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Biomedical subjects

A E Harding

Publications and source records attributed to A E Harding.

At least 109 records · Page 6Linked to original sources
PubMed1993

Evidence for locus heterogeneity in autosomal dominant torsion dystonia.

Idiopathic torsion dystonia (ITD) is most commonly an autosomal dominant disorder with reduced penetrance and variable expression. A locus on the distal long arm of chromosome 9 has been identified in one large non-Jewish and several Jewish families in the United States. Linkage analysis in a large Australian kindred with ITD, also containing two patients with Wilson's disease, excludes a locus for ITD in chromosome 9q34 or the region of chromosome 13 containing the Wilson disease gene. This study provides evidence for locus heterogeneity in autosomal dominant ITD and also gives additional information on gene order in chromosome 9q.

Adolescent↗
PubMed1993

Clinical and molecular neurogenetics in neurosurgery.

This chapter describes the basic principles of molecular genetics, particularly in relation to gene mapping and isolation (positional cloning). The application of this technology is illustrated by progress in elucidating the molecular basis of inherited tumour syndromes, including neurofibromatosis types 1 and 2 and von Hippel-Lindau disease, and molecular studies of tumourigenesis in malignant gliomas.

Brain Neoplasms↗
PubMed1993

The sensory neuropathy of Friedreich's ataxia: an autopsy study of a case with prolonged survival.

Observations have been made on a patient with Friedreich's ataxia who died 52 years after the onset of symptoms. The pathology of the brain and spinal cord was typical of this disorder. Apart from loss of dorsal root ganglion cells, severe loss of secondary sensory neurons was observed, including the nucleus dorsalis in the spinal cord, the spinal and principal trigeminal nuclei and, in particular, the mesencephalic trigeminal nucleus in the brain stem. Morphometric studies on the first sacral nerve root and on the sural nerve at levels from midthigh to ankle revealed a distally accentuated axonal loss that predominantly affected larger myelinated nerve fibres. Regenerative activity was seen, mainly in the spinal root and proximally in the sural nerve. Relative myelin thickness, assessed by a g ratios, tended to be reduced. As teased fibre studies showed only limited evidence of demyelination/remyelination and of axonal regeneration, this therefore suggests the presence of a hypomyelination. The results confirm the presence of a distal axonopathy and provide no evidence that this is preceded by axonal atrophy.

Axons↗
PubMed1993

Central nervous system involvement in Leber's optic neuropathy.

Six months after the onset of visual loss a 23-year-old male patient with Leber's optic neuropathy associated with a mitochondrial DNA mutation developed brain stem involvement with Parinaud's syndrome and oculopalatal myoclonus. Magnetic resonance imaging (MRI) revealed a high signal area in the brain stem, corresponding to a hypodense area in the CT scan that did not show contrast enhancement. Distinct diminution but not complete remission of the MRI findings was found in the 5-year follow-up, which was not accompanied by clinical improvement. Although the MRI findings were compatible with a demyelinating lesion, neither extensive evoked potential studies nor spinal fluid examination supported this.

Adult↗
PubMed1993

EEG and evoked potential findings in mitochondrial myopathies.

Electroencephalograms (EEGs) and evoked potentials (EPs) were studied in 43 patients with mitochondrial myopathies. Abnormalities were found most frequently in patients who presented predominantly or exclusively with central nervous system (CNS) dysfunction (abnormal EEGs in 18 of 21 patients, abnormal EPs in 9 of 11 patients). However, of patients presenting with ocular myopathy or proximal muscle weakness who had little or no CNS involvement clinically, 8 of 22 had abnormal EEGs and 5 of 10 had abnormal EPs, suggesting that electrophysiological tests are of value in demonstrating subclinical CNS disease in mitochondrial myopathy, although the abnormalities are not specific.

Adolescent↗
PubMed1993

A tandem duplication in the D-loop of human mitochondrial DNA is associated with deletions in mitochondrial myopathies.

About 40 per cent of patients with mitochondrial myopathies have two populations of mitochondrial DNA (mtDNA) in muscle, one of which is deleted. All patients with single mtDNA deletions and neurological disease are sporadic cases, suggesting that deletions arise as fresh mutational events. We have detected a low abundance heteroplasmic tandem duplication involving the displacement loop of mtDNA in 18 of 58 patients with deletions and 5/5 of their mothers, but not in normal subjects. The location of the duplication to a region that controls both replication and transcription of mtDNA could explain features suggesting mild mitochondrial dysfunction in the muscle biopsies of three patients' mothers, and a predisposition to deletion.

Aged↗
PubMed1993

Dementia associated with a 216 base pair insertion in the prion protein gene. Clinical and neuropathological features.

We report the clinical and neuropathological findings in a patient with a 216 base pair insertion in the prion protein (PrP) gene. She died aged 57 years after a 2.5-year illness characterized by falls, axial rigidity, myoclonic jerks and progressive dementia. There was no history of affected relatives. The pathological changes consisted of the deposition in cerebellum, basal ganglia and cortex of small plaques composed of variable amounts of amyloid and degenerative material which was associated with a marked macrophage reaction. The amyloid deposits in the cerebellum and basal ganglia gave a positive immunoperoxidase staining reaction for PrP. In some places plaques bore a resemblance to senile neuritic plaques and in the hippocampus there were abundant typical neuritic plaques giving positive staining reactions for beta-amyloid protein and tau protein, but not PrP. There were few neurons bearing neurofibrillary tangles. This is the first report of the neuropathological changes associated with this particular abnormality of the PrP gene and it seems to demonstrate a transition between the pathology of prion disease and that of Alzheimer's disease. The importance of PrP gene analysis to the understanding of neurodegenerative diseases is stressed.

Basal Ganglia↗
PubMed1993

The mitochondrial DNA transfer RNA(Lys)A-->G(8344) mutation and the syndrome of myoclonic epilepsy with ragged red fibres (MERRF). Relationship of clinical phenotype to proportion of mutant mitochondrial DNA.

The mitochondrial DNA (mtDNA) transfer RNA (tRNA)Lys A-->G(8344) mutation was identified in seven patients. These patients and their relatives were assessed clinically; in one family the mutation was deduced to be present in four generations. The phenotype in index cases was consistent with the syndrome of myoclonic epilepsy with ragged red fibres, with the core clinical features of myoclonus, ataxia and seizures. Amongst other features, progressive external ophthalmoplegia, Leigh's syndrome and stroke-like episodes were observed, well recognized in mitochondrial myopathies but novel manifestations of this genotype. Samples of blood and muscle were analysed for the proportion of mutant mtDNA using an oligonucleotide hybridization technique. The proportion of mutant mtDNA in blood was significantly greater in symptomatic than asymptomatic cases. Furthermore, the proportion of mutant mtDNA in blood correlated with age of onset of disease and clinical severity assessed by a simple scale. Study of disease associated with the tRNA(Lys) A-->G(8344) mutation provides further insight into the pathogenesis and transmission of mitochondrial diseases. Quantification of the proportion of mtDNA in tissues demonstrates that this is a major factor determining the course of disease, but other, as yet unidentified factors are also likely to play a role.

Adult↗
PubMed1993

Linkage analysis in British and French families with idiopathic torsion dystonia.

Idiopathic torsion dystonia is most commonly caused by an autosomal dominant gene or genes with reduced penetrance. An idiopathic torsion dystonia locus has been mapped to chromosome 9q34 in one large non-Jewish and several Jewish kindreds in the USA. Linkage analysis was performed in 27 (26 British, one French) small families with idiopathic torsion dystonia, three of which were Ashkenazi Jewish, using the highly polymorphic loci argininosuccinate synthetase (ASS) and Abelson oncogene (ABL) which map to 9q34. The cumulative lod score for the more informative ASS locus at a recombination fraction of 0.001 was -6.72. A large component of this score was derived from three non-Jewish families, indistinguishable clinically from the others, in which individual lod scores excluded a disease locus tightly linked to ASS. Analysis of all the data using HOMOG showed significant heterogeneity, but evidence for linkage of an idiopathic torsion dystonia gene to 9q34 in a subset of families. The allelic association observed between ASS/ABL and idiopathic torsion dystonia in Ashkenazi families in the USA was also present in British Jewish kindreds. These data suggest genetic heterogeneity in idiopathic torsion dystonia but indicate the existence of a locus for idiopathic torsion dystonia at 9q34 in both Jewish and non-Jewish kindreds in the UK.

Argininosuccinate Synthase↗
PubMed1993

Smoking and mitochondrial function: a model for environmental toxins.

Defects of the human mitochondrial respiratory chain have been associated with several diseases including, most recently, certain neurodegenerative disorders. Several studies have used platelet mitochondrial function as a means to determine the potential contribution of respiratory chain defects to the pathogenesis of Parkinson's disease. Platelet biochemistry is subject to modulation by numerous factors that may circulate in the blood, including environmental agents, some of which may be relevant to mitochondrial dysfunction and neuronal toxicity. We measured mitochondrial respiratory chain enzyme activities in platelets from 18 normal healthy non-smoking controls and compared them with those from 23 similarly healthy cigarette smoking individuals. A 24% decrease (p < 0.02) was observed in the mean NADH CoQ1 reductase (complex I) activity of the smoking group compared with that of the non-smoking group. There was no significant change in the activity of any of the other respiratory chain enzymes. This is the first demonstration in vivo of mitochondrial inhibition by a common environmental agent. The results offer a novel mechanism of action for the cellular toxicity, or even mutagenicity, associated with cigarette smoking. In addition, these data have important implications for the interpretation of platelet mitochondrial complex I activities in disease states. They are particularly relevant to our interpretation and understanding of the complex I deficiency in Parkinson's disease platelets.

Blood Platelets↗
PubMed1993

Predictive testing for Huntington's disease: after the gene. The United Kingdom Huntington's Disease Prediction Consortium.

The discovery of a mutation responsible for Huntington's disease (HD) offers the possibility of accurate predictive testing, as well as hope for treatment or prevention of this disease. We urge caution in the use of this new test as considerable ethical and counselling problems still exist, and new issues have arisen. The current guidelines for predictive testing should still apply, since it remains vital that subjects and their families have time to come to terms with the diagnosis of HD, and the implications of testing. Mutation analysis may allow the diagnosis of HD in isolated cases, or reverse a test result produced using linkage. Problems will arise as those at 25% risk may now receive a result despite the lack of support of their parent at 50% risk who may not wish to have their own status defined. In addition, couples who seek the exclusion test in pregnancy may find it difficult to investigate the pregnancy without producing information on themselves. Different centres should cooperate in maintaining the confidentiality of family members, ensuring that adequate counselling is given before results are produced which may affect the wider family.

Family↗
PubMed1993

Age at onset in Huntington's disease and methylation at D4S95.

Age at onset in Huntington's disease (HD) is variable and is influenced by parental sex, paternal age, and genetic background. Several recent models have tried to explain this variable expressivity by invoking parental imprinting and related aspects of epigenetic inheritance. Some of these mechanisms may result in variable DNA methylation at or near the HD gene. We show here that methylation at D4S95, a locus tightly linked to the HD gene, is highly variable. A comparison between patients with early onset HD, late onset HD, and normal controls showed no significant correlation between methylation and age at onset. However, we found a significant association of the age of the patient with demethylation at D4S95. Older persons tend to have lower levels of methylation at this locus. This observation is of interest with regard to studies that show an effect of paternal age, or more generally of 'ageing genes', on age at onset in HD.

Adolescent↗
PubMed1993

Transthyretin gene mutations in British and French patients with amyloid neuropathy.

Five patients, two British and three French, with late onset amyloid neuropathy were found to have mutations of the transthyretin (TTR) gene associated with the Portuguese and German types of familial amyloid polyneuropathy. Familial amyloid polyneuropathy is rare in the United Kingdom and has not previously been defined at a molecular genetic level. None of the patients had a history of affected antecedents; the role of TTR gene analysis in diagnosing known or suspected amyloid neuropathy, regardless of family history or ethnic background, is emphasised.

Aged↗
PubMed1993

A familial disorder associated with palatal myoclonus, other brainstem signs, tetraparesis, ataxia and Rosenthal fibre formation.

Three siblings presented with a progressive neurological disorder beginning in the third decade of life and characterised by palatal myoclonus, nystagmus, bulbar weakness and spastic tetraparesis. There was no evidence of intellectual deterioration or seizures. CT scan showed marked brainstem atrophy in two patients and basal ganglia calcification in one. MRI scan in one showed high signal in the brainstem and periventricular region and cerebral biopsy in this patient showed myelin loss and the presence of Rosenthal fibres. A similar disease affected the siblings' mother, maternal aunt and two of the aunt's daughters, suggesting an autosomal dominant mode of transmission of what appears to be a unique genetic disorder.

Adult↗