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J C MacMillan

Publications and source records attributed to J C MacMillan.

At least 37 records · Page 2Linked to original sources
PubMed1993

Molecular analysis and clinical correlations of the Huntington's disease mutation.

The genetic mutation underlying Huntington's disease (HD) has been identified as an expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4. We have investigated the relation of the phenotype of HD to this molecular defect and assessed the feasibility of HD mutation analysis in diagnosis and prediction. Analysis of DNA from 449 HD patients (351 familial and 98 apparently isolated cases) revealed the mutation in more than 95% of patients from both groups. No molecular difference was found between patients presenting with psychiatric symptoms and those in whom chorea or other motor defects were the principal features; additionally, there was a wide range of age at onset for any specific repeat number, though the small group with juvenile onset and presenting with rigidity showed the largest expansions. The findings suggest that molecular analysis will be an accurate and specific diagnostic test for HD and valuable in presymptomatic detection in individuals at risk. However, such testing will require considerable caution to avoid serious difficulties; the well-established guidelines developed for the use of linked markers in relation to the prediction of HD should continue to be followed, though they will require reassessment in relation to use in diagnosis.

Adult↗
PubMed1993

Charcot-Marie-tooth disease 1A (CMT1A) associated with a maternal duplication of chromosome 17p11.2-->12.

We report here the second case of Charcot-Marie-Tooth disease 1A (CMT1A) with a cytogenetically visible de novo direct duplication of 17p11.1-->17p12. A male child who was initially referred for developmental delay and dysmorphism was subsequently shown to have significantly reduced motor nerve conduction velocities characteristic of CMT1A. This patient was not informative for the DNA markers mapping to the CMT1A region; however, with DNA markers pA10-41 and EW503 that map proximally and distally with respect to the disease locus, a dosage difference was observed between the two alleles. Comparison with parental genotypes indicated a de novo maternal duplication. Pulsed field gel analysis using probe VAW409R3a indicated that a 500-kb SacII junction fragment usually associated with CMT1A was absent in this patient. These findings confirm that the disease phenotype is probably caused by a gene dosage effect.

Charcot-Marie-Tooth Disease↗
PubMed1993

Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.

The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.

Adolescent↗
PubMed1993

Cataract and myotonic dystrophy: the role of molecular diagnosis.

Myotonic dystrophy (dystrophia myotonica), the commonest and most variable of the muscular dystrophies of adult life, has long been known to be associated with cataract, while slit-lamp examination for specific lens opacities has been one of the principal methods of presymptomatic detection of gene carriers. The recent discovery that the myotonic dystrophy mutation is an unstable DNA sequence, composed of varying numbers of CTG triplet repeats, now allows a specific molecular test for this disorder, as well as explaining the phenomenon of anticipation. A series of case reports is presented to illustrate the important practical applications of this development in relation to ophthalmic aspects of the disorder. Reassessment of the specificity of the ophthalmic changes may be required and it will be important for molecular analysis to be used alongside ophthalmic studies, when determining whether family members carry the mutation for myotonic dystrophy.

Adult↗
PubMed1993

Identification of an expanded CAG repeat in the Huntington's disease gene (IT15) in a family reported to have benign hereditary chorea.

Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by the onset of non-progressive chorea in childhood and the absence of cognitive impairment. Using primers flanking the (CAG)n repeat in IT15, expansion of which is associated with HD, we have detected an abnormal PCR product in four affected members from one family where affected subjects were originally reported to have BHC. The expanded allele contains 38 repeats in the affected parent and this undergoes further enlargement to 39 and 45 repeats in the two affected offspring. We conclude that the diagnostic criteria for BHC should include a normal result from analysis for the (CAG)n expansion identified in HD.

Adult↗
PubMed1993

Size of the unstable CTG repeat sequence in relation to phenotype and parental transmission in myotonic dystrophy.

A clinical and molecular analysis of 439 individuals affected with myotonic dystrophy, from 101 kindreds, has shown that the size of the unstable CTG repeat detected in nearly all cases of myotonic dystrophy is related both to age at onset of the disorder and to the severity of the phenotype. The largest repeat sizes (1.5-6.0 kb) are seen in patients with congenital myotonic dystrophy, while the minimally affected patients have repeat sizes of < 0.5 kb. Comparison of parent-child pairs has shown that most offspring have an earlier age at onset and a larger repeat size than their parents, with only 4 of 182 showing a definite decrease in repeat size, accompanied by a later age at onset or less severe phenotype. Increase in repeat size from parent to child is similar for both paternal and maternal transmissions when the increase is expressed as a proportion of the parental repeat size. Analysis of congenitally affected cases shows not only that they have, on average, the largest repeat sizes but also that their mothers have larger mean repeat sizes, supporting previous suggestions that a maternal effect is involved in the pathogenesis of this form of the disorder.

Adolescent↗
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

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

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↗
PubMed1991

Single-gene neurological disorders in South Wales: an epidemiological study.

Single-gene neurological disorders account for a significant proportion of the work load of any regional genetics unit. In an attempt to assess the likely impact of recombinant DNA technology on these debilitating diseases, a population prevalence study of the major neurogenetic diseases was carried out in the South Wales region of Great Britain. The minimum overall prevalence of these disorders was estimated to be 58.6/100,000 population.

Adolescent↗
PubMed1989

Chronic paroxysmal hemicrania.

Chronic paroxysmal hemicrania consists of unilateral paroxysmal headaches, commonly in women, and relieved by indomethacin. Two patients with the condition are reported, one of whom had essential thrombocythaemia and the headaches remitted when the platelet count returned to normal. Platelet function may be worth exploring in these headaches.

Adult↗
PubMed1978

Internal configuration of saphenous-coronary anastomoses as studied by the cast-injection technique.

A study of the internal configuration of saphenous vein--to--coronary artery anastomoses was undertaken to examine the effect of technical factors. One hundred fifty anastomoses were constructed in isolated swine hearts and epoxy-resin casts were made of the anastomoses by pressure-injection. The effects of interrupted sutures, continuous suture, vein tailoring, vein-to-artery size ratio, and end-to-side and side-to-side anastomoses were evaluated. We made several observations: (1) The external appearance of an anastomosis is not a reliable indicator of internal configuration. (2) Interrupted suturing consistently produces an internal configuration with minimal deformity. (3) Unless special precautions are taken with continuous suturing, severe deformities may occur. Very fine suture spacing and knotting distal corner sutures are recommended. (4) Proper vein-to-artery size ratio and "cobra-head" vein tailoring are desirable. (5) Side-to-side anastomoses are similarly significantly affected by suture techniques, vein graft size, venotomy size, and orientation. The study of the internal configuration of saphenous-coronary anastomoses is a simple and readily available method which should be useful to all coronary surgeons in assessing and perfecting their techniques.

Animals↗
PubMed1978

Clinical spectrum of septic pulmonary embolism and infarction.

Management of septic pulmonary embolism now suggests a predictability of the clinical course which often allows an early decision regarding the need for definitive thoracotomy. Sixty patients have been treated within the past 5 years. Antibiotics were employed in all patients, administered whenever possible according to cultures. In 12 patients thoracotomy was required. This involved decortication and varying amounts of pulmonary resection from wedge excision to pneumonectomy. Early appreciation of septic pulmonary embolism and prompt thoracotomy can frequently obviate the need for tardy open drainage procedures with consequent prolonged recovery. Sources of emboli must be controlled. Interruption of the inferior vena cava, vein excision, aggressive control of peripheral abscesses, and excision of the tricuspid valve may be required. Reliance on antiocagulants alone to control emboli is dangerous, and proper surgical intervention and antibiotic therapy reduce the need for long-term anticoagulation.

Adult↗