Neu Laxova syndrome (NLS) is a genetic disorder affecting many parts of the body. Babies born with NLS usually grow poorly during pregnancy (intrauterine growth restriction). At birth, they may be small (low birth weight and short in length) and their facial features are usually different and distinct. The babies may have a small head (microcephaly), sloping forehead, and widely spaced eyes (hypertelorism). Babies with NLS may also have extra fluid (edema) in their hands and feet, brain abnormalities, and rigid, stiff muscles. Other birth defects may affect the baby's arms, legs, skin, genitals, kidneys, and heart. Not every baby with NLS will have every sign or symptom of NLS.

Neu Laxova syndrome (NLS) is caused by changes or mutations in one of three different genes, PHGDH, PSAT1, PSPH. The mutations cause too little L-serine (an amino acid) to be made. There must be a mutation in both copies of one of these genes, which means NLS is inherited in an autosomal recessive manner. NLS can be diagnosed both prenatally by an ultrasound or after birth. The diagnosis is suspected by signs and symptoms, but may be confirmed by genetic testing (prenatally by chorionic villi sampling (CVS) or amniocentesis; after birth by genetic blood test).

There is no cure or treatment for NLS at this time, but L-serine supplementation may prove to be an effective treatment in the future if the NLS is found early during a pregnancy.

Neu Laxova syndrome (NLS) can be caused by mutations in three different genes, PHGDH, PSAT1, and PSPH. The syndrome is currently classified in type 1 and type 2 when caused by mutations in the genes PHGDH and PSAT1, respectively. The mutations in PSPH causing NLS have not yet been classified as a different type.

These 3 genes, PHGDH, PSAT1 and PSPH, are the instructions (code) for making the enzymes needed to make the amino acidL-serine. L-serine has important functions in the body. Since L-serine is an amino acid, it is one of the building blocks used to make many different proteins our body needs. It is also used to make other important compounds needed throughout our body and helps the brain develop normally.

Neu Laxova syndrome (NLS) can be considered as part of a group of diseases known as “serine biosynthesis defects”. Serine biosynthesis defects result from different mutations in the PGDH, PSAT, or PSPH genes that lead to serine deficiency throughout the whole body (systemic). The serine biosynthesis diseases include:

• Neu-Laxova syndrome - the most severe form
• Infantile serine biosynthesis deficiency - intermediate form with growth deficiency, small head, brain malformations, severe developmental delay, and severe neurological problems including seizures and stiff and rigid muscles (affects ability to move and develop speech).
• Childhood serine biosynthesis disease - the mildest form with normal growth and brain development, milder developmental delay, and seizures.

The difference between NLS and the other related syndromes is the amount of working protein that is made. In the case of NLS, the mutations in the genes do not allow very much working protein to be made at all. In other words, because of the mutation, one of the enzymes needed to make L-serine is almost completely inactive, so very little L-serine can be made in the body.

Understanding that the symptoms of these diseases are caused by having too little L-serine is very important for future treatment, because giving L-serine before the neurological damage happens may be prove to be an effective therapy.

Normal Function

The PHGDH gene provides instructions for making the parts (subunits) that make up the phosphoglycerate dehydrogenase enzyme. Four PHGDH subunits combine to form the enzyme. This enzyme is involved in the production (synthesis) of the protein building block (amino acid) serine. Specifically, the enzyme converts a substance called 3-phosphoglycerate to 3-phosphohydroxypyruvate in the first step in serine production. Serine is necessary for the development and function of the brain and spinal cord (central nervous system). Serine is a part of chemical messengers called neurotransmitters that transmit signals in the nervous system. Proteins that form cell membranes and the fatty layer of insulation (myelin) that surrounds many nerves also contain serine.

Serine can be obtained from the diet, but brain cells must produce their own serine because dietary serine cannot cross the protective barrier that allows only certain substances to pass between blood vessels and the brain (the blood-brain barrier).

Health Conditions Related to Genetic Changes

Phosphoglycerate dehydrogenase deficiency

At least eight mutations in the PHGDH gene have been found to cause phosphoglycerate dehydrogenase deficiency. This condition is characterized by an unusually small head size (microcephaly), severe developmental delay, and recurrent seizures that are difficult to treat (intractable epilepsy). Most of the mutations that cause this condition change single amino acids in the phosphoglycerate dehydrogenase enzyme. The mutations result in the production of an enzyme with decreased function. As a result, less 3-phosphoglycerate is converted into 3-phosphohydroxypyruvate than normal and serine production is stalled at the first step. The lack of serine likely prevents the production of proteins and neurotransmitters in the brain and impairs the formation of normal cells and myelin. These disruptions in normal brain development lead to microcephaly, severe developmental delay, and the other signs and symptoms of phosphoglycerate dehydrogenase deficiency.

Other Names for This Gene

• 3-PGDH
• 3-phosphoglycerate dehydrogenase
• 3PGDH
• D-3-phosphoglycerate dehydrogenase
• epididymis secretory protein Li 113
• HEL-S-113
• PDG
• PGAD
• PGD
• PGDH
• SERA

Genomic Location

This gene encodes a member of the class-V pyridoxal-phosphate-dependent aminotransferase family. The encoded protein is a phosphoserine aminotransferase and decreased expression may be associated with schizophrenia. Mutations in this gene are also associated with phosphoserine aminotransferase deficiency. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene have been defined on chromosomes 1, 3, and 8. [provided by RefSeq, Jul 2013]

The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome. [provided by RefSeq, Jul 2008]

L-Serine, an Endogenous Amino Acid, Is a Potential Neuroprotective Agent for Neurological Disease and Injury

Central nervous system (CNS) lesions are major causes of human death and disability worldwide, and they cause different extents of motor and sensory dysfunction in patients. Thus, it is crucial to develop new effective neuroprotective drugs and approaches targeted to the heterogeneous nature of CNS injury and disease. L-serine is an indispensable neurotrophic factor and a precursor for neurotransmitters. Although L-serine is a native amino acid supplement, its metabolic products have been shown to be essential not only for cell proliferation but also for neuronal development and specific functions in the brain. Growing evidence has suggested that L-serine regulates the release of several cytokines in the brain under some neuropathological conditions to recover cognitive function, improve cerebral blood flow, inhibit inflammation, promote remyelination and exert other neuroprotective effects on neurological injury. L-serine has also been used to treat epilepsy, schizophrenia, psychosis, and Alzheimer’s Disease as well as other neurological diseases. Furthermore, the dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine generally support the safety of L-serine. The high significance of this review lies in its emphasis on the therapeutic potential of using L-serine as a general treatment for numerous CNS diseases and injuries. Because L-serine performs a broad spectrum of functions, it may be clinically used as an effective neuroprotective agent.

Neu-Laxova syndrome (NLS) is inherited in an autosomal recessive manner. This means a a baby must have a mutation in both copies of one of the three gene which can cause NLS. In other words, a baby with NLS will have a mutation in both copies of the PHGDH, PSAT1 or PSPH gene.

Babies with NLS inherit one mutated copy of the gene from each parent, who is referred to as a carrier. Carriers of an autosomal recessive condition, like NLS, usually do not have any signs or symptoms (they are unaffected). When 2 carriers of an autosomal recessive condition have children, each child has a:

• 25% chance to be affected
• 50% chance to be an unaffected carrier like each parent
• 25% chance to be unaffected and not a carrier

The brother or sister of a baby with NLS will have a 2/3 (66%) chance of being a carrier of NLS and a 1/3 chance of not being a carrier. The only way a carrier of NLS has a risk of having a child with NLS is if their partner carriers a mutation in the same NLS related gene. However there are other related forms of L-serine biosynthesis defects which are also caused by mutations in the same genes, so talking to a genetic counselor or genetic specialist before becoming pregnant is important.