The following is adapted from the first chapter of my book the CMMRD book.
While rare conditions are those that affect less than one in 2,000 people, ultra-rare conditions affect one in 50,000. This puts CMMRD in a league of its own as it affects an estimated one in a million patients.
CMMRD stands for Constitutional Mismatch Repair Deficiency and it’s a genetic condition that increases a person’s risk of getting different types of cancer. It is related to another genetic condition called Lynch syndrome, which also increases cancer risk. But while Lynch syndrome occurs when a person inherits faulty genes from one parent, CMMRD occurs when both parents have Lynch syndrome and the person inherits faulty genes from both parents. To understand how CMMRD is inherited, let’s first explain Lynch syndrome further.
Mismatch Repair Genes: The Editors of Our Bodies’ Books
Lynch syndrome is a genetic condition that increases a person’s cancer risk. It used to be known as hereditary non-polyposis colorectal cancer (HNPCC). People with Lynch syndrome have an up to 80% risk of getting bowel cancer. It can also increase the risk of getting gynaecological, stomach, kidney, liver, skin and brain cancer, depending on which of your genes are affected. The genes are called MLH1, MSH2, MSH6, PMS2, and EPCAM, and if you have Lynch syndrome in the family you may have come across these names. These are mismatch repair (MMR) genes.
Mismatch repair genes repair mistakes that occur during DNA replication. As they look for mistakes and correct them, I like to think of these genes as the editors or proofreaders of our bodies. Imagine a tiny person sitting at a desk inside your body, with stacks of paper piled high in front of them. That person is your editor, your mismatch repair gene. And the paper is the DNA that needs to be checked. The editor takes their red pen and corrects all of the mistakes. For a real editor, these might be spelling errors, grammatical errors, inconsistencies or incorrect facts. Mismatch repair genes, the editors of your DNA, will be correcting mistakes in DNA replication that could otherwise lead to cancer if left uncorrected. Of course, for a real editor, the stakes are not very high – a spelling mistake in a book or newspaper isn’t a matter of life or death. Mistakes in DNA, however, can be catastrophic. This is why your MMR genes are so important. The editor finishes the corrections and the paper is taken away so that the printed publication can be finished correctly – or so that your DNA can be repaired and all is well.
Because they repair DNA, mismatch repair genes help prevent us from getting cancer, which I suppose in this metaphor is the worst possible grammatical error (even worse than mixing up your and you’re). Lynch syndrome is when these mismatch repair genes or editors are “broken” due to alterations or mutations, so they don’t do their job properly. Imagine the editor’s desk is empty, or they are sleeping at their desk, or making paper aeroplanes instead of working. However you think of it, the editor or MMR gene is not doing its job – leaving mistakes uncorrected and increasing cancer risk.
We each inherit two copies of each gene from our parents. So if your mother has Lynch syndrome (in other words, one of her two copies of the gene has a mutation) and your father does not have Lynch syndrome, you might inherit a normal gene from each parent and not have Lynch syndrome. Or you might inherit your mother’s mutated gene and also have Lynch syndrome. The chances of getting Lynch syndrome if one parent has it are 50%.
It’s worth noting here that Lynch syndrome itself is not rare. It’s estimated that 1 in 400 people in the UK have Lynch syndrome, but only 5% know they have it.
CMMRD: “Double” Lynch Syndrome
Now that we understand Lynch syndrome, we can explain what CMMRD is by thinking again about families and how these problems with the genes are passed on. We’ve talked about what could happen if one parent has Lynch syndrome. But what if they both have it? The mother has one normal gene and one with a mutation. So does the father. The child might therefore inherit the mother’s normal gene and the father’s normal gene and not have Lynch syndrome at all. Or the child might have inherited the mother’s normal gene and the father’s mutated gene, or the mother’s mutated gene and the father’s normal gene. This would mean they have one normal gene and one mutation, and would therefore have Lynch syndrome. Finally, there are those who inherit their mother’s mutated gene and their father’s mutated gene. These people have CMMRD, also known as Biallelic Mismatch Repair Deficiency or BMMRD. If Lynch syndrome increases cancer risk, what I often refer to as “double Lynch syndrome” increases it even more. CMMRD increases the risk of cancer including bowel, brain, and blood cancer such as leukaemia or non-Hodgkin lymphoma.
Aside from the cancer risk, people with CMMRD may have changes in skin colouring – patches of skin or spots that are darker than the surrounding area, known as café-au-lait spots. Sometimes they may have lighter patches of skin or freckling. Some also have Lisch nodules, which are benign growths in the iris that don’t affect the person’s vision.
There is no cure for CMMRD and no treatment other than regular screening and the subsequent treatment of any cancers that may develop. As it is so rare, not much is known about CMMRD at the moment and the guidelines around recommended screening are often updated to take the latest research and findings into consideration.
CMMRD almost always results in childhood or early adult cancer. Nearly everyone with CMMRD gets cancer before the age of eighteen. The average age for getting cancer with CMMRD is just seven and a half years old. However, I didn’t get my first cancer until I was 22, and at the time of publishing this page, I’m 38 years old, if that’s of any comfort. Researchers are also currently working on a Lynch syndrome vaccine, which also signals hope to those of us with CMMRD.
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Interested in reading more? The CMMRD book explains more about the condition and my experiences of living with it.
These websites also provide further information and support:
The International Replication Repair Deficiency Consortium (IRRDC)
