Nonketotic Hyperglycinemia is an autosomal recessive disorder.
This means for a child to have Nonketotic Hyperglycinemia they inherited two copies of the mutated gene (one from each parent). A child with only one copy will be a carrier. Carriers are in no way affected by the NKH or have any signs or symptoms of the disorder. They can, however, pass the mutation to their children. Parents of a child with NKH are both carriers.
Autosomal simply means that it’s found in a chromosome that is not an allosome (a sex chromosome). This means it’s not gender specific.
Recessive means the allele (a section of the gene) would not typically code a functional protein (but the dominant allele would). A child with Nonketotic Hyperglycinemia has inherited two recessive genes, and does not have a dominant allele to code the correct protein).
As an example of recession/dominance, consider the inheritance of seed shape in peas.
Peas may be round (associated with allele R) or wrinkled (associated with allele r). In this case, three combinations of alleles (genotypes) are possible: RR, Rr, and rr. The RR individuals have round peas and the rr individuals have wrinkled peas.
In Rr individuals the R allele masks the presence of the r allele, so these individuals also have round peas. Thus, allele R is dominant to allele r, and allele r is recessive to allele R. This use of upper case letters for dominant alleles and lower case ones for recessive alleles is a widely followed convention.
The relevant part of this is that to have NKH the child needs to inherit genes from BOTH parents. If NKH was a dominant disorder, the child would only need to inherit one gene from one parent.
If both parents carry the mutation for Nonketotic Hyperglycinemia, the odds of their children having NKH are:
- 25% chance of inheriting both mutations and being affected by NKH
- 50% chance of inheriting only one copy and becoming an NKH carrier
- 25% chance of being unaffected and not inherting the NKH genes
Additionally, each child will have the same chances of inheriting the mutated gene. To be clear – having a child with NKH does not lessen the chances of the next child from inheriting NKH. Each child has a 25% chance of being affected by NKH.
When your child is diagnosed with NKH, a genetic test will be sent off the confirm the diagnosis. It takes 2-3 months to come back, and when you get the letter it can be very confusing.
There are several different kinds of mutations:
Missense mutation
This is a single point mutation where a single nucleotide (one rung on the dna ladder) has mutated. This causes a codon which creates a different amino acid than was intended.
Nonsense mutation
This is also a single point mutation, but with the single nucleotide mutation, it creates a premature stop codon, or a premature stop codon in the transcribed mRNA. This causes a truncated/incomplete protein which can’t be used.
Deletion mutation
This is where a part of a chromosome or a sequence of DNA is lost during DNA replication.
Splice mutation
This is where the mutation inserts, deletes or changes a number of nucleotides in the spot where a splicing takes place (while processing of precursor messenger RNA).
Missense Mutations
It’s helpful to know that each rung on the DNA ladder (called nucleotides) contributes to a set of three – called a codon. All the amino acids are made up a codon.
For example:
- GCA is the codon for alanine
- AGA is the codon for arginine
- TCA the codon for serine
There are 64 possible codons, but only 20 amino acids, so more than one codon may code for a single amino acid. For example, GCA, GCC, and GCG all mean alanine. You can view the codon table here.
If your genetic code switches one of those nucleotides because of a mutation in the gene, the codon will make a different amino acid.
Example:
- TCA the codon for serine
- The mutation switches the second C for a T
- TTA the codon for Leucine
- Where the glycine cleavage system is expecting serine, it’s now getting Leucine, and the protein is now nonfunctional.
That is the essence of a missense mutation.
When you’re given a genetics laboratory report, it can be confusing to understand. But there will be a panel result. It may look like this:
GLDC: c.395C>T; p.(Ser132Leu)
To break down into easier to understand parts:
- GLDC – This is gene the mutation was found it. Typically NKH mutations are found in the GLDC gene or the AMT gene
- c.395 – This is the codon location within the gene of where the mutation can be found
- C>T – This is the mutation. Where the nucleotide should use C (Cystosine), T (Thymine) is being used instead.
- p.(Ser132Leu) – This is the protein created as a result of the mutation. Where Seriene (Ser) was expected, Leucine (Leu) is now being created instead. 132 is the location where this is happening. Side note: this reflects the codon of the mutation. If you divide 395/3 (for the three nucelotides in the codon) you’ll get the location of the protein. Example 395/3 = 132. They point to the same place in the gene.
