Nonketotic Hyperglycinemia (NKH)

What is nonketotic hyperglycinemia? 

Nonketotic hyperglycinemia (NKH) is a rare, metabolic disorder that can present in the classic form or as a variant. It is estimated to impact one of every 76,000 people in the world.

What are the symptoms of nonketotic hyperglycinemia?

Most commonly, NKH presents in the severe, classic form. These symptoms present within the first week of birth, and they are fatal for some affected individuals. All others will require ventilation for 10-20 days. The symptoms of this type of NKH are apnea, seizures, coma, lethargy, and low muscle tone. After this initial period passes, affected individuals will experience severe developmental delay, seizures, orthopedic issues, problems with feeding, and issues with airway maintenance. For many, this final symptom ends up being fatal. 

The less severe form of classic NKH may see the onset of symptoms soon after birth or during infancy. The initial presentation is very similar to that of severe NKH, but there is variable developmental progress afterward. These individuals will have mild to profound developmental delay, and may also experience hyperactivity and behavioral issues. 

Turning towards the variants of NKH, the symptoms depend on the specific variant one presents. Possible symptoms associated with this form are the loss of skills already achieved, optic neuropathy, a weak heart, issues with the white matter in the brain, balance or spasticity problems, seizures, acid in the blood, and increased resistance of blood flow in the lungs.  

What causes nonketotic hyperglycinemia?

Affected individuals do not have a properly functioning glycine cleavage enzyme system, meaning that the body cannot properly break down the amino acid glycine. It goes on to accumulate, causing the characteristic symptoms. In classic NKH, this occurs when one of the genes that is responsible for the proteins of the glycine cleavage enzyme system is mutated. The responsible genes are GLDC and AMT, both of which are inherited in an autosomal recessive pattern. 

If an affected individual has issues with the glycine cleavage enzyme system but no mutated genes that correspond to its proteins, then they have variant NKH. Genes that have been found to cause NKH include LIPT1, LIPT2, NFU1, BOLA3, LIAS, GLRX5, IBA56, and ISCA2.

How is nonketotic hyperglycinemia diagnosed?

If a family is aware of a history of NKH, then prenatal screening can be performed, giving the diagnosis before birth. In other cases, doctors will test one’s cerebrospinal fluid (CSF), blood, and/or urine for enzyme activity and glycine levels. Molecular analysis can be performed to confirm a diagnosis. 

What are the symptoms of nonketotic hyperglycinemia?

There is no cure for NKH, but there are treatment options to improve patient outcomes. Sodium benzoate reduces serum glycine levels, which can lower the number of seizures and increase alertness. Dextromethorphan is often prescribed for the same reasons. Further treatment is symptomatic. 

Where can I find out more about nonketotic hyperglycinemia?

• NORD
• U.S. National Library of Medicine
• Very Well Health