Adult-onset ornithine transcarbamylase (OTC) deficiency unmasked by the Atkins' diet.

BACKGROUND & AIMS: Late-onset symptoms of urea-cycle disorder may lead to a life-threatening disease which is often undetected. We report the clinical and metabolic manifestations of acute hyperammonemic encephalopathy in a 47-year-old asymptomatic man with ornithine transcarbamylase (OTC) deficiency. The hyperammonemic encephalopathy was unmasked by a high-protein Atkins diet. METHODS: Genetic analysis of the patient's family, 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects was performed using polymerase chain reaction amplification and DNA sequencing of the OTC gene. RESULTS: Treatment with hemodialysis, provision of adequate calories to prevent catabolism, and protein elimination for 24h followed by protein restriction and ammonia scavenging medications effectively lowered the patient's plasma ammonia level and resulted in full recovery. Genetic analysis of the OTC gene revealed a novel hemizygous missense mutation in exon 5 (c.477T>G), leading to an isoleucine-to-methionine substitution in codon 159 (Ile159Met). Further genetic analysis of the patient's family yielded the mutation in many of them, although findings were negative in 89 unrelated Ashkenazi Jewish and 50 unrelated Europeans subjects. CONCLUSIONS: This is the first reported case of an adult urea-cycle defect unmasked by the Atkins diet. Measurements of serum ammonia level must be part of the basic work-up in all patients presenting with encephalopathy of unknown origin even in the absence of liver dysfunction. Awareness of this important association can contribute to prompt diagnosis and life-saving treatment. Correct diagnosis is also important to prevent future recurrences and to provide genetic counselling for family members.

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers.

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

The Tyr978X BRCA1 mutation: occurrence in non-Jewish Iranians and haplotype in French-Canadian and non-Ashkenazi Jews.

BACKGROUND: The Tyr978X BRCA1 mutation is a founder mutation detected in high-risk Iraqi-Iranian Jewish families as well as in the general non-Ashkenazi population. The same mutation was also reported in non-Jewish high-risk women from Canada. Its occurrence in non-Jewish individuals from Iran has never been tested. OBJECTIVE: Assess the occurrence rate of Tyr978X BRCA1 germline mutation in the general population of Iranian non- Jewish individuals and compare the BRCA1-linked haplotype of Jewish and non-Jewish mutation carriers. METHODS: PCR amplification of the relevant fragment of the BRCA1 gene, followed by restriction enzyme digestion that differentiates wild type from mutant allele. For haplotyping, 7 BRCA1-linked markers were used. The tested population included 442 apparently healthy Iranian non-Jewish individuals, and 17 mutation carriers from Israel and Canada. RESULTS: The Tyr978X BRCA1 mutation was not detected in any Iranian non-Jewish individual. The intragenic haplotype of all Jewish Israeli mutation carriers was identical, but differed from that of Canadian non-Jews in two intragenic markers. CONCLUSIONS: The Tyr978X BRCA1 mutation which is a founder mutation in Jews, may be a hot spot in non-Jewish high risk women, and probably does not represent a rare sequence variant in Iranian non-Jews.

Smoking and the risk of breast cancer among carriers of BRCA mutations.

The effect of cigarette smoking on the risk of breast cancer is controversial, although most studies show little or no effect. It has been suggested that smoking may reduce the risk of developing hereditary breast cancer. We completed a case-control study on 1,097 women with breast cancer who were BRCA1 or BRCA2 mutation carriers and 1,097 age-matched controls with a mutation in the same gene but without breast cancer. There were no statistically significant differences between the cases and controls in terms of the number of current and ex-smokers (41.2% and 40.4%, respectively) or the age at smoking commencement (18.2 years and 18.5 years, respectively). There were no statistically significant differences between cases and controls regarding beginning smoking within 5 years of menarche (OR = 1.03; 95% CI 0.83 to l.28) or before the first pregnancy (OR = 1.09; 95% CI = 0.90 to 1.33). In conclusion, contrary to our previous report, smoking does not appear to be a risk factor for breast cancer among carriers of BRCA mutations.

Insulin-like growth factor I polymorphism and breast cancer risk in Jewish women.

BACKGROUND: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients. OBJECTIVE: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls. METHODS: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212 sporadic and 56 carriers of either a BRCA1 or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent autoradiography. RESULTS: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only (3/536, 0.6%). CONCLUSIONS: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.