Background for non-doctors

Overview of serine deficiency

Serine deficiency is a rare, inherited, metabolic disorder that interferes with normal growth and development, particularly in the central nervous system. Unlike similar neurodevelopmental disorders, serine deficiency can be treated. Treatment benefits all children identified with serine deficiency. Early diagnosis and treatment are the key elements for the greatest success.

What are the clinical signs and symptoms of serine deficiency?

Nearly all children with serine deficiency are born with an abnormally small head (called microcephaly) that is congenital (i.e.: present at birth). Other predominant characteristics include: spastic quadriplegia (the muscles are stiff and contract in an uncontrolled way in both the arms and legs), seizures (abnormal nerve conduction that results in a broad array of symptoms from odd sensations of smell and taste to abnormal muscle movement and loss of consciousness), and severe psychomotor retardation (slowed mental and physical activity).

How does a child develop serine deficiency?

Serine deficiency is inherited. Serine deficiency is a recessive disorder, which means that two copies of the affected gene (one from each parent) are necessary for the signs and symptoms of the disorder to be present. The parents have a 25% chance of having a child with serine deficiency. Both boys and girls have an equal chance of developing serine deficiency if the affected gene is present.

How is serine deficiency treated?

As reported in the literature, children diagnosed with serine deficiency have been given serine (and in some cases glycine) orally. The outcome of treatment with oral serine ranges from improvement of seizure control and well being in older children to normal psychomotor (mental and physical) development in a child who was diagnosed and treated prenatally (the mother was treated with oral serine during pregnancy). 

How is the diagnosis of serine deficiency confirmed?

Following clinical examination, confirmation of the diagnosis of serine deficiency can be made by measuring serine levels. Serine levels can be measured in the plasma (following a period of fasting) and in the cerebral spinal fluid (CSF). CSF levels are the most reliable as the levels of serine and glycine remain low independent of meal. 

In addition, the activity of the 3-PGDH enzyme can be measured in cultured skin fibroblasts. Skin samples (biopsies) are generally, but not exclusively, collected from the forearm and can be then cultured in the laboratory. The fibroblasts (or cells that are involved in wound healing) divide readily in culture and are useful for testing of metabolic and/or chromosomal disorders.

What is Serine?

Serine is an amino acid. Amino acids are the building blocks of proteins. In addition, some amino acids act as messengers between nerve cells or are used by the body to make other complex molecules. 

There are 20 different (alpha) amino acids and all of these are important for the normal function of our bodies. We get the amino acids we need through two sources: our bodies can make them from other molecules or we can get them from our diet. Amino acids that we have to get from our diets because our bodies can’t make them are called “essential” amino acids. All other amino acids are considered “non-essential” to the diet but are still important for normal body function. 

Serine is called a non-essential amino acid. Although we do get some serine from the diet, the major sources of serine are through metabolic pathways (the way we use food molecules for energy) in our organs and tissues. One significant source of serine in the brain is via a three-step process that begins with a common substance produced during the normal metabolism (or breakdown) of sugars and ends with serine. Each step in this process is facilitated or accelerated (catalyzed) by an enzyme. 

Serine is used in the body in several ways. First, serine plays a central role in the production of the “myelin sheath.” Myelin acts as insulation for nerve cells and speeds the conduction of nerve impulses. The parts of the brain and spinal cord that contain large amounts of myelin appear white and are called the “white matter” of the brain. Breakdown or absence of myelin interferes with nerve impulses. Second, serine is important in the growth and development of cells by acting as the starting material for the building blocks of our genetic material (DNA and RNA). Serine also acts as the starting material for the body’s production of nerve messengers (neurotransmitters) and lipid messenger molecules, which play an important role in the normal development of the nervous system.

Some specifics about the biology of serine deficiency

Children who have serine deficiency have low levels of serine in their bodies. This is caused by a defect in one of the enzymes in the three-step process described above. All but one of the children reported so far in the literature have a defect in the enzyme 3-phosphoglycerate dehydrogenase (3-PGDH). 

With few exceptions, enzymes are proteins and are therefore made up of a chain of amino acids that is folded into a 3-dimensional structure. The order of these amino acids is determined by the body’s genetic code or the DNA. In children with serine deficiency scientists have found a change in one amino acid in the 3-PGDH enzyme that results in a decrease in the activity of that enzyme. This decrease in activity slows down the production of serine that ultimately results in less serine in the body.