Nonketotic hyperglycinemia (NKH) is a rare genetic disorder caused by a defect in the enzyme system that processes glycine. This leads to glycine accumulation in the body’s tissues and fluids, especially the brain. NKH often carries a challenging prognosis, leading families to seek information about long-term survival. This article explores living with NKH, highlighting cases that offer a broader perspective on potential outcomes.
Understanding Nonketotic Hyperglycinemia
Nonketotic hyperglycinemia stems from an inherited defect in the glycine cleavage system (GCS). This metabolic error results in high levels of glycine, which acts as a neurotransmitter in the brain and spinal cord, disrupting normal neurological function. The disorder is inherited in an autosomal recessive pattern, meaning an individual must inherit two copies of a mutated gene, one from each parent, to develop the condition.
The symptoms of NKH vary, but the most common presentation is the severe, or classic, form, typically appearing shortly after birth. Affected newborns often exhibit extreme sleepiness, weak muscle tone, and breathing difficulties requiring ventilator support. If these infants survive, they commonly experience profound intellectual disability, abnormal muscle stiffness, feeding challenges, and seizures. Most children with severe NKH do not achieve expected developmental milestones such as sitting up or grasping objects.
A distinction exists between the severe/classic and attenuated/variant forms of NKH. Individuals with attenuated NKH have some residual enzyme function, allowing for partial glycine processing. This residual activity leads to milder symptoms and a different developmental trajectory, with onset potentially occurring later in infancy or childhood.
Long-Term Survival and Notable Cases
While NKH often presents with a difficult prognosis, particularly for the severe form, documented cases exist of individuals living well beyond early childhood. Reports highlight individuals who have reached their teens, twenties, and even later adulthood. These long-term survivors typically have attenuated forms of the condition, where some glycine processing capacity remains.
One publicly reported case describes a 53-year-old male with attenuated NKH, diagnosed in his preschool years along with his younger sister. This individual experienced developmental and physical delays but maintained a relatively stable health course for decades. Life for these long-term survivors can involve varying degrees of developmental progress, with many learning to walk and interact with others, sometimes utilizing sign language or other communication methods.
Despite ongoing challenges such as delayed development, spasticity, or hyperactivity, these individuals demonstrate a spectrum of abilities and achievements. Living into adulthood offers hope and illustrates possibilities beyond the severe initial prognosis associated with NKH. These cases underscore the wide variability in outcomes depending on specific genetic mutations and resulting residual enzyme activity.
Factors Influencing Prognosis
The type of NKH an individual has is the largest factor determining their long-term outcome. Individuals with attenuated forms of NKH have a more favorable prognosis compared to those with the severe form. This difference is directly related to the residual function of the glycine cleavage enzyme system; even a small amount of residual enzyme activity (e.g., 5-18%) can lead to a milder disease course, dictated by specific genetic mutations.
Certain genetic mutations, like missense mutations, are more common in attenuated NKH patients, allowing for some enzyme activity. Mutations resulting in a complete lack of enzyme activity are more common in severe cases. Early diagnosis and treatment also play a role in managing the condition’s severity and influencing developmental outcomes, particularly for those with attenuated forms. Biochemical markers can also provide insights into the likely severity of the disease.
Management and Treatment Strategies
Current management strategies for NKH focus on reducing glycine accumulation and mitigating its effects on the brain, rather than offering a cure. Two main medications are used. Sodium benzoate helps remove excess glycine from the body by binding to it, allowing the combined molecule to be excreted. This lowers glycine levels in the blood and cerebrospinal fluid, which can improve alertness and aid in seizure management.
Another medication, dextromethorphan, acts as an antagonist at N-methyl-D-aspartate (NMDA) receptors in the brain. Glycine overstimulates these receptors, and dextromethorphan can help control seizures and improve neurological function. A low-glycine diet may also be recommended to reduce the body’s glycine load. While these interventions can reduce symptoms and improve quality of life, particularly when started early in individuals with attenuated NKH, they do not correct the underlying genetic defect.