What are the other Names for this Condition? (Also known as/Synonyms)

• NLS (Neu Laxova Syndrome)

What is Neu Laxova Syndrome? (Definition/Background Information)

• Neu Laxova Syndrome (NLS) is a genetic disorder affecting many parts of the body. Babies born with NLS usually grow poorly during the pregnancy (intrauterine growth restriction)
• At birth, they will 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, and 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 and 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

(Source: Neu Laxova Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Who gets Neu Laxova Syndrome? (Age and Sex Distribution)

• Neu Laxova Syndrome is a rare congenital disorder. The presentation of symptoms occur at birth
• Both males and females may be affected
• Worldwide, individuals of all racial and ethnic groups may be affected

What are the Risk Factors for Neu Laxova Syndrome? (Predisposing Factors)

• A positive family history is an important risk factor, since Neu Laxova Syndrome may be inherited

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Neu Laxova Syndrome? (Etiology)

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 acid L-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, brain malformations, small head,, 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

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

• 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

(Source: Neu Laxova Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Neu Laxova Syndrome?

The signs and symptoms of Neu Laxova Syndrome may include:

• Abblepharon
• Absent eyelashes
• Agenesis of corpus callosum
• Bifid uterus
• Calcaneovalgus deformity
• Camptodactyly
• Cataract
• Cerebellar hypoplasia
• Choroid plexus cyst
• Cleft upper lip
• Clinodactyly
• Cryptorchidism
• Dandy-Walker malformation
• Decreased fetal movement
• Finger syndactyly
• Generalized edema
• Hydranencephaly
• Hypertelorism
• Intrauterine growth retardation
• Joint contracture of the hand
• Lissencephaly
• Macrotia
• Microcephaly
• Micrognathia
• Micromelia
• Microphthalmia
• Patent ductus arteriosus
• Patent foramen ovale
• Polyhydramnios
• Proptosis
• Pterygium
• Pulmonary hypoplasia
• Radial deviation of finger
• Renal agenesis
• Rocker bottom foot
• Short neck
• Short umbilical cord
• Sloping forehead
• Small placenta
• Spina bifida
• Stillbirth
• Thick lower lip vermilion
• Toe syndactyly
• Transposition of the great arteries
• Ventricular septal defect
• Yellow subcutaneous tissue covered by thin, scaly skin

(Source: Neu Laxova Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

How is Neu Laxova Syndrome Diagnosed?

Neu Laxova Syndrome is diagnosed on the basis of the following information:

• Complete physical examination
• Thorough medical history evaluation
• Assessment of signs and symptoms
• Laboratory tests
• Imaging studies
• Biopsy studies, if necessary

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Neu Laxova Syndrome?

The complications of Neu Laxova Syndrome may include:

• Severe physical deformities
• Neurological abnormalities

Complications may occur with or without treatment, and in some cases, due to treatment also.

How is Neu Laxova Syndrome Treated?

There is no cure for Neu Laxova Syndrome, since it is a genetic condition. The treatment is usually given to manage the signs and symptoms and any complications that develops.

How can Neu Laxova Syndrome be Prevented?

Currently, Neu Laxova Syndrome may not be preventable, since it is a genetic disorder.

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

Regular medical screening at periodic intervals with tests and physical examinations are recommended.

What is the Prognosis of Neu Laxova Syndrome? (Outcomes/Resolutions)

• Most cases of Neu Laxova Syndrome have a poor prognosis. Many affected newborns either are stillborn, or die soon after birth or during the first weeks of life
• However, Neu Laxova Syndrome can be considered as part of the “serine biosynthesis defects” which includes Neu Laxova and other conditions that are less severe and may have a better outcome

(Source: Neu Laxova Syndrome; Genetic and Rare Diseases Information Center (GARD) of National Center for Advancing Translational Sciences (NCATS), USA.)

Additional and Relevant Useful Information for Neu Laxova Syndrome:

The following DoveMed website link is a useful resource for additional information:

https://www.dovemed.com/diseases-conditions/rare-disorders/