Nonketotic hyperglycinemia

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Nonketotic hyperglycinemia is a disorder characterized by abnormally high levels of a molecule called glycine in the body (hyperglycinemia). The excess glycine builds up in tissues and organs, particularly the brain. Affected individuals have serious neurological problems.

Nonketotic hyperglycinemia has two forms, the severe form and the attenuated form. Both forms usually begin shortly after birth, although in some cases, signs and symptoms can begin in the first few months of life. Only the attenuated form begins later in infancy. The forms are distinguished by the seriousness of the signs and symptoms. Severe nonketotic hyperglycinemia is more common. Affected babies experience extreme sleepiness (lethargy) that worsens over time and can lead to coma. They can also have weak muscle tone (hypotonia) and life-threatening breathing problems in the first days or weeks of life. Most children who survive these early signs and symptoms develop feeding difficulties, abnormal muscle stiffness (spasticity), profound intellectual disability and seizures that are difficult to control. Most affected children do not achieve normal developmental milestones, such as drinking from a bottle, sitting up, or grabbing objects, and they may lose any acquired skills over time.

The signs and symptoms of the attenuated form of nonketotic hyperglycinemia are similar to, but milder than, those of the severe form of the condition. Children with attenuated nonketotic hyperglycinemia typically reach developmental milestones, although the skills they achieve vary widely. Despite delayed development, many affected children eventually learn to walk and are able to interact with others, often using sign language. Some affected children develop seizures; if present, seizures are usually mild and can be treated. Other features can include spasticity, involuntary jerking movements (chorea), or hyperactivity.

Individuals with nonketotic hyperglycinemia can also have certain changes in the brain, which can be seen using magnetic resonance imaging (MRI). For example, in children with the severe form of the condition, the tissue that connects the left and right halves of the brain (the corpus callosum) is smaller than average.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Mutations in the GLDC or AMT gene cause nonketotic hyperglycinemia. About 80 percent of cases result from mutations in the GLDC gene, while AMT gene mutations cause about 20 percent of all cases.

The GLDC and AMT genes provide instructions for making enzymes that work together as a group. This group, known as the glycine cleavage system, is responsible for breaking down glycine into smaller pieces when it is no longer needed. Glycine is an amino acid, which is a building block of proteins. Glycine also acts as a neurotransmitter, which is a chemical messenger that transmits signals in the brain. Too much glycine can disrupt brain function.

In addition, the breakdown of glycine by the glycine cleavage system produces a molecule called a methyl group. This molecule is added to and used by a vitamin called folate. Folate is required for many functions in the cell and is important for brain development.

Mutations in either the GLDC or AMT gene impair the system's ability to break down glycine. Some mutations reduce the activity of the glycine cleavage system, while others completely eliminate its activity. When the function of the glycine cleavage system is disrupted, excess glycine can build up in the body's organs and tissues. In addition, the production of methyl groups for use by folate is reduced. It is unclear how these abnormalities contribute to the developmental disability, seizures, breathing difficulties, and other features characteristic of nonketotic hyperglycinemia.

The activity level of the glycine cleavage system helps determine the severity of the disorder: GLDC or AMT gene mutations that completely eliminate the system's activity result in severe nonketotic hyperglycinemia, while mutations that preserve some activity cause attenuated nonketotic hyperglycinemia.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Nonketotic hyperglycinemia is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Typically, the parents of an individual with the condition each carry one copy of the mutated gene, but they usually do not show signs and symptoms of the condition. In very rare cases, one of the mutations occurs during the formation of reproductive cells (eggs or sperm) in an affected individual's parent or in early embryonic development. These are known as de novo mutations.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Nonketotic hyperglycinemia is estimated to affect at least 1 in 76,000 people worldwide. In Finland, the condition occurs in about 1 in 55,000 newborns, and in British Columbia, Canada, it occurs in about 1 in 63,000 newborns.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal metabolic brain imaging by MRS · Very frequent (99-80%)

An anomaly of metabolism in the brain identified by magnetic resonance spectroscopy (MRS).

EEG abnormality · Very frequent (99-80%)

Abnormality observed by electroencephalogram (EEG), which is used to record of the brain's spontaneous electrical activity from multiple electrodes placed on the scalp.

EEG with burst suppression · Very frequent (99-80%)

The burst suppression pattern in electroencephalography refers to a characteristic periodic pattern of low voltage (<10 microvolts) suppressed background and a relatively shorter pattern of higher amplitude slow, sharp, and spiking complexes.

Hyperglycinemia · Very frequent (99-80%)

An elevated concentration of glycine in the blood.

Hypoplasia of the corpus callosum · Very frequent (99-80%)

Underdevelopment of the corpus callosum.

Hypotonia · Very frequent (99-80%)

Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.

Recurrent singultus · Very frequent (99-80%)

A contraction of the diaphragm that repeats several times per minute. In humans, the abrupt rush of air into the lungs causes the epiglottis to close, creating a hic sound. Also known as synchronous diaphragmatic flutter (SDF), or singultus, from the Latin singult, the act of catching one's breath while sobbing. The hiccup is an involuntary action involving a reflex arc.

Seizure · Very frequent (99-80%)

A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.

Other findings in the same source

From: Orphanet

Additional reported features include Generalized myoclonic seizure (Frequent (79-30%)); Lethargy (Frequent (79-30%)); Poor suck (Frequent (79-30%)); Respiratory acidosis (Frequent (79-30%)); Breathing dysregulation (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Nonketotic hyperglycinemia is Neurology, with a neurologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which nervous-system findings help explain the symptoms?
• Would an assessment of walking, communication or daily function be helpful?
• Are rehabilitation or other specialist services relevant?

Treatment discussions and follow-up

Where the source describes treatments, these are an overview of possible care, not a prescription for an individual. Ask which option applies to the confirmed diagnosis, what benefit is expected, what adverse effects to watch for and how progress will be assessed. Availability, approvals and local practice can differ from the country described in the source.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.