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Biomedical subjects

J E Wraith

Publications and source records attributed to J E Wraith.

At least 73 records · Page 4Linked to original sources
PubMed1995

Magnetic resonance imaging in phenylketonuria: reversal of cerebral white matter change.

OBJECTIVES: To investigate the extent to which the abnormalities in cerebral white matter in adolescents and adults with phenylketonuria (PKU) are reversible. METHOD: Magnetic resonance imaging (MRI) of the brain was repeated in 41 patients with PKU (age range, 14 to 49 years) after an interval (median, 9 months; range, 3 to 12 months) of dietary intervention. Scans were scored according to the extent of the white matter involvement. After an initial MRI, five patients returned to a strict low-phenylalanine diet with amino acid supplement; 21 patients started a low-protein diet (1 gm/kg) with amino acids supplement; and 15 patients made no dietary alteration. RESULTS: Scans improved in all five patients who returned to a strict low-phenylalanine diet, in 5 of the 21 patients on the low-protein diet plus amino acid supplement, and in 4 of the 15 patients who made no dietary change. There was a significant association between change in the MRI findings and in the blood phenylalanine concentration (Pearson correlation: r = 0.55; p < 0.0002) and between change in the MRI and in the phenylalanine level at the time of the second scan (r = 0.58; p < 0.0001). Improvement was seen primarily in those in whom phenylalanine levels were reduced to less than 900 mumol/L. There was no obvious change in MRI score after 3 weeks of strict phenylalanine restriction for the two adults who underwent serial scanning. CONCLUSION: The MRI changes in PKU are at least partially reversible by lowering the blood phenylalanine concentration.

Adolescent↗
PubMed1995

The presenting features of mucopolysaccharidosis type IH (Hurler syndrome).

The presenting features of 39 patients with mucopolysaccharidosis (MPS) type IH are described. The mean age at diagnosis was approximately 9 months and it is difficult to see how this can be reduced without consideration of newborn screening. An earlier age at diagnosis is likely to lead to better results following therapy such as bone marrow transplantation. Clinical features which should arouse suspicion of MPS IH include frequent ENT surgery and recurrent herniae. Clinical vigilance is needed for early diagnosis.

Age Factors↗
PubMed1995

Absence of acidosis in the initial presentation of propionic acidaemia.

The clinical presentation and results of the initial biochemical and haematological investigations in 11 newborn term infants with propionic acidaemia are described. All patients had neurological symptoms. Only four had clinically important acidosis, but all had a raised blood ammonia. A diagnosis of propionic acidaemia should be considered in all newborn infants with unexplained neurological deterioration even in the absence of a metabolic acidosis.

Acidosis↗
PubMed1995

Mucopolysaccharidosis IVA: identification of a common missense mutation I113F in the N-Acetylgalactosamine-6-sulfate sulfatase gene.

Mucopolysaccharidosis IVA is an autosomal recessive lysosomal storage disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. The recent isolation and characterization of cDNA and genomic sequences encoding GALNS has facilitated identification of the molecular lesions that cause MPS IVA. We identified a common missense mutation among Caucasian MPS IVA patients. The mutation was originally detected by SSCP, and successive sequencing revealed an A-->T transversion at nt 393. This substitution altered the isoleucine at position 113 to phenylalanine (I113F) in the 622 amino acid GALNS protein and was associated with a severe phenotype in a homozygote. Compound heterozygotes with one I113F-allele mutation have a wide range of clinical phenotypes. Transfection experiments in GALNS-deficient fibroblasts revealed that the mutation drastically reduces the enzyme activity of GALNS. Allele-specific oligonucleotide or SSCP analysis indicated that this mutation accounted for 22.5% (9/40) of unrelated MPS IVA chromosomes from 23 Caucasian patients, including 6 consanguineous cases. Of interest, the I1e 113-->Phe substitution occurred in only Caucasian MPS IVA patients and in none of the GALNS alleles of 20 Japanese patients. These findings identify a frequent missense mutation among MPS IVA patients of Caucasian ancestry, that results in severe MPS IVA when homoallelic, and will facilitate molecular diagnosis of most such patients and identification of heterozygous carriers. In addition to this common mutation, 10 different point mutations and 2 small deletions were detected, suggesting allelic heterogeneity in GALNS gene.

Base Sequence↗
PubMed1994

Magnetic resonance imaging of the brain in phenylketonuria.

Abnormalities of magnetic resonance imaging (MRI) of the brain occur in some patients with phenylketonuria but the clinical importance of this finding is not clear. In order to determine the frequency and functional significance of changes on MRI we investigated 77 adolescent and adult patients with phenylketonuria. Patients aged 14-49 years and taking a restricted diet of 1 g/kg protein underwent clinical examination, IQ testing, neurophysiological investigation, and MRI of the brain. Patients aged between 10-14 years taking a low phenylalanine diet with amino acid supplements had MRI of the brain only. Biochemical control was assessed from: the lifetime blood phenylalanine determined from the mean blood concentration throughout life; the accumulated time for each patient that phenylalanine was < 120 mumol/L; the accumulated time for each patient that phenylalanine was > 1200 mumol/L); mean blood concentration in the first 4 years of life; and the mean blood phe concentration in the 5 years prior to imaging. MRI changes, compatible with a disturbance in the water content of white matter, were present in all but 1 patient. The severity of abnormality was most strongly associated with the blood phenylalanine concentration at the time of imaging. Clinical and neurophysiological abnormalities were less common and usually mild. 3 patients had prolonged central motor conduction time, 7 had prolonged visual evoked potentials, and 5 had impaired peripheral sensory nerve conduction. There was no significant association between the extent of MRI abnormalities and IQ, and the presence of neurophysiological, or clinical abnormalities. An abnormal brain scan in PKU may reflect present biochemical control rather than indicate significant neurological damage. As yet there is little evidence that in most patients with PKU these MRI changes are of clinical importance.

Adolescent↗
PubMed1994

Anaesthesia and mucopolysaccharidoses. A review of airway problems in children.

The airway problems encountered during anaesthesia in all children with mucopolysaccharidoses presenting for a surgical procedure from 1988 to September 1991 are reviewed. Thirty-four patients underwent 89 anaesthetics for 110 procedures. The results reveal a high incidence of airway problems. The overall incidence of difficult intubation was 25% and failed intubation 8%. In those children with Hurler's syndrome, the difficult intubation incidence was 54% and failed intubation incidence 23%. Other potential anaesthetic problems such as cardiac anomalies and obstructive sleep apnoea are also reviewed.

Adolescent↗
PubMed1993

Long-term clinical progress in bone marrow transplanted mucopolysaccharidosis type I patients with a defined genotype.

Two mucopolysaccharidosis type I (MPS-I) patients, subjected to bone marrow transplantation (BMT) more than 10 years ago, have recently had their alpha-L-iduronidase genotypes defined. Both patients, homozygous for the relatively common W402X mutation, received BMT when they were 14 and 11 months of age, and are now 12 and 14 years old, respectively. Untreated MPS-I patients, homozygous for W402X, have an extremely severe clinical phenotype with rapid clinical deterioration and death before 6 years of age. The 12-year-old patient, with limited mobility, is coping well at school, while the other patient is wheelchair-bound with severe disability in his lower limbs, and attends a school for the physically handicapped. Both patients have less than normal intelligence with slowly continuing losses. A third MPS-I patients, diagnosed at the age of 6 months, was felt, prior to BMT at 14 months, to have a severe phenotype. Twelve years post-BMT, he is ambulatory, albeit with restricted movement, and has normal intelligence. This patient did not have a defined MPS-I genotype and had alpha-L-iduronidase protein and activity consistent with a less severe outcome than the first two patients. We conclude that BMT has significantly slowed down the clinical regression of the W402X phenotype. We propose that if further gains are to be made, BMT should be performed within the first few months of life. Early diagnosis is therefore essential.

Adolescent↗
PubMed1992

Combined deficiencies of the pyruvate dehydrogenase complex and enzymes of the respiratory chain in mitochondrial myopathies.

In six patients with mitochondrial (encephalo-) myopathy investigations of skeletal muscle revealed a defect of pyruvate dehydrogenase complex (PDHC) in combination with one or more respiratory chain complex deficiencies. A combination of defects of this kind has not been reported previously. Five of the six patients presented within the 1st year of life and had a severe clinical course. Intrafamilial variability of the clinical course in dizygotic twins both suffering from a cytochrome c oxidase deficiency and one of them also from a PDHC deficiency suggests an additional effect of PDHC deficiency on the clinical symptoms. Immunoblot studies of PDHC in five of the patients revealed no abnormalities in their subunit pattern, rendering a defect of mitochondrial protein import or assembly unlikely. The finding of a combined PDHC and respiratory chain deficiency has implications for the diagnostic approach, for therapy and genetic counselling. The exact pathogenetic mechanism of this combination of defects remains to be elucidated.

Female↗
PubMed1992

Mucopolysaccharidosis type I (Hurler syndrome): linkage disequilibrium indicates the presence of a major allele.

Two polymorphisms exist in the alpha-L-iduronidase (IDUA) gene, the gene that is defective in mucopolysaccharidosis type I (MPS I), viz. a KpnI polymorphism and a variable number of tandem repeats (VNTR) polymorphism with three common alleles. The analysis of allele and haplotype frequencies for these two polymorphisms in the normal population and in MPS I patients revealed the presence of linkage disequilibrium. The frequency of the 2,2 (VNTR, KpnI) allele in MPS I patients was 57% compared with only 37% in the normal population. The implications for the presence of a major MPS I allele and the ability to predict patient phenotype are discussed.

Alleles↗
PubMed1991

First-trimester diagnosis of Hunter syndrome: very low iduronate sulphatase activity in chorionic villi from a heterozygous female fetus.

Iduronate sulphatase activity was determined in uncultured chorionic villi from four fetuses at risk for Hunter syndrome. All fetuses were shown to be female by chromosome analysis. Biopsy material from three fetuses showed iduronate sulphatase activity within normal limits whilst the fourth fetus showed activity reduced to 7 per cent of our control mean. The importance of fetal sexing in prenatal diagnosis of this condition is emphasized as female carrier fetuses may show iduronate sulphatase activity reduced to levels observed in affected males.

Chorionic Villi Sampling↗
PubMed1991

Frequent deletions at Xq28 indicate genetic heterogeneity in Hunter syndrome.

Hunter syndrome is a human X-linked disorder caused by deficiency of the lysosomal exohydrolase iduronate-2-sulphatase (IDS). The consequent accumulation of the mucopolysaccharides dermatan sulphate and heparan sulphate, in the brain and other tissues, often results in death before adulthood. There is, however, a broad spectrum of severity that has been attributed to different mutations of the Hunter syndrome gene. We have used an IDS cDNA clone to localise the IDS gene to Xq28, distal to the fragile X mutation (FRAXA). One-third of Hunter syndrome patients had various deletions or rearrangements of their IDS gene, proving that different mutations are common in this condition. Deletions of the IDS gene can include a conserved locus that is tightly linked to FRAXA, suggesting that deletion of nearby genes may contribute to the variable clinical severity noted in Hunter syndrome. The cDNA clone was also shown to span the X chromosome breakpoint in a female Hunter syndrome patient with an X;autosome translocation.

Blotting, Southern↗