Genetics: March 2008 Archives

According to Fox News, the FBI has shortened its list of suspects who perpetrated the 2001 "anthrax letter attacks" to about 4, and 3 of those suspects are scientists with links to the bioweapons research facility at Fort Detrick, Maryland (USAMRIID). The 3 USAMRIID suspects are described as a former deputy commander, a leading "anthrax" scientist, and a microbiologist, whose writing samples have been obtained by the FBI. The current short list apparently does not include former "person of interest" and USAMRIID scientist Steven Hatfill.

It is presently believed that the attacks were perpetrated by placing a "weaponized" powder version of Bacillus anthracis, which was taken from Fort Detrick, inside the mailed letters. Fox News obtained an e-mail (the date of which was not provided), in which USAMRIID scientists discussed how the B. anthracis powder that was provided by the FBI for analysis was "nearly identical" to that made by a colleague, whose name was deleted from the e-mail.

The B. anthracis strain identified in the 2001 anthrax attacks belongs to the Ames strain, and its genotype (62) indicates that it was originally obtained from a dead cow in Texas in 1981. According to leading B. anthracis investigators, the Ames strain is now apparently rare in nature but is in widespread use in laboratories. Consequently it is believed that the strain of the 2001 anthrax attacks was obtained from a laboratory involved in B. anthracis study.

The big trick in the investigation has been to narrow the attack strain to a single laboratory—a very big trick, since B. anthracis generally and the Ames strain specifically are highly genetically conserved. Just last year, B. anthracis expert Paul Keim and colleagues at Northern Arizona University published their identification of 6 single nucleotide polymorphisms* (SNPs) that merely distinguish the Ames strain from other B. anthracis strains, including close genetic relatives.

However, in a March 18 letter to the Letters in Applied Microbiology, the same investigators reported that they were able to identify 6 distinct genotypes of a single B. anthracis clone (obtained from a 2005 outbreak in South Dakota) by using 4 highly mutable single nucleotide repeat (SNR) markers. SNRs are variable-number tandem repeats in the DNA sequence that exhibit very high mutation rates. The authors concluded, "SNR markers are powerful tools for detailed tracking of natural B. anthracis outbreaks and could also prove useful in forensic investigations."

It seems logical that investigators would be using (or have used) SNR markers in an attempt to subtype various Ames strain isolates from different laboratories.

*Six SNPs were highly specific for the Ames strain: 4 were on the chromosome; 1 was on the pX01 plasmid; and 1 was on the pX02 plasmid.

Another question prompted by the case of Hannah Poling is whether children with autistic features should be screened for mitochondrial disorders. When Hannah exhibited autistic regression after a series of vaccinations at the age of 19 months, she was ultimately found to demonstrate mitochondrial dysfunction (Poling JS et al. J Child Neurol. 2006;21:170-172). The authors (including Hannah's neurologist father) suggested that "oxidative stresses from immune activation" may lead to autistic regression in children with compromised mitochondrial function.

Poling and company then conducted a follow-up, retrospective study of patients with autism, who had not been diagnosed with metabolic disorders. They found that AST levels were elevated in 38% (vs 15% in age-matched controls; P < .0001), and that serum creatinine was elevated in 47%. The authors concluded that "further metabolic evaluation is indicated in autistic patients and that defects of oxidative phosphorylation might be prevalent."

The recommendation to evaluate autistic children metabolically was made by Pons et al (J Pediatr. 2004;144:81-85), who described several autistic children with the mitochondrial DNA mutation that typically causes MELAS.* These authors concluded that "autistic features may be the expression of mitochondrial dysfunction in a developing brain" and that "analysis of mitochondrial metabolism should be considered in autistic patients with associated neurologic findings or evidence of maternal transmission."

However, in a review article published that same year (Lerman-Sagie T et al. J Child Neurol. 2004;19:397-381), investigators at Tel Aviv University concluded that "mitochondrial diseases are probably a rare and insignificant case of pure autism" and further advised that care should be taken when ascribing autism to identified mitochondrial abnormalities. Detection of mitochondrial dysfunction may be the result of laboratory shortcomings, or mitochondrial dysfunction may be unrelated to clinically manifest autism.

The following year, a population-based Portugese study of autistic school children (Oliveira G et al. Dev Med Child Neurol. 2005;47;185-189) found elevated plasma lactate levels in approximately 20% of those tested and mitochondrial dysfunction in a surprisingly high 7%. Unfortunately there were no distinguishing features, such as clinical phenotype or family history, to aid the differentiation between autistic children with mitochondrial dysfunction and those without.  

The bulk of the data to date (and there is little "bulk") indicate that the likelihood of identifying mitochondrial dysfunction in an autistic child is low, but probably not insignificant. Also Oliveria and colleagues remind us that the tissue distribution of mutant mitochondrial DNA is variable and could explain possible false-negative evaluations for mitochondrial dysfunction in cases of autism.

*MELAS = mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke.