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Biomedical subjects

J E Wraith

Publications and source records attributed to J E Wraith.

At least 37 records · Page 2Linked to original sources
PubMed1998

Strategies for the treatment of cystathionine beta-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years.

Strategies for the treatment of cystathionine beta-synthase (CBS) deficiency include (1) increasing residual enzyme activity by giving pyridoxine in those patients with vitamin responsive variants, (2) reducing the load on the affected pathway with a low methionine diet and supplementing the diet with cysteine; and (3) giving betaine in order to utilise alternative pathways to remove homocyst(e)ine. In our experience of over 30 years in the diagnosis and management of patients with CBS deficiency, a normal outcome can only be achieved in patients diagnosed and treated from infancy. Pyridoxine combined with folic acid prevents further deterioration in pyridoxine responsive patients. Dietary treatment of patients with non-pyridoxine responsive CBS deficiency becomes more difficult outside childhood but since late complications are not uncommon must be continued for life. Betaine can be effective in this group but compliance is often poor.

Adolescent↗
PubMed1998

Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease).

Genomic DNA from 57 unrelated MPS II (Hunter's disease) patients was analysed for mutations of the iduronate sulphatase (IDS) gene. The aim of the study was threefold: to identify the primary genetic lesion in patients, to investigate the correlation between genotype and phenotype, and most importantly, to provide reliable carrier testing for female members once the family mutation was identified. In 42 patients, point mutations were identified involving single base substitutions, deletions, or insertions. These included four new nonsense mutations (R8X, C84X, E245X, Y466X), six new missense mutations (D45N, N115Y, P228L, P266R, E434K, I485K, W502C), three new insertions (c70C71ins, c652C654ins, c709G710ins), six new deletions (c500delC, c705delC, c1023delA, c1049delA, c1141delC, c1576delG), and five new mutations involving splice sites (IVS1-2 a-->g, IVS2-10 t-->g, IVS5 + 2 t-->g L236L, IVS7 + 2 t-->c). One patient had a new seven base deletion in exon 9 (c1482-1488del). Four patients were shown to have complete deletions of the IDS gene and two deletions involved one or more exons. Previously described mutations present in these patients were Q80X, P86L, R172X, G374G, S333L, R443X, and R468Q. In eight patients, no mutation was detected throughout the entire coding region. Most mutations that result in MPS II appear to be unique. Absence of the probands' mutations in eight of nine maternal grandmothers suggests many mutations have arisen recently. Prediction of the clinical phenotype from the identified genotype was difficult in some families, and further studies using reverse transcription polymerase chain reaction are needed to confirm the predicted effects on the IDS mRNA suggested by genomic analysis.

Adolescent↗
PubMed1997

Towards gene therapy of Hurler syndrome.

Allogeneic bone marrow transplantation is the most effective treatment for Hurler's syndrome. However, due to a lack of matched related donors and unacceptable morbidity of matched unrelated transplants, this therapy is not available to all patients. Therefore we have been developing an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. A number of different gene transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of haemopoietic colonies as around 50%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. Indeed a possible disadvantage has been identified for the use of intensive transduction procedures. The enzyme is secreted into the medium and functional localisation has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This pre-clinical work forms the basis for a clinical trial of gene therapy for Hurler syndrome.

Bone Marrow Cells↗
PubMed1997

Fourteen novel mucopolysaccharidosis IVA producing mutations in GALNS gene.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by a deficiency of the lysosomal N-acetylgalactosamine-6-sulfate sulfatase. Here, we report our analysis of data on 21 patients of diverse ethnic and geographic origins studied by SSCP and sequencing analysis. Sixteen mutations were detected, including 14 new mutations (11 missense, one premature termination, one splice site alteration, and one cryptic site alteration). The donor splice site mutation (IVS4 + 1G-->A) predicts that normal splicing will be abolished and that translation would lead to an immediate premature termination (W141X). Another novel nucleotide change outside the coding sequence is an intronic alteration (IVS9-42C-->T:ggtcggtgcggttggtgc) creating a potential cryptic donor site. The nucleotide sequence surrounding this alteration is highly suggestive of a consensus donor splice site. All 12 missense and nonsense mutations were shown by transient expression to abolish or greatly reduce GALNS activity, thereby providing an explanation as to why they produce MPS IVA. All mutations were readily confirmed by restriction enzyme or by allelic specific oligonucleotide analysis (ASO). These findings, coupled with previously reported mutations, bring the total of different mutations to 41 among independent families with MPS IVA, illustrating the extensive allelic heterogeneity among mutations producing MPS IVA.

Chondroitinsulfatases↗
PubMed1997

MRI of the brain and craniocervical junction in Morquio's disease.

We reviewed MRI of the brain and cervical spine in 11 patients with Morquio's disease. No abnormality was seen in the brain. The odontoid peg was abnormal in all patients, with varying degrees of cord compression due to an anterior soft tissue mass and indentation by the posterior arch of the atlas. The degree of cord compression was more marked than suggested by the symptoms and signs. We recommend MRI of the cervical spine in children with Morquio's disease before the development of neurological symptoms, to optimise the timing and type of surgical intervention.

Adolescent↗
PubMed1997

Refsum disease is caused by mutations in the phytanoyl-CoA hydroxylase gene.

Refsum disease is an autosomal-recessively inherited disorder characterized clinically by a tetrad of abnormalities: retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia and elevated protein levels in the cerebrospinal fluid (CSF) without an increase in the number of cells in the CSF. All patients exhibit accumulation of an unusual branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), in blood and tissues. Biochemically, the disease is caused by the deficiency of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal protein catalyzing the first step in the alpha-oxidation of phytanic acid. We have purified PhyH from rat-liver peroxisomes and determined the N-terminal amino-acid sequence, as well as an additional internal amino-acid sequence obtained after Lys-C digestion of the purified protein. A search of the EST database with these partial amino-acid sequences led to the identification of the full-length human cDNA sequence encoding PhyH: the open reading frame encodes a 41.2-kD protein of 338 amino acids, which contains a cleavable peroxisomal targeting signal type 2 (PTS2). Sequence analysis of PHYH fibroblast cDNA from five patients with Refsum disease revealed distinct mutations, including a one-nucleotide deletion, a 111-nucleotide deletion and a point mutation. This analysis confirms our finding that Refsum disease is caused by a deficiency of PhyH.

Adult↗
PubMed1997

Novel mutations in Sanfilippo A syndrome: implications for enzyme function.

Sanfilippo syndrome type A or mucopolysaccharidosis IIIA (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by the deficiency of sulfamidase. The resulting lysosomal storage of heparan sulfate may lead to severe neurodegeneration preceded by progressive dementia, often combined with aggressive and hyperactive behaviour. A total of 109 patients from four different geographic areas were screened for the common mutation R245H and two other previously identified mutations. SSCP analysis of exons was used to characterize the unknown alleles. We identified 16 novel sequence variants, 12 of them likely to be pathogenic. The majority of the pathogenic variants were single base pair changes leading to missense mutations. Several single base pair deletions/insertions and one nonsense mutation were also identified. Altogether, we were able to characterize 55% of the pathogenic alleles. Sequence homology between sulfamidase and N-acetylgalactosamine 4-sulfatase, the first sulfatase to have its tertiary structure defined, suggests that amino acid residues R74 and T79, which were found to be mutated, are likely to be involved in the formation of the active site of sulfamidase. R245H accounts for 31% of the Sanfilippo A alleles in Australasia, for 19.2% of the alleles in patients from the UK and has a high frequency of 57.8% in patients from The Netherlands. The identification of mutations common in certain geographic regions or ethnic groups will help in the diagnosis of MPS IIIA and allow carrier testing and improved genetic counselling.

DNA Primers↗
PubMed1997

Bone marrow transplantation for mucopolysaccharidosis type I: experience of two British centres.

Bone marrow transplantation was carried out on 38 patients with mucopolysaccharidosis type I over a period of 15 years. The donor was an HLA identical relative in 10 cases, an HLA non-identical relative in 16 cases, and an HLA identical unrelated volunteer donor in 12 cases. Ten patients received a second transplant. One patient received three transplants. Thirteen engrafted patients have survived five years or more. Most patients have shown an arrest or slowing down of psychomotor regression. However, dysostosis multiplex has progressed. Careful selection of patients may be necessary to ensure optimum results.

Bone Marrow Transplantation↗
PubMed1997

Mutation analysis in 46 British and Irish patients with Gaucher's disease.

DNA from 46 unrelated patients with Gaucher's disease was analysed for 10 known mutations: 84GG(c84 G 85ins), N370S (c1226G), L444P (c1448C), R463C (c1504T), R496H (c1604A), IVS2+1, D409H (c1342C), RecNcil (c1448C-1498C), RecTL (c1342C-1498C), and c1263del (c1264-1318del). Fifty four mutations (90%) were identified in 30 patients with type I disease. These included a previously undescribed recombinant mutation RecA456P (c1448C-1484C). Thirteen (54%) of 24 type II alleles were identified, including one new point mutation N462K (c1503G) and one new 55bp deletion also incorporating the RecTL mutations c1263del+RecTL (c1264del-1498C). All four type III patients were homozygous for the L444P point mutation. Generally, patients with one copy of the N370S mutation had mild adult onset disease, regardless of the nature of their second mutation. Three exceptions had childhood onset disease and genotypes N370S/R463C, N370S/RecA456P, and N370S/?. The L444P/L444P genotype was thought to be associated with neurological disease. Two type I patients with this genotype who exhibited no central nervous system disease were identified, however. The R463C and c1263del mutations were found to be present at a higher frequency than reported in other populations and they should be included in any mutation screen of this population. The recombinant mutations RecA456P and c1263del+RecTL have not been previously described and are the fourth and fifth recombinant mutations identified in the glucocerebrosidase gene.

Adult↗
PubMed1997

Methionine and serine formation in control and mutant human cultured fibroblasts: evidence for methyl trapping and characterization of remethylation defects.

The conversion of labeled formate to methionine and serine, as a measure of remethylation of homocysteine to methionine and folate coenzyme cycling, has been studied in control and mutant human fibroblasts. Fibroblasts in monolayer culture were incubated with [14C]formate, and labeled methionine sulfone and serine were determined in hydrolysates of oxidized cell proteins. In control cells, methionine and serine were clearly measurable (n = 21, 1.7-5.5 and 2.4-9.7 nmol/mg protein/16 h, respectively). In contrast, methionine formation was reduced in cells from patients with methylenetetrahydrofolate reductase (MR) deficiency (MR mutant, n = 11, 0.05-0.44), combined methylmalonic aciduria/homocystinuria [cobalamin(cbl)C/D mutant, n = 12, 0.014-0.13), and methionine synthase deficiency (MS mutant, n = 3, 0.04-0.23). Furthermore, serine formation was low in cblC/D mutant (0.08-0.98) and MS mutant (0.17-0.94) cells, but normal or high in MR mutant cells (5.2-11.4). Growth of cblC/D mutant cells in medium supplemented with high concentrations of hydroxo-cbl resulted in significant increases of both methionine and serine formation. Taken together these findings provide clear evidence for the existence of the formate to serine pathway described by W. B. Strong and V. Schirch in cultured fibroblasts and indicate that disturbed MS function due to a specific genetic disorder is associated with reduced serine formation in vitro, which reflects availability of reduced folate coenzymes. The correction of this defect by vitamin B12 alone, in cblC/D mutant cell lines, correlates well with the clinical response in the patients and fits in well with the idea that reduced availability of folate coenzymes occurs in functional MS deficiency, in agreement with the methyl trap hypothesis.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1996

Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler syndrome) in human bone marrow.

Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for alpha-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder. Various gene-transfer protocols have been assessed including the effect of intensive schedules of exposure of bone marrow to viral supernatant and the influence of growth factors. With these protocols, we have demonstrated successful gene transfer into primitive CD34+ cells and subsequent enzyme expression in their maturing progeny. Also, by using long-term bone marrow cultures, we have demonstrated high levels of enzyme expression sustained for several months. The efficiency of gene transfer has been assessed by PCR analysis of hemopoietic colonies as 25-56%. No advantage has been demonstrated for the addition of growth factors or intensive viral exposure schedules. The enzyme is secreted into the medium and functional localization has been demonstrated by reversal of the phenotypic effects of lysosomal storage in macrophages. This work suggests that retroviral gene transfer into human bone marrow may offer the prospect for gene therapy of Hurler syndrome in young patients without a matched sibling donor.

Antigens, CD34↗
PubMed1996

Mucopolysaccharidosis IVA: a comparative study of polymorphic DNA haplotypes in the Caucasian and Japanese populations.

Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by deficiency of the lysosomal enzyme N-acetylgalactosamine-6-sulphate sulphatase (GALNS). The genetic heterogeneity at the GALNS locus was studied in 62 mutant alleles and 376 normal alleles in the Caucasian population and also in 40 mutant and 100 normal alleles in the Japanese population. For this study, six different restriction fragment length polymorphisms (RFLPs) at the GALNS locus were analysed to search for the frequency of each RFLP produced by StyI, SphI, RsaI, HaeIII, StuI and HapII restriction endonucleases. We detected a total of 27 haplotypes in the Caucasian and Japanese population. Of these 27 haplotypes, 18 haplotypes were present in the Caucasian population and the most common of these was haplotype 1 (ABHcde) in both mutant and normal alleles. In contrast, in the Japanese population we found 20 of the 27 haplotypes and the most common in mutant and normal alleles was haplotype 2 (abhcDE). Within these two populations a parent in the MPS IVA family has an average probability of greater than 77% (in the Caucasian population 77.27% and in the Japanese population 78.26%) of being heterozygous, and hence informative for linkage, at one or more GALNS RFLP sites. Our results delineate the molecular heterogeneity of MPS IVA haplotypes, as well as their significant interpopulation variation, and make prenatal diagnosis and carrier detection possible in the majority of families with one affected child.

Acetylgalactosamine↗
PubMed1996

Mucopolysaccharidosis type IVA (Morquio syndrome): a clinical review.

Patients with MPS IV have a clinical disorder quite different from other MPS conditions. The major treatment issue revolves around the prevention of cervical myelopathy, although the other aspects of this multisystem disease should not be forgotten. Management is inevitably multidisciplinary and the paediatrician should play a lead role in the coordination of services for affected patients. The timing of occipito-cervical fusion and the selection of patients for this procedure remain unclear. A prophylactic approach to surgery is suggested in this review, although it is by no means clear that all patients will invariably develop cervical myelopathy if left untreated. Parents of affected children need considerable support in dealing with the affected child and the children themselves need help to try to come to terms with their severe physical disabilities. The Society for Mucopolysaccharide Diseases (55 Hill Avenue, Amersham, Bucks HP6 5BX, UK) has offered many parents and affected individuals considerable help as well as raising significant sums for research. Finally, it is important to remember the genetic nature of the disease and the possibility of prenatal diagnosis in subsequent pregnancies.

Heart Diseases↗
PubMed1996

Magnetic resonance imaging of the brain, neck and cervical spine in mild Hunter's syndrome (mucopolysaccharidoses type II).

Magnetic resonance imaging (MRI) of the brain, neck and cervical spine of five patients with the mild variant of Hunter's syndrome (iduronate sulphate sulphatase deficiency, mucopolysaccharidosis Type II, MPS II) are described and compared with the few available reports in the literature. The most prominent abnormalities in the brain include ventriculomegaly and brain atrophy, the presence of well defined cystic areas of decreased signal on T1- and increased signal on T2-weighted images, of the thalamus, basal ganglia and brain stem, and decreased signal on T1-weighted and increased signal changes on T2-weighted sections of the periventricular and subcortical white matter. A giant cisterna magna was present in four patients and a J-shaped sella in three. Thickening of the soft tissue posterior to the odontoid peg was present with associated canal stenosis in all cases resulting in compression of the cervical cord in four cases. All patients had ill-defined decreased signal on T1-weighted and increased signal changes on T2-weighted sections within the cord. In some, this was associated with cord expansion. Airway narrowing was a common finding. Disc dehydration and the classical platyspondyly with antero-inferior beaking of the vertebral bodies was seen.

Adolescent↗