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Article in Nature 17 Oct 2007
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Is it genetic?
An inadequate guide to a sometimes very hard question -- [this page is unfinished]
Why is this question important? If a given clinical finding, a trait, a disease in a person cannot confidently be ascribed to genetics, the search for a variant in the DNA could be fruitless. Many traits we display have a genetic cause -- we look like our parents for that reason. But we are also subject during the course of our prenatal development and during life to many non-genetic factors that can influence our looks, our feelings, our health. Trauma, mental or physical, is an obvious example but diet, medications, and environmental impacts also influence our biology.
Genetics is the study of variation and heredity. If a specific trait is passed down with each generation, it is relatively easy to conclude the trait is caused by a variant in the DNA. This is a much more straightforward proposition if the trait is in an animal or plant that can be bred and the trait followed in many different individuals of the species. Mendel with his pea plants was able to show that short or tall plants, smooth or wrinkled seeds, red or white flowers followed a certain pattern of heredity which we now associate with his name as Mendel's Laws of Heredity.
In clinical medicine it has been appreciated from the time of Hippocrates that certain traits ran in families, that certain diseases were "carried" by family members and could be passed on. It took the rediscovery of Mendel's work at the end of the 19th century to give a firm scientific foundation to these observations. Since that time more than 3000 conditions have been ascribed to causes genetic. Many are very rare and few physicians have seen them. Others are quite familiar to most people such as hemophilia or cystic fibrosis or sickle cell anemia. These have been cataloged in Mendelian Inheritance in Man (aka MIM) by Dr. Victor McKusick.
The classical hallmark of a genetic condition is a trait or set of traits that are inherited with a recognizable pattern of inheritance through multiple generations. Those classic patterns are autosomal dominant or recessive and X-linked. The larger the families, the more generations that can be studied, the easier it is to be definitive regarding these patterns of inheritance.
Many traits are known to have a genetic cause because the trait has been observed in multiple family members with some pattern of inheritance. If such a trait is found in an isolated case, there can be confidence that it is genetic even without family members carrying the trait. Many other traits have been observed in animals and studies of those animals have established the trait as genetic. The challenge for clinicians and their families arises when there appears a trait that is sometimes isolated, sometimes associated with other traits. The hunt begins for those other traits.
Most people have one or two "funny things" about them. They may have a birth mark or webbing between two toes or a dimple on their lower back. Some of these even run in families and hence have a clear genetic cause, but when only one or two of these traits are found in an individual or family, they generally have no clinical significance. When a person has six or more such traits, it takes on more significance; there is a greater likelihood that a single DNA variant could cause all six traits. Such a collection of traits has even more significance if those traits are known to run together. Indeed, the word syndrome comes from a Greek word meaning to run together. Many genetic conditions have a distinct constellation of traits that collectively are specific for that condition. Most patients with the Marfan Syndrome have dislocated lenses, aortic root dilatation, are tall and thin, have long spidery fingers, etc. Each of these traits can be found in isolation in people and in those cases are likely the result of different genetic variations but in the patient with the Marfan Syndrome, all the findings are owing to a single variation in the fibrillin 1 gene.
A very careful inventory by a skilled observer can catalog traits in a patient and often this will yield a diagnosis. It can be a long involved process because some traits are subtle such as the pattern of fingerprints, some are not present until later in life, or some traits cannot be observed easily because they involve internal organs such as the shape of the aorta. But the first step in trying to establish the genetic nature of a condition is to document any physical variations from what most might consider "normal".
A child developing in utero is subject to many influences beyond the genetic program being played out. The mother's metabolism does much to shield the developing fetus from outside influences but drugs and infections can and do have their effects on development. It is well known that thalidomide, the drug introduced in the 1950's to induce sleep, severely interfered with limb development. Viral infections during pregnancy such as reubella have their own devastating effects on the fetus. These are examples where genetics is NOT playing a significant role. But many of these conditions have their own set of traits that run together so after careful examination and judicious testing suggested by the findings can generally establish the cause of clinical findings after birth.
An additional cause to understand the genetic nature of a trait is to provide guidance on whether the trait might be expected to appear in the affected person's children. Clinical geneticists often use the term sporadic to refer to affected patients with no relatives carrying the trait. Sporadic, depending on the context, can mean genetic, genetic but non-recurring, or even non-genetic. Perhaps it is better to be explicit. If a patient is alone among the family in carrying a trait or traits, we refer to the patient as a simplex case. Whether the trait carries risk of recurrence is an entirely separate matter and is dependent on the genetic nature of the trait.
My daughter
Gene-Toxin Interaction= cause?
I have just read Brendan Maher’s article ("His Daughter's DNA," Nature 449 (18 Oct. 07), 773-776) on your valiant search for the source of your daughter’s birth defect. While my knowledge of the biology of the TGF-beta system and myostatin is limited to a brief computer search, I have a suggestion for a radically different approach based on the evidence that (as Maher put it) "the extracellular matrix does more than passively hold cells together; it mediates communication between them." On the outside chance that it will help, I hope you’ll find time to read this long letter.
Over the last decade, I’ve been working on the principal communicative -- signaling system in humans: the central nervous system. My work is unusual because it links cognitive neuroscience, genetics, neurotoxicology, and behavior. My hunch is that focusing on signaling systems rather than traditional genetic processes (which code for the production of specific proteins, or structures) will be useful because signaling systems generally have developed regulatory processes such as start/stop enzymes. Moreover, since genes code for biochemical outcomes that can be disturbed by environmental toxins, increasing attention is now being given to gene-environment interaction of varied sorts. For example, such conditions as autism, ADHD, Schizophrenia, and Alzheimer’s may sometimes be produced by the combination of a genetic mutant (which creates a vulnerability) and an environmental insult (which has differential effect on those who are genetically vulnerable).
Such effects of neurotoxins can be associated with phenotypic development or with reversible traits. For example, exposure to excessive lead or alcohol in the first trimester of pregnancy has been associated with permanent defects in brain structure (apparently due to an interference with normal epigenetic pathways). Such an insult might have played a role in your daughter’s case, but this is not an area in which I have expertise. Nor do I know if some medications have this effect.
My own work concerns harmful effects on behavior and cognition due to uptake of lead, manganese, and other environmental toxins. This work is based on studies by others showing that high levels of circulating lead or manganese are associated with higher rates of violent crime, substance abuse, and learning disabilities. Our work uses geographic data to trace the association between exposure to toxic chemicals and dysfunctional behavior and development.
This might be a relevant paradigm for your daughter’s case because, broadly speaking, a basic mechanism in this effect of toxins on behavior is interference with normal inhibitory pathways in the brain. Assume it’s correct that myostatin is a signaling protein that “is produced primarily in skeletal muscle cells, circulates in the blood & LYMPH and acts on muscle tissue, apparently by slowing down the development of muscle stem cells” (Wikipedia entry, “myostatin”). This suggests that genes interfering with myostatin could well be associated with excessive development of muscle by turning off a mechanisms for slowing muscle development.
An analogous process in brain function has played an essential role in my research. Lead is a neurotoxin that blocks the regulatory function of the neurotransmitter dopamine (which plays a central role in behavior control because, depending on the neuronal circuit, dopamine can be either excitatory or inhibitory – which is why it is so important for “executive function”). Violent criminals are often found to have high blood lead (as is also sometimes the case with children with ADHD). Genes can have a parallel effect, as in dopaminergic gene mutations (D2, D4, or D5 dopamine receptor mutants and a Dopamine transporter mutant) recently linked to ADHD. This isn’t, however, the main mechanism I have in mind as possible in your daughter’s case.
My work on the link between lead or manganese toxicity and violent crime led a senior chemical engineer, Myron J. Coplan, to ask me if I had studied fluorosilicic acid (H2SiF6) and sodium silicofluoride (Na2SiF6). These chemical compounds are now used for over 90% of all water fluoridation in the U.S. even though the silicofluorides weren’t tested for safety before their approval by the Public Health Service in 1950. Indeed, in 2002 the National Toxicology Program nominated fluorosilicic acid for study because it’s toxicology is “unknown” – but since that time there is no evidence of studies being completed or even commissioned. As you will see from the data analyses in our work, we find that communities treating water sith silicofluorides have significantly higher rates of violent crime, substance abuse, and learning deficits. Moreover, children absorb more lead from environmental exposures.
Why, you’ll ask, is this relevant? In 1974-75, a study by Johannes Westendorf revealed that silicofluorides inhibit the enzyme acetylcholinesterase. Acetylcholine (ACh) is a major agonic (excitatory) neurotransmitter. Acetylcholinesterase (AChE) is the enzyme that breaks down ACh. Silicofluorides are AChE inhibitors – that is, they turn off the off switch (so to speak). Thus our statistical findings reflect a major effect that arises from an environmental toxin that inhibits the regulatory inhibitory neurotransmitter system. (For a summary of all this work and Westendorf’s thesis, see: <http:www.dartmouth.edu/~rmasters/AHABS>).
A similar inhibition of a regulatory or inhibitory mechanism sounds like a basic problem in the entire cluster of conditions like Marfan’s (where “the genes for two TGF-beta receptors … seem to disable the TGF-beta receptors’ and therefore have the seemingly puzzling “activating effect on the pathway” (Maher, p. 755). Since this suggests that a toxin might be combined with the gene mutation you’ve found in your daughter, could it also follow that silicofluoride-treated water is the toxin in question?
Alas, I can’t answer that. Although fluorosilicic acid is used by the San Francisco water system (which serves a number of other communities in addition to the city), I don’t know if you and your wife live in Palo Alto or elsewhere – AND, sadly, the CDC’s Fluoridation Census (which we use to identify the compound used in water supplies throughout the country) merely indicates that Palo Alto water is fluoridated but does NOT – for some reason – list the chemical used. This gives rise to some simple questions:
1. What community do you live in, and what chemical is used to fluoridate the water (if indeed it is fluoridated)?
2. Do you live in an house built before lead paint was banned or have other reasons to suspect that during pregnancy your wife might have been exposed to high levels of lead or another toxin (e.g., using Mexican pottery with colored designs painted with lead based paint, hobbies or other activities, consuming alcohol or pharmaceutical or recreational drugs, etc.) This is relevant to toxic uptake in the first trimester of pregnancy as a major factor in your daughter’s condition.
3. Is there anything, such as high lead levels in your household water (which can leach from brass fixtures if chlorine – esp. when combined with other compounds – is in the water)?
4. Have you ever done a test for toxic burdens in your wife and daughter (and yourself)? I can easily provide you with a simple kit used to sample head hair (which I’ve done in prior research for children in polluted communities, working with a top grade laboratory); the results give levels of a wide variety of toxins, so this could help answer my overall questions above.
It’ll doubtless help to describe what’s involved, since head hair testing of toxins is not as invasive as a traditional blood test. The head hair test kits that I’ll send contain my requisition form to be completed with your information, instructions on where to cut a little hair from the nape of the neck, a clever cardboard scale to weigh the head hair sample to be sure it’s enough for analysis, and a little plastic sac in which you put the sample of head hair after labeling; for each sample, all you need do then is put the requisition form and the hair sample in the envelope provided and drop them in the mail. (No trip to a doctor and nothing scary for your daughter). Results are returned to me and I’ll send you an explanation as well as the data provided in the lab results. (I realize that lead levels today don’t tell us anything about lead exposure/uptake during your wife’s pregnancy, but a first step is to find whether there is a chronic source of exposure that is still present.) The cost of this is trivial and it’ll be my contribution to your quest. (Any questions, call me at home: 603 643 4205). To go further, however, I'll need your email or snailmail contact information (e.g., to send you copies of my publications).
In hopes this might help, sincerely,
Roger D. Masters
As evidence of my prior work (indicating that I'm not a crank, which is probably a danger you confront), feel free to look me up in WHO'S WHO IN AMERICA.