What is Non Ketotic Hyperglycinemia?
Nonketotic Hyperglycinemia (NKH), also known as glycine encephalopathy, is a rare, inherited metabolic disorder that affects the brain and central nervous system. It is caused by a disruption in the body’s ability to properly break down glycine, an amino acid that plays an important role in normal brain function.
When glycine builds up to toxic levels, it interferes with normal neurological activity, leading to severe and often lifelong complications.
How NKH Affects the Body
Glycine is essential for healthy brain signaling, but in individuals with NKH, glycine accumulates in the brain and spinal fluid. This excess glycine overstimulates certain receptors in the brain, disrupting normal neurological development and function.
As a result, individuals with NKH may experience:
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Severe and difficult-to-control seizures
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Developmental delays
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Low muscle tone or abnormal movement patterns
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Feeding and swallowing difficulties
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Breathing challenges
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Impaired cognitive and motor function
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The severity and presentation of NKH can vary, but it is always a serious, complex condition that requires specialized, ongoing care.
Types of NKH
Nonketotic Hyperglycinemia exists on a spectrum, with symptoms and outcomes that can vary widely between individuals. The most common classifications are based on severity and genetic cause.
GLDC and AMT
NKH is caused by changes in genes responsible for the glycine cleavage system, which normally helps regulate glycine levels in the body. The two most common genes involved are GLDC and AMT.
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GLDC-related NKH is the most common form and accounts for the majority of NKH cases.
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AMT-related NKH is less common but can result in similarly severe or attenuated presentations.
Both genetic forms can lead to either classic severe or classic attenuated NKH, and genetic testing is essential for accurate diagnosis and care planning.
Classic Severe
Classic severe NKH typically presents in the newborn period, often within the first days of life. Infants may experience profound neurological symptoms, including severe seizures, difficulty breathing, low muscle tone, and impaired responsiveness.
This form of NKH is associated with significant developmental challenges and requires intensive, lifelong medical care. Seizures are often difficult to control, and affected individuals may have complex medical needs.
Classic Attenuated
Classic attenuated NKH presents with similar features but with reduced severity. Symptoms may appear later in infancy or early childhood and can include developmental delays, seizures, movement disorders, and learning challenges.
Individuals with attenuated NKH may achieve developmental milestones to varying degrees, though ongoing medical care and therapeutic support are typically required. Outcomes can differ widely from person to person.
In addition to the classic severe and classic attenuated forms, there are several less common and atypical presentations of Nonketotic Hyperglycinemia. These include transient neonatal hyperglycinemia, in which symptoms may appear shortly after birth but improve over time as glycine levels decrease, as well as atypical or late-onset forms that can emerge later in infancy, childhood, or adolescence with variable neurological, developmental, or behavioral features. Rare genetic variants involving other components of the glycine cleavage system have also been identified, though these forms are not well understood and remain an active area of research. The wide variability across these presentations highlights the complexity of NKH and reinforces the need for continued research and individualized care.
Current Treatment Options
There is currently no cure for Nonketotic Hyperglycinemia. Treatment focuses on managing symptoms and reducing the effects of elevated glycine levels in the brain. This may include medications intended to lower glycine concentrations, drugs that target overactive neurotransmitter receptors, and anti-seizure medications to help control epilepsy, which is often severe and difficult to manage. Supportive care is a critical component of treatment and may involve feeding support, respiratory care, physical and occupational therapy, and coordinated management by multiple medical specialists. Treatment plans are highly individualized, and responses can vary significantly between patients.
Research Efforts and Progress
Research into NKH is ongoing but limited by the rarity of the condition. Current research efforts focus on understanding the underlying disease mechanisms, improving diagnostic accuracy, refining symptom management strategies, and exploring potential new therapies. Because NKH affects fundamental neurological pathways, research is complex and often slow-moving. Much of the progress in this field depends on targeted funding, collaboration between researchers, and nonprofit-led initiatives that help bridge gaps not covered by traditional research funding sources.
Why Continued Research Is Critical
NKH remains underdiagnosed, underfunded, and poorly understood compared to more common neurological disorders. Existing treatments address symptoms but do not stop disease progression or reverse neurological damage. Continued research is essential to develop more effective therapies, identify potential disease-modifying approaches, and improve quality of life for individuals living with NKH. Advancing this work requires sustained investment, advocacy, and collaboration across the medical and research communities.