Mental Retardation
Mental retardation is defined by subnormal scores on standardized testing. Intelligence quotient (IQ) cutoffs of 90, 70, and 50 are commonly considered to be the boundaries for mild, moderate, and severe mental retardation.
Population Genetics
Twin studies performed 40–60 years ago showed an MZ twin concordance of 100% (N = 83) and a DZ twin concordance of 55% (N = 10). These studies would undoubtedly be performed today with separation according to specific etiologies. Adoption studies have not been performed.
The recurrence of risk (ie, the risk to siblings of an affected child) for mental retardation has been estimated at 9.5–23%, depending on severity of the disorder and the mother’s reproductive history. For mothers who have already had more than one retarded child, the risk is 25–50% for siblings.
Specific Etiologic Causes
Many medical syndromes are manifest as mental retardation, such as specific errors of metabolism and chromosomal anomalies. It is estimated that 4% of human conceptions are chromosomally abnormal but that 85–90% of these are selectively eliminated as spontaneous abortions. Of live births, 6% may have a genetic or developmental abnormality of some type, including 0.5% surviving with a chromosomal abnormality, 4% with another developmental anomaly, and 1.5% with a single-gene disorder of some type. Single-gene causes of mental retardation include dominant diseases (eg, tuberous sclerosis, neurofibromatosis, Sturge-Weber syndrome, Hippel-Lindau disease, and craniosynostosis), recessive diseases (Hurler’s syndrome, Hunter’s syndrome, galactosemia, G-6 phosphodehydrogenase deficiency, and familial hypoglycemia), and several recessive aminoacidurias and lipid-related disorders. Many more are listed in McKusick’s compendium Mendelian Inheritance in Man.
If we consider disorders that cause mental retardation according to their frequency in the population, we may see the following: (1) Down syndrome accounts for mental retardation in 1.5 persons per 1000 and is the most common single cause of the condition. The prevalence of Down syndrome varies greatly and is determined primarily by maternal age. (2) Familial microcephaly is present in about 1 out of 40,000 births but may account for a significant proportion of mental retardation because of effects in heterozygotes. (3) Fragile X syndrome accounts for about 0.5 out of 1000 births, and other X chromosome syndromes account for another 1 out of 1000 births. (4) All metabolic causes together are responsible for 1 out of 1000 births, and chromosomal abnormalities account for 3 out of 1000 births. We discuss Down syndrome and fragile X syndrome here.
Down Syndrome
Down syndrome is caused by a triplication of genetic material on a portion of chromosome 21. The area is presently being localized precisely using molecular techniques combined with cytogenetics. Sections of 21q22.2 and 21q22.3 are likely involved, although some research implicates 21q21. The areas implicated include genes for amyloid and superoxide dismutase. The ETS-2 protooncogene is also near this area, and its presence may be related to an increased incidence of leukemia in persons with Down syndrome and their relatives. Human 21q21–22.3 is homologous to portions of mouse chromosome 16. A mouse model of Down syndrome has been developed based on a laboratory-generated translocation involving this area.
The reasons for triplication, or nondisjunction, in Down syndrome are not entirely clear. The likely etiologic factors are environmental rather than genetic, and vulnerability for the condition does not seem to be inherited. A small proportion of patients with Down syndrome have a translocation rather than a triplication.
As noted previously, the clearest correlate is maternal age; yet it has been known for some years that the origin of the nondisjunction may be paternal instead of maternal. Serum markers (eg, decreased-fetoprotein and estriol and increased human chorionic gonadotropin) may be able to contribute to prenatal determination and may aid in the selection of women for referral to amniocentesis.
It has been reported that an association exists between Alzheimer’s disease and Down syndrome within certain families, but this does not seem to be generally true.
Fragile X Syndrome
Fragile X syndrome is named after a cytogenetic observation in which cultured cells from some patients show chromosomal breakage under appropriate conditions. Human chromosomes actually have multiple fragile sites. Fragile X syndrome (breakage at Xq27.3) is merely the best known. The syndrome itself was originally described by Martin and Bell, who described a large pedigree with mental retardation segregating in an X-linked recessive pattern.
Fragile X syndrome is the most common form of X-linked mental retardation and is, in general, the most common heritable form (Down syndrome is genetic but not inherited). It is estimated that 1 out of 850 persons carry the defect. Of those, 4 out of 5 males will express the clinical phenotype, compared to 1 out of 3 females (thus some homozygotes are nonpenetrant and some heterozygotes are penetrant). Tests are now available to determine carrier status in nonpenetrant individuals; the error rate should now be 5% or less with available probes and new polymorphisms that are being developed at a rapid rate. The precise genetic error in the Xq27.3 region is now known to be a triplet repeat of variable length. More repeats (associated with greater severity of illness) occur as the gene is passed to succeeding generations. When the number of repeats exceeds a threshold, clinical manifestations are seen.
Most female heterozygotes do not have mental retardation; however, schizotypal features have been demonstrated in about one third of a sample of carriers, and a weaker association was found with chronic or intermittent affective disorders. Several studies have suggested a connection with autistic disorder. One study described a family in which fragile X syndrome segregated with bipolar affective disorder; data were consistent with linkage to the Xq27 area.
