Amerindian Origin of Familial ALS Mutation Reported, Yet Disease Rare Among Native Americans

A new study suggests that a common genetic mutation responsible for familial amyotrophic lateral sclerosis probably originated with Native Americans, but is rare today among Amerindians, because the population could have developed a compensatory mechanism to counter the defect

A mutation responsible for as many as one in five cases of familial amyotrophic lateral sclerosis (FALS) in white North Americans probably originated with Native Americans, and dates back to the earliest contact between Europeans and Amerindians 400 years ago, according to a study in the May 12 issue of Neurology, which appeared online first on Jan. 28.

However, FALS and other forms of ALS are rare in Native Americans today, suggesting that the mutation either became extinct over time or that the people evolved a compensatory mechanism to counter the defect, according to lead author Teepu Siddique, MD, professor of neurology at Northwestern University in Chicago.

He and an international team of researchers scanned the DNA of North American and European whites, Native Americans, Hispanics, and African-Americans, as well as DNA samples from China and Japan.

Specifically, they searched for founder mutations in the gene for Cu, Zn superoxide dismutase (SOD1), which was first linked to FALS in 1993. They compared individual haplotypes in the genomes near a specific SOD1 defect that has more recently been linked to FALS, an alanine to valine mutation at codon 4 (A4V). Haplotypes are lengths of DNA fragments that contain sets of single nucleotide polymorphisms (SNPs), which can be used to identify common genetic origins between individuals.

They sequenced the entire common genomic region around SOD1-all of the SNPs - to determine whether polymorphisms in either previously unknown coding or non-coding regions might be responsible for the more aggressive form of SOD1 A4V-mediated FALS. They discovered five new SNPs in those with the A4V defect.

The SOD1 A4V mutation causes an aggressive form of pure lower motor neuron ALS associated with rapid disease progression and death. Survival from symptom-onset averages just over one year, versus three years for sporadic ALS. Of more than 100 mutations identified to date, the SOD1 A4V mutation accounts for fully one-half of all cases of SOD1-related FALS in the US. In North America, FALS SOD1 A4V is the most common SOD1 mutation, but it is rare in Europeans.

This mutation has had two separate origins in the course of human evolution, one in Europe and the other in Amerindians, who probably carried it into North America from Asia, according to the authors.

They continued: It is likely that A4V was introduced into the white population from the Amerindians about 400 to 500 years ago at about the time of the Jamestown and Plymouth landings. In our databank of over 500 FALS cases, none are Amerindian.

That FALS appears to be uncommon among Native Americans could mean that the population is simply underrepresented in terms of reported cases, or that the defect somehow failed to survive through multiple generations and became extinct, according to Carmel Armon, MD, professor of neurology at Tufts University School of Medicine in Springfield, MA, who wrote an editorial accompanying the study.

Dr. Armon, who is also chief of neurology at Baystate Medical Center in Springfield, asked the neurological community's help in addressing whether the paucity of cases is due to underreporting. Dr. Carmon encouraged investigators to publish reports of patients with ALS of Amerindian descent, with appropriate institutional review board oversight, and refer them (or their blood samples) to the authors of the current study.

Dr. Armon noted that a similar 2008 genome study by researchers at Massachusetts General Hospital's Institute of Neurodegeneration (MGH-MIND), published in the journal Neuroscience Letters, suggests that the mutation may have originated in Asia. That study, which also involved North American patients with SOD1 A4V ALS, identified a shared common conserved haplotype near the A4V mutation and was statistically more like Asian samples (Chinese and Japanese) than those from Europeans.

According to the MGH-MIND paper, the Asian mutation originated 540 generations, or roughly 12,000 years, ago. Thus the A4V mutation may have been carried to North America by the forebears of Native Americans when they migrated across the Bering Strait, according to Dr. Armon.

Masanori Nakagawa, MD, professor and chairman of neurology at the Research Institute for Neurological Diseases and Geriatrics of Kyoto University of Medicine in Japan, studies SOD1 A4V mutations in Japanese families with ALS. In 2003, he and his colleagues reported in a Neurology study that while the duration of FALS is relatively consistent for each SOD1 A4V mutation, the rate differs among the different mutations, and that turnover of mutant SOD1 correlated with a shorter disease survival time.

The current paper is interesting, especially because the founder, which accounts for 82 percent of the North American A4V patients, was genetically similar to the Amerindian version, but no ALS patients in their databank of over 500 FALS cases, he told Neurology Today in an e-mail.

Nonetheless, it might be wrong to compare the haplotype in Japanese and North American ALS patients with A4V mutation, because of other genetic differences.

In a 2003 study of SOD1 H46R, another mutation, among large Japanese families in a region of Japan with high rates of FALS, he and his associates confirmed that individuals with FALS with these mutations had uniform initial symptoms and slow progression, with intra-familial variation in severity. Moreover, they discovered that inclusion body formation was not necessary in FALS patients carrying the mutation.

The genetic backgrounds of Amerindians and Japanese may be more similar than in Europeans with FALS, noted Dr. Nakagawa. If the disease is in fact rare among Native Americans, examining genetic differences in SOD1 between Japanese and North American patients with A4V mutation might reveal whether a protective or susceptibility genetic factor is involved.