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Biomedical subjects

P S Harper

Publications and source records attributed to P S Harper.

At least 19 recordsLinked to original sources
PubMed1992

Five years experience of predictive testing for myotonic dystrophy using linked DNA markers.

We report on a 5 year experience in providing presymptomatic and prenatal molecular diagnostic services for myotonic dystrophy, using closely linked markers, representing 235 completed results in 161 families. Only 10 analyses (4.3%) proved uninformative, but a further 5 requests (1.9%) could not be reported because of uncertainty in clinical status. Seven of 81 (8.6%) patients considered to be at low risk on clinical grounds were found to be at high risk of carrying the gene. The importance of interpreting molecular results in conjunction with clinical findings is emphasised by the illustrative examples provided. Careful clinical examination and appropriate investigation remain a cornerstone of diagnosis in myotonic dystrophy and are crucial if errors in assigning genotype status by molecular means are to be minimised.

Adolescent↗
PubMed1992

Unstable DNA sequence in myotonic dystrophy.

A variable DNA sequence has been detected in patients with myotonic dystrophy. We set out to determine whether identification of this specific molecular defect would improve clinical management of patients and families with myotonic dystrophy. 127 affected patients who were studied had an expanded DNA fragment not seen in 73 normal controls. The increase in length of the fragment correlated broadly with disease severity, and we noted expansion of the sequence in successive generations of the same family. Progressive expansion of the affected gene provides a molecular explanation for an apparently earlier onset in successive generations (anticipation) in myotonic dystrophy and supports the role of an unstable repeat sequence as the basis of the defect. The specificity of this finding will assist in accurate diagnosis of myotonic dystrophy and genetic counselling of affected families.

Adolescent↗
PubMed1992

Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy.

Myotonic dystrophy is the commonest adult form of muscular dystrophy, with an estimated incidence of 1 per 7,500, although this is likely to be an underestimate because of the difficulty of detecting minimally affected individuals. It is a multisystem autosomal dominant disorder of unknown biochemical basis. No case of new mutation has been proven. We have isolated a human genomic clone that detects novel restriction fragments specific to individuals with myotonic dystrophy. A two-allele EcoRI polymorphism is seen in normal individuals, but in most affected individuals one of the normal alleles is replaced by a larger fragment, which varies in length both between unrelated affected individuals and within families. The unstable nature of this region may explain the characteristic variation in severity and age at onset of the disease. A second polymorphism at this locus is in almost complete linkage disequilibrium with myotonic dystrophy, strongly supporting our earlier results which indicated that most cases are descended from one original mutation.

Blotting, Southern↗
PubMed1992

The epidemiology of Huntington's disease.

The available information on the world distribution of Huntington's disease (HD) from population surveys and death rate analysis is summarised and discussed in the light of genetic studies. It is concluded that most European populations, both Northern and Southern, show a relatively high prevalence (4-8 per 100,000), and that the disorder may also be frequent in India and parts of central Asia. HD is notably rare in Finland and in Japan, but data for Eastern Asia and Africa are inadequate. The disorder may have been underestimated in the American black population. Populations derived from recent European immigration show frequencies and origins of HD comparable to those expected from their own origins and expansion; there is no evidence to suggest that the HD gene has spread disproportionally and its selective effect may be close to neutral. Multiple separate introductions of the gene have been the rule in large populations. Several major foci of HD exist as the result of rapid population expansion. It is likely that a number of separate mutations for HD will be shown to be responsible for the disease, but that the high frequency of HD in European populations will prove to be the result of one or a very small number of mutations, probably of great antiquity.

Asia↗
PubMed1992

Genetic heterogeneity in X-linked amelogenesis imperfecta.

The AMELX gene located at Xp22.1-p22.3 encodes for the enamel protein amelogenin and has been implicated as the gene responsible for the inherited dental abnormality X-linked amelogenesis imperfecta (XAI). Three families with XAI have been investigated using polymorphic DNA markers flanking the position of AMELX. Using two-point linkage analysis, linkage was established between XAI and several of these markers in two families, with a combined lod score of 6.05 for DXS16 at theta = 0.04. This supports the involvement of AMELX, located close to DXS16, in the XAI disease process (AIH1) in those families. Using multipoint linkage analysis, the combined maximum lod score for these two families was 7.30 for a location of AIH1 at 2 cM distal to DXS16. The support interval around this location extended about 8 cM proximal to DXS92, and the AIH1 location could not be precisely defined by multipoint mapping. Study of recombination events indicated that AIH1 lies in the interval between DXS143 and DXS85. There was significant evidence against linkage to this region in the third family, indicating locus heterogeneity in XAI. Further analysis with markers on the long arm of the X chromosome showed evidence of linkage to DXS144E and F9 with no recombination with either of these markers. Two-point analysis gave a peak lod score at DXS144E with a maximum lod score of 2.83 at theta = 0, with a peak lod score in multipoint linkage analysis of 2.84 at theta = 0. The support interval extended 9 cM proximal to DXS144E and 14 cM distal to F9.(ABSTRACT TRUNCATED AT 250 WORDS)

Amelogenesis Imperfecta↗
PubMed1992

Molecular analysis for the myotonic dystrophy mutation in neuromuscular disorders.

A variable expansion of an unstable CTG repeat has been identified as the causal mutation for myotonic dystrophy. Standard molecular genetic techniques can now supplement traditional assessment protocols in a variety of clinical neurological situations where diagnostic uncertainty prevailed. Southern analysis using DNA probes which identify the expanded sequence, supplemented by direct PCR analysis for repeat number, provides a specific sensitive diagnostic test for myotonic dystrophy.

Adult↗
PubMed1992

Analysis of mutations at the neurofibromatosis 1 (NF1) locus.

A panel of 200 unrelated NF1 individuals has been screened for mutations using a panel of specific clones for the entire gene. DNA analysis on conventional Southern blots indicated that (20) 10% of NF1 patients showed aberrant bands. Small lesions involving nucleotide alterations were detected in a further 10 patients; 5 of these alterations have been fully characterised and are the novel mutations in the NF1 gene. A number of mutations were identified in exon 2. Identical mutations in this exon in two unrelated individuals involved an insertion of cytosine into codon 5662 and resulted in an inappropriate stop codon. This mutation also created a new MnlI site. Another novel mutation in exon 2 resulted from the insertion of thymidine at nucleotide 5678, which also created an inappropriate stop codon. We have so far completed the screen of exons 1-9 of the NF1 gene for the identification of mutations and have found no evidence of clustering of such mutations in the gene.

Amino Acid Sequence↗
PubMed1992

Presymptomatic testing for late-onset genetic disorders: lessons from Huntington's disease.

Huntington's disease is an inherited, neurodegenerative disorder, usually of adult onset. Since the identification of linked markers, more than 1000 presymptomatic tests have been performed worldwide and multiple ethical issues have been encountered in relation to informed consent, testing of children, exclusion testing during pregnancy, and confidentiality. Further ethical problems are anticipated after identification of the causal mutation (or mutations). As Huntington's disease is a model for other disorders of adult onset for which testing is becoming possible, the successful resolution of these ethical issues is of great importance. A failure to do so might discredit genetic testing as a whole.

Child↗
PubMed1992

The Charcot-Marie-Tooth syndrome: perceptions of disability and projected use of DNA diagnostic tests.

The Charcot-Marie-Tooth group of disorders cause significant morbidity in a proportion of the individuals affected. We have shown that there is a significant correlation between the objective neurological assessment of their dysfunction and the individual's subjective perception of their disability. We have also documented the observation that individuals expressing an intention to use prenatal DNA diagnostic services and terminate an "affected" fetus are more severely affected by their disorder than those who would not, or who were unsure about their use of molecular genetic testing.

Adolescent↗
PubMed1992

Anal abnormalities in childhood myotonic dystrophy--a possible source of confusion in child sexual abuse.

Myopathic involvement of the perianal musculature is one of the less well recognised features of myotonic dystrophy in children and may present with physical signs suggestive of sexual abuse. Details of six children with myotonic dystrophy are presented to emphasise the importance of considering an underlying myopathic condition in the differential diagnosis of anal laxity.

Adolescent↗
PubMed1992

Charcot-Marie-Tooth disease type 1a (CMT1a): evidence for trisomy of the region p11.2 of chromosome 17 in south Wales families.

The gene for Charcot-Marie-Tooth disease type 1a (CMT1a) has been localised to chromosome 17p11.2. Locus D17S122 is recognised by the DNA probe pVAW409R3 which detects an MspI polymorphism with three alleles in the normal population. Subjects with CMT1a show evidence of trisomy for this region of chromosome 17 by displaying either all three alleles or a dosage effect when only two alleles are present. This phenomenon was seen in 10 out of 11 families with type I hereditary motor and sensory neuropathy (HMSN) where affected subjects were heterozygous for the MspI polymorphisms. This mutation is likely to have arisen from a non-reciprocal recombination event between non-sister chromatids of homologous chromosomes at meiosis I. The detection of this partial trisomy offers a rapid method for the diagnosis of CMT1a in families not suitable for linkage analysis.

Alleles↗
PubMed1992

Minimal expression of myotonic dystrophy: a clinical and molecular analysis.

A clinical and molecular study is reported of 83 patients considered to be minimally affected with myotonic dystrophy (DM). These had been identified in three ways: 60 subjects were identified on clinical grounds and were divided into those with and those without neuromuscular involvement (groups I and II); nine subjects were at high risk of carrying the DM gene but had a normal phenotype (group III); and 14 were parents of definitely affected patients where neither parent showed clinical abnormalities (group IV). PCR analysis of the CTG repeat in the DM gene showed a range of 70 to 230 repeats for the younger at risk patients in group III, while the asymptomatic gene carriers in group IV had 53 to 60 repeats. The sensitivity of diagnosis by EMG was found to be 39%. For ophthalmic signs this was 97.5%. This suggests that assignment on the basis of minimal clinical features carries a significant error. Molecular analysis, in conjunction with established clinical investigations, should prove valuable in the identification and exclusion of minimal myotonic dystrophy.

Adult↗
PubMed1992

Specific molecular prenatal diagnosis for the CTG mutation in myotonic dystrophy.

The results of DNA analysis for the specific mutation of myotonic dystrophy are reported in eight pregnancies (two studied retrospectively) in six families. Four results were normal; in the other four, large DNA expansions were found, comparable to the range seen in severely affected children with congenital onset of the disorder. The results agreed with those obtained by linked DNA markers in the six cases where they were available. We conclude that specific molecular prenatal diagnosis of myotonic dystrophy is feasible, and that an abnormal result may also give a guide to possible severity, though this should be interpreted with caution until greater experience is available.

Base Sequence↗
PubMed1992

Severity of chest disease in cystic fibrosis patients in relation to their genotypes.

A detailed comparison of the severity of chest disease with mutational status was carried out by cross sectional study of 127 cystic fibrosis patients, aged 1 to 31 years, living in Wales. Lung disease was classified according to severity, depending on pulmonary function tests (carried out on 76 patients) and chest radiograph status; information was obtained also on age at diagnosis in relation to severity of chest disease and colonisation with Pseudomonas species. Genotypes were determined by analysis for the mutations delta F508, delta I507, G551D, R553X, G542X, R117H, R560T, 1717--IG > A, and 621 + 1G > T. CF patients homozygous positive and heterozygous for the delta F508 deletion showed a significant decline of lung function with age. Unlike other studies, we did not find patients homozygous positive for the delta F508 deletion to have poorer lung function compared with heterozygous patients. Patients with the genotype 621 + IG > T/delta F508 tended to have more severe chest disease than the delta F508 homozygous patients in the same age group. There was some evidence that four patients heterozygous for R117H have mild chest disease.

Adolescent↗