Among all the rare hereditary diseases, Alström syndrome (AS) is probably the rarest. For one thing, it numbers only 175 victims throughout the world, spread over 22 countries. For another, its litany of horrendous signs and symptoms lists 10 major organ-system manifestations observed in most AS cases, plus nearly 28 present in some, but not all, sufferers.

Symptoms develop over the first five or 10 years. Sometimes its small victims incur cardiac myopathy in the first two years. If they survive it, they frequently develop diabetes in their second decade of life, and most will be blind by age 20. Life span is shortened, but intelligence remains normal.

The first AS patient in history was a 14-year-old boy who came to the medical attention of Swedish psychiatrist Carl-Henry Alström (1907-1993). The lad had retinal degeneration and obesity as well as neurological hearing loss. He produced two second cousins, a boy and girl, with similar but more severe features, plus insulin-resistant diabetes. Alström published a scientific account of this condition in 1959. It soon became known as Alström syndrome.

For 40 years the etiology of AS remained a mystery, while its worldwide body count grew. Now the April 2002 issue of Nature Genetics carries two closely parallel articles that mitigate, though do not dispel, the puzzle.

One bears the title “Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alström syndrome.” Its senior author is molecular biologist and biochemist Jürgen Naggert, at the Jackson Laboratory in Bar Harbor, Maine.

The second paper is titled: “Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causing Alström syndrome.” Its senior author is molecular geneticist David Wilson, at Southampton University in the UK.

Same Mutant Gene; Varied Finder Strategy

“The contrast between the two papers, although they’ve identified the same gene,” Wilson told BioWorld Today, “is that we’ve used different strategies to identify it. Naggert’s article employed a traditional family mapping approach where they were able to identify a certain number of genes in a critical region of chromsome 2. Then they mutation-screened each individual gene and found ALMS1 that way.

“That contrasted with our approach,” Wilson continued, “whereby we identified a unique patient who had Alström’s syndrome and a chromosomal translocation. The novelty in our paper is that using balanced translocations to identify genes is very useful for dominant disorders and X-linked disorders. It’s the first time it’s been used for an autosomal recessive disorder. The implications are twofold,” Wilson continued. “One is directed to families with Alström’s syndrome, which more or less leads to a diagnostic test. We can make predictions as to what recurrence might occur in further pregnancies.

“In addition,” he added, “one can answer the questions parents ask: Why did it happen?’ We now have a specific answer to that question. Also, Can you use this new information to treat my child?’ I think that whether a specific treatment will ever be developed for AS is a little further off. But if it ever were to be,” he noted, “the information that we just published would be required first, before you develop a treatment.

“The wider implication for this gene is that it causes AS, a component of which is insulin-resistant diabetes. Is it possible, we asked, that this gene could contribute to a diabetes that affects a lot of people worldwide? While AS is very rare, is it possible that different mutations could cause a milder disease?”

“Our paper, like Wilson’s,” Naggert told BioWorld Today, “identified the mutations in the gene that cause the disabilities in AS. That’s pretty much it,” he added, “since we didn’t find any similarity to other genes that would tell us what the protein is doing. To us, it’s another clue in trying to figure out the chemical pathways important in obesity and Type II diabetes. That’s why we searched for the gene to begin with. AS was known to be a single-gene disease, so these mutations one can easily identify in humans.

“The idea behind this is that it’s unlikely common forms of obesity would be due to the same gene. In order to understand obesity, we need to understand their pathways.

“In this case it seems that both the obesity and the diabetes are caused by the same gene. At least the gene is expressed in the places where you would expect the origin of both diseases. In common forms of Type II diabetes the simple model is that you have an obesity gene, and in addition you have diabetes susceptibility genes. Then you will become obese and diabetic. In themselves, these diabetes susceptibility genes don’t cause any problem.”

Creating KO Mice Minus ALMS1 Mutant Gene

“But in this Alström syndrome case we don’t know because it’s expressed both in the hypothalamus and the pancreas. It may very well be that if we could make an animal model in which we only disturbed the gene in the pancreas, that may not do anything. We would again have to combine it with obesity. But we wouldn’t know that at present.

“We have no indication what the normal functions of the genes are right now,” Naggert observed. “There’s nothing to tell us what they are doing, so we have lots of work ahead. We’re now doing functional genomics first making antibodies. We haven’t started mouse experiments, yet. We are looking for antibodies in wild-type mice, and are in the process of making a knockout mouse model lacking the ALMS1 gene so that we can recapitulate what is happening in humans. And if the mouse allows us to do conditional KOs we can knock it out only in the pancreas and see if it can cause diabetes by itself. We are injecting the constructs right now, so it will take a little while untill we get those mice.

“In the course of our work we’ve met many AS patients,” Naggert said. “Especially in a mouse place when you suddenly work on humans, all of a sudden you can see where potential applications of your research are. So we are trying to figure out how in the future we can help ALMS1 sufferers. That’s very important to us,” Naggert concluded, “not only as a mouse model for obesity.”