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CVS & Mitochondrial Disease

Evidence for the involvment of mitochondrial DNA (mtDNA) in CVS is increasing. This is a complex subject for a non-scientist to follow. Dr. John Hayman produced a really helpful overview of the basics of mitochondrial disease. He suggests that Charles Darwin may have been a sufferer. He shows how an inherited trait can lead to different outcomes in children of the same parents, in a more complicated way than we are used to thinking of genetic disease transmission from parent to child.

Insights into CVS from Charles Darwin's illness

John Hayman, Associate Professor

Department of Pathology, The University of Melbourne, Australia

Darwin

Charles Darwin’s symptoms

Charles Darwin suffered a debilitating, almost lifelong illness with many very varied symptoms. Of these, the most incapacitating complaints were of episodic nausea, vomiting, retching and flatulence. These symptoms were characteristic of CVS in that they had various triggers, including any form of stress and even pleasurable events (‘positive stress’). He also obtained relief from water exposure (the ‘water cure’), as do many patients today. Darwin also had symptoms that may be experienced by some CVS sufferers such as abdominal pains, recurrent headaches, visual disturbances, dizziness, lethargy, sweating, heat and cold intolerance, palpitations and motion sickness (seasickness).

As well as all this, Darwin had symptoms that are not considered part of CVS. He suffered from attacks of ‘eczema’, diagnosed in retrospect as atopic dermatitis. He also had psychiatric symptoms with episodes of fear, sometimes a feeling that he was dying and periods of hysterical crying. In later life, he had several ‘stroke-like’ episodes with transient partial paralysis, memory loss and an inability to speak.

All of these symptoms are consistent with a mitochondrial disorder; in Darwin’s case this was most likely a relatively common mutation known as the A3243G mtDNA mutation. This diagnosis is discussed more fully in a paper in Genetics (Hayman 2013). Mitochondrial abnormalities, and this mutation in particular, have been shown to be associated with some cases of CVS.

Mitochondria and cell division

Mitochondria are cellular organelles (distinct structures within cells) that provide almost all the energy requirements for the cell in the form of an energy molecule called ATP. Mitochondria contain their own DNA (mtDNA) which is not the same as the DNA most of us are familiar with contained in the cell nucleus. Each cell contains several hundred to several thousand mitochondria depending on the cell’s energy requirements.

When a cell divides (see figure 1 for a visual overview of this process), the DNA contained in its nucleus copies and makes two new cells. In nearly every case, the new cells will be identical in terms of nuclear DNA. Although each cell has one nucleus, the cell contains many mitochondria. The mitochondria may be different from each other – some will be healthy, whilst others may contain genetic mutations. When the cell divides, the mitochondria undergo a simple splitting process and are separated into each new cell at random. The two daughter cells (the cells that are produced) will usually have exactly the same nuclear DNA but the mixture of mitochondrial type in each of the new cells will nearly always be different to the cell they were produced from. The ratio of normal to abnormal mitochondria can vary considerably between cells (this is known as heteroplasmy).

A good analogy to make is that mitochondria are ‘shuffled’ like playing cards before being distributed between the two newly produced cells. Previously we have tended to think of a cell dividing to produce two identical copies, but discoveries involving mitochondrial DNA have radically changed that view. Two cells derived from the same original cell, and that have the same function, may behave very differently from each other because they each contain a different ‘mix’ of mitochondria.

Mitochondria graphic

Ineriting mitochondrial disease from the mother (maternal inheritance)

All mitochondria and mtDNA are maternally inherited because the few mitochondria present in the sperm do not survive in the fertilized ovum. We are used to thinking of genetic conditions being passed to children, and these are usually similar between individuals. Mitochondrial disease is very different, and more complex to understand.

Mitochondrial disease may result in a wide spectrum of symptoms and illnesses; CVS may be just one. A mother may have several children who each inherit the same mutation, yet may differ considerably in their symptoms: one child may have little or no apparent illness whilst another may suffer severe disability and shortened life expectancy. This happens because:

1. each of the mother’s ova contain a different ratio of normal to abnormal mitochondria.

Women are born with all the ova they will ever have, and many more than can ever be used in a normal lifetime. These are produced while the future woman and mother is still a developing foetus. As the ova are created by cell division, mitochondrial ‘shuffling’ occurs. The immature ovum at one particular stage of its development has relatively few mitochondria due to diminished energy requirements and random reduction of mitochondrial numbers. As a result of this reduction, more normal than abnormal mitochondria may be lost or, alternatively, more abnormal mitochondria may be absorbed. Ova at this stage may then vary considerably in the proportion of normal and abnormal mitochondria that they each contain (heteroplasmy). As the ovum matures at a later stage and mitochondria increase in number, this level of heteroplasmy is maintained. The normal and abnormal mitochondria divide at the same rate. Because of this, mature ova in the same ovary in the same mother may have very different numbers of abnormal mitochondria. As a result, offspring following the fertilization of these ova will also have very different levels of abnormal mitochondria and very differing symptoms. One may develop from an ova with mainly normal cells and possibly show no symptoms at all. Another may have mainly abnormal mitochondria and this can lead to severe disability or shortened lifespan.

2. further random distribution of mitochondria takes place amongst cells after fertilization.

After fertilization, heteroplasmy may vary even more in different tissues due to random distribution of mitochondria in the dividing cells of the developing embryo. This varying, random distribution of normal and abnormal mitochondria in different tissues in the one individual may again result in very differing symptoms.

How mitochondrial disease can be inherited from the father (paternal inheritance)

Mitochondrial disease is not always inherited from the mother, however. The majority of mitochondrial enzymes, which are needed for the mitochondria to function properly, are encoded by genes in the cell nucleus. Therefore, if genes in the nucleus are abnormal, mitochondrial dysfunction may also occur. This nuclear DNA can be passed down from the father as well as the mother and the symptoms in the children, if present, will be less variable between siblings.

Supporting family evidence for Darwin’s diagnosis

Darwin’s family history supports the diagnosis of a mitochondrial disorder with his mother, his maternal uncle Tom, their youngest sibling Mary Anne, and their mother (Darwin’s maternal grandmother) all having symptoms consistent with the same mtDNA mutation. Darwin’s brother Erasmus also had symptoms and two of his sisters developed symptoms in later life.

How the high-energy requirements of particular cells may result in CVS and the other symptoms displayed by Darwin

CVS has been called a ‘brain-gut’ disorder; more specifically it should be considered a disorder of brain and gut neuroendocrine cells. Peripheral neuroendocrine cells are found among the cells lining the stomach and intestines and in the organs associated with the gut such as the pancreas. They are also present in the bronchi, bladder and endocrine glands. Central neuroendocrine cells are present in the brain, mostly in the hypothalamus. These cells produce many different hormones, mostly small protein molecules (peptides) that have a cell to cell signalling (paracrine) function as well as endocrine functions. Neuroendocrine cells of the gut produce many hormones that induce secretion and involuntary (smooth) muscle contraction, with names such as motilin, secretin and gastrin, together with other hormones that have an inhibitory or ‘turn-off’ effect, such as somatostatin. The action of these hormones, together with the action of the autonomic nervous system, is to regulate intestinal function.

These neuroendocrine cells have particularly high energy requirements because as well as producing the various hormones, they also need ATP in high concentration. ATP stabilizes the granules within the cells, granules that contain the hormones. This allows for storage and may prevent premature hormone release.

Other cells in the body with high energy requirements are neurons, the cells lining cerebral blood vessels (cerebral endothelial cells), cardiac conducting cells (Purkinje fibers), the cells of brown fat and skeletal muscle cells. All these cells have large numbers of mitochondria and as a result, like neuroendocrine cells, are particularly susceptible to mitochondrial failure. Symptoms of a mitochondrial disorder may generally be related to dysfunction of these cells. For example, lactic acid, an organic acid produced in excess when there is failure of mitochondrial energy production, results in lactic acidosis. These high levels of lactic acid affect the brain, resulting in panic and fear symptoms.

Darwin’s symptoms can be related, directly or indirectly, to dysfunction of these cells. His CVS symptoms may have been due to excessive or inappropriate release of excitatory peptide hormones as a result of granule instability or, alternatively, to failure of inhibitory hormone production. The fact that his vomiting characteristically occurred several hours after a meal suggests that it was failure of this ‘turning off’ mechanism (somatostatin secretion) rather than an excessive stimulatory effect.

What we can learn from these insights today

CVS remains a difficult diagnostic problem and there is as yet no one defining criterion for its diagnosis. Diagnosis depends on a characteristic clinical history and the elimination of other causes for episodic vomiting. A family history of sickness may be helpful in making a diagnosis and should include inquiry into both paternal and maternal illnesses. Rather than just episodic nausea and vomiting and migraine headache, other symptoms may be relevant. These include additional gastrointestinal symptoms such as occur with irritable bowel syndrome, heat and cold intolerance, palpitations, fibromyalgia and abnormal fatigue, excessive motion sickness and persistent vomiting during pregnancy. Darwin’s illness and the illnesses of his other family members show how the one defect in mitochondrial function may produce much variation in symptoms. Mitochondrial function may be measured and the common abnormalities of mtDNA can be detected.

Circulating peptide hormone levels may also be measured, although these tests are not widely available. It would be of great interest to know what these levels are in patients, both when they are free of symptoms and during an attack. From his symptoms, it would seem that Darwin’s somatostatin levels may have been deficient some hours after a meal. We cannot measure Darwin’s levels but we are able to measure levels in patients today. If these levels are low, synthetic somatostatin (octeotride) administration could improve symptoms.

A study of Darwin’s illness shows the variety of symptoms – symptoms that include typical CVS events – that may occur with the one mtDNA mutation. His illness suggests ways in which this distressing disorder could be more specifically investigated and even indicates new treatment modalities. In summary, Darwin and his illness may still teach us more about our own biology.

References

Hayman, John (2013) ‘Charles Darwin’s Mitochondria’, Genetics, 194, (1), pp 21-25.

(A more in depth discussion about the A3243G mtDNA mutation and its suspected role in the conditions suffered by Charles Darwin and his family.)