Which are the causes of Sepiapterin Reductase Deficiency?

Sepiapterin Reductase Deficiency (SRD) is a rare genetic disorder that affects the production of neurotransmitters in the brain. It is caused by mutations in the SPR gene, which provides instructions for making the enzyme sepiapterin reductase. This enzyme is essential for the synthesis of tetrahydrobiopterin (BH4), a cofactor required for the production of several important neurotransmitters, including dopamine, serotonin, and norepinephrine.

1. Genetic Mutations: The primary cause of SRD is mutations in the SPR gene. These mutations can disrupt the normal function of sepiapterin reductase, leading to a deficiency of BH4. The mutations can be inherited from one or both parents or occur spontaneously during early development.

2. Impaired Tetrahydrobiopterin Synthesis: The mutations in the SPR gene result in reduced or absent sepiapterin reductase activity. This leads to impaired synthesis of BH4, which is crucial for the conversion of phenylalanine to tyrosine and the production of neurotransmitters. Without sufficient BH4, the synthesis of dopamine, serotonin, and norepinephrine is disrupted, leading to neurological symptoms.

3. Neurotransmitter Imbalance: The deficiency of BH4 in SRD disrupts the balance of neurotransmitters in the brain. Dopamine, serotonin, and norepinephrine play essential roles in regulating mood, behavior, and cognitive function. When their levels are imbalanced, it can result in a wide range of neurological symptoms, including developmental delay, intellectual disability, movement disorders, and psychiatric symptoms.

4. Impact on Neurological Development: The reduced availability of BH4 affects the development and function of the nervous system. Neurotransmitters are crucial for proper brain development and communication between neurons. In SRD, the impaired synthesis of neurotransmitters can lead to abnormal brain development and functioning, contributing to the characteristic symptoms of the disorder.

5. Inheritance Pattern: SRD can be inherited in an autosomal recessive manner, meaning that both copies of the SPR gene must be mutated for the disorder to manifest. If an individual inherits one mutated copy of the gene from each parent, they have a 25% chance of developing SRD. However, individuals with only one mutated copy of the gene are carriers and typically do not show symptoms.

In conclusion, Sepiapterin Reductase Deficiency is primarily caused by genetic mutations in the SPR gene, leading to impaired synthesis of BH4 and an imbalance of neurotransmitters in the brain. This disruption in neurotransmitter production and function affects neurological development and can result in a range of symptoms associated with SRD.