Fragile X and X-linked intellectual disability: four decades of discovery.

X-Linked intellectual disability (XLID) accounts for 5%-10% of intellectual disability in males. Over 150 syndromes, the most common of which is the fragile X syndrome, have been described. A large number of families with nonsyndromal XLID, 95 of which have been regionally mapped, have been described as well. Mutations in 102 X-linked genes have been associated with 81 of these XLID syndromes and with 35 of the regionally mapped families with nonsyndromal XLID. Identification of these genes has enabled considerable reclassification and better understanding of the biological basis of XLID. At the same time, it has improved the clinical diagnosis of XLID and allowed for carrier detection and prevention strategies through gamete donation, prenatal diagnosis, and genetic counseling. Progress in delineating XLID has far outpaced the efforts to understand the genetic basis for autosomal intellectual disability. In large measure, this has been because of the relative ease of identifying families with XLID and finding the responsible mutations, as well as the determined and interactive efforts of a small group of researchers worldwide.

Fragile X Syndrome: Introduction.

Fragile X syndrome (FXS) is one of the most common reasons for intellectual disability (ID). First described in the 1940s, it took many years to understand the disease. The awe-inspiring breakthroughs in both science and technology facilitated the recognition of the unique inheritance pattern and the genetic mechanism of fragile X. In this chapter we describe the history and evolution of our understanding of FXS as mirrored by advances in genetics.

Forty years from markers to genes.

There have been incredible advances made in human genetics over the past 40 years. I have set out in the next few pages to describe just some of these changes and to illustrate how they unfolded through my own experiences.

Fragile X families in a northern Swedish county--a genealogical study demonstrating apparent paternal transmission from the 18th century.

Eleven families including 35 cases with fra(X) mental retardation (MR) were traced genealogically using the Research Archives at Umeå University. Seven of the cases were women with fra(X). All of the families originated partly or totally from the county of Västerbotten. It was possible to link 7 of the index families to common ancestors over an 8-11 generation span. The remaining 4 families were not traced to the same ancestors. However, they were linked together pair-wise over a 7-8 generation span. Transmission of the fra(X) mutation was studied in these families. In the pedigree analyses, priority was given to maternal transmission. In 2 families the fra(X) mutation was transmitted solely through females over 7 or 8 generations respectively. Within 9 families the mutation was transmitted by males in 2-5 generations in order to reach common ancestors.

Fragile X families in a northern Swedish county: a genealogical study of possibly affected individuals in the nineteenth century.

Most studies of fragile X [fra(X)] families are able to document mental impairment only by family history. Using Swedish historical archives and the unique parish catechetical meeting records it is possible to document qualitative phenomena such as literacy for over 100 years. In this way it was possible to identify 7 individuals with mental retardation living in the nineteenth century in an earlier published fra(X) pedigree. Four of them were female. At the present time another 4 severely mentally retarded females with the fra(X) syndrome have been diagnosed in this family. The high prevalence of mentally retarded females might indicate a variant form of the fra(X) syndrome in this family.

Sixty years of X-linked mental retardation: a historical footnote.

X-linked mental retardation (XLMR) is a most exciting field of modern medical genetics. It made spectacular advances over the last twenty years, after the advent of molecular genetics. The discovery of the FMR1 gene unraveled the cause of the most common form of heritable mental retardation and provided the prototype of dynamic mutations. New genes continue to be mapped to the X chromosome and more and more are being cloned and characterized, clarifying the nosology of XLMR and, more importantly, adding to our understanding of the mechanisms of intellectual development, normal and abnormal. Looking back to a more or less recent past may provide clues for future discoveries.

The fragile X syndrome: history, diagnosis, and treatment.

The fragile X (marker X) syndrome is a relatively common form of X-linked mental retardation. The karyotypic hallmark of the syndrome consists of a pronounced constriction near the terminus of the long arm of the X chromosome (fragile site), expressed in vitro only under conditions where thymidylate production is blocked (reduced folate levels and/or addition of methotrexate or 5-fluorodeoxyuridine). Clinical features associated with the syndrome include macroorchidism, large or prominent ears, and significant emotional dysfunction. In the present review, historical, diagnostic, biochemical, and clinical aspects of this syndrome are presented. Recent anecdotal reports of clinical improvement following high dose folic acid treatment will be discussed.

[A historical description of the association of macro-orchidea, mental retardation and cranial dysmorphia in males (fragile X chromosome syndrome) by A.B. Richerand]. / Descripción histórica de la asociación de macroorquidia, retraso mental y dismorfia craneal en varones (síndrome del cromosoma X frágil) por A.B. Richerand.

INTRODUCTION: Anthelme Baltasar Richerand practiced medicine as Chief Surgeon of the Hospital de S. Luis in Paris and was professor of the Faculty of Medicine of that city during the first quarter of the XIX century. His greatest work was titled Nouveaux Eléments de Physiologie, a book considered to be the standard work on physiology of its time and was translated into several languages, including Spanish. DEVELOPMENT: In chapter CLV of this work there is the first description of associated macro-orchidia and mental retardation in males, with respect to three cases attended by the author. CONCLUSIONS: The fragile X chromosome syndrome is the commonest cause of hereditary male mental retardation associated with macro-orchidia. It is also known as the eponymous syndrome of Martin-Bell in honour of the first description published by these authors in 1943. However, the first recognition of the association of macro-orchidia with mental retardation in males was by Richerand at the beginning of the XIX century.

Visualizing carrier status: fragile X syndrome and genetic diagnosis since the 1940s.

What does it look like to be the carrier of a genetic disease? Carrier status may be determined through the visual analysis of both genotypic and phenotypic evidence. Over the past 70 years, clinical geneticists have depended upon multiple strategies for identifying disease carriers within a family. This has included pedigree analysis, which was based upon clinical observations of individual family members and, in recent decades, cytogenetic and molecular methods. Newer techniques have offered novel opportunities to actually see the suspected etiological markers of certain genetic diseases, such as Fragile X syndrome. The visualization of these markers has both clarified and confused previously observed inheritance patterns, in some cases leading to the development of newly distinct diagnostic categories. As a result, what it means to be affected by, or the carrier of, a genetic disease has continuously evolved.