FANCONI ANEMIA ANIEMIA

BY : RAMYA RAYAPATI 15MSG0020

Fanconi anemia (FA) is a very rare genetic disease with an incidence of  1 in 160,000 individuals worldwide.

Fanconi anemia is a condition that affects many parts of the body. People with this condition may have bone marrow failure, physical abnormalities, organ defects, and an increased risk of certain cancers.

Fanconi anemia is the result of a genetic defect in a cluster of proteins responsible for DNA repair.

What genes are related to Fanconi Anemia :

Mutations in at least 15 genes can cause Fanconi anemia. Proteins produced from these genes are involved in a cell process known as the “FA pathway.”

The FA pathway is turned on (activated) when the process of making new copies of DNA, called DNA replication, is blocked due to DNA damage.

 The FA pathway sends certain proteins to the area of damage, which trigger DNA repair so DNA replication can continue.

The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs).

 ICLs occur when two DNA building blocks (nucleotides) on opposite strands of DNA are abnormally attached or linked together, which stops the process of DNA replication. 

ICLs can be caused by a buildup of toxic substances produced in the body or by treatment with certain cancer therapy drugs.

Eight proteins associated with Fanconi anemia group together to form a complex known as the FA core complex.

 The FA core complex activates two proteins, called FANCD2 and FANCI. The activation of these two proteins brings DNA repair proteins to the area of the ICL so the cross-link can be removed and DNA replication can continue.

Eighty to 90 percent of cases of Fanconi anemia are due to mutations in one of three genes, FANCA,FANCC, and FANCG.

 Mutations in any of the many genes associated with the FA core complex will cause the complex to be nonfunctional and disrupt the entire FA pathway.

 As a result, DNA damage is not repaired efficiently and ICLs build up over time.

The ICLs stall DNA replication, ultimately resulting in either abnormal cell death due to an inability make new DNA molecules or uncontrolled cell growth due to a lack of DNA repair processes. 

Cells that divide quickly, such as bone marrow cells and cells of the developing fetus, are particularly affected.

 The death of these cells results in the decrease in blood cells and the physical abnormalities characteristic of Fanconi anemia.

When the buildup of errors in DNA leads to uncontrolled cell growth, affected individuals can develop acute myeloid leukemia or other cancers.

How do people inherit Fanconi anemia?

Fanconi anemia is most often inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations.

The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Very rarely, this condition is inherited in an X-linked recessive pattern. The gene associated with X-linked recessive Fanconi anemia is located on the X chromosome

Other Functions of FA genes :

DNA Repair Cell Cycle control Oxygen sensitivity Apoptosis and Telomere maintenance Haemopoiesis

SIGNS AND SYMPTOMS : Low Birth Weight

Short Stature

This is a thirty year old boy suffering from Fanconi Anemia.

Café-au-lait spots

Absence of or malformity in hands and arms, for example the absence of a thumb or the presence of polydactyly .

Presence of only one kidney or of a horseshoe kidney

PATHOGENESIS

Clinically, hematological abnormalities are the most serious symptoms in FA. By the age of 40, 98% of FA patients will have developed some type of hematological abnormality.

However, there are a few cases in which older patients have died without ever developing them. Symptoms appear progressively, and often lead to complete bone marrow failure and many other diseases. 

Bone marrow failure :

Major haematological complication associated with FA is bone marrow failure, defined as inadequate blood cell production.

Detection of decreasing blood count is generally the first sign used to assess necessity of treatment and possible transplant. 

Patients are initially responsive to androgen therapy and haemopoietic growth factors, these have been shown to promote leukemia,  and have severe side effects, including hepatic adenomas and adenocarcinomas

Acute myeloid leukemia :

FA patients are at elevated risk for the development of acute myeloid leukemia (AML), defined as presence of 20% or more of myeloid blasts in the marrow or 5 to 20% myeloid blasts in the blood.

Myelomonocytic and acute monocytic are the most common subtypes observed. Many MDS patients will evolve into AML.

Furthermore, the risk of developing AML increases with the onset of bone marrow failure.

Although risk of developing either MDS or AML before the age of 20 is only 27%, this risk increases to 43% by the age of 30 and 52% by the age of 40.

Myelodysplastic syndromes

MDS, formerly known as preleukemia, are a group of bone marrow neoplastic diseases that share many of the morphologic features of AML.

Changesin erythroid, granulocytic and megakaryocytic precursors, than what is usually seen in cases of AML. These changes results in delayed apoptosis or a failure of programmed cell death. When left untreated, MDS can lead to AML in about 30% of cases. 

SCREENING DEB test (diepoxybutane analysis.) MMC test Prenatal screening Carriers of Fanconi Anemia

Blood test Rapid means of screening population at large

Immunoblotting and immunofluorescence Subtyping

Retroviral vectors

DIAGNOSIS DEB and MMC tests

Diagnosis typically occurs before the age of twelve (Fanconi Anemia Research Fund, Inc., 2006).

MMC test is used to diagnose Fanconi Anemia at the University of Kentucky.

Subtyping via use of retroviruses needs to be incorporated into standard protocol when diagnosing a patient with Fanconi Anemia.

TREATMENT Retrovirus mediated gene tranfer

Lentivirus mediated gene transfer

RISKS OF GENE THERAPY Retrovirus potential to stimulate oncogenes.

Lentivirus association with arthritis and encephalitis in goats, leukemia in cattle, anemia in horses, and immunodeficiency in cats, cattle, primates, and humans.

GENETIC COUNSELINGProvide knowledge about:

What Fanconi Anemia isWhat symptoms are associatedWho can be affectedWhat the disorder means for the future of the individualWhat treatments are available and their risks and benefitsImportance of screening other family members at risk

SUMMARY Fanconi Anemia is an autosomal recessive disorder that

predisposes individuals to a variety of cancers.

Screening techniques exist, such as the DEB and MMC tests, that should be used to screen the population at large.

Subtyping of which FA gene(s) is (are) mutated should become standard protocol with diagnosis.

Gene therapy may someday eliminate Fanconi Anemia.