Darwin’s illness revisited

I am grateful to Prof Fiddian-Green for his comments on my article
and his
suggested alternative diagnosis of phaeochromocytoma. CVS is certainly not

a common disorder but it is not excessively rare. The prevalence has been
estimated to be between 0.04% and 1.9% in two different childhood
series.[1] The possibility of a mitochondrial disorder is strongly
suggested
by the maternal inheritance pattern shown in several studies and has been
confirmed by finding mtDNA abnormalities.[2] The episodic nature of the
illness is explained by cycles being brought on by various ‘triggers’ that
can
be fatigue, infection, excitement or food allergy.

Darwin first had symptoms that could have been due to a
phaeochromocytoma (palpitations) when he was waiting to board ship in
Plymouth in October 1831. He died in 1882 at the age of 73 with ischaemic
heart disease.[3] Symptoms from his chronic illness improved if anything
in
his last years of life; on these grounds a tumour, even a benign tumour,
is
unlikely.

Many of Darwin’s symptoms (and those of CVS patients) can be related
to
neuroendocrine dysfunction, in particular the action of peptide hormones
such as gastrin, secretin, substance P acting without the inhibitory
effect of
other hormones such as somatostatin. The diffuse neuroendocrine system
consists of cells containing neurosecretory granules that as well as the
particular peptide hormone have a high concentration of ATP.[4] This
functions partly as an osmotic regulator, partly as a buffer, maintaining
low
(acidic) pH, and after secretion, may act as an antagonist to other
secreted
hormones. ATP is generated in mitochondria and if there is mitochondrial
failure ATP production is compromised, neuroendocrine granule stability is

lost and there is diminished extracellular regulation of excitatory
peptide
hormones.

Rather than a tumour of neuroendocrine cells (phaeochromocytoma) I
propose that Darwin’s illness related in part to neuroendocrine
dysfunction,
dysfunction that in turn was caused by intermittent mitochondrial failure.

1. Pareek, N., D.R. Fleisher, and T. Abell, Cyclic vomiting syndrome:
what
a gastroenterologist needs to know. Am J Gastroenterol, 2007. 102(12): p.
2832-40.

2. Boles, R.G., K. Adams, and B.U. Li, Maternal inheritance in cyclic

vomiting syndrome. Am J Med Genet A, 2005. 133A(1): p. 71-7.

3. Colp, R., Darwin's Illness. 2008, Gainesville: University Press of
Florida.

4. Payne, C.M., Phylogenetic considerations of neurosecretory granule

contents: role of nucleotides and basic hormone/transmitter packaging
mechanisms. Arch Histol Cytol, 1989. 52(Suppl): p. 277-292.

Competing interests:
None declared