Background: Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive disorder characterized by albinism, mucocutaneous bleeding, and storage of ceroid material in macrophages (Hermansky and Pudlak, 1959). Many of these patients develop pulmonary fibrosis and colitis from which about 68% eventually die (Witkop et al, 1990). Patients that are not easily identified by physical characteristics (mostly HPS-3 patients) may have serious hemorrhagic complications when suffer severe injuries or surgical interventions. HPS is a rare disease worldwide, but it is the most common single-gene disorder among persons of Puerto Rican descent (Witkop et al, 1990). Two founder mutations (HPS-1 and HPS-3) account for most HPS cases in Puerto Rico (PR). The first one is widely prevalent in the Northwestern region (Oh et al, 1996) and the other (HPS-3) appeared in a small mid-central region of the island (Anikster et al,2000). HPS-3 patients usually present minimal skin pigmentation deficiency and thus diagnosis of albinism often is missed. Visual acuity problems often are detected late in infancy and childhood. This usually results in poor school progress, late diagnosis and treatment of patients, and delayed counseling of parents. Objective: To determine the prevalence of HPS-3 in Puerto Rican (PR) newborns using DNA pooling technique. Design/Methods: An aleatory sample of 4,690 PR infants born in 2005 (representing approximately 10% of annual PR births) was tested for the HPS-3 mutation, using DNA extracted from dried blood samples (Drocopoli et al, 1996). PCR analysis was carried out as described (Oh et al, 1996; Anikster et al,2000). Samples were tested in DNA pools of 5 newborns each. The validation of the PCR pooling technique for HPS-3 had been carried out in earlier studies in our laboratory by testing 1,500 newborn dried blood samples individually and in 300 total 5-sample pools. All positive samples detected individually were also unequivocally identified as positive when tested in pools. Results: Among the 4,690 newborns tested, 56 presented the HPS-3 mutation and they were confirmed in repeated testing. Two newborns were found to be HPS-3 homozygous. This finding was confirmed several times. The HPS-3 carrier frequency in the island-wide newborn population was 1:84 (1.19%). Both homozygous infants were born close to but outside of the high prevalence region previously reported in PR (Anikster et al,2001). Forty five percent of infants heterozygous for the HPS-3 mutation and one homozygous were found in the high prevalence area and the surrounding 10 miles radius; the other 56% of cases were distributed throughout the rest of the island. Conclusions: Our study has shown that the high prevalence area previously described by Anikster et al, where the founder mutation was identified has been spreading out throughout the rest of the island. Apparently, this is the result of rapid mobility of the Puerto Rican population during the last decades. Our data also demonstrate that the relatively high prevalence of the HPS-3 mutation (1.19%) justifies universal newborn screening. The use of DNA pooling reduces time and labor in newborn screening thus facilitating early diagnosis and treatment of children with HPS-3 and the provision of genetic counseling to patient’s parents and relatives.

Background Hermansky-Pudlak Syndrome (HPS) is an autosomal recessive disorder characterized by albinism, mucocutaneous bleeding, and storage of ceroid material in macrophages1. Patients that are not easily identified by physical characteristics (mostly HPS-3 patients) may have hemorrhagic complications with trauma or surgery. Objective To determine the prevalence of HPS-3 in Puerto Rican newborns using DNA pooling technique. Design/Methods Twelve percent of annual Puerto Rican births were tested randomly by PCR for the HPS-3 mutation, using pooled DNA extracted from dried blood samples. Results HPS-3 mutation was detected in 75 samples. Two newborns were found to be homozygous. Carrier frequency was 1:85 (1.18%). Conclusions The HPS-3 carrier frequency found (1.18%) justifies universal newborn screening in Puerto Rico. DNA pooling reduces time and labor in newborn screening thus facilitating early diagnosis and treatment of children with HPS-3 and the provision of genetic counseling to parents and relatives.

4944 Introduction: The clinical efficacy of doxorubicin is severely limited by its cardiotoxicity. Antioxidants represent the largest class of chemicals examined as potential protective agents and for which there is continuing interest. Dexrazoxane is the current agent used for the control of doxorubicin related cardiotoxicity. However, in large trials the incidence was reduced only by 50% (1). Vitamin E, a known antioxidant and free radical scavenger agent, has been evaluated in the past as a cardio protective drug in animal models receiving doxorubicin but contradictory conclusions regarding this effect have been reported (2, 3). We hypothesized whether Vitamin E has an effect in cardioprotection in rats receiving doxorubicin. Design and Methods: Three groups of 6 Rats each were used for the experiment. Group 1 received doxorubicin 1.5mg/kg intraperitoneally (IP) weekly for 9 weeks for a total cumulative dose of 13.5mg/kg. Group 2 received Vitamin E 100 IU/kg/weekly by IP injection, 48 hours prior to the doxorubicin. Group 3 received 0.5 cc of saline solution 0.9% IP weekly for 9 weeks as control group. Functional parameters including plasmatic nitric oxide (NO) levels and cardiac ejection fraction (EF) were determined on each group at the end of the experiment. Results: Doxorubicin treatment significantly increased plasmatic NO concentration when compared with controls (35.30 ± 5.63 mM vs. 14.72 ± 2.66 mM, n=6, P=0.016); however, in the group of rats receiving Vitamin E prior to doxorubicin, NO did not have a significant decrease (from 35.30 ± 5.63 mM to 31.77± 8.91 mM n=6, P=0.75). Regarding EF, doxorubicin treatment decreased EF significantly when compared with saline controls rats (59 ± 5.61% vs. 77 ± 3.89 %, n=6, P<0.05); however, in the group of rats receiving Vitamin E prior to doxorubicin, EF did not have a significant improvement (from 59 ± 5.61% to 69.17 ± 4.4, n=6, P=0.24). Conclusion: These results suggest that Vitamin E does not prevent or reduce cardiac injury in rats treated with doxorubicin. Different alternatives including other antioxidants could be explored in an attempt to decrease cardiotoxicity produced by doxorubicin and to improve the effect of the standard cardioprotective agent used Dexrazoxane. Further studies are necessary. References: 1. Swain SM. Adult multicenter trials using dexrazoxane to protect against cardiac toxicity. Semin Onco 1998; 25 (4 Suppl 10):43-7 2. Breed JG, Zimmerman AN, Dormans JA, Pinedo HM. Failure of the antioxidant vitamin E to protect against adriamycin-induced cardiotoxicity in the rabbit. Cancer Res 1980; 40:2033-8 3. Myers CE, McGuire W, Young R. Adriamycin: amelioration of toxicity by alpha-tocopherol. Cancer Treat Rep 1976; 60:961-2 Disclosures: No relevant conflicts of interest to declare.