X-Linked Mental Retardation Health Article

Definition

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.

Description

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.

Genetic profile

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.

Demographics

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.