Which are the causes of Nonketotic Hyperglycinemia?

Nonketotic Hyperglycinemia (NKH) is a rare genetic disorder that affects the breakdown of the amino acid glycine in the body. It is caused by mutations in the genes responsible for the enzymes involved in glycine metabolism. This condition leads to an accumulation of glycine in the brain and other tissues, resulting in severe neurological symptoms.

Genetic mutations: The primary cause of NKH is mutations in the genes GLDC, AMT, and GCSH, which encode the enzymes glycine decarboxylase, aminomethyltransferase, and glycine cleavage system H protein, respectively. These mutations disrupt the normal function of these enzymes, leading to impaired glycine metabolism and subsequent glycine accumulation.

Glycine cleavage system dysfunction: The glycine cleavage system is responsible for breaking down glycine into smaller molecules, which can be further metabolized for energy production. In NKH, the dysfunction of this system impairs the conversion of glycine, resulting in its accumulation in the body.

Autosomal recessive inheritance: NKH is inherited in an autosomal recessive manner, meaning that an affected individual must inherit two copies of the mutated gene (one from each parent) to develop the disorder. If both parents are carriers of the mutated gene, each child has a 25% chance of inheriting two copies and developing NKH.

Neurological damage: The accumulation of glycine in the brain leads to severe neurological damage, which is the hallmark of NKH. Excessive glycine inhibits the function of neurotransmitters, such as gamma-aminobutyric acid (GABA), resulting in abnormal brain development and function.

Neonatal onset: NKH typically presents in the neonatal period, with symptoms appearing shortly after birth or within the first few months of life. Infants with NKH may exhibit poor feeding, lethargy, seizures, hypotonia (low muscle tone), and developmental delays.

Metabolic crisis: In some cases, NKH can be triggered by metabolic stressors, such as infections, fever, or fasting. These stressors can exacerbate the symptoms and lead to a metabolic crisis, characterized by a sudden worsening of neurological symptoms and metabolic imbalances.

Diagnosis: The diagnosis of NKH is based on clinical symptoms, elevated glycine levels in the blood and cerebrospinal fluid, and genetic testing to identify mutations in the associated genes. Early diagnosis is crucial for implementing appropriate treatment strategies.

Treatment: Unfortunately, there is currently no cure for NKH. Treatment mainly focuses on managing symptoms and providing supportive care. This may include medications to reduce glycine levels, dietary interventions, physical and occupational therapy, and early intervention programs to support developmental delays.

Research and future prospects: Ongoing research aims to better understand the underlying mechanisms of NKH and develop potential therapeutic approaches. Gene therapy and enzyme replacement therapy are among the emerging strategies being explored to address the genetic defects and restore normal glycine metabolism.