Thank you to Rachel Alvarez, Director of Operations for Cure CMD for the following in depth information on Levi's diagnosis. Buckle up!

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The LMNA gene is composed of 12 exons, making it on average (compared to the size of other genes that lead to a CMD) fairly small.  For comparison, one of the largest genes we have, aptly named Titin, mutations in which can also lead to a CMD, has 363 exons!

 

What the heck is an exon?

Genes are made up of exons on introns.  Generally speaking, exons are the "coding" regions of the gene while introns are the "non-coding" regions of the gene. They alternate - exon, intron, exon, intron.  Consider them like blocks in a neighborhood - they all have a range of locations or addresses that are delineated by the beginning and ending of an exon and the beginning and ending of an intron. It was originally thought that introns were largely unimportant since they didn't get translated into new RNA - but we are now finding disease causing mutations in introns - meaning we can't ignore these areas of the gene like we once thought.

 

The LMNA gene regulates proteins called Lamin A and Lamin C - both critical components to the nuclear envelope.

 

What the heck is a nuclear envelope?

Our body is made up of cells - millions and billions of cells.  Each cell has a nucleus, that contains a copy of our DNA or our body's "blueprint". The supporting structure (or membrane) surrounding the nucleus that separates it from the other stuff in the cell is called the nuclear envelope.  The nuclear envelope is not a solid wall, but a highly regulated porous membrane that lets specific things in and out. As you can imagine, the nuclear envelope plays an incredibly critical role, and in the case of LMNA mutations, that membrane, or nuclear envelope has trouble regulating what comes in and out of the nucleus, and even has trouble maintaining its shape and strength, sometimes folding in on itself disrupting that flow.

 

Many mutations in LMNA are de novo or spontaneous, meaning a random occurrence during fetal development and not a direct inheritance from a parent with the same mutation.  Because of this, even when a person is found to have a mutation in the LMNA gene, it is often difficult to be absolutely sure that it is the cause of disease symptoms.  In other diseases, where inheritance can be traced from one or both parents to the offspring, making the call of "pathogenicity" or "this is the disease causing mutation" a bit more easier.  The upside to LMNA mutations often being mostly spontaneous is that siblings are much less likely to be affected, and the disease causing mutation is less likely to be passed on to future generations.

 

Levi has an in-frame deletion in Exon 1, specifically c.91_93delGAG, which causes the amino acid Glutamine to behave abnormally.

 

What the heck is an amino acid?

Amino acids are the building blocks of protein and carry out a significant portion of our body's functionality - from metabolism to tissue repair to waste elimination.  There are twenty amino acids, and Glutamine is one of them. Glutamine or Glutamic acid is one of the most abundant of the twenty and is critical in the building of proteins used in muscle.

 

Levi has a deletion - meaning part of the genetic code is simply missing - from position 91 to position 93 in Exon 1 - specifically the string G-A-G is missing. 

 

What the heck is G-A-G?

DNA is made up of 4 components, called nucleic acids - Adenine, Cytosine, Guanine, Thymine, or A-C-T-G. When we look at Levi's DNA and compare it to "normal" DNA, the place where we expect to see the string G-A-G in Exon 1, it's not there.

 

Do you find it interesting that the missing components in Levi's DNA are the first 3 letter of our family name?!

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Because many CMD related LMNA mutations are spontaneous, it can be expected that there will be a wide number of varying mutations. So I am not at all surprised that we can currently only find 3 other people with Levi's specific mutation in the public databases and publications. It doesn't mean that there aren't more out there - I'm absolutely sure there are given the small size of the LMNA gene - genetic testing is just not widely available around the world, and many neurologists don't know where to even begin ordering genetic testing because they don't know what they are looking at, or how to interpret results if they do get a hit in LMNA. Levi's mutation is classified as a "VOUS" or "variant of unknown significance" - even here in the U.S., where we have more diagnostic tools than most anywhere else in the world - because the lab who analyzed Levi's DNA had not seen another person with that exact mutation before.  Until LOTS more people get tested and those results are submitted to one of the larger, publicly viewable databases, many people with LMNA-CMD will continue to go undiagnosed, or classified as having a VOUS.  As more clinicians and researchers submit their VOUS results - and eventually we see say, 10 or 100 VOUS submissions with the same mutation - it makes a pretty compelling argument that the mutation should be reclassified as pathogenic.