A novel mutation in ABCD1 unveils different clinical phenotypes in a family with adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder. The disease is the consequence of mutations in the ABCD1 gene that encodes the peroxisomal membrane protein ALDP which is involved in the transmembrane transport of very long-chain fatty acids. We describe a family with six members carrying a novel heterozygous mutation IVS4+2T>A (c.1393+2T>A) of the ABCD1 gene, highlighting the wide range of phenotypic manifestations of ALD and the importance of genetic screening before any pregnancy in asymptomatic women whose carrier status is unknown.

Frequency of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from Trentino, North East Italy.

OBJECTIVE: Triple negative breast carcinomas (TNT) are infiltrating breast carcinomas (BC) with negative oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor receptor 2 (HER-2) expression, and are associated with frequent BRCA1/BRCA2 mutations. The aim of the present study is to analyze the frequency and distribution of TNT in our population where a breast cancer screening program for women aged between 50 and 69 years is effective since 2001 with 85% accrual. METHODS: We investigated the records of 2112 consecutive BC and 153 interval BC (i.e. BC detected in the screened negative women in the interval between screening rounds). Tumours with complete negative expression of ER, PgR and Her2 were considered TNT; tumours with negative ER and PgR status and faint Her2 expression (score 1) were considered as possible TNT (pTNT). RESULTS: We identified 82 (3.8%) TNT and 20 (0.9%) pTNT in the series of 2112 consecutive BC and 7 TNT and 1 pTNT (5.2%) in the series of 153 interval BC. In the consecutive series, TNT/ pTNT were observed in 6.5% patients below 50 years and in 4.3% of patients above 50 years. A high proliferation rate (Ki-67 labelling > 36%) was observed in 87.8% of TNT (median labelling 56.3%) and in 60% of pTNT (median labelling 48.4%). CONCLUSIONS: Since TNT/pTNT occurring in women < 50 years is a criterion for selecting patients whom genetic counselling and BRCA1 testing should be offered, our study is of help in foreseeing the workload of the Unit of Medical Genetics and the Laboratory of Molecular Pathology.

Efficacy of copper oxide wire particles against gastrointestinal nematodes in sheep and goats.

Profitable sheep and goat production in the USA is severely limited by gastrointestinal nematode (GIN) parasitism, particularly by Haemonchus contortus. Copper oxide wire particles (COWP) have anti-parasitic properties in the diet of small ruminants, but efficacy of COWP may differ between sheep and goats. In a study with weaned kids (Kiko x Spanish cross, 6 months old) and lambs (Katahdin or Dorper x Blackface crosses, 5 months old), grazing the same pasture area in Central Georgia, 2g of COWP in a gel capsule was given to half the animals of each species, while the other half were given no COWP. Fecal and blood samples were taken weekly to determine GIN fecal egg counts (FEC) and blood packed cell volume (PCV). After COWP treatment, animals were grazed for 4 weeks and then slaughtered, with adult GIN recovered from the abomasum and small intestines for counting and identification to species. For both sheep and goats, COWP treatment reduced EPG (P<0.05), increased PCV (P<0.05), and lowered abomasal GIN numbers (P<0.05). For EPG, these differences were 82.5 and 90.5% for sheep and goats, respectively, 26 days after treatment, while adult H. contortus were 67.2 and 85.8% lower for COWP-treated sheep and goats, respectively. In this study, COWP treatment was equally effective against H. contortus infection in lambs and kids and appears to be an effective method of controlling H. contortus infection for up to 6 weeks in small ruminants following weaning.

Administration of copper oxide wire particles in a capsule or feed for gastrointestinal nematode control in goats.

Widespread anthelmintic resistance in small ruminants has necessitated alternative means of gastrointestinal nematode (GIN) control. The objective was to determine the effectiveness of copper oxide wire particles (COWP) administered as a gelatin capsule or in a feed supplement to control GIN in goats. In four separate experiments, peri-parturient does (n=36), yearling does (n=25), weaned kids (n=72), and yearling bucks (n=16) were randomly assigned to remain untreated or administered 2g COWP in a capsule (in Experiments 1, 2, and 3) or feed supplement (all experiments). Feces and blood were collected every 7 days between Days 0 and 21 (older goats) or Day 42 (kids) for fecal egg counts (FEC) and blood packed cell volume (PCV) analyses. A peri-parturient rise in FEC was evident in the untreated does, but not the COWP-treated does (COWP x date, P<0.02). In yearling does, FEC of the COWP-treated does tended to be lower than the untreated (COWP, P<0.02). FEC of COWP-treated kids were reduced compared with untreated kids (COWP x date, P<0.001). FEC of treated and untreated bucks were similar, but Haemonchus contortus was not the predominant nematode in these goats. However, total worms were reduced in COWP-fed bucks (P<0.03). In summary, it appeared that COWP in the feed was as effective as COWP in a gelatin capsule to reduce FEC in goats. COWP administration may have a limited effect where H. contortus is not the predominant nematode.

Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature.

Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene, and characterized by typical face, moderate-to-severe mental retardation, epilepsy, Hirschsprung disease, and multiple congenital anomalies, including genital anomalies (particularly hypospadias in males), congenital heart defects, agenesis of the corpus callosum, and eye defects. Since the first delineation by Mowat et al. [Mowat et al. (1998); J Med Genet 35:617-623], approximately 179 patients with ZEB2 mutations, deletions or cytogenetic abnormalities have been reported primarily from Europe, Australia and the United States. Genetic defects include chromosome 2q21-q23 microdeletions (or different chromosome rearrangements) in few patients, and ZEB2 mutations in most. We report on clinical and genetic data from 19 Italian patients, diagnosed within the last 5 years, including six previously published, and compare them with patients already reported. The main purpose of this review is to underline a highly consistent phenotype and to highlight the phenotypic evolution occurring with age, particularly of the facial characteristics. The prevalence of MWS is likely to be underestimated. Knowledge of the phenotypic spectrum of MWS and of its changing phenotype with age can improve the detection rate of this condition.

Holt-Oram syndrome associated with anomalies of the feet.

Holt-Oram syndrome (HOS) (OMIM 142900) is characterized by upper-extremity malformations involving the radial, thenar, or carpal bones and a personal and/or family history of congenital heart defects (CHDs). It is inherited in an autosomal dominant manner. The TBX5 gene located on chromosome 12 (12q24.1) is the only gene currently known to be associated with HOS and is associated with variable phenotypes. We report on the clinical and molecular characterization of a HOS family with three affected individuals and a novel mutation (Lys88ter). We discuss genotype-phenotype correlations, the presence of foot anomalies in one affected individual, and the role of atypical features in HOS differential diagnosis.

Survival of male patients with incontinentia pigmenti carrying a lethal mutation can be explained by somatic mosaicism or Klinefelter syndrome.

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.