Background for doctors

What is L-serine?

L-Serine is classified as a nutritionally non-essential amino acid. While the main source of essential amino acids is from the diet, non-essential amino acids are normally synthesize by humans and other mammals from common intermediates. As shown below, L-serine is biosynthesized from a glycolytic intermediate, 3-phosphoglycerate (3-PG), in a three-step process involving the enzymes: 3-phosphoglycerate dehydrogenase (3-PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). 

L-Serine can also be derived in a reversible reaction from glycine; through degradation of protein and phospholipids; and through dietary intake. The primary pathway maintaining adequate serine concentrations is likely to depend on tissue type and stage of development (de Koning et al., 2003).


What is the role of L-serine?

L-Serine plays a role in cell growth and development (cellular proliferation). The conversion of L-serine to glycine by serine hydroxymethyltransferase results in the formation of the one-carbon units necessary for the synthesis of the purine bases, adenine and guanine. These bases when linked to the phosphate ester of pentose sugars are essential components of DNA and RNA and the end products of energy producing metabolic pathways, ATP and GTP. In addition, L-serine conversion to glycine via this same enzyme provides the one-carbon units necessary for production of the pyrimidine nucleotide, deoxythymidine monophosphate, also an essential component of DNA

L-Serine is a precursor for the neurotransmitters glycine and D-serine, and indirectly through L-cysteine, for the neurotransmitter taurine.

  • As described above, glycine can be synthesized from L-serine and is an inhibitory neurotransmitter.
  • Glycine acts alone by binding to the glycine receptor on the post-synaptic membrane or together with glutamate as a co-agonist.
  • L-Serine can also be converted to D-serine through a serine racemase. D-serine is an endogenous agonist of the NMDA receptor. 
  • L-Cysteine, which can be formed from L-serine through the trans-sulfuration pathway, is the precursor for proteins, glutathione, taurine, coenzyme A and inorganic sulfate.
  • Taurine is an inhibitory neurotransmitter and is likely to play a role in pre- and post-natal development of the central nervous system.

L-Serine derived phospholipids play a central role in the production of myelin and act as lipid messenger molecules. 

  • The condensation of serine with palmitoyl-CoA is the first step in the synthesis of sphingosine. Sphingosine serves as the core of sphingolipids, which include the sphingomyelins (primarily in brain and other nervous tissue) and glycosphingolipids. Sphingolipids are abundant in the myelin sheath and are present in all membranes. 
  • Phosphatidylserine, which is derived from L-serine, is an important messenger for apoptosis. Apoptosis, or programmed cell death, plays a critical role in the normal development of the nervous system. 

For a comprehensive and recent review of the role of serine in disease and development please see de Koning et al, 2003.


What is L-serine deficiency?

L-Serine deficiency is a rare, inherited, metabolic disorder of L-serine biosynthesis. The majority of the cases reported in the literature so far show a decrease in 3-phosphoglycerate dehydrogenase (3-PGDH) activity resulting in low fasting serum and CSF L-serine levels. Children with L-serine deficiency present with congenital microcephaly, then go on to develop severe psychomotor retardation and intractable seizures. 

Two mutations have been identified in the gene encoding human 3-PGDH located on chromosome one (1p12 or 1q12). These mutations result in a substitution of valine for methionine at position 490 (V490M) of the enzyme in most of the cases reported, or a V425M substitution in one reported case (Klomp et al, 2000, Pind et al, 2002) .
A single case of 3-phosphoserine phosphatase (3-PSP) deficiency has also been reported resulting in low CSF L-serine levels. No molecular data were reported on this patient.


How does a person develop L-serine deficiency?

The predominant type of L-serine deficiency affects the function of 3-phosphoglycerate dehydrogenase (3-PGDH) through a mutation in the gene encoding this enzyme (Klomp et al, 2000, Pind et al, 2002). 3-PGDH deficiency is an autosomal recessive disorder. This means that children with 3-PGDH deficiency have inherited two copies of the affected gene (homozygous), one from each of their parents. People who are heterozygous for the gene (have one affected gene) show no traits associated with 3-PGDH deficiency. 


What is the prevalence of L-serine deficiency?

The prevalence of L-serine deficiency is currently unknown. Since the first case was identified in 1996 (Jaeken et al., 1996) only a handful of children with the disorder have been reported in the literature. Potentially many more cases exist but have yet to be identified. In one report, 400 hundred individuals of Jewish decent were screened and one was found to be heterozygous for the predominant 3-PGDH gene mutation compared to no cases identified in a group of 400 randomly selected non-Jewish individuals. From this data, the frequency of heterozygosity in this population is as much as 1 in 70 individuals or as little as 1 in 16,000 (Pind et al., 2002). More research is needed in this area. 


How is L-serine deficiency diagnosed?

Nearly all children born with L-serine deficiency presented with congenital microcephaly. In addition, hallmark signs of L-serine deficiency include severe psychomotor retardation, seizures, spastic quadriplegia and in some patients, nystagmus, megaloblastic anemia, cataract and hypogonadism. 

In children born with L-serine deficiency, a low level of serine in the cerebral spinal fluid (CSF) is the most reliable indicator for both 3-phosphoglycerate dehydrogenase (3-PGDH) and 3-phosphoserine phosphatase (3-PSP) deficiency. In some, but not all cases, CSF glycine levels were below normal. In the fasted state, plasma serine and to a lesser extent, plasma glycine levels are below normal levels. Urine amino acid levels are normal. (de Koning and Klomp. 2004)

Confirmation of 3-phosphoglycerate dehydrogenase deficiency (3-PGDH) can be made by measuring low levels of enzyme activity in cultured skin fibroblasts. (Jaeken et al, 1996)


How is L-serine deficiency treated?

As reported in the literature, children diagnosed with L-serine deficiency have been given L-serine orally. L-Serine is absorbed readily and crosses the blood-brain barrier via a neutral amino acid carrier. Since L-serine has low affinity for this carrier and it has to compete with other neutral amino acids for transport, high doses of L-serine are necessary to achieve normal CSF levels. In some cases, the children were treated with glycine in addition to their L-serine dose. A recent review by de Koning and Klomp (2004) contains specific dosing recommendations and reported side effects of treatment. 

Most cases of L-serine deficiency have been diagnosed in children between the ages of 1 and 7 years of age (de Koning et al., 2002). In two cases, L-serine treatment was started early. In a case study published in the Lancet by de Koning et al (2004), the authors report identification of 3-PGDH deficiency in a fetus determined through prenatal testing of the chorionic villi. Treatment of the mother with high doses of L-serine was started at 26 weeks gestation when a gradual reduction in head circumference was noted. At birth the girl’s head circumference was normal and at 4 years of age her growth, psychomotor development, and neurological status are all normal. 

In a second case report by Pineda et al 2000, a 7 month old girl diagnosed with 3-PGDH deficiency was treated with oral L-serine. At 3 years of treatment the girl was “seizure free” and showed some “catch up” of head circumference and psychomotor development. “…after 3 years of treatment, she has just started to walk, speaks single words and has a mild spastic diplegia.” (de Koning et al., 2002)

In older children, oral supplementation with L-serine is effective in the treatment of seizures even in some patients with persistent medically intractable seizures although not all patients remained seizure free upon long-term follow-up. White matter volume as measured by MRI was increased even in the older children.


References:

de Koning TJ, Duran M, Van Maldergem L, Pineda M, Dorland L, Gooskens R, Jaeken J, Poll-The BT. Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids. J Inherit Metab Dis. 2002 May;25(2):119-25.

de Koning TJ, Snell K, Duran M, Berger R, Poll-The BT, Surtees R. L-serine in disease and development. Biochem J. 2003 May 1;371(Pt 3):653-61.    

de Koning TJ, Klomp LW.  Serine-deficiency syndromes. Curr Opin Neurol. 2004 Apr;17(2):197-204.

de Koning TJ, Klomp LW, van Oppen AC, Beemer FA, Dorland L, van den Berg I, Berger R. Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet. 2004 Dec 18;364(9452):2221-2.

Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis. Arch Dis Child. 1996 Jun;74(6):542-5.

Klomp LW, de Koning TJ, Malingre HE, van Beurden EA, Brink M, Opdam FL, 
Duran M, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van den Berg IE, 
Berger R. Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency—a neurometabolic disorder associated with reduced L-serine biosynthesis. Am J Hum Genet. 2000 Dec;67(6):1389-99. Epub 2000 Oct 27.  


Pind S, Slominski E, Mauthe J, Pearlman K, Swoboda KJ, Wilkins JA, Sauder P, Natowicz MR.  V490M, a common mutation in 3-phosphoglycerate dehydrogenase deficiency, causes enzyme deficiency by decreasing the yield of mature enzyme. J Biol Chem. 2002 Mar 1;277(9):7136-43. Epub 2001 Dec 20.

Pineda M, Vilaseca MA, Artuch R, Santos S, Garcia Gonzalez MM, Aracil A, Van Schaftingen E, Jaeken J. 3-phosphoglycerate dehydrogenase deficiency in a patient with West syndrome. Dev Med Child Neurol. 2000 Sep;42(9):629-33.