Inheriting Nonketotic Hyperglycinemia

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.

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.

Side note:
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.

Understanding your Nonketotic Hyperglycinemia Mutation

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.


  • 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.1108 – 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.

Chromosomes, DNA and Genes

Every cell in your body contains a nucleus. In that nucleus, there is a chemical that contains chromosomes. There are 46 chromosomes – split into 22 pairs. Each pair is one chromosome from each parent. Twenty-two of these pairs (called autosomes) is the same in both males and females. The 23rd pair defines the gender.

The GLDC gene is found in Chromosome 9. The AMT gene is found in Chromosome 3.

Each chromosome contains a strand of DNA, one long molecule that carries the code for all your genetic information. This strand of DNA is arranged into sections, called genes.

A gene is coded into a pair of interlocking units – two strands that wrap around each other to resemble a twisted ladder.

These rungs are made of nitrogen-containing chemicals called bases. There are four different bases:

A – Adenine
T- Thymine
C – Cystosine
G – Guanine

The bases like to pair off together.  A (Adenine) always pairs with T (Thymine) – A & T, and C (Cystosine) always pairs with G (Guanine) – C & G. These are called base pairs.

The sides of the ladder are made of sugar and phosphate molecules (called a backbone). Each strand is composed of one sugar molecule, one phosphate molecule, and a base – this is called a nucleotide.

The order of these nucleotides defines the genetic instructions – like a recipe. This is called the DNA sequence.

Transcription: DNA to RNA

By using the DNA Sequence – a specific ordering of nucleotides – there are regions of the gene that are like start and stop signs.

The two we are interested in is the promoter region, and the regulatory region.

There are proteins – called General Transcription Factors. They’re like little traffic workers holding a sign post. The General Transcription Factor binds to the regulatory region.

With the General Transcription Factor pointing to the right spot, the DNA worker – the RNA Polymerase enzyme is able to bind to the start position of the gene.

To get going, the DNA worker – the RNA Polymerase enzyme – needs a bit of a kick. So when the General Transcription Factors + the RNA Polymerase are in place, an activator will bind to the regulatory region. This tells the RNA Polymerase enzyme to get going