X-Linked Mental Retardation Health Article

Signs and symptoms

About 150 different conditions have been described as of 2005. These can either be malformation syndromes, in which affected patients have mental retardation and multiple birth defects; neuromuscular syndromes, in which patients have mental retardation and abnormalities in various nerves and muscles; metabolic syndromes have a defect in a specific biochemical pathway; or dominant syndromes in which the disorder is inherited in an X-linked dominant fashion with most affected males dying before birth.

The most common known cause of inherited mental retardation is fragile X syndrome, which accounts for 20% of XLMR. It was first described in the late 1970s; the gene was discovered in 1991. Persons from all ethnic and social backgrounds can be affected. It results from a mutation in the fragile X mental retardation (FMR1) gene found on the X chromosome. This gene contains information needed for making the FMR protein, which is thought to regulate communication between various cells by eliminating unwanted communication neural pathways.

The FMR1 gene contains two distinct regions, one of which is called the promoter region. This region is composed of repeating units or building blocks called nucleotides arranged in a specific sequence. A normal person has 30 such units and can make normal amounts of the FMR protein. When a person has between 55 and 200 units, the gene becomes partially inactivated. They can still make some amount of FMR protein and are said to have a pre-mutation. The pre-mutation occurs in one in 250–300 females and one in 1,000 males. The amount of FMR protein in the body determines the severity of effects due to fragile X. Therefore, patients with a premutation may have few, if any, symptoms and may not even know that they are carrying an abnormal gene. A pre-mutation can be transmitted silently over generations, but with each generation, the number of units increases and there is a higher chance of manifesting the condition (anticipation).

When a person has more than 200 units, the gene itself becomes completely inactivated, making it impossible to produce any FMR protein. The full mutation occurs in one in 3,600 males and one in 4,000–6,000 females. As females have two X chromosomes in each cell, even if one X has the full mutation, the other X carries the normal FMR1 gene, making it possible to produce at least some FMR protein. Therefore, females are less often and less seriously affected than males. Females who do not express the disease, but carry the abnormal gene are called carriers..

If a father carries the FMR1 mutation, he will transmit the mutation to all his daughters but cannot transmit it to his sons, as males receive only the Y chromosome. On the other hand, if a mother carries the mutation on one of her X chromosomes, each of her children (boys or girls) will have a 50% chance of inheriting the FMR1 mutation, depending on which X chromosome they receive.

There is a considerable variability in disease severity of fragile X syndrome in males, with many of the physical symptoms becoming more apparent only after puberty. Prior to puberty, the most common findings include speech delay, developmental delay, and mental retardation. The most noticeable and consistent effect is on intelligence. More than 80% of affected males have an IQ of less than 70, whereas the effect on IQ in an affected female is variable. It is uncommon for persons with fragile X to have severe mental retardation, and most have IQ in the range of 40–85. Females may show normal cognitive development with only mild learning disabilities and a normal IQ. People with fragile X have good memory skills for pictures and visual patterns, but have poor verbal knowledge. They also have poor abstract thinking, organizational skills, and problem-solving capabilities. Despite such limitations, many of them can be trained to acquire jobs and skills to take care of themselves.

Children with fragile X tend to develop certain physical characteristics by the time of puberty. They have a long face or jaw, large protruding ears, and do not grow as tall as other members in the family. Males with fragile X have large testicles, but this does not affect sexual development. They also have problems with connective tissues. They may be flat footed, have loose hyper-extensible joints, and "floppy" heart valves. Later in life, they can manifest hand tremors and difficulty walking. Women with fragile X undergo menopause early due to premature cessation of ovarian function, thus affecting their reproductive capabilities. About 25% of patients have seizures.

Most persons with fragile X syndrome, especially boys, have a lot of anxiety in social situations and become nervous and uncomfortable. They also tend to be easily upset and overwhelmed by sensory stimulation due to sights and sounds and deviance from normal routine. This may emerge as aggression in adolescent boys. Females tend to have less anxiety and are not usually aggressive. Boys have language problems, including speaking, writing, and acquiring social communication skills. Common behavior disturbances include attention deficit disorder, repetitive hand flapping, autistic behaviors, and gaze aversion, and 20% meet full criteria for autism.

Rett's syndrome (RS) is the second leading cause of XLMR and the leading cause of mental retardation in girls. It was first described in 1966; the gene was identified in 1999. RS is caused by mutation in the MECP2 gene that causes abnormal truncation of the gene. The MECP2 gene contains information for production of methyl cytosine binding protein 2, which normally helps to turn off other genes appropriately at various points along the process of brain development. If this does not occur, the overactive genes interfere with normal brain maturation and lead to abnormal "wiring" and overload of the brain's electrical system. Other types of mutation in the same MECP2 gene can result in mild mental retardation, tremor, psychosis, or learning disability, both in boys and girls, without producing classic RS..

RS almost exclusively occurs in females with a prevalence of one in 10,000–20,000. In males, the mutation is lethal, and most are severely affected or die before or soon after birth. There is also a phenomenon of preferential inactivation of the normal X chromosome leading to the disease expression even in the female. The affected girl develops normally during the first five months of life. During this period, the child exhibits autistic behaviors. She can be calm and quiet, without making good eye contact, and without showing much interest in toys. After this, head growth slows down and the child loses whatever purposeful hand movements that had already developed. Around three years, the girl child develops repetitive hand washing or hand wringing gestures, loses ability to speak, has trouble sleeping, becomes irritable, and develops an unsteady gait. Varying degrees of mental retardation are present. These children also have seizures.

WEST SYNDROME West syndrome, also known as the infantile spasm-mental retardation syndrome, is caused by mutations in the ARX (aristaless-related homeobox) gene. This is the third most common genetic mutation leading to XLMR. It can occur in both boys and girls and is characterized by developmental delay, mental retardation, and a specific type of seizures called salaam fits or infantile spasms. During the seizures, the children either have a flexion spasm where the body is bent over in a self-hugging position or an extension spasm where the neck and body are arched backwards.

Mutations in the ARX gene can also result in various developmental defects like lissencephaly (abnormal accumulation of fluid in the brain, replacing the cerebral hemispheres), absence of the corpus callosum, microcephaly, and urinary and genital abnormalities, without causing the classic West syndrome.

Non-syndromic X-linked mental retardation (NSXLMR) is represented by a heterogeneous group of disorders in which the only recognizable abnormality is mental retardation without other accompanying physical manifestations. As of 2004, about 78 families with NSXLMR had been described and mutations in 15 genes had been linked with them.