome is considered vital.

In fact, the technology to do so has become so advanced that it is now possible to predict disorders that have no known human patients. To that end, a team of researchers from the Hadassah Medical Center in Israel has confirmed one such discovery.

Dubbed MPS II-E – or Dierks’ disorder, after its discoverer Dr Thomas Dierks from Bielefeld University – the disorder was first theorised back in 2012 despite the fact that there were no known patients in existence with the genetic condition.

But now, in a paper published to Genetics in Medicine, the team has confirmed the first cases of Dierks’ disorder after it found consistent symptoms of progressive blindness in three patient families, indicating the presence of a previously unknown genetic defect.

A total of five patients were identified with the disorder after their results were compared with those found in mice tested on during earlier studies by Dierks.

First discovery

To create the blueprint for the original disorder back in 2012, the researchers switched off the gene responsible for producing the enzyme arylsulfatase G in mice, resulting in the accumulation of carbohydrate in the ‘recycling plants’ of the cells.

This accumulation then increases the size of the recycling plants – referred to as lysosomes – until the cell is destroyed, bringing about the disorder.

When these results were compared with the new patients, the team found that their cell cultures were producing the same arylsulfatase G enzyme, leading to them becoming ‘seriously damaged’.

What surprised Dierks and the team, however, was that there was a delayed response in humans because large parts of the carbohydrate molecule integral to the disorder’s development – heparan sulphate –  can be degraded without arylsulfatase G, meaning it takes more time to accumulate.

“They did not start to show the symptoms before the age of 40,” Dierks said. “Based on our studies with mice, we assumed that the symptoms would emerge much earlier, perhaps after 10 years.”

Enzyme replacement therapy

The expectation is now that this order can be tested in more people across the globe, leading to more people being diagnosed with it and, in the meantime, effective treatments can be developed using enzyme replacement therapy.

“The required enzyme can be produced biotechnologically with the help of cell cultures,” Dierks said.

“However, the brain is hard for the enzyme to reach. Moreover, the disorder has to be diagnosed through gene tests before the symptoms appear if treatment is to commence before damage has become irreparable.”

Colm Gorey was a senior journalist with Silicon Republic