LAM Treatment Alliance Fast Tracking Treatment Research

LAM is a disease that kills women from all races, classes and countries -- primarily while in their child bearing years. It affects the lungs, kidneys, lymphatic system, and at times the brain. There is no known cure, but we are working hard to find one. Learn More About LAM

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About LAM Science

LAM and TSC

LAM and Tuberous Sclerosis Complex (TSC), are clearly related, and two genes have been identified that result in manifestations of TSC that also have relationships with LAM--the TSC1 gene on chromosome 9 and the TSC2 gene on chromosome 16. To date, the genotypic data from individuals with sporadic LAM have implicated the TSC2 gene in the disease, although there are some individuals with TSC who have a mutation in the TSC1 gene who have been diagnosed with LAM.

It is likely that having either or both diseases is a matter of low-level mosaicism. The LAM Treatment Alliance and the TS Alliance are currently supporting efforts to use 454 Life Sciences sequencing technology to find the mutation of the TSC gene in patients even when it is present in <10% of the cells in any given cell population (from lung, chyle* etc). that mutational information will be made accessible to the interested research community as soon as it is available. It is possible that other disease causing or modifying genetic changes in both diseases have not yet been identified.

*Chyle is a fluid consisting of a mixture of lymphatic fluid (lymph) and chylomicrons that has a milky appearance. Chylomicrons are small fat globules composed of protein and lipid (fat) which are combined in the lining of the intestine. Chylomicrons are found in the blood and in lymphatic fluid where they serve to transport fat from its port of entry in the intestine to the liver and to adipose (fat) tissue.

LAM and Women

There is a clear sex difference in the incidence of LAM with an estimated 100% of the cases of sporadic LAM occurring in women, and only rare cases of pulmonary LAM occurring in men with TSC. Recent studies have shown that 30% to 40% of women with TSC have radiological signs of LAM. It is not clear what the natural history of LAM is in these women since routine lung screening to pick up asymptomatic disease is relatively recent and prior to that only women with TSC and symptomatic pulmonary disease would be diagnosed with LAM.

The Role of Hormones

The role that hormones / hormone producing organs/ structures play in causing, triggering or exacerbating the onset and progression of disease in individuals with LAM is unclear. Since many women with TSC and LAM, and some women with sporadic LAM, will remain asymptomatic, even during puberty, pregnancy and menopause, hormones may play a role in disease progression, but they are clearly not the only cause. Likewise, the fact that continued decline in pulmonary function has been observed in some pre and post menopausal women with sporadic LAM who have undergone oophorectomy (the removal of one or both ovaries by surgery, also known as ovariectomy) seems to call for other explanations for disease progression. For women with sporadic LAM, it remains unclear if hormones are a trigger of disease, if there is another trigger that may account for observed progression during pregnancy (perhaps the stress of pregnancy), hypoxia, or other factors cause the onset or exacerbation of symptoms in previously asymptomatic individuals. Some women do not seem to have experienced progression of their disease despite giving birth to one or more children.

The Cell of Origin

The cell of origin is not currently known in LAM and TSC. The heterogeneous cells found in the lungs of individuals with LAM are thought to go on to cause destruction of surrounding lung tissue, cysts and declining lung function. It is also unclear what the cell of origin is for the cells found in the angiomyolipomas (AMLs) in the kidneys (and livers), retroperitoneum, blood, urine, lymphatics and lymph nodes in both individuals with LAM and TSC.

LAM cells throughout the body are currently identified by the gold standard - loss of heterozygosity or LOH for TSC1/2. Other phenotypic cell markers vary depending on the location of these cells. The fact that cells with the same genetic mutation can be found in both the lung and the kidney of women with LAM, and that LAM cells with this same mutation can be found in the transplanted lungs from male donors led to the model of benign metastatic spread from the kidney to the lungs. But since not all women with LAM have kidney lesions, the search for the cell of origin and even a primary lesion has continued with important implications for effectively treating LAM and TSC. The current thinking in the field is that the LAM cell has evolved or differentiated from a Neural Crest Stem Cell origin. We are actively supporting work that might validate this hypothesis. Doing so has strong implications for modeling and effectively treating the disease.