Fragile X Syndrome (FXS)
Spinal Muscular Atrophy (SMA)
Specimen Type: 2X3 ml EDTA Blood
TAT: 7-14 working days
Fragile X Syndrome
What is fragile X syndrome (FXS)?
Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and cognitive impairment. Usually, males are more severely affected by this disorder than females.
Affected individuals usually have delayed development of speech and language by age 2. Most males with fragile X syndrome have mild to moderate intellectual disability, while about one-third of affected females are intellectually disabled. Children with fragile X syndrome may also have anxiety and hyperactive behaviour such as fidgeting or impulsive actions. They may have attention deficit disorder (ADD), which includes an impaired ability to maintain attention and difficulty focusing on specific tasks. About one-third of individuals with fragile X syndrome have features of autism spectrum disorders that affect communication and social interaction. Seizures occur in about 15 percent of males and about 5 percent of females with fragile X syndrome.
Most males and about half of females with fragile X syndrome have characteristic physical features that become more apparent with age. These features include a long and narrow face, large ears, a prominent jaw and forehead, unusually flexible fingers, flat feet, and in males, enlarged testicles (macroorchidism) after puberty.
How common is fragile X syndrome?
Fragile X syndrome occurs in approximately 1 in 3,600 – 1 in 4,000 males and 1 in 4,000 to 1 in 8,000 females, which is currently recognised as second most common chromosomal disorder after Down’s Syndrome in frequency.
What genes are related to fragile X syndrome?
Mutations in the FMR1 gene cause fragile X syndrome. The FMR1 gene provides instructions for making a protein called fragile X mental retardation 1 protein, or FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses, which are specialized connections between nerve cells. Synapses are critical for relaying nerve impulses.
Nearly all cases of fragile X syndrome are caused by a mutation in which a DNA segment, known as the CGG triplet repeat, is expanded within the FMR1 gene. Normally, this DNA segment is repeated from 5 to about 40 times. In people with fragile X syndrome, however, the CGG segment is repeated more than 200 times. The abnormally expanded CGG segment turns off (silences) the FMR1 gene, which prevents the gene from producing FMRP. Loss or a shortage (deficiency) of this protein disrupts nervous system functions and leads to the signs and symptoms of fragile X syndrome.
Males and females with 55 to 200 repeats of the CGG segment are said to have an FMR1 gene premutation. Most people with a premutation are intellectually normal. In some cases, however, individuals with a premutation have lower than normal amounts of FMRP. As a result, they may have mild versions of the physical features seen in fragile X syndrome (such as prominent ears) and may experience emotional problems such as anxiety or depression. Some children with a premutation may have learning disabilities or autistic-like behavior. The premutation is also associated with an increased risk of disorders called fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS).
How do people inherit fragile X syndrome?
Fragile X syndrome is inherited in an X-linked dominant pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. (The Y chromosome is the other sex chromosome.) The inheritance is dominant if one copy of the altered gene in each cell is sufficient to cause the condition. X-linked dominant means that in females (who have two X chromosomes), a mutation in one of the two copies of a gene in each cell is sufficient to cause the disorder. In males (who have only one X chromosome), a mutation in the only copy of a gene in each cell causes the disorder. In most cases, males experience more severe symptoms of the disorder than females.
In women, the FMR1 gene premutation on the X chromosome can expand to more than 200 CGG repeats in cells that develop into eggs. This means that women with the premutation have an increased risk of having a child with fragile X syndrome. By contrast, the premutation in men does not expand to more than 200 repeats as it is passed to the next generation. Men pass the premutation only to their daughters. Their sons receive a Y chromosome, which does not include the FMR1 gene.
Spinal Muscular Atrophy
What is spinal muscular atrophy (SMA)?
Spinal muscular atrophy is a genetic disorder that affects the control of muscle movement. It is caused by a loss of specialized nerve cells, called motor neurons, in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). The loss of motor neurons leads to weakness and wasting (atrophy) of muscles used for activities such as crawling, walking, sitting up, and controlling head movement. In severe cases of spinal muscular atrophy, the muscles used for breathing and swallowing are affected. There are many types of spinal muscular atrophy distinguished by the pattern of features, severity of muscle weakness, and age when the muscle problems begin.
Type I spinal muscular atrophy (also called Werdnig-Hoffman disease) is a severe form of the disorder that is evident at birth or within the first few months of life. Affected infants are developmentally delayed; most are unable to support their head or sit unassisted. Children with this type have breathing and swallowing problems that may lead to choking or gagging.
Type II spinal muscular atrophy is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with type II can sit without support, although they may need help getting to a seated position. Individuals with this type of spinal muscular atrophy cannot stand or walk unaided.
Type III spinal muscular atrophy (also called Kugelberg-Welander disease or juvenile type) has milder features that typically develop between early childhood and adolescence. Individuals with type III spinal muscular atrophy can stand and walk unaided, but walking and climbing stairs may become increasingly difficult. Many affected individuals will require wheelchair assistance later in life.
The signs and symptoms of type IV spinal muscular atrophy often occur after age 30. Affected individuals usually experience mild to moderate muscle weakness, tremor, twitching, or mild breathing problems. Typically, only muscles close to the center of the body (proximal muscles), such as the upper arms and legs, are affected in type IV spinal muscular atrophy.
The features of X-linked spinal muscular atrophy appear in infancy and include severe muscle weakness and difficulty breathing. Children with this type often have joint deformities (contractures) that impair movement. In severe cases, affected infants are born with broken bones. Poor muscle tone before birth may contribute to the contractures and broken bones seen in these children.
Spinal muscular atrophy, lower extremity, dominant (SMA-LED) is characterized by leg muscle weakness that is most severe in the thigh muscles (quadriceps). This weakness begins in infancy or early childhood and progresses slowly. Affected individuals often have a waddling or unsteady walk and have difficulty rising from a seated position and climbing stairs.
An adult-onset form of spinal muscular atrophy that begins in early to mid-adulthood affects the proximal muscles and is characterized by muscle cramping of the limbs and abdomen, weakness in the leg muscles, involuntary muscle contractions, tremors, and a protrusion of the abdomen thought to be related to muscle weakness. Some affected individuals experience difficulty swallowing and problems with bladder and bowel function.
How common is spinal muscular atrophy?
Spinal muscular atrophy affects 1 in 8,000 people. The prevalence is just after Thalassemia.
What genes are related to spinal muscular atrophy?
Mutations in the SMN1, UBA1, DYNC1H1, and VAPB genes cause spinal muscular atrophy. Extra copies of the SMN2 gene modify the severity of spinal muscular atrophy.
The SMN1 and SMN2 genes provide instructions for making a protein called the survival motor neuron (SMN) protein. The SMN protein is important for the maintenance of specialized nerve cells called motor neurons. Motor neurons are located in the spinal cord and the brainstem; they control muscle movement. Most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is full size and functional.
Mutations in the SMN1 gene cause spinal muscular atrophy types I, II, III, and IV. SMN1 gene mutations lead to a shortage of the SMN protein. Without SMN protein, motor neurons die, and nerve impulses are not passed between the brain and muscles. As a result, some muscles cannot perform their normal functions, leading to weakness and impaired movement.
Some people with type II, III, or IV spinal muscular atrophy have three or more copies of the SMN2 gene in each cell. Having multiple copies of the SMN2 gene can modify the course of spinal muscular atrophy. The additional SMN proteins produced from the extra copies of the SMN2 gene can help replace some of the SMN protein that is lost due to mutations in the SMN1 gene. In general, symptoms are less severe and begin later in life as the number of copies of the SMN2 gene increases.
Mutations in the UBA1 gene cause X-linked spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is involved in a process that targets proteins to be broken down (degraded) within cells. UBA1 gene mutations lead to reduced or absent levels of functional enzyme, which disrupts the process of protein degradation. A buildup of proteins in the cell can cause it to die; motor neurons are particularly susceptible to damage from protein buildup.
The DYNC1H1 gene provides instructions for making a protein that is part of a group (complex) of proteins called dynein. This complex is found in the fluid inside cells (cytoplasm), where it is part of a network that moves proteins and other materials. In neurons, dynein moves cellular materials away from the junctions between neurons (synapses) to the center of the cell. This process helps transmit chemical messages from one neuron to another. DYNC1H1 gene mutations that cause SMA-LED disrupt the function of the dynein complex. As a result, the movement of proteins, cellular structures, and other materials within cells are impaired. A decrease in chemical messaging between neurons that control muscle movement is thought to contribute to the muscle weakness experienced by people with SMA-LED. It is unclear why this condition affects only the lower extremities.
The adult-onset form of spinal muscular atrophy is caused by a mutation in the VAPB gene. The VAPB gene provides instructions for making a protein that is found in cells throughout the body. Researchers suggest that this protein may play a role in preventing the buildup of unfolded or misfolded proteins within cells. It is unclear how a VAPB gene mutation leads to the loss of motor neurons. An impaired VAPB protein might cause misfolded and unfolded proteins to accumulate and impair the normal function of motor neurons.
Other types of spinal muscular atrophy that primarily affect the lower legs and feet and the lower arms and hands are caused by the dysfunction of neurons in the spinal cord. When spinal muscular atrophy shows this pattern of signs and symptoms, it is also known as distal hereditary motor neuropathy. The various types of this condition are caused by mutations in other genes.
How do people inherit spinal muscular atrophy?
Types I, II, III, and IV spinal muscular atrophy are inherited in an autosomal recessive pattern, which means both copies of the SMN1 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Extra copies of the SMN2 gene are due to a random error when making new copies of DNA (replication) in an egg or sperm cell or just after fertilization.
SMA-LED and the late-onset form of spinal muscular atrophy caused by VAPB gene mutations are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.
X-linked spinal muscular atrophy is inherited in an X-linked pattern. The UBA1 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
What is Huntington disease?
Huntington disease is a progressive brain disorder that causes uncontrolled movements, emotional problems, and loss of thinking ability (cognition).
Adult-onset Huntington disease, the most common form of this disorder, usually appears in a person’s thirties or forties. Early signs and symptoms can include irritability, depression, small involuntary movements, poor coordination, and trouble learning new information or making decisions. Many people with Huntington disease develop involuntary jerking or twitching movements known as chorea. As the disease progresses, these movements become more pronounced. Affected individuals may have trouble walking, speaking, and swallowing. People with this disorder also experience changes in personality and a decline in thinking and reasoning abilities. Individuals with the adult-onset form of Huntington disease usually live about 15 to 20 years after signs and symptoms begin.
A less common form of Huntington disease known as the juvenile form begins in childhood or adolescence. It also involves movement problems and mental and emotional changes. Additional signs of the juvenile form include slow movements, clumsiness, frequent falling, rigidity, slurred speech, and drooling. School performance declines as thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50 percent of children with this condition. Juvenile Huntington disease tends to progress more quickly than the adult-onset form; affected individuals usually live 10 to 15 years after signs and symptoms appear.
How common is Huntington disease?
Huntington disease affects an estimated 3 to 7 per 100,000 people.
What genes are related to Huntington disease?
Mutations in the HTT gene cause Huntington disease. The HTT gene provides instructions for making a protein called huntingtin. Although the function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in the brain.
The HTT mutation that causes Huntington disease involves a DNA segment known as a CAG trinucleotide repeat. This segment is made up of a series of three DNA building blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder.
An increase in the size of the CAG segment leads to the production of an abnormally long version of the huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind together and accumulate in neurons, disrupting the normal functions of these cells. The dysfunction and eventual death of neurons in certain areas of the brain underlie the signs and symptoms of Huntington disease.
How do people inherit Huntington disease?
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. An affected person usually inherits the altered gene from one affected parent. In rare cases, an individual with Huntington disease does not have a parent with the disorder.
As the altered HTT gene is passed from one generation to the next, the size of the CAG trinucleotide repeat often increases in size. A larger number of repeats is usually associated with an earlier onset of signs and symptoms. This phenomenon is called anticipation. People with the adult-onset form of Huntington disease typically have 40 to 50 CAG repeats in the HTT gene, while people with the juvenile form of the disorder tend to have more than 60 CAG repeats.
Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington disease, but they are at risk of having children who will develop the disorder. As the gene is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into the range associated with Huntington disease (36 repeats or more).
What is MTHFR gene?
The official name of this gene is “methylenetetrahydrofolate reductase (NAD(P)H).”
MTHFR is the gene’s official symbol.
What is the normal function of the MTHFR gene?
The MTHFR gene provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids, the building blocks of proteins. Methylenetetrahydrofolate reductase is important for a chemical reaction involving forms of the vitamin folate (also called vitamin B9). Specifically, this enzyme converts a molecule called 5,10-methylenetetrahydrofolate to a molecule called 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. The body uses methionine to make proteins and other important compounds.
How are changes in the MTHFR gene related to health conditions?
homocystinuria - caused by mutations in the MTHFR gene
At least 40 mutations in the MTHFR gene have been identified in people with homocystinuria, a disorder in which the body is unable to process certain amino acids properly. Most of these mutations change single amino acids in methylenetetrahydrofolate reductase. These changes impair the function of the enzyme, and some cause the enzyme to be turned off (inactivated). Other mutations lead to the production of an abnormally small, nonfunctional version of the enzyme. Without functional methylenetetrahydrofolate reductase, homocysteine cannot be converted to methionine. As a result, homocysteine builds up in the bloodstream, and the amount of methionine is reduced. Some of the excess homocysteine is excreted in urine.
anencephaly - associated with the MTHFR gene
Several variations (polymorphisms) in the MTHFR gene have been associated with an increased risk of neural tube defects, a group of birth defects that occur during the development of the brain and spinal cord. Anencephaly is one of the most common types of neural tube defect. Affected individuals are missing large parts of the brain and have missing or incompletely formed skull bones.
The most well-studied polymorphism related to neural tube defects changes a single DNA building block (nucleotide) in the MTHFR gene. Specifically, it replaces the nucleotide cytosine with the nucleotide thymine at position 677 (written as 677C>T). This common variant results in a form of methylenetetrahydrofolate reductase that has reduced activity at higher temperatures (thermolabile). People with the 677C>T polymorphism, particularly those with two copies of the genetic change, have elevated levels of homocysteine in their blood resulting from the reduced activity of methylenetetrahydrofolate reductase.
Researchers have studied MTHFR gene polymorphisms in individuals with neural tube defects and in their mothers, but it remains unclear how these variations could affect the developing brain and spinal cord. The increased risk of neural tube defects may be related to differences in the ability of methylenetetrahydrofolate reductase to process folate; a shortage of this vitamin is an established risk factor for neural tube defects.
Although MTHFR gene polymorphisms are associated with an increased risk of neural tube defects, these variations are common in many populations worldwide. Most people withMTHFR gene polymorphisms do not have neural tube defects, and their children are also typically unaffected. Changes in the MTHFR gene are only one of many genetic and environmental factors that are thought to contribute to these complex conditions.
spina bifida - associated with the MTHFR gene
Polymorphisms in the MTHFR gene are also associated with an increased risk of spina bifida, another common type of neural tube defect. In people with this condition, when the spine forms, the bones of the spinal column do not close completely around the developing nerves of the spinal cord. As a result, part of the spinal cord may stick out through an opening in the spine, leading to permanent nerve damage.
As described above, variations in the MTHFR gene may increase the risk of neural tube defects by changing the ability of methylenetetrahydrofolate reductase to process folate. However, these variations are common in many populations worldwide. Most people with MTHFR gene polymorphisms do not have neural tube defects, nor do their children.
other disorders – increased risk from variations of the MTHFR gene
Polymorphisms in the MTHFR gene have also been studied as possible risk factors for a variety of common conditions. These include heart disease, stroke, high blood pressure (hypertension), high blood pressure during pregnancy (preeclampsia), an eye disorder called glaucoma, psychiatric disorders, and certain types of cancer. The 677C>T polymorphism in the MTHFRgene has also been suggested as a risk factor for cleft lip and palate, a birth defect in which there is a split in the upper lip and an opening in the roof of the mouth. Studies of MTHFR gene variations in people with these disorders have had mixed results, with associations found in some studies but not in others. Therefore, it remains unclear what role changes in the MTHFRgene play in these disorders. A large number of genetic and environmental factors, most of which remain unknown, likely determine the risk of developing most common, complex conditions.
Where is the MTHFR gene located?
Cytogenetic Location: 1p36.3
Molecular Location on chromosome 1: base pairs 11,785,729 to 11,806,102
The MTHFR gene is located on the short (p) arm of chromosome 1 at position 36.3.
More precisely, the MTHFR gene is located from base pair 11,785,729 to base pair 11,806,102 on chromosome 1.