We are all unique. We are all special. But do you want to be that one in a million? The patient with a rare disease. The ‘fascinating case’. The condition that barely gets a mention in the largest medical textbooks. The one with no drugs. No clinical trials. The one your GP has never heard about and is, frankly, a little scared of. The one your specialist is, well, not that specialised in.
Most people don’t want to be that one in a million. I suspect you wouldn’t either.
A rare disease is one with a prevalence of < 1:2000. Numerous haematological conditions fulfil that criteria- AML, haemophilia, CLL, pyruvate kinase deficiency to name a few. What about a condition whose prevalence is estimated at 1:1,000,000? This is the case for CDA-1.
CDA-1: congenital dyserythropoietic anaemia Type 1. A long name, a spelling that would stump any spelling bee finalist. A mouthful that just says your bone marrow doesn’t make red blood cells properly.
You may have been diagnosed at birth. You may have been diagnosed later. You may need transfusions. You may be on interferon. You’ve probably never met anyone else with the same condition.
And no one can give you any scientifically sound prognosis or evidence-based treatment options.
CDA-1 is a condition characterised by ineffective erythropoiesis- the bone marrow is full of developing red blood cells (RBCs), however, these developing RBCs do not mature to normal red cells and eventually die during their process of maturation. The “hallmark” of the condition is the appearance of the bone marrow erythroblasts under electron microscopy.
Their ‘swiss cheese-like’ display leads to their description as “Swiss cheese heterochromatin”:
It is always inherited in a recessive manner, and to date, two genes have been described as causing it: CDAN1 and C15ORF41. Most patients have two mutations in CDAN1. Some patients have two mutations in C15ORF41. No patients have been described with one mutation in each gene. A few patients have proven CDA-1 on electron microscopy but no mutations in either gene- this suggests there is a third gene that hasn’t been found yet. We still don’t know what these genes do in developing red cells, but many clues point to their being involved with the way DNA is ‘packaged’ in the nucleus. Intriguingly, the proteins produced by these genes are found at low levels in all cells in the body, but mutations seem to affect developing red blood cells above and beyond any other cell type. Of note, no patients have been described with two null mutations, supporting the idea that these proteins seem to be absolutely required for survival. In some patients, the anaemia can be improved by the use of interferon, a treatment option that was discovered purely by chance. Patients are also at risk of non-transfusional iron overload due to inappropriately suppressed hepcidin levels. This is because hepcidin functions to regulate iron entry into our circulatory system. Therefore its suppression can precipitate a range of iron disorders.
Today for Rare Disease Day, imagine walking in the shoes of someone with CDA-1, or any other rare disease. Who do you trust? Depending on where you live, you may or may not have access to someone who has treated patients with CDA-1 before. And even if they have, and they read all the literature available on your condition, that is still precious little, all of which will be case series. Drugs that may seem promising are not the drug companies’ priority for testing in your disorder, and you may not have access to these, even off-license.
The only way forward is cooperation and collaboration, in clinical care and in research. Recently, patients have joined together with clinicians and patient support groups to determine the topics which they think require priority attention:
Interestingly, their number one issue was:
“Would a national formal network of clinicians with expertise and /or a national MDT (multidisciplinary team meeting) improve care for patients with rare inherited anaemias?”
This is partly being addressed as clinical care for patients with rare inherited anaemias, including CDA-1, now squarely falls under the remit of the centrally commissioned Haemoglobinopathy Coordinating Centres and Specialist Teams.
Patients can now be referred to the National Haemoglobinopathy Panel for complex treatment decisions. In addition to a UK network of clinicians, EuroBloodNet also provides an EU-wide network of expertise:
Nevertheless, with so few patients affected, maximum knowledge would be gained from entering as many as possible in the NIHR Rare Disease Bioresource project:
This would ensure genomics and proteomics are studied in as many patients as possible to identify disease biomarkers, novel genes, and possible new therapeutic targets.
Today, we focus on patients with rare diseases. Tomorrow and the rest of the year, they will continue to live with it. The best way we can ensure that we are doctors they can trust is to all work together, share expertise and offer all of the patients the opportunity to be part of research in their condition.
For a film with a CDA-1 patient’s words:
For more information on CDA-1:
Dr Noémi Roy