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J C MacMillan

Publications and source records attributed to J C MacMillan.

At least 19 recordsLinked to original sources
PubMed2005

Serum TGF-beta 1 and TNF-alpha levels and cardiac fibrosis in experimental chronic renal failure.

OBJECTIVES: To characterize dynamics of changes of serum levels of TGF-beta1 and TNF-alpha in rats with cardiac fibrosis (CF) occurring during chronic renal failure (CRF), and to reveal the character pf correlations of these factors with amounts of cardiac collagen. DESIGN AND METHODS: CRF was induced by unilateral nephrectomy and by electrocoagulation of 25% of the cortex of remnant kidney. Post-operative checkpoints were 2, 4, and 6 months. Serum TGF-beta1 and TNF-alpha levels were measured by ELISA. RESULTS: CF became pronounced only at 6 months of CRF, while serum TGF-beta1 concentrations reached maximum at 4 months, i.e., at the checkpoint preceding the development of CF. Multiple regression showed cardiac collagen to correlate with both serum TGF-beta1 levels and time from the onset of CRF. Sensitivity and specificity of TGF-beta1 as serum marker of CF were 86% and 75%.

Animals↗
PubMed2003

Adult onset Krabbe disease may mimic motor neurone disease.

Krabbe's disease (galactocerebrosidase deficiency) rarely presents in adults, usually with predominantly upper motor neurone clinical features. We report a case in whom the clinical features were similar to motor neurone disease. Nerve conduction studies and neuroimaging were important in leading to the correct diagnosis. Differences in adult-onset presentations are described.

Age of Onset↗
PubMed2001

Telemedicine and clinical genetics: establishing a successful service.

There is a surprising lack of published experience on the use of videoconferencing in clinical genetics. Patients were randomly allocated to either a telegenetic (cases) or face-to-face (control) conventional clinic. The telegenetic consultation was done by videoconferencing, using ISDN lines at 384 kbit/s. Evaluation by the doctor and counsellor took place immediately after each appointment. The patient was asked to evaluate the appointment by telephone questionnaire about four weeks after the event. Forty-two patients were invited to participate and 33 (79%) returned their consent forms. Four patients declined to participate and were seen in ordinary face-to-face clinics. Preliminary results showed that the assessment of the telegenetics consultations by doctors, counsellors and patients was very favourable, and they responded positively when asked if they would be happy to use telemedicine in the future. For use in selected consultations, videoconferencing does appear to fulfil a useful role in clinical genetics.

Attitude of Health Personnel↗
PubMed2000

Jagged1 (JAG1) mutation detection in an Australian Alagille syndrome population.

Alagille syndrome (AGS) is an autosomal dominant disorder characterized by abnormal development of the liver, heart, skeleton, eye, and face. Mutations in the Jagged1 gene (JAG1) have been found to result in the AGS phenotype and both protein truncating mutations and missense mutations have been identified. Using single stranded conformational polymorphism analysis we have screened 22 AGS affected individuals from 19 families for mutations within Jagged1. Twelve distinct Jagged1 mutations were identified in 15 (68.2%) of the 22 AGS cases, seven of which are novel. The mutations include three small deletions (25%), two small insertions (16.6%), three missense mutations (25%), two nonsense mutations (16.6%), and two splice-site mutations (16.6%). These mutations are spread across the entire coding sequence of the gene and most are localized to highly conserved motifs of the protein predicted to be important for Jagged1 function. One-half of the mutations found in this study are located between exons 9 and 12, a region constituting only 12% of the coding sequence. A splice-donor site mutation in intron 11 was shown to cause aberrant splicing of Jagged1 mRNA, consequently terminating translation prematurely in exon 12. The results of this study are consistent with the proposal that either haploinsufficiency for wild type Jagged1 and/or dominant negative effects produced by mutated Jagged1 are responsible for the AGS phenotype.

Alagille Syndrome↗
PubMed1999

Clinical and genetic study of Friedreich ataxia in an Australian population.

Friedreich ataxia is an autosomal recessive disorder caused by mutations in the FRDA gene that encodes a 210-amino acid protein called frataxin. An expansion of a GAA trinucleotide repeat in intron 1 of the gene is present in more than 95% of mutant alleles. Of the 83 people we studied who have mutations in FRDA, 78 are homozygous for an expanded GAA repeat; the other five patients have an expansion in one allele and a point mutation in the other. Here we present a detailed clinical and genetic study of a subset of 51 patients homozygous for an expansion of the GAA repeat. We found a correlation between the size of the smaller of the two expanded alleles and age at onset, age into wheelchair, scoliosis, impaired vibration sense, and the presence of foot deformity. There was no significant correlation between the size of the smaller allele and cardiomyopathy, diabetes mellitus, loss of proprioception, or bladder symptoms. The larger allele size correlated with bladder symptoms and the presence of foot deformity. The duration of disease is correlated with wheelchair use and the presence of diabetes, scoliosis, bladder symptoms and impaired proprioception, and vibration sense but no other complications studied.

Adolescent↗
PubMed1999

Mendelian segregation of normal CAG trinucleotide repeat alleles at three autosomal loci.

Segregation ratio distortion (SRD) with preferential transmission of expanded CAG alleles has been reported in Machado-Joseph disease (MJD/SCA3), spinocerebellar ataxia type I (SCA1), and dentatorubral-pallidoluysian atrophy (DRPLA). We have examined the transmission frequencies of alleles in normal heterozygotes at these disease loci in 377 pairs of twins and their parents and find no evidence for SRD.

Adolescent↗
PubMed1998

Huntingtin protein colocalizes with lesions of neurodegenerative diseases: An investigation in Huntington's, Alzheimer's, and Pick's diseases.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease associated with a CAG trinucleotide repeat expansion in a large gene on chromosome 4. The gene encodes the protein huntingtin with a polyglutamine tract encoded by the CAG repeat at the N-terminus. The number of CAG repeats in HD are significantly increased (36 to 120+) compared with the normal population (8-39). The pathological mechanism associated with the expanded CAG repeat in HD is not clear but there is evidence that polyglutamine is directly neurotoxic. We have immunolocalized huntingtin with an in-house, well-characterised, polyclonal antibody in HD, Alzheimer's disease (AD), and Picks disease (PiD) brains. Control brain tissue sections were from head injured and cerebral ischaemia cases. In HD, huntingtin was immunopositive in the surviving but damaged neurons and reactive astrocytes of the caudate and putamen. However, in AD and PiD the immunostaining was largely restricted to the characteristic intracellular inclusion bodies associated with the disease process in each case. In AD, huntingtin was localized only in the intracellular neurofibrillary tangles and dystrophic neurites within the neuritic amyloid plaques but not with the amyloid. In PiD, strongly positive huntingtin immunostaining was present within cytoplasmic Pick bodies. Our findings suggest huntingtin selectively accumulates in association with abnormal intracytoplasmic and cytoskeletal filaments of neurons and glia in neurodegenerative diseases such as HD, AD, and PiD. Cells in the CNS appear sensitive to damage by the aggregated, toxic levels of huntingtin and evidence of its interaction with neurofilaments could provide information about its potential role in the aetiology of HD.

Adult↗
PubMed1998

Arteriohepatic dysplasia (Alagille syndrome; Watson-Alagille syndrome).

Alagille syndrome (AS) (arteriohepatic dysplasia, Alagille-Watson syndrome) is a multi-system disorder with hepatic, skeletal, eye, cardiac and renal manifestations. It results from mutation of the JAG1 gene, located on chromosome 20, which encodes a ligand for Notch receptor(s). The interactions of Notch receptors and their ligands are crucial in controlling cell fate decisions in a variety of developmental processes. AS varies in its severity, even in the same family, from asymptomatic gene carriers through to lethality due to inoperable cardiac or end-stage liver disease. However, advances in medical and surgical therapy have improved the prognosis at the severe end of the spectrum. It is hoped that the enhanced understanding of the biology of AS resulting from the cloning of the JAG1 gene will enable us to develop additional strategies for more effective treatments.

Alagille Syndrome↗
PubMed1998

PAK3 mutation in nonsyndromic X-linked mental retardation.

Nonsyndromic X-linked mental retardation (MRX) syndromes are clinically homogeneous but genetically heterogeneous disorders, whose genetic bases are largely unknown. Affected individuals in a multiplex pedigree with MRX (MRX30), previously mapped to Xq22, show a point mutation in the PAK3 (p21-activated kinase) gene, which encodes a serine-threonine kinase. PAK proteins are crucial effectors linking Rho GTPases to cytoskeletal reorganization and to nuclear signalling. The mutation produces premature termination, disrupting kinase function. MRI analysis showed no gross defects in brain development. Immunofluorescence analysis showed that PAK3 protein is highly expressed in postmitotic neurons of the developing and postnatal cerebral cortex and hippocampus. Signal transduction through Rho GTPases and PAK3 may be critical for human cognitive function.

Animals↗
PubMed1997

Dentatorubral and pallidoluysian atrophy (DRPLA). Clinical and neuropathological findings in genetically confirmed North American and European pedigrees.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant disorder that clinically overlaps with Huntington's disease (HD) and manifests combinations of chorea, myoclonus, seizures, ataxia, and dementia. DRPLA is caused by a CAG triplet repeat (CTG-B37) expansion coding for polyglutamine on chromosome 12 and exhibits the genetic phenomenon of anticipation. This neurodegenerative disease has only rarely been reported in non-Japanese pedigrees, and there are only a few neuropathological studies in genetically confirmed patients. We report 10 cases of DRPLA from two North American and two British pedigrees in which CTG-B37 expansions have been demonstrated within each kindred (54-83 repeats), individually in 8 of the 10 cases, and describe the neuropathological findings in 4 cases. Members of DRPLA kindreds have a wide range of clinical phenotypes and markedly variable ages at onset. The neuropathological spectrum is centered around the cerebellifugal and pallidofugal systems, but neurodegenerative changes can be found in many nuclei, tracts, and systems. Evidence of CTG-B37 triplet repeat expansion should be sought in HD-like cases that are negative for expanded triplet repeats within the HD IT15 gene or in autopsy cases with degeneration of the dentatorubral or pallidoluysian systems.

Adult↗
PubMed1996

Partial characterisation of murine huntingtin and apparent variations in the subcellular localisation of huntingtin in human, mouse and rat brain.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat in a gene coding for a protein of unknown function. We have raised a polyclonal antibody against a 12 amino acid peptide (residues 2110-2121 of human huntingtin) which specifically recognises huntingtin on Western blots of human, rat and mouse brain. We have characterised huntingtin expression in the mouse. The protein was detected on Western blots of all mouse tissues examined, with the highest expression seen in brain. Human, mouse and rat brain were fractionated by differential centrifugation and discontinuous Percoll gradients. The fractions were analysed by Western blotting for huntingtin and synaptophysin (a synaptic vesicle localised protein). In mouse brain, huntingtin was localised in the soluble S3 fraction; in rat brain it was localised in the soluble S3 fraction and also in the membrane P2 and P3 fractions; in both normal and HD-affected human brain, huntingtin was membrane bound with a distribution essentially the same as that of synaptophysin. These observed differences in the subcellular localisation of huntingtin between mouse and human brain are important in the context of mouse models for HD.

Adult↗
PubMed1996

Neuropathological diagnosis and CAG repeat expansion in Huntington's disease.

OBJECTIVE: To correlate the degree of CAG repeat expansion with neuropathological findings in Huntington's disease. METHODS: The CAG repeat polymorphism was analysed in a large series of brain samples from 268 patients with a clinical diagnosis of Huntington's disease in which full neuropathological data was available. RESULTS: Analysis by polymerase chain reaction was successful in 63% of samples (169 of 268). Repeat expansions were detected in 152 of 153 (99%) samples with a neuropathological diagnosis of Huntington's disease. The exceptional case (22 CAG repeats) showed mild but definite pathological changes and had a typical clinical illness with a positive family history; it raises the possibility that an alternative mutation in the Huntington's disease gene may be responsible although it is more likely that a mutation in another gene has resulted in an Huntington's disease-like phenotype. Four of 16 cases without pathological changes of Huntington's disease also possessed an expanded repeat sequence; a glioblastoma masked the pathological changes of Huntington's disease in one case but the other three cases had a typical clinical history and a positive family history. These three cases may reliably be classified as Vonsattel's Huntington's disease grade 0. Three of 12 cases with a normal repeat length and no morphological changes of Huntington's disease showed other neuropathology; two had Alzheimer's disease and the other had multiple sclerosis. Review of the clinical notes of two other cases indicated a diagnosis of tardive dyskinesia complicating phenothiazine treatment of schizophrenia. The remaining pathology negative/expansion negative cases had been referred because of a family history of Huntington's disease; all but one were themselves symptom free. Apart from emphasising the possibility that an alternative mutation may result in a clinical phenocopy of Huntington's disease, this case suggests that such a clinical phenocopy may occur without gross or light microscopical neuropathological changes (Vonsattel's Huntington's disease grade 0). CONCLUSIONS: The study confirms the value of molecular genetic analysis in cases of suspected Huntington's disease and shows the importance of detailed neuropathological study in the few cases of suspected Huntington's disease with normal CAG repeat lengths.

Adult↗
PubMed1995

Molecular diagnostic analysis for Huntington's disease: a prospective evaluation.

The availability of mutation analysis for the CAG repeat expansion associated with Huntington's disease has prompted clinicians in various specialties to request testing of samples from patients displaying clinical features that might be attributable to Huntington's disease. A series of 38 cases presenting with clinical features thought possibly to be due to Huntington's disease were analysed prospectively. In 53% of such cases presenting initially with chorea and 62.5% with psychiatric symptoms an expansion was identified, a considerable lower proportion than found in previous series where the diagnosis was considered definite on clinical and genetic grounds. Mutation analysis is likely to be of considerable value in the diagnosis of Huntington's disease, especially where the family history in previous generations is inadequate or apparently negative.

Adolescent↗
PubMed1994

The Charcot-Marie-Tooth syndrome: clinical aspects from a population study in South Wales, UK.

The Charcot-Marie-Tooth (CMT) syndrome comprises a heterogeneous group of disorders affecting the peripheral nerves and anterior horn cells of the spinal cord. They constitute a significant proportion of the burden of disability caused by single gene neurological disorders, with a disease prevalence of 16.7 per 10(5) of the South Wales adult population. The clinical and genetic characteristics of these diseases in the population are described. In those cases identified as type I hereditary motor and sensory neuropathy (HMSN I), we have shown that it is possible to correlate disease severity with age, and that there is no clinical evidence for imprinting, manifest either in age of onset or disease severity.

Adolescent↗