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Myelokathexis
From Wikipedia, the free encyclopedia

Myelokathexis is a congenital disorder of the white blood cells that causes severe, chronic leukopenia (a reduction of circulating white blood cells) and neutropenia (a reduction of neutrophil granulocytes). The neutropenia derives from the accelerated apoptosis of the neutrophil precursor. This phenotype is observed due to abnormal expression of genes implicated in the apoptotic pathway. There are also cases of myelokathexis characterized by high expression of CXCR4 (a chemokine receptor and neutrophil retention factor) which will lead to "defective neutrophil egress from bone marrow". The mutations in either the apoptotic pathway or the CXCR4 gene resulting in myelokathexis is inherited in an autosomal dominant manner.

Symptoms and lethality
Patients with myelokathexis show recurrent bacterial and fungal infections, most commonly sinopulmonary and cutaneous infections. Total leukocyte count was less than 1.0 x 109 and absolute neutrophil count ranged from 0 to 0.5 x 109/L. Depending on the severity, individuals affected can live well into adult years, suggesting mutations in genes leading to myelokathexis are not necessarily neonatal lethal. Younger patients observe hypogammaglobulinemia (susceptibility to infections that would have been typically fought off by antibody responses).

Mechanistic pathway
Cell death pathway is regulated by both pro apoptotic and anti-apoptotic factors. In the case of myelokathexis, the protein products of the proto-oncogenes bcl-x and bcl-2 are key factors in characterizing the symptoms of this disorder. Bcl-x, a regulator of apoptosis in the hematopoietic system is down regulated in the bone marrow-derived granulocyte precursor cells in patients with myelokathexis. The neutrophil precursor population showed 50-60% of cells to be in the stages of apoptosis characterized by membrane blebbing, condensation of heterochromatin and cell fragmentation.

Separate from the apoptotic pathway, myelokathexis is demonstrated in individuals with a missense mutation in the C-terminus of the CXCR4 gene leading to a gain of function in this chemokine receptor. The increased expression of the receptor leads to the hyperactivity of signaling from its ligand, CXCL12. Although the exact mechanism for causing myelokathexis through this pathway is not fully explained, it is hypothesized that this leads to a downstream of events eventually resulting in disruption of the immunological pathway.

Treatment
Treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) is shown to be successful in treating some cases of myelokathexis. Bcl-x expression was nearly absent before G-CSF treatment and increased significantly to comparable levels of a healthy person.

Treatment of myelokathexis with plerixafor is also shown to be effective when treating patients with the gain of function mutation in the CXCR4 receptor. The molecule acts an antagonist to the receptor to relieve the symptoms associated with hyperactivity of the receptor.