There are different categories of Nonketotic Hyperglycinemia, and it can be very very confusing when trying to understand – especially because NKH can be so varied. Essentially, the categories point to different parts of NKH.
- Classic vs Variant – This refers to where the mutation that causes NKH lies.
- Severe vs Attenuated/Mild – This refers to the severity of NKH. It’s a good indicator of outcome.
- Onset – This refers to the age at which NKH presents itself.
- Transient NKH – This is a very (very!) rare type of NKH that resolves itself as a child grows.
Classic vs Variant NKH
Nonketotic Hyperglycinemia is caused by two mutations that affect the Glycine Cleavage Mutation. If there is only one mutation, the child is a carrier and not affected by NKH.
There are four genes that make up the These genes are:
- the P protein known as Glycine Decarboxylase (encoded by the GLDC gene)
- the H protein known as a lipoic Acid-Containing Protein (encoded by the GCSH gene)
- the L protein known as dihydrolipoamide dehydrogenase (encoded by the GCSL or DLD gene)
- the T protein known as aminomethyltransferase (encoded by the GCST or AMT gene)
This is what the Glycine Cleavage System looks like in biochemistry short hand:
If the child has mutation in one of those four genes that make up the Glycine Cleavage System, they will have Classic NKH. Their mutation is directly in the Glycine Cleavage System.
However, the Glycine Cleavage System is part of a much larger system – the Folate One Carbon Metabolism System (the FOCM). There are many sections in the FOCM that feed into the Glycine Cleavage system.
If the child has a mutation in one of the systems that feed into the Glycine Cleavage System – there is a problem with one of the proteins required for the Glycine Cleavage System to work. This is called Variant NKH.
Neonatal, Infantile and Late Onset NKH
Neonatal Onset NKH
Typically NKH presents at birth, in the neonatal period after an uneventful and unremarkable birth. Approximately a third of mothers report an increased number of hiccups during pregnancy (at least once a week) suggesting that NKH begins prior to birth.
Once born, symptoms are noted between 6 hours and days of birth. Typically with hypotonia (floppiness), progressive lethargy, intractable seizures, and
apnea (which is the suspension of breathing, where there is no breathing movement). Babies who survive this respiratory crisis usually regain spontaneous breathing control between two and three weeks of life.
Infantile Onset NKH
In Infantile Onset NKH children present with elevated glycine levels and seizure activity after 6 months of age, with typical grown and development.
Because these children are much older, and do not present with hypotonia and apnea, it’s associated with a lower risk of mortality and less profound mental retardation
Late Onset NKH
Late Onset NKH presents very differently. There are no NKH symptoms at birth, and typically have normal intellectual abilities. At some point between two years and 33 years the person will start to develop symptoms (such as hypotonia – low muscle tone and extreme lethargy, ADHD, progressive spastic paraparesis – stiffness in the legs which make it difficult to move and loss of vision).
A minuscule number of children have been found to have Transient NKH. (Source). Initially they present with the same symptoms and blood results as classic NKH neonates.
However, levels of glycine in plasma and cerebrospinal fluid typically normalize within eight weeks. In five of the six cases, there were no neurological issues found. A single patient was severely retarded at nine months.
It’s thought Transient NKH is caused by low activity of the glycine cleavage system in the immature brain and liver of the neonate, which the child grows out of as they mature.
Transient Nonketotic Hyperglycinemia is very very rare, though it is very difficult currently to determine the difference between transient + classic NKH without a genetic screening (due to this length of time taken for a genetic screening – approximately 2 months – this isn’t a viable screening method at the time of diagnosis).
Severity of NKH
Because NKH mutations are so varied (in this study, 578 NKH families were identified, and between them, 410 unique mutations were found) – the GCS can be stopped at different parts of the process depending on where the mutation is.
This means that each child will have some variance in symptoms, tolerance of medications and outcome.
There are categories of severity.
There is no clear research on the splits between severity, what their outcomes are and what their development is like. This is a very rough overview from what we, as parents, have seen. Please take what follows as a grain of salt. Each child has their own unique mutations and will respond and develop in their own way. Have hope.
Children that can’t process any glycine have severe NKH. This means the protein created by child’s DNA with the mutation is not able to used to process glycine at all.
This study categorised children on a Developmental Scale. For children whose sole developmental milestone consisted of the ability to smile were given a developmental age of ≤6 weeks and categorised as severe NKH.
It’s impossible to confirm severity from glycine CSF/plasma scores. If there are high levels of glycine a doctor will most likely diagnose a severe outcome, despite the unreliability of this. The best way to confirm severity is to run a developmental quotient assessment when the child is 2 years of age or older.
Some children – due to the where the mutation break is – are able to process a small amount of glycine (5% – 18%). These children have attenuated NKH. Attenuated means ‘weakened effect’. This may change their mid to long term outcome and be slightly higher functioning than severe children, they experience equally tough and difficult symptoms.
This previously was called ‘Mild’ NKH, however, attenuated children are not mild, and can have difficult to manage seizures and behavioural problems.
Because there are still wildly varying levels of attenuated NKH, they are split into three broad categories:
A child ages two years or older with a developmental quotient score (an score to determine the child’s developmental age vs their chronological age) of
However, they may with time, learn to hold their head up and sit with support. They may learn to roll, and be able to tolerate some food orally.
A child ages two years or older with a developmental quotient score of ≥ 20 and < 50 would indicate Attenuated Intermediate NKH. These children may have improved fine motor skills (be able to close flip switches etc), feed themselves, walk and/or talk.
A child ages two years or older with a developmental quotient score of ≥ 50 would indicate Attenuated Mild NKH.
There is a range here. Those with a DQ closer to their ate (with a score of 90+) may appear to be neurotypical, though are developmentally delayed in their early years. Recently, a child with very very mild attenuated mild NKH graduated a neurotypical high school.
Other children closer to a score of 50 may have more difficulties. They may walk and/or talk but with less ease, and/or have developmental delays.