Editor—Prader-Willi syndrome (PWS) is a genetically determined disorder in which the absence of expression of one or more maternally imprinted gene(s) in the chromosomal region 15q11-13 results in a characteristic facial appearance, learning disabilities (mental retardation), and severe overeating behaviour owing to an abnormal satiety response to food intake, together with a range of other behaviours. Initially, as reported by Prader et al ,1 PWS was conceived as a syndrome of obesity, short growth, cryptorchidism, and mental retardation following hypotonia in the neonatal period. As more and more people with PWS were reported and research into the syndrome began, behavioural characteristics and other clinical features were added, culminating in the consensus diagnostic criteria.2Concurrently, the genetics of the disorder were receiving attention. First was the discovery that for many there was a visible chromosomal deletion in the proximal part of the long arm of chromosome 15 (15q11-13). Reports of an apparently similar deletion being associated with a phenotypically very different syndrome (Angelman syndrome, AS),3 and the observation that PWS was the result of a deletion on the chromosome 15 of paternal origin, and AS the chromosome 15 of maternal origin, led to the recognition that gender specific imprinting of genes at that locus accounted for two diverse syndromes being associated with apparently similar chromosomal deletions.4 Maternal chromosome 15 disomies, mutations of an imprinting centre, and chromosomal translocations accounted for non-deletion cases of PWS.5 

In published reports on Prader-Willi syndrome (PWS), prevalence has been variously quoted as “about 1 in 25 000 live births”,6 “between one in 25 000 and one in 10 000 live born children”,7 “[estimates] vary 6-fold from 1 in 5000 to 10 000; 1 in 10 000; 1 in 15 000; 1 in 25 000; to 1 in 10 000 to 30 000”.8 Only two estimates …

/pdf/population-prevalence-and-estimated-birth-incidence-and-3nplb54490.pdf

Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region

Editor—Anderson-Fabry disease (AFD) is a sphingolipid storage disorder resulting from the deficiency of the lysosomal enzyme α-galactosidase. Unlike most other lysosomal diseases, the inheritance is X linked. Disease manifestations in female heterozygotes have been reported, but are considered to be rare and usually mild.1 Asymptomatic corneal dystrophy (cornea verticillata and posterior lenticular cataract) is present in about 70% and is useful for heterozygote detection. About 30% of women have minimal angiokeratomas and <10% have infrequent attacks of neuropathic pains.1 However, female heterozygotes with severe and early cerebrovascular disease, strokes, and renal failure have been documented, but these serious manifestations were estimated to occur in only 1%.1 Because this is an X linked disorder, these severe manifestations in females were explained by skewed X inactivation.2 

Case reports are open to selection bias and there are no reported data on the frequency and severity of AFD manifestations in a large cohort of carriers. Women are not usually evaluated in the clinic unless they present with serious AFD complications, but they do attend for genetic counselling when their son or male relative is diagnosed with the disease.

During regular reviews of AFD families in the genetic clinic, we have observed multiple and more frequent AFD manifestations in female carriers than expected. Owing to the lack of clinical data and present health care policy, we were unable to perform clinical investigations. Therefore, a large cohort study using an AFD specific questionnaire was performed to establish the mortality and the frequency of all AFD manifestations in obligate carrier females.

All known (n=80) obligate carrier females, who were over the age of 18 and had demographic data recorded in the AFD register, were asked to participate in this study. Sixty (75%) agreed and provided data; non-responders were reminded on one …

Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females

Clinical implications of cystic fibrosis transmembrane conductance regulator mutations

Over the past decade, nearly 1,000 variants have been identified in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classic and atypical cystic fibrosis (CF) patients worldwide, and an enormous wealth of information concerning the structure and function of the protein has also been accumulated. These data, if evaluated together in a sequence comparison of all currently available CFTR homologs, are likely to refine the global structure-function relationship of the protein, which will, in turn, facilitate interpretation of the identified mutations in the gene. Based on such a combined analysis, we had recently defined a "functional R domain" of the CFTR protein. First, presenting two full-length cDNA sequences (termed sCFTR-I and sCFTR-II) from the Atlantic salmon (Salmo salar) and an additional partial coding sequence from the eastern gray kangaroo (Macropus giganteus), this study went further to refine the boundaries of the two nucleotide-binding domains (NBDs) and the COOH-terminal tail (C-tail), wherein NBD1 was defined as going from P439 to G646, NBD2 as going from A1225 to E1417, and the C-tail as going from E1418 to L1480. This approach also provided further insights into the differential roles of the two halves of CFTR and highlighted several well-conserved motifs that may be involved in inter- or intramolecular interactions. Moreover, a serious concern that a certain fraction of missense mutations identified in the CFTR gene may not have functional consequences was raised. Finally, phylogenetic analysis of all the full-length CFTR amino acid sequences and an extended set of exon 13--coding nucleotide sequences reinforced the idea that the rabbit may represent a better CF model than the mouse and strengthened the assertion that a long-branch attraction artifact separates the murine rodents from the rabbit and the guinea pig, the other Glires.

A Combined Analysis of the Cystic Fibrosis Transmembrane Conductance Regulator: Implications for Structure and Disease Models

We characterized the 3272-26A-->G mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, creating an alternative acceptor splice site in intron 17a, that competes with the normal one, although we predict from consensus values, with lower efficiency. We analyzed five Cystic Fibrosis (CF) Portuguese patients with the 3272-26A-->G/F508del genotype. Besides clinical and haplotype characterization of those patients, we report here results from CFTR transcript analysis in nasal brushings from all five patients. RT-PCR analysis supports alternative splicing in all patients and carriers, but not in controls. By sequencing, we determined that the alternative transcript includes 25 nucleotides from intron 17a, which predictively cause frameshift and a premature stop codon. The use of this alternative splice site causes a reduction in the levels of normal transcripts from the allele with this mutation and, most probably, of normal protein as well. By immunocytochemistry of both epithelial primary cell cultures and slices from CF polyps, CFTR protein is detected at the cell membrane, with three different antibodies. Ussing chamber analysis of one nasal polyp shows a high sodium absorption, characteristic of CF. Altogether, the results suggest that the main defect caused by the 3272-26A-->G mutation is a reduction in normal CFTR transcripts and protein and therefore this mutation should be included in class V, according to Zielenski and Tsui.

Cystic fibrosis patients with the 3272-26A-->G mutation have mild disease, leaky alternative mRNA splicing, and CFTR protein at the cell membrane.

We report the clinical features of 21 unrelated cystic fibrosis (CF) patients from Portugal and Spain, who carry the mutation R1066C in the CFTR gene. The current age of the patients was higher in the R1066C/any mutation group (P < 0.01), as compared to the deltaF508/deltaF508 group. Poor values for lung radiological involvement (Chrispin-Norman) and general status (Shwachman-Kulcycki) were observed in the R1066C/any mutation group (P < 0.005 and P < 0.0004). A slightly, but not significantly worse lung function was found in the R1066C/any mutation group when compared with the deltaF508/deltaF508 patients. No significant differences were detected regarding the age at diagnosis, sweat Cl-values, or percentiles of height and weight between the two groups. Neither were significant differences observed regarding sex, meconium ileus (4.7% vs. 11.1%), dehydration (10.5% vs. 14.7%), or pancreatic insufficiency (PI) (100% vs. 97.8%). The proportion of patients with lung colonization by bacterial pathogens was slightly, but not significantly higher in the R1066C/any mutation group (70.0%), as compared with the deltaF508/deltaF508 group (57.5%). Other clinical complications were significantly more frequent in the R1066C/any mutation patients(P < 0.02) than in the deltaF508/deltaF508 group. The two homozygous R1066C/R1066C patients died at the ages of 3 months and 7 years. The data presented in this study clearly demonstrate that the R1066C mutation is responsible for a severe phenotype similar to that observed in homozygous deltaF508 patients. The poor clinical scores and complications of patients with the R1066C mutation are probably related to their slightly longer survival.

Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: Study of 19 heterozygous and 2 homozygous patients

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Missense mutation R1066C in the second transmembrane domain of CFTR causes a severe cystic fibrosis phenotype: Study of 19 heterozygous and 2 homozygous patients