Nonketotic hyperglycinaemia

Overview

Nonketotic hyperglycinaemia (NKH), also known as glycine encephalopathy, is a rare genetic disorder affecting the metabolism of glycine. Glycine is an amino acid that serves as a building block for proteins and also functions as a neurotransmitter in the brain. In NKH, the body cannot break down glycine effectively, leading to its accumulation in tissues and fluids, particularly in the brain [PMID:33678438]. This build-up is toxic to the central nervous system.

The condition typically presents in the newborn period or early infancy, though rarer forms with later onset exist. The severity can vary, but NKH often leads to profound neurological problems. It is estimated to affect approximately 1 in 60,000 live births globally.

Symptoms & clinical features

The symptoms of NKH arise from the toxic effects of excess glycine on the brain. In the severe neonatal form, symptoms usually appear within the first few days of life. These can include poor feeding, lethargy (lack of energy), hypotonia (floppy muscle tone), and seizures that may be difficult to control [PMID:20301758]. Babies may also experience apnoea (periods of not breathing) and coma.

In milder forms, symptoms might appear later in infancy or childhood. These can include developmental delay, intellectual disability, epilepsy, and problems with movement control. The specific symptoms and their severity depend on the residual activity of the glycine cleavage system.

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Affected organs

The primary organ affected by nonketotic hyperglycinaemia is the brain and central nervous system. The accumulation of glycine, particularly in brain tissue, disrupts normal brain function and development. This can lead to structural changes in the brain over time.

While the main impact is neurological, the disorder is fundamentally a metabolic one, affecting the body's chemical processes for breaking down amino acids. However, clinical manifestations are predominantly observed in the brain.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Nonketotic hyperglycinaemia encompasses a spectrum of severity. The neonatal form is generally the most severe, often associated with a very poor prognosis and significant neurological impairment. Infants with this form typically have severe developmental delays and may not survive beyond early childhood due to complications such as respiratory failure.

Later-onset or attenuated forms of NKH tend to be less severe, with individuals experiencing varying degrees of developmental delay, intellectual disability, and epilepsy. The long-term outlook for these individuals is variable and depends on the specific genetic change and the effectiveness of management strategies. Current therapies do not cure NKH, but aim to manage symptoms and reduce glycine levels.

Genetic causes

Nonketotic hyperglycinaemia is caused by pathogenic variants in genes responsible for the glycine cleavage system. This system is a group of enzymes critical for breaking down glycine in the body's cells. The main genes involved are GLDC, AMT, and GCSH [PMID:20301758].

The GLDC gene provides instructions for making glycine decarboxylase, a key enzyme in the system. The AMT gene encodes aminomethyltransferase, another essential enzyme. The GCSH gene produces the H-protein subunit, which is also vital for the system's function. Pathogenic changes in any of these genes disrupt the glycine cleavage system, leading to the accumulation of glycine to toxic levels in the body, particularly in the brain.

• AMT
  aminomethyltransferase
  The AMT gene provides instructions for producing aminomethyltransferase, an enzyme vital for the breakdown of glycine within the body.
• GCSH
  glycine cleavage system protein H
  The GCSH gene provides instructions for a protein crucial to the glycine cleavage system, which processes the amino acid glycine within the body.
• GLDC
  glycine decarboxylase
  The *GLDC* gene provides instructions for making the glycine decarboxylase enzyme, a critical component of the glycine cleavage system responsible for breaking down glycine in the body.

Inheritance pattern

Nonketotic hyperglycinaemia has an autosomal recessive inheritance pattern. This means that a child must inherit two altered copies of the same gene - one from each parent - to develop the condition. Parents who each carry one altered copy of the gene are known as carriers. Carriers typically do not show symptoms of the condition themselves because they have one working copy of the gene.

If both parents are carriers of an NKH-causing gene, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered copies and develop the condition. There is also a 1 in 2 (50%) chance the child will be a carrier like their parents, and a 1 in 4 (25%) chance the child will not inherit any altered copies of the gene.

Diagnosis & testing

Diagnosis of nonketotic hyperglycinaemia is often suspected based on clinical symptoms, especially in newborns with severe neurological signs. Initial biochemical investigations typically involve measuring glycine levels in blood plasma and cerebrospinal fluid (CSF). A significantly elevated glycine concentration in CSF relative to plasma is highly suggestive of NKH [PMID:33678438].

Confirmation of the diagnosis is made through genetic testing, which looks for pathogenic variants in the GLDC, AMT, or GCSH genes. This testing can be accessed via the NHS Genomic Medicine Service (GMS) pathways. A clinician, often a paediatrician or metabolic specialist, would typically refer a patient for genetic testing. NHS R-codes for metabolic disorders, including NKH, facilitate access to these diagnostic tests.

Management & lifestyle

Currently, there is no cure for nonketotic hyperglycinaemia, and management focuses on reducing glycine levels and managing symptoms. Treatment often involves medications such as sodium benzoate, which helps the body remove glycine, and dextromethorphan, which can help block the effects of glycine on brain receptors [PMID:33678438]. These treatments are initiated under the guidance of metabolic specialists.

Symptomatic management includes anticonvulsant medications for seizures and supportive care for feeding and breathing difficulties. Regular monitoring by a multidisciplinary team, including neurologists, dietitians, and physiotherapists, is crucial. Families can access support through clinical genetics services and genetic counsellors within the NHS.

UK care pathway

In the UK, individuals suspected of having nonketotic hyperglycinaemia would typically enter the NHS Genomic Medicine Service (GMS) pathway. Referral to a paediatrician or metabolic specialist is the usual first step. These specialists can then initiate biochemical investigations and refer for genetic testing, which is available through the GMS to confirm the diagnosis using relevant R-codes for rare metabolic conditions. Genetic counsellors play a vital role in providing information and support to families throughout this process.

Related conditions

While NKH is a distinct condition, other disorders can present with similar neurological symptoms or metabolic disturbances. Conditions like pyridoxine-dependent epilepsy or other inborn errors of metabolism affecting amino acid pathways might initially be considered in the differential diagnosis. Genetic testing is crucial for accurately distinguishing NKH from these other conditions and guiding appropriate management.

Frequently asked questions