Autosomal recessive retinitis pigmentosa (arRP) is characterized by considerable allelic and nonallelic heterogeneity. Mutations have been described in the rhodopsin gene (RHO), the genes encoding the α and β subunits of rod phosphodiesterase (PDEA and PDEB) and the gene encoding the α subunit of the cGMP-gated channel (CNCG). In addition, linkage studies in single extended pedigrees have defined two new arRP loci, at 1q and 6p. In order to identify the disease gene in a Spanish consanguineous arRP family, a linkage analysis was undertaken. After testing 102 polymorphic markers, a significant positive lod score (Ζ max =3.64 at θ=0) was obtained with marker D1S188 at 1p13-p21, the same region where the Stargardt and fundus flavimaculatus (FFM) loci were previously defined. Exhaustive ophthalmologic examination of the patients clearly distinguished the disease from the Stargardt and FFM phenotypes, and revealed an atypical form of arRP with choroidal atrophy as a distinctive feature. 3Retinitis pigmentosa is a clinically and genetically heterogeneous group of retinal degenerations characterized by progressive loss of night and peripheral vision and, eventually, severe visual loss (9). As is the case of the autosomal dominant (adRP) and the X-linked (xlRP) forms of the disease, autosomal recessive retinitis pigmentosa (arRP) is characterized by allelic and nonallelic heterogeneity. Mutations cosegregating with the disease have been described in the rhodopsin gene (RHO) (15,24), the genes encoding the α and β subunits of rod phosphodiesterase (PDEA and PDEB, respectively) (3,10,21,28, 29) and the gene encoding the α subunit of the cGMP-gated channel (CNCG) (6). In addition, genetic linkage studies in single extended pedigrees have identified two new arRP loci, at 1q (18, 30) and 6p (14).Among the Spanish population, 39% of the RP pedigrees show an autosomal recessive pattern of inheritance (arRP) (2). Here we report the case of a Spanish consanguineous arRP family (M-33) with six out of seven sibs affected (Fig.1). Ophthalmologic examination of both parents revealed no manifestation of RP; the father (who died aged 72), showed no symptoms other than glaucoma, whereas the mother (aged 82) is totally asymptomatic. This fact, together with the consanguinity (second-cousin marriage), indicate an autosomal recessive pattern of inheritance. Clinical evaluation of the affected members suggested an aggressive form of the disease, with night blindness as the first symptom appearing in the first decade of life (mean age of onset, 8 years), followed by a decrease in visual acuity, starting at 14 years of age. Fundus examination and fluorescein angiographies (Fig.2) of the affected sibs in the fourth decade of life revealed papillary pallor, attenuated vessels, peripheral scattered pigmentation, bone spicule-like pigmentation reaching some areas of the macula and severe atrophy of the retinal pigment epithelium (RPE). At present, the older sibs show a complete scotoma while the youngest (around 45 years of age) still ...

A family affected with autosomal dominant retinitis pigmentosa (RP) is presented. Two clinically affected patients (mother and daughter) were heterozygous for the same novel missense mutation (Val137Met) of the rhodopsin gene (RHO). Both heterozygous and homozygous cases were observed among their few symptomatic relatives. Wide clinical variation was exhibited among the individuals with mutations in this family. None of the controls showed this change in RHO, nor has it been previously reported in other RP families. No other RHO mutation was observed. Additional genetic or environmental factors could play a role in modulating the penetrance and clinical expression of this RHO mutation.

severe pulmonary and intestinal disease including ileus at birth and liver cirrhosis at the age 5 years, whereas the other one developed much better with only mild pulmonary changes. Clinical follow-up evaluation of our patient, a 5-year-old girl, was evocative of an intermediary status. Diagnosis of CF was established from positive sweat test at the age of 21 months. At the present time, she shows pulmonary disease and pancreatic insufficiency but not liver disease and develops well under therapy. REFERENCESDeufel A, Deufel T, Golla A, Achatz H, Bertele-Harms R, Roscher AA, Meitinger T (1994) Three novel mutations (1506s S466X, 1651A-T) in exon 10 Zielenski], Rozmahel R, Boron D, Kerem B, Gnelczak Z, Riordan JR, Rommens], Tsui L (1991) Genomic. DNA sequence of the Cystic Fibrosis Transmembrane of the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) detected in patients of southern german descent. Hum Mutat 3:64-66.In 1994, a gene for hereditary breast and ovarian cancer (BRCAI) was isolated by positional cloning (Miki et al., 1994). Mutations in BRCAI are thought to be responsible for more than 80% of inherited breast and ovarian cancer (Easton et al., 1993). Women who harbour BRCAl germline mutations are estimated to have a 85-90% lifetime risk of breast cancer and an elevated risk of ovarian cancer.From the Max-Delbriick-Center (Berlin) collection of families with hereditary breast cancer (Easton et al., 1993) several families were selected for intensive investigation. Genomic DNA was prepared from blood samples and polymerase chain reaction (PCR)-amplified, using the primer pairs indicated by Friedman et al. (1994). The following SSCP analysis (Grade et al., 1994) revealed an aberrant banding pattern in exon 12 of the BRCAl gene in one family that could not be seen in other breast cancer families. Direct sequencing in both directions (sense and antisense strand) of the exon 12 PCR-amplified fragments was performed after alkali strand denaturation and separation of biotinylated primers with streptavidin-coated magnetic beads (Dynal, Oslo, Norway) using the Sequenase Terminator Single-Stranded DNA Sequencing Kit (Applied Biosystems, La Jolla, CA). A heterozygous two base pair (2-bp) deletion was identified in position 4282-4283 (reviewed, but not shown). This deletion leads to the creation of a TGA stop at codon 1389 and a predicted truncation of the BRCAl protein. 4282delAG could not be detected in the BRCA1 gene of 50 unrelated and unaffected individuals.One allele of the BRCAl gene is deleted in three members of the family. Familial history showed that mammary carcinomas occurred at an age of 35, 32, and 33, respectively. One patient suffered on ovarian cancer at an age of 56. This family is a clear example of an early-onset breast-ovarian cancer syndrome. ACKNOWLEDGMENTSWe thank I. Siimnich and H. Zeidler for technical assistance. This work was supported in part by MEC grant RRK13. REFERENCESEaston DF, Bishop T, Ford D, Crockford & the Breast Cancer Linkage Consortium (1993) Genetic linkage analy...

Drug-induced pancreatitis occurs rarely but should be considered when more common causes have been ruled out. While simple to treat, mortality increases should it progress to a necrotizing process. Here, we present the case of a patient simultaneously using two drugs associated with pancreatitis, which we considered acted synergistically and consequently worsened the patient's outcome.

Retinitis Pigmentosa (RP) is a group of inherited retinopathies which affect approximately 1 in 4,000 individuals. The disorder can be classified on the basis of inheritance; dominant, recessive and X-linked forms have been well documented. The existence of genetic heterogeneity within autosomal dominant RP (adRP) had been previously demonstrated. As a result of extensive linkage studies in 2 large Irish families and 1 American pedigree three adRP genes have been mapped. adRP genes have been localised to chromosome 3q close to the rod photoreceptor gene, rhodopsin; to chromosome 6p close to another transmembrane photoreceptor gene, peripherin/RDS and to the pericentric region of chromosome 8, although the causative gene in this region has not yet been identified. Here we report the results of a linkage study in a Spanish family, who exhibit an early-onset form of adRP. The adRP gene segregating in this family has been excluded from the three known adRP loci on chromosomes 3q, 6p and 8 using a series of both intragenic microsatellite markers from the rhodopsin and peripherin/RDS genes and markers flanking the three known loci. These results provide definitive evidence for the existence of a fourth adRP locus, further emphasising the genetic heterogeneity that exists within adRP.