Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis

Smit DL, Mensenkamp AR, Badeloe S, Breuning MH, Simon MEH, van Spaendonck KY, Aalfs CM, Post JG, Shanley S, Krapels IPC, Hoefsloot LH, van Moorselaar RJA, Starink TM, Bayley J‐P, Frank J, van Steensel MAM, Menko FH. Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation‐dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole‐gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.     

Menstrual migraine in a representative Dutch population sample: prevalence,disability and treatment

We assessed the prevalence of menstrual migraine and its restrictions on daily activities in a representative Dutch population sample of 1181 Dutch women, aged 13-55 years. Further, we evaluated the potential role of oral contraceptives, and how menstrual migraine is treated. More than half suffered from menstrual complaints, a substantial proportion reported headache or migraine as a frequent problem. Use of oral contraceptives seemed to reduce the occurrence of menstrual complaints, but not the occurrence of headache and migraine. In our study, the prevalence of menstrual migraine (3%) is lower than in the literature, most probably because we did not use a selected group of patients but a population-based sample of ordinary women. It was confirmed that attacks of menstrual migraine are more severe, of longer duration, and more resistant to treatment than migraine attacks at other times of the month.     

Clinical,biochemical and molecular characterization of peroxisomal diseases in Arabs

Shaheen R, Al‐Dirbashi OY, Al‐Hassnan ZN, Al‐Owain M, Makhsheed N, Basheeri F, Seidahmed MZ, Salih MAM, Faqih E, Zaidan H, Al‐Sayed M, Rahbeeni Z, Al‐Sheddi T, Hashem M, Kurdi W, Shimozawa N, Alkuraya FS. Clinical, biochemical and molecular characterization of peroxisomal diseases in Arabs. Peroxisomes are single membrane‐bound cellular organelles that carry out critical metabolic reactions perturbation of which leads to an array of clinical phenotypes known as peroxisomal disorders (PD). In this study, the largest of its kind in the Middle East, we sought to comprehensively characterize these rare disorders at the clinical, biochemical and molecular levels. Over a 2‐year period, we have enrolled 17 patients representing 16 Arab families. Zellweger‐spectrum phenotype was observed in 12 patients and the remaining 5 had the rhizomelic chondrodysplasia punctata phenotype. We show that homozygosity mapping is a cost‐effective strategy that enabled the identification of the underlying genetic defect in 100% of the cases. The pathogenic nature of the mutations identified was confirmed by immunofluorescence and complementation assays. We confirm the genetic heterogeneity of PD in our population, expand the pool of pathogenic alleles and draw some phenotype/genotype correlations.     

Conventional or physicochemical approach in intensive care unit patients with metabolic acidosis

Introduction  

Metabolic acidosis is the most frequent acid–base disorder in the intensive care unit. The optimal analysis of the underlying mechanisms is unknown.     

Novel tools for extraction and validation of disease‐related mutations applied to fabry disease

Genetic disorders are often caused by nonsynonymous nucleotide changes in one or more genes associated with the disease. Specific amino acid changes, however, can lead to large variability of phenotypic expression. For many genetic disorders this results in an increasing amount of publications describing phenotype‐associated mutations in disorder‐related genes. Keeping up with this stream of publications is essential for molecular diagnostics and translational research purposes but often impossible due to time constraints: there are simply too many articles to read. To help solve this problem, we have created Mutator, an automated method to extract mutations from full‐text articles. Extracted mutations are crossreferenced to sequence data and a scoring method is applied to distinguish false‐positives. To analyze stored and new mutation data for their (potential) effect we have developed Validator, a Web‐based tool specifically designed for DNA diagnostics. Fabry disease, a monogenetic gene disorder of the GLA gene, was used as a test case. A structure‐based sequence alignment of the alpha‐amylase superfamily was used to validate results. We have compared our data with existing Fabry mutation data sets obtained from the HGMD and Swiss‐Prot databases. Compared to these data sets, Mutator extracted 30% additional mutations from the literature. Hum Mutat 31:1026–1032, 2010. © 2010 Wiley‐Liss, Inc.     

Gut intraepithelial lymphocyte counts in neonates, infants and children

Intraepithelial lymphocyte (IEL) counts were histologically assessed in the jejunum, ileum and appendix of 39 neonates (0–28 days), 32 infants (1–9 months) and 13 children (1–9 years). Small intestinal mucosa samples were obtained from 73 autopsies, and from 8 surgical and 3 aspirative biopsies. IEL counts of specimens from the jejunum, ileum and appendix gave similar results in the same patient. The number of IEL counts was significantly lower in neonates for all three segments. The difference between infants and children was more marked in the jejunum than in the ileum, although this was not significant. In the appendix, there was no difference between the different age groups. Our results indicate that postnatal expansion of IEL occurs homogeneously along the gut after the neonatal period.