X-Linked Mental Retardation
X-linked mental retardation (XLMR) broadly refers to a group of inherited disorders characterized by varying degrees of mental retardation, caused by mutations in various genes present on the X chromosome. Mental retardation is defined as the failure to develop cognitive abilities and achieve a level of intelligence and adaptive behavior that is appropriate for a particular age group. XLMR is mostly seen in boys, usually manifests before the age of 18, and is characterized by an overall intelligence quotient (IQ) of less than 70, along with functional deficits in adaptive behavior like daily living, and social and communication skills.
The X chromosome was so named initially to mean unknown, as the functions of the genes carried on it were not clear. The United States Census of 1890 was the first to collect data that showed that more boys than girls were mentally disabled, and it was suspected that this was due to the difference in the sex chromosomes present in males and females. It was only in 1970 that the most common cause of XLMR, fragile X syndrome was described in detail; its mutated gene (FMR1) was not identified until 1991. Mutations in the MECP2 gene are the second most common cause of XLMR, and result in Rett's syndrome. This gene was identified in 1999. Since 2004, about 200 XLMR disease types have been described. With the help of the Human Genome Project, of the 150–200 candidate genes on the X chromosome, mutations in about 50 have been identified as being responsible for different XLMR diseases.
XLMR is broadly divided into syndromic and nonsyndromic disorders. Syndromic XLMR (S-XLMR) refers to conditions in which mental retardation is accompanied by characteristic and easily recognizable physical and/or neurological features. In non-syndromic XLMR (NSXLMR), mental retardation is the only key feature without any other distinctive physical or neurological features. Two thirds of XLMR cases are thought to be non-syndromic. In both syndromic and non-syndromic XLMR, affected persons are mostly boys who have developmental delay or mental retardation of variable severity and who usually have another affected male maternal relative (e.g., maternal uncle). With rapid advances in genetics afforded by the Human Genome Project, it is now possible to detect some of the mutations known to cause mental retardation even before the child is born, leading to effective counseling and prevention strategies.
The complete sequence of the X chromosome was identified in 2005 and it confirmed that an unusually large number of its genes carry information for proteins important for brain functions. Most of the mutated genes in XLMR are thought to be intelligence genes that influence development, cell migration, formation and maintenance of neural networks, and cell-to-cell communication in the brain. The majority of the genes identified so far are linked to syndromic XLMR. It is now recognized that different mutations in the same gene can give rise to either S-XLMR or NS-XLMR.
Females have two X chromosomes and males have one X and one Y chromosome (which determines the male sex). The X chromosome in the male is always derived from the mother. A female uses only one of her two X chromosomes in each cell and randomly inactivates the other X chromosome. Thus, if only one of her X chromosomes has a defective gene, only some of her cells will suffer. The severity of XLMR in the female will consequently depend on the percentage of cells in which the mutated gene is expressed. On the other hand, men have only one X chromosome, so any defective brain genes from that chromosome are invariably expressed.
About 2–3% of the population has mental retardation due to genetic and non-genetic factors (e.g., birth injuries, infections, and developmental anomalies). XLMR is thought to account for approximately 20% of genetic causes of mental retardation and accounts for the 20–30% excess of mental retardation observed in males in comparison to females. Although accurate numbers are difficult to estimate, the prevalence of XLMR may be approximately one in 600 males and one in 400 female carriers.
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
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.
The diagnosis of XLMR should be considered in all children with autistic behaviors, mental retardation, developmental delay, or unexplained speech delay; 80–90% of patients with fragile X syndrome are not yet correctly diagnosed. Because the symptoms of fragile X can be quite subtle, especially in young children, and because it is so frequent in the general population, many medical specialists recommend testing for fragile X syndrome. This is, however, not a routine screening test for all children. Testing for FMR1 mutation is possible in people of any age and even before birth.
A variety of diagnostic tests based on DNA, chromosomal, or protein analysis is available. Chromosomal tests look for the fragile, or broken, portion of the X chromosome under a microscope, but are generally not very sensitive. Protein tests measure the amount of FMR protein produced by the cells and can determine the severity of the disorder. A DNA-based test to diagnose fragile X was developed in 1992 and is based on detecting an increased number of repeating units. This test is quite accurate, and it can detect both carriers and fully affected individuals. Samples from blood, hair root, or a scraping from inside the cheek can be used to carry out the test. In a pregnant woman, amniotic fluid or cells from the placenta, called chorionic villus, are used to detect the mutation. Similarly, genetic testing can be done in specialized laboratories for the other common gene mutations associated with XLMR, such as Rett's syndrome.
Currently, there is no cure for any of the conditions associated with XLMR. Best results are obtained when medications are combined with educational, social, and occupational therapy. Early intervention when the child's brain is still developing is advocated in order to maximize its long-term potential. A team comprising of a neurologist, genetic specialist, psychologist, behavioral specialist, physical, occupational, and speech therapists should work with the family and caregivers to ensure that the child receives appropriate therapy based on individual needs. This team can also assess the patient's level of independence and ensure appropriate transition from adolescent to young adult.
The U.S. Food and Drug Administration Agency (FDA) has not approved any specific medication for treatment of fragile X or its symptoms. But several medications have been tried on an empiric basis to ameliorate specific symptoms and problems associated with this disorder. Seizures and mood instability can be treated with drugs used primarily in epilepsy, such as carbamazepine, valproate, gabapentin, and topiramate.
The Individuals with Disabilities Act of 1997 ensures free education for children with mental retardation and special cognitive needs until high school or until they reach 21 years. This law also ensures that children are taught in a non-restrictive environment tailored to their special needs. Speech therapists can help in language acquisition and devise innovative ways for nonverbal communication. Occupational therapists can assist the child with adaptive equipment to help overcome physical disabilities. Physical therapists help in designing programs and activities to promote posture, gait, and balance. Behavioral therapists can work with the family and the child in identifying strategies and coping skills to deal with social situations and avoiding aggression.
The Fragile X Research Foundation (FRAXA) funds several endeavors to help find a cure for this disease. Ongoing research is focused on repairing the defective gene, replacing the defective gene, supplying the deficient protein, or substituting the deficient protein with another protein.
Children with fragile X syndrome have a fairly normal life expectancy. With early diagnosis and treatment, they can grow into independent individuals. Similarly, children with Rett's syndrome usually survive to adulthood and middle age.
Fenichel, Gerald M. Clinical Pediatric Neurology, 4th edition. Philadelphia: W.B. Saunders Company, 2001.
Check, Erika. "The X Factor." Nature 434 (March 2005): 266–267.
Ropers, Hilger H., and Ben C. J. Hamel. "X-linked Mental Retardation." Nature 6 (Jan. 2005): 46–57.
Wiesner, Georgia L., Suzanne B. Cassidy, Sarah J. Grimes, Anne L. Matthews, and Louise S. Acheson. "Clinical Consult: Developmental Delay/Fragile X Syndrome." Primary Care: Clinics in Office Practice 31 (2004): 621–625.
International Rett Syndrome Association. 9121 Piscataway Road, Clinton, MD 20735. (800) 818 RETT. (April 24, 2005.) <http://www.rettsyndrome.org>.
National Fragile X Foundation. P.O. Box 190488, San Francisco, CA 94119. (800) 688 8765. (April 24, 2005.) <http://www.nfxf.org>.
National Institute of Child Health and Human Development. P.O. Box 3006, Rockville, MD 20847. (800) 370 2943. (April 24, 2005.) <http://www.nichd.nih.gov>.
Fragile X Research Foundation (FRAXA). 45 Pleasant Street, Newburyport, MA 01950. (978) 462 1866. (April 24, 2005.) <http://www.fraxa.org/>.
National Institute of Child Health and Human Development (NICHD). "Families and Fragile X Syndrome." NICHD Publication No. 03-3402. 2004.
Chitra Venkatasubramanian, MBBS, MD