Study of Samoan genes cracks disease mystery

A landmark sharing of genome data from Samoa helped two United States-based families finally learn the cause of their children’s rare mitochondrial disease this year.

The unexplained disorder had already claimed the life of the eldest of three children in one family, all affected by the same disorder, and affected another child in a different family. Both had one Samoan parent, leading researchers to investigate the link. 

Clinician and scientist Dr. Mariella Simon from the Children’s Hospital in Orange County joined forces with the Samoan Obesity, Lifestyle and Genetic Adaptations Study Group (O.L.a.G.A), which has collected genomic data from around 1,200 Samoans.

They were able to search through the database and eventually confirmed that a variant of the mitochondrial gene called ECHS1 is common to 28 per cent of the Samoan population.

In both the families, their Samoan parent had contributed this common ECHS1 gene variant, but it had come up against a rarer ESCHS1 mutation in the non-Samoan parent, causing disease.

Dr. Simon is from the Division of Metabolic Disorders of the C.H.O.C. and studies in the Department of Human Genetics at the University of California. 

She told the Samoa Observer that for these two families, who had been down a “diagnostic odyssey,” the findings have meant better opportunities for more effective treatment.

That 28 per cent of Samoans carry the ECHS1 variant is not a cause for concern, Dr. Simon said. There are fewer than 100 reported cases of ECHS1 related disease in the world, and the chances of a child having the disease if both their parents carry an ECHS1 mutation is just 25 per cent.

“ECHS1 is rare and why did we spend so much time on these two families? Because it’s important to them. One family lost a child, the other family has a little daughter and they didn’t know what this girl had,” the researcher said.

“They really pursued a diagnostic odyssey, they went everywhere trying to figure out what their daughter had, and they didn’t know what she had.

“At this point they are so happy to know what their daughter has, they don’t have to pursue therapies anymore when they know it can’t help.”

Now that their doctors know where their mitochondrial diseases come from, they have placed the children on a valine restricted diet, which has already resulted in improvements in their alert and mobility levels.

Among other issues, the disease causes dystonia, which causes muscles to contract uncontrollably and gives the impression that the body is frozen.

“Their hands and bodies are very stiff, and they can’t move their face. When they want to laugh they can’t really smile.”

Dr. Simon said both families report their children’s movements have been improved since starting the valine restricted diet. 

“Particularly the little boy we see in the clinic all the time has gotten quite a bit better, more responsive. The parents have told us he is much more responsive and seems to be in less discomfort too.

“It’s a tough diet, his older brother is quite mildly affected compared to him and has a hard time keeping the diet because it’s not very tasty, it’s a formula with that protein removed, so to a teenager it’s tough.”

Dr. Steven McGarvey from the Department of Epidemiology in the International Health Institute from the Brown University School of Public Health is one of the original O.L.a.G.A. study group researchers.

He happened to be in Samoa in the middle of last year when Dr. Simon emailed him asking for a look into their database of genetic data collected in 2010.

Dr. McGarvey went straight to the Ministry of Health and asked senior leadership, including Director-General Leausa Dr. Take Naseri for permission, and after a few weeks, they said yes.

He said this experience proves the value in data sharing, but also in doing it safely and ethically. 

For now the O.L.a.G.A database is not public, but discussions about how to make it so while guaranteeing benefits for the owners of the data – the people of Samoa.

“This whole thing happened while I was in Samoa working with a team there, including the Ministry of Health ethics committee, about our desire to make public certain aspects of our whole-genome sequence data for exactly this reason, for other scientists to be able to look up publically available data and answer questions that might be important to them,” Dr. McGarvey said. 

“To be able to say we did a small little thing to help, that means a lot to us emotionally […] we contributed to this very real human progress here.”

“Collaboration is incredibly important between different groups that may do completely different things, and that is the beauty of the scientific community and data sharing,” Dr. Simon said.

The researchers do not yet know why the ECHS1 gene variant is so common in Samoan people, but they have learned it causes mitochondria to make less of the ESCH1 gene product. 

If this product level drops below 40 per cent it can cause serious health issues to begin, possibly affecting the brain, intestinal system, and muscles. 

“Much more study is required before confidently predicting risk for health conditions among Samoans influenced by this genetic variant,” the researchers say.

“The patients with ECHS1 disease described in our study all had one common ECHS1 variant associated with Samoan ethnic background and an additional severe and very rare ECHS1 mutation from the other non-Samoan parent.”

Many Samoan people end up with two ECHS1 variants, one from each parent (making them a homozygote). So far this has not proven to be a health risk.

“Since severe ECHS1 mutations are so rare, and since ECHS1 homozygotes appear healthy we would not expect to find people of Samoan descent at increased risk for this disorder. 

“Nonetheless, further study of this gene variant and associated developmental disorders should be considered among Samoan communities.”

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