Nonketotic hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare, severe, genetic metabolic disorder. It affects the body’s ability to properly process glycine, an amino acid, leading to its buildup, particularly in the brain and nervous system.
Understanding Nonketotic Hyperglycinemia (NKH)
Nonketotic hyperglycinemia arises from a defect within the glycine cleavage system (GCS), a group of enzymes responsible for breaking down glycine. This system typically converts glycine into carbon dioxide, ammonia, and other molecules, which are then used by the body or excreted. When the GCS is impaired, glycine accumulates to toxic levels throughout the body, especially in the brain and cerebrospinal fluid (CSF).
Glycine functions as a neurotransmitter in the central nervous system, helping to transmit signals between brain cells. However, excessively high concentrations of glycine become neurotoxic, disrupting normal brain function. The term “nonketotic” differentiates this condition from other disorders that might also cause elevated glycine levels but are associated with ketone body production.
Genetic Roots of NKH
NKH is an autosomal recessive disorder, meaning an individual must inherit two copies of a mutated gene, one from each parent, to develop the condition. Parents who carry one copy of the mutated gene typically do not show symptoms themselves. There is a 25% chance for two carrier parents to have a child affected by NKH with each pregnancy.
The primary genes involved in NKH are GLDC, AMT, and, less commonly, GCSH. These genes provide instructions for producing components of the glycine cleavage system. When these genes are mutated, the glycine cleavage system cannot function effectively, leading to the characteristic buildup of glycine.
Clinical Manifestations of NKH
Nonketotic hyperglycinemia presents in various ways, with the severe neonatal form being the most common and often appearing shortly after birth. Infants with this severe form frequently exhibit profound lethargy, which can worsen and lead to a coma. They also experience weak muscle tone, known as hypotonia, making them appear “floppy.”
Breathing difficulties, including episodes of apnea where breathing temporarily stops, are also common. Many affected infants develop difficult-to-control seizures and may experience hiccups. For those who survive the initial neonatal period, severe intellectual disability and significant developmental delays are typical long-term outcomes.
Rarer forms of NKH, such as attenuated or late-onset types, may present with milder symptoms or appear later in infancy or childhood. While symptoms in these forms are less severe, they can still include developmental delays, seizures, and other neurological challenges. The severity of symptoms often correlates with the residual activity of the glycine cleavage system; less activity typically leads to more severe manifestations.
Diagnosis and Management Approaches for NKH
Diagnosing nonketotic hyperglycinemia begins with clinical suspicion based on an individual’s symptoms. Biochemical testing then plays an important role, measuring glycine levels in both blood plasma and cerebrospinal fluid. A significantly elevated glycine concentration, especially an increased ratio of glycine in the CSF compared to plasma (a CSF:plasma glycine ratio often above 0.08), strongly indicates NKH.
Genetic testing, specifically sequencing of the GLDC, AMT, and GCSH genes, provides a confirmatory diagnosis by identifying specific mutations. Brain imaging, such as an MRI, can also show characteristic patterns of brain changes, further supporting the diagnosis. Early diagnosis is important for initiating management strategies.
Currently, there is no cure for NKH, so management focuses on alleviating symptoms and providing supportive care. Medications reduce glycine levels in the body, such as sodium benzoate, which helps the body excrete excess glycine. Dextromethorphan, a drug that blocks certain glycine receptors in the brain, can help reduce the neurotoxic effects of glycine and manage seizures.
Anticonvulsant medications are prescribed to help control the intractable seizures often seen in NKH, though these can be challenging to manage. Supportive therapies are important and include nutritional management, often involving a protein-restricted diet, to limit glycine intake. Physical, occupational, and speech therapies are implemented to help individuals reach their developmental potential and manage their physical challenges.
Long-Term Outlook for Individuals with NKH
The long-term outlook for individuals with nonketotic hyperglycinemia is poor, particularly for those with the severe neonatal form. A high mortality rate is observed, with many infants not surviving beyond the neonatal period or early childhood. Estimates suggest approximately 80% of babies with severe NKH may not survive the neonatal phase.
For survivors, severe outcomes are common, including profound intellectual disability and intractable seizures resistant to standard treatments. Significant neurological impairment persists throughout their lives. While the prognosis for attenuated forms of NKH can be variable, individuals still experience developmental delays and may require extensive, lifelong supportive care. Ongoing medical and therapeutic interventions are necessary to manage the complex needs of this condition.