The Genetics of Functional Disorders, Including Cyclic Vomiting and Chronic Fatigue:
The “functional disorders” comprise a group of related conditions that involve combinations of vague and/or nonspecific “functional” symptoms, including pain, fatigue, nausea, vertigo/dizziness, anxiety, depression, as well as many others. Common functional disorders include migraine, irritable bowel, major depression, generalized anxiety, tinnitus, and POTS. Often severe, uncommon but not rare, functional disorders include cyclic vomiting syndrome (CVS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia, and complex regional pain syndrome (CRPS). Functional symptoms are subjective, experienced by the individual and thus “real”, but rarely showing objective signs clear to others. In addition, standard laboratory testing is generally negative, although subtle signs leading to the underlying biological causes(s), if present, are often unrecognized. Thus, diagnosis is difficult, often inaccurate, and generally delayed. Unfortunately, many of these people are thought of as having “non-organic” or “not real” disease, shunted solely to mental health (e.g. somatization, conversion), and even labeled as fictitious (e.g. Munchausen, medical child abuse) or drug seekers.
Functional disorders have high degrees of co-morbidity (overlap), in that it is common for an individual to be affected with a few or several of these conditions. Functional disorders also have a substantial genetic component, in that close relatives are at substantially higher risk for having one or more of these conditions. It is not uncommon for families to have several affected members suffering from different, and often multiple, functional disorders.
One of Dr. Boles’ major focuses over the last decades has been in the care of individuals and families with multiple functional disorders. Dr. Boles has conducted and published research papers on the genetics of many of these conditions, especially CVS. The last few years has demonstrated continued rapid improvements in terms of the technology enabling genetic testing, the number and types of genetic tests that are clinically and commercially-available, and the knowledge base used to interpret test results. Dr. Boles has been applying the latest in genetic testing in his large patient base with functional conditions, especially CVS, migraine, ME/CFS, and CRPS.
The genetics of functional disorders is extremely complicated. Some of the more frequently-identified genetic scenarios are:
Genetic Testing of Functional Disorders, Including CVS:
There are a number of genes that has identified as associated with the functional disorders, and hundreds more in the same pathways that may be associated with them. Variants in these genes can be of any size, ranging from a single nucleotide to millions of nucleotides. These variants can be in the chromosomes or in the mitochondrial DNA (mtDNA). They can be novel (never seen before) or quite common (risk factors). They can affect unique or repeat sequences of the genome (DNA). Finally, these variants can be within genes, or in-between genes, meaning they would be missed by whole exome sequencing (WES). This extraordinary genetic heterogeneity means:
In many cases, whole exome sequencing and full mtDNA sequencing is a good alternative.
In many cases, singleton sequencing (patient only) is appropriate.
In Dr. Boles’ medical practice, he finds that genetic testing is often very helpful in treating people with functional disorders. There are several medications often used for these disorders, they take time to show a positive effect, and negative (side) effects are common. It is Dr. Boles’ practice, in most cases, to base drug treatment on the underlying cause/risk factor(s) of disease in each individual, determined by genetic testing. He oftentimes bases the dosing prescribed on the results of genetic testing as well.
Sequencing of all of the genes (WES) can now be done routinely, and many different laboratories offer this testing. Sequencing of all of the DNA (WGS) is also now offered by several laboratories. The difficulty is in interpreting the sequence of (literally) tens of thousands of sequence variants in every person. Unfortunately, most of the genes associated with functional disease have not yet been published, and thus it is common for treatable anomalies found by sequencing to be unrecognized and the test to be labeled as “negative”. Another issue is that laboratories use an ACMG-inspired, monogenic and strict allopathic approach, which fails to recognize many low-risk treatment options for potential disease risk factors.
Dr. Boles Practice:
Genetic laboratories issue standard reports that are constrained by narrow interpretations, or are non-specific and non-committal, resulting in much confusion for providers and patients. Risk factor variants are generally neither identified nor discussed. Laboratories also have a very limited understanding of the complexities of the disease in the individual patient, and family. However, Dr. Boles will:
The primary focus is always on finding effective treatment. Many of the genetics pathways associated with functional disorders are treatable, often including energy/mitochondrial metabolism, other metabolic pathways, ion channels, and neurotransmitters. Unfortunately, not every patient receives a diagnosis, not every variant is treatable, and not every treatment tried is successful. However, Dr. Boles results at this time include at least moderate improvement in most children. For CVS, about 90+% are in remission, although this may take a while to achieve. Having essentially the entire DNA sequence on file also allows for additional treatment options as knowledge increases.
Dr. Boles is a pediatrician, but he does see a limited number of young adults who are in their 20s at the time of the initial visit.
Logistical and Cost Structure:
Dr. Boles is not in-network anywhere, and his practice is self-pay (cash, check, credit card, PayPal), including all visits (#1 and 4 above) and sequencing interpretation costs (#3 above). You will receive a superbill to assist you to submit for out-of-network reimbursement. Some families receive full reimbursement, some nothing, and many somewhere in-between. It is difficult to predict.
The functional disorders are highly genetic, and often times more than one family member is affected, especially affected siblings. Many families will choose to have only the more-affected child as the “patient”, and pay the above-listed costs only. Findings identified and treatments discussed regarding the “patient” often apply to other family members as well. Other families will choose to have both siblings evaluated as “patients”. The cost for this is $1,000 per patient for initial visit (instead of $1,200), and follow-up costs remain $500 per patient. DNA testing interpretation costs are $850/$1,000 for the first patient, and $500 for every patient thereafter.