Hyperammonemia Neurological Manifestations

Pathophysiology and Severity

The American College of Physicians and other medical societies suggest that ammonia crosses the blood-brain barrier and is metabolized to glutamine by astrocytes, leading to increased intracellular osmolality, cerebral edema, and release of inflammatory cytokines 1
High levels of extracellular potassium and glutamate released by astrocytes cause neuronal damage, according to the National Institute of Neurological Disorders and Stroke 1
Elevated glutamine levels contribute to both hepatic encephalopathy and ammonia-related neurotoxicity, as stated by the European Association for the Study of the Liver 1
Normal blood ammonia concentrations are ≤35 μmol/L (<60 μg/dL), as defined by the American Association for Clinical Chemistry 1
Hyperammonemia is defined as >100 μmol/L (170 μg/dL) in neonates or ≥50 μmol/L (85 μg/dL) in term infants, children, and adults, according to the Society for the Study of Inborn Errors of Metabolism 1
Levels >200 μmol/L (341 μg/dL) are associated with poor neurological outcomes, as reported by the Child Neurology Society 1

Tremors are a neurological manifestation of hyperammonemia, as documented by the American Academy of Neurology 2, 3
Dysarthria (speech difficulty) is documented as a symptom, which can manifest as expressive aphasia, according to the American Speech-Language-Hearing Association 2, 3
Other neurological symptoms include confusion, lethargy, and dizziness, as listed by the National Institute of Mental Health 3
Hypotonia, migraine-like headache, ataxia (impaired coordination), learning disabilities, neurodevelopmental delay, seizures, and hemiplegia are also associated with hyperammonemia, as reported by the American Academy of Pediatrics 3
Coma can occur in severe cases of hyperammonemia, as stated by the Neurocritical Care Society 3

Primary causes of hyperammonemia include urea cycle disorders (UCDs) due to congenital enzyme deficiencies, as described by the Society for Inherited Metabolic Disorders 1
Secondary causes include organic acidemias (methylmalonic acidemia, propionic acidemia), drug-induced (particularly valproic acid), and liver disease or acute kidney injury, as listed by the American Society of Nephrology 1

Ammonia accumulation drives increased conversion of glutamate to glutamine by astrocytes, depleting glutamate stores while simultaneously causing toxic accumulation of both ammonia and glutamine, according to the American College of Medical Genetics and Genomics 4
The enzyme glutamine synthase converts ammonia to glutamine from glutamate, primarily in astrocytes when the urea cycle fails to detoxify ammonia normally, as stated by the National Institute of Diabetes and Digestive and Kidney Diseases 4
The enzyme glutamate dehydrogenase (GDH) converts glutamate to α-ketoglutarate, releasing ammonia that would normally enter the urea cycle, as reported by the European Society of Human Genetics 4