10. Siegel, L. (1984) ‘Home environmental influences on cognitive development in preterm and full-term children during the first 5 years.’ In Gottfried, A., Gottfried, A. (Eds.) Home Environment and Early Cognitive Development. New York: Academic Press. pp. 197-234. 1 1 . Hawdon, 3 . M., Hey, E., Kolvin, 1.. Fundudis, T. (1990) ‘Born too small-is outcome still affected?’ Developmental Medicine and Child
Neurology, 32, 943-953. 12. Field, T. (1983) ‘Early interactions and interaction coaching of high-risk infants and parents.’ In Perlmutter, M. (Ed.) The Minnesota Symposia in Child Psychology, Vol. 16. Hillsdale, NJ: Erlbaum. pp. 1-34. 13. Infant Health and Development Program (1990) ‘Enhancing the ou!comes of low-birthweight, premature infants. Journal of !he American Medical Association, 263, 3035-3042.
The Fragile X Syndrome
that appeared to be sex-linked. MARTIN and BELL’ described a pedigree of mental retardation in males that showed sex linkage. In 1969, LUBS*, through serendipidy and insight, first described the fra (x) marker when using a tissue medium to elicit the fragile site in a family in which there were two males and an apparently unaffected female with what later became known as the fra (x) syndrome. During the next few years several laboratories were unable to replicate his findings, exce t in Australia. However, SLITHERLAND’ solved the mystery by demonstrating that the expression of the fragile site on the x chromosome depended on the type of culture medium used, specifically one in which folic acid and thymidine were restricted. This then opened the way for investigators to re-evaluate X L M R . TURNERand colleagues” identified Xlinked mental retardation associated with macro-orchidism, which was not associated with any hormonal abnormalities. Later, TURNERand colleagues” and SUTHERLAND and ASHFORTH”documented the association between mental retardation and macro-orchidism and the fra (x) chromosome. Finally, RICHARDS and colleague^^^^ l4 re-evaluated the Martin and Bell pedigree and were able to show both macro-orchidism and the cytogenetic marker on the x chromosome which, with the recent sequencing of the gene at the fragile site, brings this intriguing history full circle. The involvement of females was recognized even in the Martin-Bell pedigree, with ‘slowness’ described in some of the females. More detailed studies in the 1980s have shown that approximately 50
THE syndrome characterized by the
fragile x (fra x) chromosome is the most common human chromosomal anomaly associated with heritable mental retardation, and the second most frequent chromosomal cause of mental retardation after Down syndrome’. Its description and genetic delineation indeed reflect the most recent advances in cytogenetics and molecular biology, which have culminated in the identification and mapping of the gene at the fragile x site, ~ q 2 7 . 3 * . The ~. purpose of this annotation is to present a historical overview of the syndrome, to describe the physical, histological, behavioral, and cognitive characteristics of affected individuals, to present some of the most recent cytogenetic findings, and to review the management of fra (x) patients.
826
Historical background Since the latter part of the nineteenth century, it has been noted that a large number of mentally retarded individuals are males4sS. However, for many years no genetic explanation was provided for this finding until LEHRKE,in his 1969 Ph.D. thesis, and whose hypothesis was later published in 19726, argued that this phenomenon was due to x-linked genes and that x-linked mental retardation (XLMR) was responsible for a large proportion of mental retardation. It is of interest that before Lehrke’s work, others described a pattern of mental retardation
per cent of heterozygotes do not demonstrate the fra (x) chromosome cytogenetically and are usually unaffected”. Of the cytogenetically positive girls, 25 per cent are intellectually impaired, with an intelligence quotient (la)
Neurology, 32, 943-953. 12. Field, T. (1983) ‘Early interactions and interaction coaching of high-risk infants and parents.’ In Perlmutter, M. (Ed.) The Minnesota Symposia in Child Psychology, Vol. 16. Hillsdale, NJ: Erlbaum. pp. 1-34. 13. Infant Health and Development Program (1990) ‘Enhancing the ou!comes of low-birthweight, premature infants. Journal of !he American Medical Association, 263, 3035-3042.
The Fragile X Syndrome
that appeared to be sex-linked. MARTIN and BELL’ described a pedigree of mental retardation in males that showed sex linkage. In 1969, LUBS*, through serendipidy and insight, first described the fra (x) marker when using a tissue medium to elicit the fragile site in a family in which there were two males and an apparently unaffected female with what later became known as the fra (x) syndrome. During the next few years several laboratories were unable to replicate his findings, exce t in Australia. However, SLITHERLAND’ solved the mystery by demonstrating that the expression of the fragile site on the x chromosome depended on the type of culture medium used, specifically one in which folic acid and thymidine were restricted. This then opened the way for investigators to re-evaluate X L M R . TURNERand colleagues” identified Xlinked mental retardation associated with macro-orchidism, which was not associated with any hormonal abnormalities. Later, TURNERand colleagues” and SUTHERLAND and ASHFORTH”documented the association between mental retardation and macro-orchidism and the fra (x) chromosome. Finally, RICHARDS and colleague^^^^ l4 re-evaluated the Martin and Bell pedigree and were able to show both macro-orchidism and the cytogenetic marker on the x chromosome which, with the recent sequencing of the gene at the fragile site, brings this intriguing history full circle. The involvement of females was recognized even in the Martin-Bell pedigree, with ‘slowness’ described in some of the females. More detailed studies in the 1980s have shown that approximately 50
THE syndrome characterized by the
fragile x (fra x) chromosome is the most common human chromosomal anomaly associated with heritable mental retardation, and the second most frequent chromosomal cause of mental retardation after Down syndrome’. Its description and genetic delineation indeed reflect the most recent advances in cytogenetics and molecular biology, which have culminated in the identification and mapping of the gene at the fragile x site, ~ q 2 7 . 3 * . The ~. purpose of this annotation is to present a historical overview of the syndrome, to describe the physical, histological, behavioral, and cognitive characteristics of affected individuals, to present some of the most recent cytogenetic findings, and to review the management of fra (x) patients.
826
Historical background Since the latter part of the nineteenth century, it has been noted that a large number of mentally retarded individuals are males4sS. However, for many years no genetic explanation was provided for this finding until LEHRKE,in his 1969 Ph.D. thesis, and whose hypothesis was later published in 19726, argued that this phenomenon was due to x-linked genes and that x-linked mental retardation (XLMR) was responsible for a large proportion of mental retardation. It is of interest that before Lehrke’s work, others described a pattern of mental retardation
per cent of heterozygotes do not demonstrate the fra (x) chromosome cytogenetically and are usually unaffected”. Of the cytogenetically positive girls, 25 per cent are intellectually impaired, with an intelligence quotient (la)
