Spina bifida can be caused by uninherited genetic mutations | UCL News

Genetic mutations which occur naturally during the earliest stages of an embryo’s development can cause the severe birth defect spina bifida, finds a new experimental study in mice led by UCL scientists.

The study, published in Nature Communications, explains for the first time how a ‘mosaic mutation’ – a mutation which is not inherited from either parent (either via sperm or egg cell) but occurs randomly during cell divisions in the developing embryo – causes spina bifida.

Specifically the scientists, based at UCL Great Ormond Street Institute of Child Health, found that when a mutation in the gene Vangl2 (which contains information needed to create spinal cord tissue) was present in 16% of developing spinal cord cells of mouse embryos, this was sufficient to produce spina bifida.

Researchers say the findings add to scientists’ understanding of how and why mosaic mutations can affect and disrupt cell function, including those of neighbouring cells, helping cause birth defects.

For parents, the findings may help reduce the burden felt by those who believe their child inherited spina bifida from them via genes, and believe future children could also inherit the condition. This is often discussed during genetic counselling.

Spina bifida and current knowledge

Spina bifida is one of a group of birth defects called neural tube defects, affecting the brain or spinal cord. They happen in the first month of pregnancy, often before a woman even knows that she is pregnant. People born with this condition suffer nerve damage because part of their spinal cord remains exposed while in the womb. Advances in recent years now allow surgeons in a few centres around the world, including at Great Ormond Street Hospital and University College London Hospital, to perform surgery on foetuses in the womb to reduce the neurological consequences of their condition*.

Some neural tube defects can be prevented by taking folic acid supplements before and during early pregnancy, yet these conditions continue to affect around one in every thousand pregnancies globally. Researchers say they do not fully understand why mosaic mutations occur – though environmental factors may be involved – and cannot yet draw a link with taking (or not) folic acid during pregnancy. Notwithstanding this they say folic acid is known to help embryonic cells make DNA and encourage all expectant mothers to add folic acid to their diets from before conception.

Commenting on the potential causes, Principle Investigator, Dr Gabriel Galea (UCL Great Ormond Street Institute of Child Health), said: “Some environmental factors are known to increase the risk of these conditions occurring and very few affected individuals or their parents receive a meaningful genetic diagnosis. The discovery that mosaic mutations, which cause spina bifida, may not be inherited from either parent, and are not necessarily present in blood or saliva commonly used for genetic testing, may explain why.”

Genetic mutations

Genetic mutations happen in every cell throughout development. In order to grow from a fertilised egg cell into a foetus, each of our cells must replicate and divide in order to increase in number and grow. Cells must copy their DNA every time they divide, but mistakes can happen which change the DNA sequence in the daughter cells. These DNA code mistakes, called mutations, are then inherited by all cells derived from that cell. If these mutations happen in germ cells – the egg and sperm cells – they are inherited from parent to offspring. Many mutations do not happen in germ cells, but rather in cells which give rise to specific tissue types. These are known as mosaic mutations.

Experimental study approach

In humans with spina bifida a number of gene mutations have been identified, but in many cases it had not been known whether they could cause spina bifida.

In this experimental study, researchers caused a specific mutation, which inactivates a single gene called Vangl2 in mouse embryos. This gene is part of a cellular signalling pathway which tells cells which way they are facing within a tissue. Mutations in this pathway had been identified in people who have neural tube defects, and recent reports from the USA and China previously found mosaic Vangl2­-pathway mutations in 15% of human foetuses with spina bifida. For the cellular signalling pathway to function normally, cells must interact with their neighbours in order to communicate directional information.

For the study, researchers induced this mutation of Vangl2 in a small proportion of cells which form the developing spinal cord of mice. This was done in a number of mouse embryos. Researchers then counted the proportion of spinal cells which harboured this mutation in those which had successfully covered their spinal cord with skin (ie had developed normally), versus those which had an exposed spinal cord (had spina bifida).

Researchers found that when the mutated Vangl2 gene was present in just 16% of developing spinal cord cells, spina bifida occurred.

They say, these results show that the cellular signalling process is surprisingly vulnerable to the uninheritable mosaic mutations. Each mutant cell stops each of its neighbouring cells from functioning to promote spinal cord development. And each cell has six neighbouring cells on average, massively amplifying the effects of each mutant cell.

Explaining the findings, Dr Galea, a Wellcome Clinical Research Career Development Fellow, said: “We found that the requirement for cells to talk to each other makes them exquisitely vulnerable to mutations in the signalling pathway that Vangl2 acts in. We now need to understand whether this vulnerability extends to other genes which could cause spina bifida. Detecting these mosaic mutations in living people will require technological advances and careful analysis of tissues resected during surgery.”

* A team from UCL, UCLH and GOSH has operated on the abnormally developed spinal cords of two babies in the womb, in a medical first for the UK (October 2018)

Links

• Research paper published in Nature Communications
• Dr Gabriel Galea’s academic profile
• UCL Great Ormond Street Institute of Child Health
• To learn more about spinal cord development, watch Dr Gabriel Galea’s UCL Lunch Hour Lecture

Image

• Advanced microscopy image of the developing spinal cord, Credit: Dr Gabriel Galea

Media contact

Henry Killworth

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E: h. killworth [at]ucl.ac.uk

Spina bifida can be caused by uninherited genetic mutations — ScienceDaily

Genetic mutations which occur naturally during the earliest stages of an embryo’s development can cause the severe birth defect spina bifida, finds a new experimental study in mice led by UCL scientists.

The research, published in Nature Communications, explains for the first time how a ‘mosaic mutation’ — a mutation which is not inherited from either parent (either via sperm or egg cell) but occurs randomly during cell divisions in the developing embryo — causes spina bifida.

Specifically the scientists, based at UCL Great Ormond Street Institute of Child Health, found that when a mutation in the gene Vangl2 (which contains information needed to create spinal cord tissue) was present in 16% of developing spinal cord cells of mouse embryos, this was sufficient to produce spina bifida.

Researchers say the findings add to scientists’ understanding of how and why mosaic mutations can affect and disrupt cell function, including those of neighbouring cells, helping cause birth defects.

For parents, the findings may help reduce the burden felt by those who believe their child inherited spina bifida from them via genes, and believe future children could also inherit the condition. This is often discussed during genetic counselling.

Spina bifida and current knowledge

Spina bifida is one of a group of birth defects called neural tube defects, affecting the brain or spinal cord. They happen in the first month of pregnancy, often before a woman even knows that she is pregnant. People born with this condition suffer nerve damage because part of their spinal cord remains exposed while in the womb. Advances in recent years now allow surgeons in a few centres around the world, including at Great Ormond Street Hospital and University College London Hospital, to perform surgery on foetuses in the womb to reduce the neurological consequences of their condition*.

Some neural tube defects can be prevented by taking folic acid supplements before and during early pregnancy, yet these conditions continue to affect around one in every thousand pregnancies globally. Researchers say they do not fully understand why mosaic mutations occur — though environmental factors may be involved — and cannot yet draw a link with taking (or not) folic acid during pregnancy. Notwithstanding this they say folic acid is known to help embryonic cells make DNA and encourage all expectant mothers to add folic acid to their diets from before conception.

Commenting on the potential causes, Principle Investigator, Dr Gabriel Galea (UCL Great Ormond Street Institute of Child Health), said: “Some environmental factors are known to increase the risk of these conditions occurring and very few affected individuals or their parents receive a meaningful genetic diagnosis. The discovery that mosaic mutations, which cause spina bifida, may not be inherited from either parent, and are not necessarily present in blood or saliva commonly used for genetic testing, may explain why.”

Genetic mutations

Genetic mutations happen in every cell throughout development. In order to grow from a fertilised egg cell into a fetus, each of our cells must replicate and divide in order to increase in number and grow. Cells must copy their DNA every time they divide, but mistakes can happen which change the DNA sequence in the daughter cells. These DNA code mistakes, called mutations, are then inherited by all cells derived from that cell. If these mutations happen in germ cells — the egg and sperm cells — they are inherited from parent to offspring. Many mutations do not happen in germ cells, but rather in cells which give rise to specific tissue types. These are known as mosaic mutations.

Experimental study approach

In humans with spina bifida a number of gene mutations have been identified, but in many cases it had not been known whether they could cause spina bifida.

In this experimental study, researchers caused a specific mutation, which inactivates a single gene called Vangl2 in mouse embryos. This gene is part of a cellular signalling pathway which tells cells which way they are facing within a tissue. Mutations in this pathway had been identified in people who have neural tube defects, and recent reports from the USA and China previously found mosaic Vangl2¬-pathway mutations in 15% of human foetuses with spina bifida. For the cellular signalling pathway to function normally, cells must interact with their neighbours in order to communicate directional information.

For the study, researchers induced this mutation of Vangl2 in a small proportion of cells which form the developing spinal cord of mice. This was done in a number of mouse embryos. Researchers then counted the proportion of spinal cells which harboured this mutation in those which had successfully covered their spinal cord with skin (ie had developed normally), versus those which had an exposed spinal cord (had spina bifida).

Researchers found that when the mutated Vangl2 gene was present in just 16% of developing spinal cord cells, spina bifida occurred.

They say, these results show that the cellular signalling process is surprisingly vulnerable to the uninheritable mosaic mutations. Each mutant cell stops each of its neighbouring cells from functioning to promote spinal cord development. And each cell has six neighbouring cells on average, massively amplifying the effects of each mutant cell.

Explaining the findings, Dr Gabriel Galea said: “We found that the requirement for cells to talk to each other makes them exquisitely vulnerable to mutations in the signalling pathway that Vangl2 acts in. We now need to understand whether this vulnerability extends to other genes which could cause spina bifida. Detecting these mosaic mutations in living people will require technological advances and careful analysis of tissues resected during surgery.”

* A team from UCL, UCLH and GOSH has operated on the abnormally developed spinal cords of two babies in the womb, in a medical first for the UK (October 2018).

Spinal hernia in a newborn child: symptoms, treatment

Spinal hernia in newborns is a fairly rare, but very severe developmental pathology that occurs in only 0. 1-0.3% of children. And almost 2/3 of children remain chained to a wheelchair for life. Congenital spina bifida can be determined at the stage of pregnancy.

Causes of spinal hernia in newborns

Why manifestations of spinal hernia in newborns may occur is not well understood. Therefore, one can only name the factors that can influence the development of pathology, based on the opinion of leading professors of medical sciences. Risk factors include:

• a pregnant woman’s lack of adequate amounts of folic acid, also known as vitamin B9, as well as other vitamins, is now recognized as the main cause of spina bifida in infants;
• pregnancy intoxication;
• early pregnancy;
• hereditary factor.

The formation of the neural tube occurs before the eighth week of gestation, and it is at this time that one or more of the listed factors can provoke the onset of pathology. As a result of this phenomenon, one or more vertebral bodies are separated in the region of the spinous process. The membranes of the spinal cord, fluid and even nerve endings can go into such a gap.

Forms of spinal hernia in newborns

A spinal hernia in a child can be divided according to its location and structural features. Where the protrusion is located is very important, since further treatment, the complexity of the symptoms and its elimination will depend on this factor. The easiest variety is hidden splitting, when one vertebra is slightly deformed, which will not bring much discomfort to the child. If the defect is more serious, a hernial split occurs when a clearly visible protrusion is detected, which is visible under the skin. In severe cases, the spinal cord itself comes out into this protrusion. If we talk about where the spinal hernia is located in a child, we can distinguish:

• cervical – the rarest, affects the upper parts of the spinal cord, innervation can occur in the neck and face, respectively, coordination is disturbed, and malfunctions of the lungs and heart occur;
• chest – occurs more often in the neck, but much less often in the lumbar, and the pathology can affect the work of the arms and legs, lungs, heart, stomach, spleen, liver, etc . ;
• lumbosacral – occurs most often, affects the functioning of the pelvic organs, kidneys and lower extremities.

Whatever the protrusion, the severity of the condition will be determined depending on its size.

Symptoms of spinal hernia in newborns

A photo of a spinal hernia in newborns is often found on the Internet, and almost every pregnant woman is afraid of this pathology. To determine if a newborn has such a disease, look for signs of a hernia. These include:

• paralysis of limbs, disorders and nutrition, paresis;
• pelvic troubles, fecal incontinence;
• malfunctions of the heart, lungs, gastrointestinal tract and endocrine system.

All these symptoms may be accompanied by secondary complications, which include muscle atrophy, edema, trophic ulcers and lack of skin thermoregulation, etc.

Diagnostics

To determine the presence of the disease, the doctor collects an anamnesis of a small patient, and also conducts a complete examination of him. If there were no abnormalities during pregnancy, doctor will determine the health status of the child, taking into account his age. He will check how well the muscles are developed, whether there is any weakness, difficult muscle activity, etc. In addition, to determine the presence of the disease and the consequences of spinal hernia in newborns, you will need:

1. Visit neurologist .
2. Carry out a light scan, called transillumination, to identify the obsession of the protrusion.
3. Myelography with contrast – allows you to determine the damage to the spinal cord.
4. MRI or CT.
5. Visit a neurosurgeon who will determine the need for surgery and give prognosis.

Timely detection of the disease will increase the chances of a successful cure for the baby from the disease.

Treatment

The disease is usually treated with surgery. It can be performed both before and after birth.

Perinatal surgery

It can be prescribed at 19-26 weeks of gestation and is recognized as the most effective method of ridding a child of a hernia. The operation will close the anatomical anomaly in the spinal column, as a result of which the spinal cord returns to its place and is protected from influences. Among the reasons for the appearance of a spinal hernia in newborns in this case may be natural childbirth, therefore, after the operation, the woman will be delivered by caesarean section. This method allows you to ensure the most normal life for the child. Among the shortcomings of the method is that such operations, like those for premature babies, are performed only abroad. At the moment, there are only a few specialists capable of performing such an operation in Russia.

Postpartum surgery

This type of treatment is possible in the first few days after birth, then it does not make sense. Surgery will remove the growth, but there will be significant developmental problems and additional surgery may be needed. Life expectancy is affected not only by the type of hernia, but also by the presence of hydrocephalus.

Rehabilitation

Your healthcare provider will be able to tell if a baby’s spinal hernia can be treated with ozone gas, and will also determine what rehabilitation measures are needed. If we are talking about foreign clinics, then often they have sanatorium branches where doctors monitor the child’s condition after the intervention. Rehabilitation may include massages and exercise therapy.

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can the fetus be saved? — ZdorovyeInfo

Home All articles of the section “The child will be” Spinal hernia: is it possible to save the fetus?

Spinal hernia can be detected even before birth: in this case, doctors advise to terminate the pregnancy. Otherwise, most likely, the child will be born paralyzed.

Can spinal hernia be treated? What to do if this diagnosis was made during your pregnancy? We tell you everything you need to know in such cases.

What is this pathology?

This birth defect begins in the first 8 weeks of pregnancy, during the formation of the neural tube of the fetus. In a child, a segment of the spine does not grow together, and the spinal cord comes out.

What threatens such an injury?

Due to the fact that the amniotic fluid injures the organs, paralysis and hydrocephalus develop. This leads to disability: paralysis of the legs and arms, muscle atrophy, urinary and fecal incontinence.

Do these consequences happen to everyone?

No, it depends on the form of the pathology:

• Latent spina bifida is a non-fusion of one vertebra without a hernia. Such an injury usually does not interfere with the normal development of the child, but will still require surgery;
• Spina bifida with herniation is a severe disease that affects the spinal cord and brain. The disease leads to the most severe consequences, up to tumors (lipomas, fibromas).

Who can have such a child?

Doctors still do not know the exact causes of spinal hernias. But there are risk factors:

• Hereditary genetic anomalies;
• Infections during pregnancy;
• Early pregnancy;
• Use of alcohol, drugs prohibited during pregnancy;
• Deficiency of vitamins and nutrients: especially folic acid.

How to diagnose a hernia in a fetus?

Ultrasound and test for germ protein (alpha-fetoprotein) is needed. A study of amniotic fluid can finally confirm the diagnosis: they are checked for defects in the neural tube of the fetus.

Is it possible to give birth to a healthy child with such a diagnosis?

Until recently, there was very little chance: the operation was performed in the first weeks of life, and the child often remained disabled.

However, Russian doctors – obstetrician-gynecologist and academician of the Russian Academy of Sciences Mark Kurtser and neurosurgeon Andrey Prityka have learned to operate on babies in the womb: they cut the uterus , take out the fetus, open the spinal canal, remove the hernia and sew up the skin.