“Disorders of DNA Repair: When the Lifeguard of the Gene Pool Goes on Strike” – 3/8/14 – Victor Wang

On Tuesday, February 11, Dr. Kenneth Kraemer of the Dermatology Branch at the National Cancer Institutes and NIH spoke to students and faculty during the weekly seminars in the Biochemistry department. The focus of his lecture was on two extremely rare genetic disorders, Xeroderma Pigmentosum (XP) and Trichothiodystrophy (TTD). Roughly translating to “dry skin” and “brittle hair,” respectively, both skin disorders result from a defect in the body’s nucleotide excision repair. In the case of XP, there are roughly 1 in 1 million individuals in the United States that are affected, while in Japan that number is as high as 1 in 20 thousand. This disease affects people of all races and genders, and can result in extreme sun freckling and sun sensitivity as early as the infant years, while cancers can rapidly manifest by the age of 9. The high rates of XP in Japan are attributed to a supposed founder mutation that entered the gene pool about 100 generations, or 2000 years, ago. Although it is a recessive disorder, it is unclear why it has remained in the gene pool thus far. Currently, no known heterozygous advantage has been identified. XP symptoms are largely caused by a defective response to UV radiation. Patients show sun sensitivity, a 10,000-fold increase in cancer and skin pigmentation rates, ocular abnormalities and some neurologic abnormalities.

The median age of onset of nonmelanoma skin cancer in XP patients is 9 years of age, compared to 67 years in the general population, while that of melanoma is 22 years, versus 55 years in the general population. This large difference in the age of onset suggests a different mechanism of induction between the two cancers. XP patients have a 38-year reduction in average lifespan compared to the general population. They show signs of enlarged ventricles in the brain and some show neurologic degeneration with cachexia, or a severe form of metabolic wasting. The causes for these phenomena are unknown, but one hypothesis points to the presence of cyclopurines: without the normal nucleotide excision repair in the body, endogenous forms of oxidative damage can further cause unrepaired damage to the body.

It has been reported that some TTD patients show collodian membranes at birth, brittle scalps and eyebrow hair, tiger-tail banding of the hair, spoon-shaped nails and dysmyelination. TTD patients are not particularly cancer prone, but they also exhibit ocular and neurologic abnormalities. Much of the mechanism of how these symptoms arise is unknown. Because these diseases are so rare, it is difficult to find a significant population to test hypotheses. What is known is that there is some form of UV hypersensitivity involved with XP, while there is some form of developmental defect in TTD.

Support groups have been designed for XP patients, as well as customized forms of sun protection suits. One patient’s suit was so effective that it actually led to a deficiency in Vitamin D and broken bones because of the lack of sunlight. Today, physicians know to give Vitamin D supplements to these patients. Another remarkable surgical method was successful in extending an XP patient’s life past the age of 60. To remove all of the man’s face skin tumors, they replaced it with skin from his abdomen, which was largely shielded by the sun. With proper sun protection, no new cancers arose on his face. Lastly, preliminary experiments have shown that the oral Isotretinoin retinoid, Accutain, which is also used to treat acne, has been shown to prevent new skin cancer formation in XP patients, with some side effects including dry skin and cheilitis, or inflammation of the lips. Taken together, although genetic disorders are rare, investigating these conditions can help reveal the mechanisms of normal function. These individuals still require the help and support of the scientific and medical communities.

Leave a Reply