3: Cyclic Vomiting Syndrome and Mitochondrial Dysfunction and treatment
Cyclic Vomiting Syndrome and Mitochondrial Dysfunction and treatment
Mitochondria are small organelles within the cell responsible for energy production and other critical functions. Mitochondrial diseases result from failures of the mitochondria, specialized compartments present in every cell of the body (except red blood cells).
Mitochondria are responsible for creating more than 90% of the energy needed by the body to sustain life and support organ function. When they fail, less and less energy is generated within the cell. Cell injury and even cell death follow. If this process is repeated throughout the body, whole organ systems begin to fail.
The parts of the body, such as the heart, brain, muscles and lungs, requiring the greatest amounts of energy are the most affected. Mitochondrial disease is difficult to diagnose, because it affects each individual differently. Symptoms can include seizures, strokes, severe developmental delays, inability to walk, talk, see, and digest food, combined with a host of other complications. If three or more organ systems are involved, mitochondrial disease should be suspected. Although mitochondrial disease primarily affects children, adult onset is becoming more common. Mitochondrial dysfunction plays a role in many diseases, including CVS.
DNA mutations that affect mitochondrial function can occur in the DNA that is found in the nucleus of the cell (genomic DNA), or they can occur in the DNA that is found within the mitochondria themselves. Mitochondrial DNA is inherited differently than nuclear DNA. Most people are familiar with the inheritance of nuclear DNA, in which we have two copies of every gene, and we inherit one copy from each of our parents. However, mitochondrial DNA is inherited exclusively through the mother; therefore, mutations that affect the mitochondrial DNA can be traced through the maternal lineage of a family.
In other words, conditions such as migraines, irritable bowel syndrome, depression, and hypothyroidism, are often found in the maternal relatives of patients with CVS.
A possible relationship between cyclic vomiting syndrome and mitochondrial dysfunction was suggested by the finding that in some families, CVS was maternally inherited. Mitochondrial DNA mutations and deletions have been reported in patients with CVS, and disease manifestations of mitochondrial dysfunction have been found in the maternal relatives of patients with CVS.
Cyclic vomiting has been reported in individuals with the A3243G ‘MELAS’ mutation in the mitochondrial DNA (mtDNA). In addition, one child with CVS, developmental delay, seizures, growth delay and additional problems was reported to have a large mtDNA deletion and duplication. CVS with or without additional problems is not rare in children with mitochondrial disorders, and among this group, ‘routine’ mtDNA analysis fails to identify previously known mtDNA mutations in most of them.
In Fleisher and Matar’s series, The cyclic vomiting syndrome: a report of 71 cases and literature review, only 3 of 71 patients had a parent with CVS. However, several families had multiple members involved, and in these familial cases of CVS, the mode of inheritance is predominantly matrilineal, suggesting that mitochondria could be involved. Boles et al. demonstrated that 86% of children with CVS and neuromuscular disease had a history of migraines on the matrilineal side. In children with CVS, two mtDNA polymorphisms (16519T and 3010A) are expressed with a high degree of frequency and may serve as a surrogate marker for predisposition to the disease.
The 16519T polymorphism is six times more common in pediatric CVS patients than in control populations. The 3010A polymorphism increases the likelihood of CVS in subjects with 16519T by as much as 17 times.
Boles’ hypothesis is that defects in mitochondrial energy production due to mutations may predispose the onset of episodes of vomiting during periods of heightened demands for energy; for example, stress or excitement.
One small (and possibly underpowered) study found that adult-onset CVS, unlike pediatric CVS, is not associated with these polymorphisms, suggesting a degree of genetic distinction.
Mitochondrial DNA mutations don’t cause CVS directly, in the way that a DNA mutation causes cystic fibrosis, for example. In some patients, mitochondrial dysfunction plays a greater role in the causation of their disease, and in other patients, it may be less of a factor. Dr. Boles explains: “In some cases it’s a clear mitochondrial disorder, they have multiple other manifestations and it drives the disease. However, in most patients, it is one of many factors in disease pathogenesis.” Patients with classical mitochondrial disorders have disease manifestations such as muscle weakness, neurological problems, autism, developmental delays, gastrointestinal disorders, and autonomic dysfunction. Some patients with CVS have these other disease manifestations, and some have only CVS symptoms.
As with many diseases, understanding as least some of the cause of CVS has allowed for the development of treatments tailored towards fixing the root cause. Co-enzyme Q10 and L-carnitine are two dietary supplements that have been used to treat a wide variety of conditions. Both supplements may be able to assist the mitochondria with energy production and thus, help compensate for mitochondrial dysfunction. A retrospective chart review study found that using these two supplements, along with a dietary protocol of fasting avoidance (having three meals and three snacks per day), was able to decrease the occurrence of, or completely resolve, the CVS episodes in some patients. In those patients who didn’t respond to treatment with supplements alone, the addition of amitriptyline or cyproheptadine, two medications that have been used for prevention of CVS episodes, helped to resolve or decrease the episodes. Treatment with the cofactors alone was well tolerated with no side effects, and treatment with cofactors plus amitriptyline or cyproheptadine was tolerated by most patients. Therefore effective treatment for prevention of CVS episodes does exist, although it may not be widely employed by most gastroenterologists.