A polymorphism in the ATM gene modulates the penetrance of hereditary non-polyposis colorectal cancer

Germ-line mutations in MLH1 and MSH2 genes predispose to hereditary non-polyposis colorectal cancer (HNPCC) syndrome, but they do not predict a specific phenotype of the disease. We speculated that the ataxia-telangiectasia mutated gene (ATM) was a candidate gene to modulate the phenotypic expression of HNPCC, as heterozygous individuals for germ-line ATM mutations have been considered at higher risk of developing epithelial malignancies. The frequency of the ATM D1853N polymorphism was evaluated in 167 individuals from 20 HNPCC families in which MLH1 or MSH2 germ-line mutations co-segregated with the disease. Among the 67 MLH1 or MSH2 mutation carriers, the ATM 1853N variant was associated with a significantly higher incidence of colorectal and other HNPCC-related cancers, when compared with individuals carrying the ATM 1853D variant [12/13 (92%) vs. 31/54 (57.5%); p = 0.02]. MLH1 and MSH2 mutation carriers who concomitantly carried the ATM 1853N variant, had an 8 times increased risk of developing colorectal and other HNPCC-related cancers (OR: 8.9; p = 0.02), when compared with MLH1 or MSH2 mutation carriers with the ATM 1853D variant. Our results suggest that the ATM D1853N polymorphism modulates the penetrance of MLH1 and MSH2 germ-line mutations.     

Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review

The clinical phenotype of heterozygous familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease. It is inherited as an autosomal dominant disorder with homozygotes having a more severe phenotype than do heterozygotes. FH can result from mutations in the low density lipoprotein receptor gene (LDLR), the apolipoprotein B-100 gene (APOB), and the recently identified proprotein convertase subtilisin/kexin type 9 gene (PCSK9). To date, over 700 variants have been identified in the LDLR gene. With the exception of a small number of founder populations where one or two mutations predominate, most geographically based surveys of FH subjects show a large number of mutations segregating in a given population. Studies of the prevalence of FH would be improved by the use of a consistent and uniformly applied clinical definition. Because FH responds well to drug treatment, early diagnosis to reduce atherosclerosis risk is beneficial. Cascade testing of FH family members is cost effective and merits further research. For screening to be successful, public health and general practitioners need to be aware of the signs and diagnosis of FH and the benefits of early treatment.     

Chronic sequels after thoracoscopic procedures for benign diseases

Objective: Chronic pains after lateral thoracotomy are present in up to 40% of cases. Chronic sequels after thoracoscopy are less common, but nevertheless, a cause for complaints by patients. Pain often reflects a recurrence of malign disease. For this reason, we only investigated patients with benign disease. Methods: We retrospectively investigated the incidence of chronic sequels in a consecutive series of 161 patients who underwent thoracoscopy for benign disease and were not converted to an open procedure. The data from all 144 patients, contactable at the time of investigation, who were at least 2 months postsurgery, were analyzed. Results: Chronic sequels were present in an overall of 31.4% of patients. Patients complained of chronic pain (20.1%), numbness distal to the incision sites (16.9%) and disaesthesia (8.3%). Painkillers are taken on a regular basis by 82.8% of patients with chronic pain. The use of Staplers, as well as the number of drains (1 vs. 2) used, were statistically significant (P>0.05) for chronic sequels. All other investigated factors, such as sex, age, and length of drainage, were not significantly different in the two groups. Conclusion: The thoracoscopic approach is not likely to impact on the prevalence of long-term postthoracotomy sequels, and therefore, further strengths are necessary to reduce this number.     

Central areolar choroid dystrophy. Report of involvement of 3 generations

Central areolar chorodial atrophy was first classified as a hereditary disease by Sorsby in 1935. The mode of inheritance can be both autosomal recessive and autosomal dominant. The authors present a case with autosomal dominant inheritance affecting three generations.     

Cutis laxa,exocrine pancreatic insufficiency and altered cellular metabolomics as additional symptoms in a new patient with ATP6AP1-CDG

Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. > 100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542 T > G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H⁺-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures. Proliferation of the patient's fibroblasts was significantly reduced and doubling time prolonged. Additionally, there were alterations in the fibroblasts' amino acid levels and the acylcarnitine composition. Especially, short-chain species were reduced, whereas several medium- to long-chain acylcarnitines (C14-OH to C18) were elevated. Investigation of the main lipid classes revealed that total cholesterol was significantly enriched in the patient's fibroblasts at the expense of phophatidylcholine and phosphatidylethanolamine. Within the minor lipid species, hexosylceramide was reduced, while its immediate precursor ceramide was increased. Since catalase activity and ACOX3 expression in peroxisomes were reduced, we assume an ATP6AP1-dependent impact on the β-oxidation of fatty acids. These results help to understand the complex clinical characteristics of this new patient.     

Ashkenazi Parkinson’s disease patients with the LRRK2 G2019S mutation share a common founder dating from the second to fifth centuries

The LRRK2 G2019S mutation is a major genetic determinant of Parkinson’s disease (PD) across the world that occurs at an elevated frequency in Ashkenazi Jews. We determined the LRRK2 haplotypes in 77 G2019S carriers, mostly Ashkenazi Jews, and in 50 noncarrier Ashkenazi PD patients, using 16 genetic markers. A single haplotype was detected in all mutation carriers, indicating that these individuals share a common founder. Using a maximum-likelihood method, we estimate that Ashkenazi Jews with G2019S share a common ancestor who lived ～1,830 (95% CI 1,560–2,160) years ago, around the second century, after the second Jewish Diaspora.