Pathophysiology
Mutations in the BLM gene, which is a member of the RecQ DNA helicase family, are associated with Bloom syndrome. DNA helicases are enzymes that unwind the two strands of a duplex DNA molecule. DNA unwinding is required for most processes that involve the DNA, including synthesis of DNA copies, RNA transcription, DNA repair, etc.
When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. The mutations in the BLM gene associated with Bloom's syndrome inactivate the BLM protein's DNA helicase activity or nullify protein expression (the protein is not made). Lack of BLM protein or protein activity leads to an increase mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.
Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom's syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom's syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.
Bloom's syndrome is inherited in an autosomal recessive fashion. Both parents must be carriers in order for a child to be affected. The carrier frequency in individuals of Eastern European Jewish (Ashkenazi Jewish) ancestry is about 1/100. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. As a consequence of this inheritance, the syndrome affects males and females equally; however, females are perhaps slightly under-diagnosed as the skin lesion can be perhaps less severe in females. Genetic counseling and genetic testing is recommended for families who may be carriers of Bloom's syndrome. For families in which carrier status is known, prenatal testing is available using cytogenetic or molecular methods. Molecular DNA testing for the mutation that is common in the Ashkenazi Jewish population is also available. There is currently no evidence to suggest that the symptoms of Bloom syndrome vary depending on the types of mutations a person inherits.
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