Fatal, Severe, and Mild
As FOD Awareness Month draws to a close, a discussion about the severity of these disorders may be helpful. FODs are largely, though not entirely, without outward expression in individuals. That is, their facial features are usually normal, as is their stature, their ability to walk and talk, and everything else by which most people judge disability. But beneath the surface, they are energy-stressed so some may need assistance. The following is an excerpt from my book.
The suggestion that any FAOD is mild may be considered false, or even offensive, by families who have legitimately struggled with FAODs that are sometimes called mild. It must be understood at the outset that such terms as “mild” or “benign” are not descriptive of all individuals with any given FAOD, but that there are documented variations in the severity of these disorders, both in the severity of the mutation and in the severity of its expression in the person. The very fact that some babies are born so damaged by these that they cannot survive while others may go decades without noticeable symptoms underscores the relative nature of terms such as mild or severe. Some, such as the forgoing example, are obvious. Others may depend largely on the individual involved. Anyone diagnosed with any FAOD must remain vigilant.
One of the more puzzling aspects of FAODs is that even among people with the same mutation, there appears to be some variability in the expression of the disease. When both parents contribute the same mutated gene (homozygous), there is the expectation that the expression of the disease will follow the pattern known about that mutation. When parents each contribute a gene that has a different mutation (compound heterozygous), that is, alleles that are mutated at different locations on the same gene or mutated in different ways, the expression is more difficult to anticipate. Some studies have shown that there may be additional factors, called susceptibility genes, that determine the severity of the disease. One such factor is seen in breast cancer where the BRCA 1 or 2 gene predisposes certain people to the disease. It does not cause the cancer but it plays a role. Something similar may be at work in people with some FAODs. There are even studies that show there may be a relationship between one’s genes and one’s food choices and the effects of those choice on one’s body. Not everyone is the same!
Note: the term heterozygous is commonly used to refer to a gene with one normal allele and one mutated allele. This would indicate a carrier.
In some diseases, science has made such strides that once diagnosed, a patient’s illness can be categorized. Cancer patients, for instance, are usually told they have “Stage 1,2,3 or 4” carcinoma of the affected organ. Heart attack patients can have tests that show exactly where blockages occur and how bad they are. This helps both the patient and the doctor deal with whatever lies ahead. FAODs are not like that.
As mentioned in Chapter One, the gene affected determines the specific disorder, but the mutation(s) involved, along with some other possible factors, determine the severity of the disorder in each individual. This can get complicated.
If both parents have contributed alleles that have identical mutations (what is known as a homozygous mutation), and those mutations have been seen before and followed in other people, the doctors may feel confident in telling a family that the disorder is either mild or severe, depending on the documented experience of those affected in the past. The mutation on the gene is called the genotype and its expression in the affected person is called the phenotype. However, it has been noted that the genotype/phenotype correlation is not always what one might expect. Even in families with more than a single affected person, the phenotype may differ significantly among individuals.
Compound heterozygous mutations, that is different mutations from each parent on the same gene, create another variation that may or may not have been seen before. It is entirely possible for a known serious mutation to be donated by one parent while the other donates a known mild variant. Then there are the unknown mutations commonly referred to as “variants of unknown significance,” that is, mutations that have been seen in patients but without enough instances or documentation to classify it as either mild or severe. So a patient could have a known and an unknown match on a single gene. Or, two unknown alleles, either homozygous or compound heterozygous, could appear. As if that were not enough, science is finding novel (new) mutations that have never been seen in any patient that has ever been documented in the medical literature. These can also be paired with known and unknown alleles as well as be homozygous or compound heterozygous, though the likelihood of two matching novel alleles is low.
Patients can be forgiven for their confusion over their diagnosis with something so complex and open to so many variations, but doctors, too, still have little to go on when assessing a patient’s condition and prognosis. The genotype gives a certain amount of information, but it is not the deciding factor in determining the severity of any disorder in any individual. In some, it will accurately predict the course of the disease in the individual but in others, it may surprise both patient and doctor. In yet others, it will simply lay the groundwork for more research.
A good example of the predictive power of common homozygous mutations is the common mutation S113L for CPT2’s myopathic, or adult-onset, variant. While 70 or so mutations have been catalogued on the CPT2 gene, the S113L mutation is responsible for about 60 percent of the myopathic mutations found. It is well documented that persons with homozygous S113L mutations will have the muscle variant of this disorder. It is termed “mild” or “benign” not because there are no serious effects from it, but because the effects seen with this usually affect only the skeletal muscles and typically occur well past birth. The other form of CPT2, the hepatocardiomuscular, or infant/childhood variant, usually shows effects in the liver and heart as well as the skeletal muscles. Sometimes called the “lethal infantile” or “fatal neonatal” CPT2, newborn screening tests are finding more infants with non-myopathic variants of what is obviously the hepatocardiomuscular form of the disorder. Such variants will show symptoms as early as birth and may involve liver, heart, kidneys, or even the brain. Sufferers of both must watch their diets and may require carnitine supplementation but few people with the S113L mutation will die of it in infancy, unlike those born with the various hepatocardiomuscular variants, who may. The myopathic form could later kill if rhabdomyolysis is allowed to progress to the point of renal failure. It is not mild in the normal sense of the word, but compared to its often-lethal cousin, it is. In this case, the genotype is fairly accurate. However, be aware that such prejudicial terms as “fatal,” “lethal” or “mild” can lead to either unnecessary hopelessness or a false sense of security.
The most common FAOD, MCAD, is an example of how people with the same genotype can exhibit many variations in severity. Its most common mutation, 985A→G, is found in 80 percent of people with homozygous MCAD. Another 18 percent of people with MCAD have this mutation on just one allele. Though more common than other FAODs, MCAD can still range in severity from mild to lethal. There are reasons for the lack of genotype/phenotype correlation, though not all are well understood. Some people appear to be aided more by what are called molecular chaperones. These are proteins that assist in the folding of other proteins. Some mutations are called “misfoldings,” that is, the genetic error causes the affected gene to assemble the protein for which it is responsible in an incomplete or erroneous fashion. Research is being conducted into the action of these chaperones to see what effect they have mitochondrial disorders. Though it is only speculation at this point, some people may be aided more by these protein-helpers than others, producing a milder phenotype than expected in an individual.
The type of mutation also has an effect on the expression in an individual. Genes have specific jobs and carry them out in a certain order controlled by a triplet of bases called a codon. When anything goes wrong with this trio of bases, it affects the gene’s production of the enzyme/protein assigned to that gene. The final trio contains information telling the gene to stop. If it is out of place work stops prematurely. If any part of a trio is missing, the gene may make an incomplete protein or none at all. What follows is a simple explanation of what can go wrong.
There are point mutations that are caused by the substitution of a single base. These may be severe, as when such a mutation results in a premature stop codon. In this case they are referred to as nonsense mutations. The protein may be truncated so severely that it ceases to function. Missense mutations, on the other hand, may be mild if the amino acid affected has been replaced with another of similar chemical properties, or severe if replaced by an amino acid with different properties. They may even be silent if the mutation specifies the same amino acid as the original.
The mutation may be a deletion, that is, the allele is missing necessary information to make the protein/enzyme for which it is responsible. If it is missing all the information it is called a null mutation. It could also be an insertion, which means additional information that does not belong on the allele appears. Deletions and insertions can also happen in combination. Deletions or insertions may be referred to as in-frame or out-of-frame, depending on whether bases have been removed or added in multiples of three. Out-of-frame mutations, also called frameshift mutations, tend to be more severe in their effects because it alters the entire genetic code beyond the point of the mutation. An in-frame mutation can still be read in sequence because the gene beyond the mutation hasn't been altered.
Any of these types of mutations can cause a misfolding. Proteins need to form specified three-dimensional shapes to carry out their jobs in the body; when one misfolds, the action of the protein is incomplete. If enough information has been deleted or corrupted, the gene is simply at a loss and cannot produce a functional protein, or fails to produce any protein, resulting in what is called a null mutation.
It is also not known how many people affected by FAODs also have other, unrelated medical issues that can worsen the progress of the disease. As FAODs are treated primarily with dietary measures, any concurrent illness that affects the diet may exacerbate the disorder. Food allergies are one example. Diseases of the liver or kidney, whether related to the FAOD or not, can make things more difficult than the genotype might suggest. Also, some people just may be more – or less – resilient overall. Even a spell of recurrent mild illnesses such as colds and stomach viruses can cause an FAOD-affected individual, especially a child, to spiral down from not eating into a full metabolic crisis quickly. Family dynamics matter. Finances matter. Psychological stress has a role.
Identifying the genotype is just the beginning. One day, science may have more knowledge and be better able to predict the expression of an FAOD in a person. Right now, the best course of action is to treat the person and his or her symptoms, not just what the disorder’s genotype, if even known, might suggest. This is important for medical personnel to understand, especially for those patients affected with commonly considered mild FAODs such as SCAD or the adult-onset CPT2. Just because the course of the disease in other patients was mild, does not mean that it will be mild in every individual who presents with the disorder. Also, both patient and medical attendants must consider that even mild FAODs, such as the myopathic CPT2 or the seemingly asymptomatic VLCAD cases now being identified can result in rhabdomyolysis, or muscle death, which sends muscle fibers into the bloodstream. This can lead to renal failure and even death. So when speaking of mild or severe FAODs, or mild or severe mutations within an FAOD, everyone should keep in mind that in this context, mild can still kill and requires all the necessary medical attention any ill patient should receive. Unfortunately, in the experience of many in the FAOD community, those affected by identified mild FAODs or mild mutations may often be dismissed or even ridiculed when seeking treatment.
So, while there are legitimate variations in severity, all FAODs must be taken seriously.