Updates on research, clinical trials and studies as of March 2006
Angiogenin mutations likely boost ALS susceptibility
Mutations in the gene for angiogenin (ANG), a protein that aids in the formation of new blood vessels, are new suspects in ALS susceptibility, says a multinational research group whose findings were published online Feb. 26 in Nature Genetics.
The team, led by Matthew Greenway and Orla Hardiman at the Royal College of Surgeons in Dublin, Ireland, included Robert Brown, professor of neurology and director of the MDA/ALS Center at Massachusetts General Hospital in Boston.
In a study of 1,629 people with ALS and 1,265 without ALS, the investigators identified seven genetic mutations (alterations) in the ANG gene in four people with familial ALS and 11 with no family history of the disease (sporadic ALS). Twelve of the 15 were of Irish or Scottish descent. Only one person, a 65-year-old man, had an ANG mutation without having ALS.
Angiogenin resembles another protein, vascular endothelial growth factor (VEGF), in that both cause the formation of new blood vessels in response to a low-oxygen environment. Unusually low levels of VEGF have been implicated as a possible factor in ALS.
The ANG gene variations may be risk factors only in some populations, Brown says, although they still may be important. “The caveat from the VEGF story is that those variants were found to be highly related to sporadic ALS only in the Belgian population,” he says. “This has not been reproduced in other populations.”
ANG mutations are “certainly overrepresented in ALS and certainly significantly overrepresented in the population of Ireland and Scotland,” Brown says.
These types of variations are being sought on a large scale at the Translational Genomics Research Institute in Phoenix (see “Gene ‘Flavor’ Differences”).
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Spinal fluid protein levels useful in ALS diagnosis
ALS doesn’t have clear biological markers (biomarkers) of disease, which are useful not only to diagnose a condition but as indicators of whether or not a treatment is working.
Neurologist Merit Cudkowicz, an MDA research grantee at Massachusetts General Hospital, and Robert Brown (see “Angiogenin Mutations”), were part of a multi-institutional group that recently identified three spinal fluid proteins for which levels are lower than normal in ALS. The researchers say these protein levels may prove useful as ALS biomarkers.
The team published its results online Feb. 15 in Neurology.
These three proteins — cystatin C, VGF (not VEGF), and a third identified so far only by its weight — were lower in concentration in the ALS patients’ spinal fluid samples than in samples from unaffected study participants.
“Finding biomarkers that can assist physicians with diagnosis would be beneficial,” Cudkowicz said. “Biomarkers are also important to help understand disease mechanisms and potential treatment pathway targets, and could also potentially help expedite clinical trials by providing ... outcome measures,” she said, adding that the group’s results need to be replicated by others and in larger sample sizes.
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