Hyperglycinemia is a rare, inherited metabolic disorder characterized by abnormally high levels of the amino acid glycine in the body. This condition typically appears shortly after birth, leading to serious neurological problems. Excess glycine accumulates in tissues and organs, especially the brain, disrupting its normal function.
Underlying Genetic Causes
Hyperglycinemia is an autosomal recessive disorder. A child must inherit two mutated gene copies, one from each parent, to develop the condition. Parents carrying one mutated gene copy are typically asymptomatic carriers. If both parents are carriers, there is a 25% chance with each pregnancy that their child will be affected.
The condition arises from a defect in the glycine cleavage system (GCS), the body’s primary mechanism for breaking down excess glycine. This multi-enzyme system is composed of four protein subunits; mutations in their encoding genes impair its function. The GLDC gene is responsible for 70-75% of cases, while AMT gene mutations account for about 20%. GCSH gene mutations are less common, contributing to less than 1% of cases.
Signs and Symptoms
The classic neonatal form is the most common and severe, with symptoms appearing within the first few days of life. Affected infants often show profound lethargy, progressing to coma. They also experience hypotonia, a significant decrease in muscle tone, making them appear “floppy”.
Seizures are frequent and challenging to control, often accompanied by myoclonic jerks—sudden muscle twitches. Common issues like persistent hiccups and severe breathing difficulties (apnea) are also common and may require ventilator support. Many infants with the severe form do not reach developmental milestones beyond those of a typical six-week-old.
Atypical or late-onset forms are less common, presenting later in infancy or adulthood. These forms exhibit a wider range of symptoms, including developmental delays, behavioral issues like irritability or aggressiveness, and milder, more manageable seizures. Some individuals with these forms might eventually learn to walk and interact, though their developmental progress varies widely.
Diagnostic Process
Diagnosis typically begins with blood and urine tests to screen for elevated glycine levels. While high glycine in these fluids is suggestive, it is not definitive, as other conditions can also cause this. The next step involves a lumbar puncture (spinal tap) to measure glycine concentrations in the cerebrospinal fluid (CSF).
The ratio of glycine in the CSF to glycine in the plasma is a key biochemical marker. A CSF-to-plasma glycine ratio greater than 0.08 generally indicates hyperglycinemia, distinguishing it from other metabolic disorders. For milder or atypical cases, this ratio may be lower but still abnormal.
A definitive diagnosis is confirmed through genetic testing, which identifies specific mutations in the GLDC, AMT, or GCSH genes responsible for the impaired glycine cleavage system. This molecular analysis helps to pinpoint the precise genetic cause, important for understanding disease severity and for genetic counseling. In some instances, enzyme activity assays on liver samples may also be performed.
Management and Treatment Approaches
There is currently no cure for hyperglycinemia, so management focuses on controlling glycine levels and alleviating symptoms. A primary treatment involves medications like sodium benzoate, which reduces glycine accumulation by binding to it in the blood, forming hippuric acid for excretion through urine.
While sodium benzoate can help normalize plasma glycine levels and may reduce seizure frequency and improve alertness, it often does not fully normalize glycine in the cerebrospinal fluid, especially in severe cases. Dextromethorphan is often used in combination with sodium benzoate. It inhibits NMDA receptors in the brain that are overstimulated by high glycine levels, which can help with seizure control and improve neurological function.
Dietary management also plays a role, involving a protein-restricted diet to limit glycine intake. This approach aims to reduce the overall glycine load on the body’s impaired cleavage system. Additionally, symptomatic therapies improve quality of life, including anti-epileptic drugs for seizures and supportive therapies like physical, occupational, and speech therapy to address developmental challenges.
Prognosis and Long-Term Outlook
The prognosis for individuals with hyperglycinemia varies considerably, correlating with the condition’s severity and specific form. For the classic neonatal form, the outlook is generally poor. Most affected infants experience profound developmental disabilities and often have a shortened lifespan, with many not surviving beyond the first year.
For atypical or milder forms, the prognosis is more varied, offering a wider range of outcomes. Some individuals may reach adulthood, though they typically still experience some degree of learning disability and neurological issues. Research efforts continue to explore more effective treatments and therapies, aiming to improve the long-term outlook for those living with this disorder.