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Biomedical subjects

A E Harding

Publications and source records attributed to A E Harding.

At least 55 records · Page 3Linked to original sources
PubMed1995

Haplotype analysis of French, British and other European patients with familial amyloid polyneuropathy (met 30 and tyr 77).

Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder originally and most frequently described in Portugal. The usual constituent amyloid fibril protein is transthyretin (TTR) and the most frequent mutation in the TTR gene associated with FAP (including all Portuguese cases) is that at position 30 (met 30). Three different TTR haplotypes have been described in association with the met 30 mutation in European patients. We studied the haplotypes of 27 families (24 French, 2 British and 1 Greek) with FAP met 30 by analysing three polymorphisms in introns of the TTR gene. We also studied 6 families (2 British, 3 French and 1 Spanish) with FAP tyr 77. There were two main haplotypes in French patients with FAP met 30, one most commonly seen in the French families of Portuguese descent which was the same haplotype as previously described in Portuguese patients (haplotype I) and another haplotype (III) detected in most informative French families not of Portuguese origin. The age of onset of symptoms was consistently later in French than in Portuguese patients and in patients with haplotype III as the disease-associated haplotype rather than haplotype I. British and French patients with the tyr 77 mutation had different haplotypes. The most likely explanation of these findings is multiple founders of both mutations.

Amyloid Neuropathies↗
PubMed1995

Sequence of the human homologue of a mitochondrially encoded murine transplantation antigen in patients with multiple sclerosis.

There is some evidence that mitochondrial genes may contribute to susceptibility to multiple sclerosis (MS), and a mitochondrial DNA-encoded peptide, the N-terminal portion of NADH-dehydrogenase subunit 1, acts as a transplantation antigen in mice. We have analysed the DNA sequence of the corresponding region of human mitochondrial DNA in 87 patients with MS, 10 with Leber's hereditary optic neuropathy in association with an MS-like illness, and 31 control subjects. This sequence appears to be highly conserved. Only three base pair changes were identified, each being found once only in one control and two patients, and these are likely to be harmless polymorphisms. There is thus no evidence that polymorphism in this region contributes to genetic susceptibility in MS.

Animals↗
PubMed1995

Antibodies to human optic nerve in Leber's hereditary optic neuropathy.

Mutations of mitochondrial DNA have now been identified in the majority of patients with Leber's hereditary optic neuropathy (LHON). However, these mutations do not explain all the clinical features of LHON, and other pathogenetic factors are likely to be operating. We have analysed serum from 69 LHON patients and their relatives, 58 controls and 14 patients with ischemic or compressive optic neuropathy. A significant proportion of LHON patients had circulating antibodies to tubulin protein. This finding supports the theory that autoimmunity may play some role in the pathogenesis of LHON.

Adult↗
PubMed1995

Impaired mitochondrial translation in human myoblasts harbouring the mitochondrial DNA tRNA lysine 8344 A-->G (MERRF) mutation: relationship to proportion of mutant mitochondrial DNA.

The mitochondrial DNA transfer RNA lysine A8344G mutation is commonly associated with the MERRF (myoclonus epilepsy with ragged red fibre) phenotype. The molecular pathogenesis of disease associated with this mutation is unclear. Theoretically, a mitochondrial tRNA mutation might affect transcription or translation, or both. We therefore studied these processes in cloned primary human myoblast cultures containing different proportions of mutant mtDNA. No abnormality of transcription was observed. However, there was a progressive decrease in mitochondrially encoded protein synthesis as the proportion of mutant mtDNA increased. Furthermore, there was evidence that subunits were differentially affected, based on selective reduction of cytochrome c oxidase subunits with relatively low proportions of mutant mtDNA.

Autoradiography↗
PubMed1995

Kearns-Sayre syndrome associated with mitochondrial DNA deletion or duplication: a molecular genetic and pathological study.

The neuropathological findings in 2 patients with Kearns-Sayre syndrome and mitochondrial DNA (mtDNA) rearrangements, one a predominant deletion and the other a predominant duplication, were remarkably similar, showing diffuse vacuolation of white matter. There were some of the pathological features of Leigh's syndrome in the spinal cord of the patient with a duplication. In the patient with a predominant deletion, rearranged mtDNA was undetectable in blood, spleen, and testis, and present in highest amounts in muscle and the brain, but relatively low in cerebellum, reflecting the ratio seen, albeit in much smaller amounts, in normal aged brains. MtDNA rearrangements in this patient were largely deletions or deletion dimers; duplicated mtDNA was present in only trace amounts in some tissues and there was none in skeletal muscle. The patient with a predominant duplication of mtDNA had higher amounts of rearranged mtDNA in blood (mainly duplicated) than muscle (mainly deleted). Correlation of these data with tissue dysfunction is probably complicated by the replicative behaviour of deleted, duplicated and normal mtDNA.

Adolescent↗
PubMed1995

The clinical features of Leber's hereditary optic neuropathy defined by the presence of a pathogenic mitochondrial DNA mutation.

One hundred and seven patients from 79 families were defined as having Leber's hereditary optic neuropathy (LHON) by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (seven families) or 14484 (12 families). Only half of the 11778 index patients had a history of similarly affected relatives; this proportion was higher with the 3460 (71%) and 14484 (100%) mutations. The ratios of affected male to female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Detailed clinical data were available for 79 patients from 55 families. Visual loss developed between the ages of 11 and 30 years in 69%, with a range of 6-62 years, and no significant differences between mutation groups or males and females. It was bilateral in all but two patients, to a median of counting fingers with a central scotoma, developing simultaneously in 22% and sequentially in 78%, with a median inter-eye delay of 8 weeks, and progressing in each eye over a period of 4-6 weeks. Nineteen patients had pain in an affected eye or on eye movements, and four experienced Uhthoff's phenomenon. Retinal microangiopathy was uncommon after 6 months from onset and was not detected in 36% of patients examined within 3 months of visual loss; the microangiopathy was particularly uncommon in the 14484 group. There was no difference in the overall visual outcome between the 11778 and 3460 groups with median final visual acuities of 1/60 and 3/60, respectively. Particularly severe visual loss occurred in one-third of women with the 11778 mutation, to vague perception of light or no perception of light in at least one eye. A multiple sclerosis-like illness was observed in 45% of females with the 11778 mutation. Prognosis was substantially better in the 14484 patients, with recovery to a final visual acuity of at least 6/24, in 71% of patients. Good visual outcome was strongly correlated with age at onset, all those with onset before 20 years having a final visual acuity better than 6/24 as opposed to only 2 out of 6 with later onset. Improvement in vision occurred as long as 4 years after onset. High alcohol and tobacco consumption, cranial or ocular trauma, young or old age at presentation, co-existing neurological disease, and recent childbirth with post-partum haemorrhage, all contributed to diagnostic difficulties in this series, usually in the absence of a family history. These problems were resolved by mtDNA analysis.

Adolescent↗
PubMed1995

Striatal D1 and D2 receptor binding in patients with Huntington's disease and other choreas. A PET study.

We have used PET to study striatal D1 and D2 receptor binding in 10 patients with either the choreic or akinetic-rigid variants of Huntington's disease and in three patients with other causes of chorea. Background rigidity and bradykinesia in choreic patients were scored with a four-point scale. PET studies showed a severe and parallel reduction of both striatal D1 and D2 receptor binding in Huntington's disease patients irrespective of their predominant phenotype (mean reduction 60%). Huntington's disease patients with rigidity showed more pronounced reduction of striatal D1 and D2 binding compared with those without rigidity. A case of chorea associated with systemic lupus erythematosus had normal D2 binding. These results suggest that the presence of chorea per se may not be determined by alterations in striatal dopamine receptor binding, but that rigidity in Huntington's disease is associated with severe striatal D1 and D2 receptor loss.

Adult↗
PubMed1995

The mitochondrial DNA transfer RNALeu(UUR) A-->G(3243) mutation. A clinical and genetic study.

The mitochondrial tRNALeu(UUR) A-->G(3243) mutation was identified in 22 unrelated patients. The probands and their relatives were assessed clinically and by quantitative mitochondrial DNA (mtDNA) analysis. While 10 probands had clinical features consistent with the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), usually associated with this mutation, 12 probands had other phenotypes including other encephalopathies, chronic progressive external ophthalmoplegia (CPEO), myoclonic epilepsy and ragged red fibres (MERRF), myopathy alone and diabetes and deafness. Histochemical analyses of muscle biopsies showed a higher proportion of cytochrome oxidase (COX) negative fibres, but fewer strongly COX reactive fibres, in patients with CPEO compared with those with MELAS. The proportion of mutant mtDNA present in blood was significantly greater in symptomatic than asymptomatic subjects, and was correlated with age in both. This correlation was not observed in patients with the tRNALys A-->G(8344) mutation. The proportion of mutant mtDNA A-->G(3243) in muscle was always greater than that in blood. Significant correlations between proportion of mutant mtDNA in blood and both age of onset of disease and a clinical severity score were observed. However, the proportion of mutant mtDNA in blood in affected and unaffected cases overlapped, preventing use of the genetic-clinical correlation for prognostic or predictive purposes. The presence of intrafamilial clustering of phenotypes and the imperfect relationship between proportion of mutant mtDNA and the presence or absence of disease suggests that other factors may determine the phenotype. To investigate this possibility further, the tRNALeu(UUR) gene was sequenced in 23 probands and six relatives. In 28 patients the sequence was normal apart from the 3243 mutation, but in members of one family there was a homoplasmic T-->C transition at position 3290 which was not found in 140 controls or 50 other patients with mitochondrial myopathy. The family with this transition had high levels of mutant mtDNA A-->G(3243), with a unique phenotype of predominant skeletal myopathy, suggesting that this second base change in tRNALeu(UUR) may influence the clinical phenotype.

Adult↗
PubMed1995

From the syndrome of Charcot, Marie and Tooth to disorders of peripheral myelin proteins.

The description of the peroneal muscular atrophy syndrome in 1886 by Charcot, Marie and Tooth was followed by an era of nosological confusion. This was partly clarified by the advent of nerve conduction studies and the definition of the most common, but heterogeneous, disorders underlying this syndrome, hereditary motor and sensory neuropathies (HMSN) types I and II. The classification of HMSN is now changing as a result of the identification of underlying mutations in genes encoding myelin proteins. Abnormalities of peripheral myelin protein 22 (PMP-22) account for dominantly inherited HMSN type I in approximately 90% of families. The commonest genetic defect is a duplication of this gene and the surrounding region of chromosome 17, although point mutations also occur. A deletion of the same region causes hereditary neuropathy with liability to pressure palsies. Point mutations of the P0 gene cause HMSN I in a small number of families. The X-linked type of HMSN is associated with defects of the connexin 32 gene, which encodes a gap junction protein. These molecular genetic advances can be translated into clinical practice, leading to improved diagnosis and genetic counselling.

Charcot-Marie-Tooth Disease↗
PubMed1995

Transthyretin gene analysis in European patients with suspected familial amyloid polyneuropathy.

We investigated 99 patients from 64 European families (51 French, 11 British, one Italian and one Spanish) with suspected familial amyloid polyneuropathy (FAP) for transthyretin (TTR) gene mutations. Thirty-nine families were found to have point mutations causing the following amino acid substitutions: Met30 (28 families), Tyr77 (five), Arg 50 (one), Ala49 (one), Gln89 (one), Ala60 (one) and one each with previously undescribed mutations at Asn35 and Gys54. The clinical picture in the patients with new and known mutations were typical of FAP, without any specific features for a particular mutation. Onset of symptoms was late (over 50 years) in many French and British patients with the Met30 and Tyr77 mutations, and only 30% of all index cases had affected relatives. We propose an approach to molecular diagnosis in European patients with FAP, apart from members of families with known mutations, based on the frequency of TTR mutations observed in this and and other studies of FAP in Europe. It is logical to screen for the Met30 and Tyr77 mutations and Ala60 in the UK, using restriction enzyme analysis. If these are absent, the TTR gene should be sequenced directly to detect less common or unknown mutations.

Adult↗
PubMed1995

Detection of the Machado-Joseph disease/spinocerebellar ataxia three trinucleotide repeat expansion in families with autosomal dominant motor disorders, including the Drew family of Walworth.

Affected members of 63 families with a variety of autosomal dominant late onset cerebellar ataxias (ADCA), and 29 patients with similar phenotypes but no affected relatives, were investigated for the trinucleotide (CAG) repeat expansion described in Japanese families with Machado-Joseph disease (MJD). This disorder had previously been shown to map to the region of chromosome 14 which also contains a locus causing ADCA in French families, spinocerebellar ataxia 3 (SCA3). The MJD/SCA3 mutation was identified in nine families with ADCA type I, and a further family in which affected members had parkinsonism, peripheral neuropathy, dystonia, and spasticity, but little evidence of cerebellar disease. Only one of the 10 families was British (the Drew family of Walworth); the others originated from India, Jamaica, Ghana, Brazil and France. There was no single clinical feature which distinguished patients with the MJD/SCA3 mutation from those with the CAG expansion on chromosome 6 (SCA1) or ADCA type I families with no known mutation. The CAG repeat length ranged from 13-41 copies on normal chromosomes and 62-80 copies on affected chromosomes. There was a significant inverse correlation between age of onset of symptoms and repeat length, but no significant effect of parental sex on repeat length or age of onset in offspring. DNA analysis for the MJD/SCA3 mutation is useful for diagnosis in patients with familial ataxic or extrapyramidal syndromes, and will aid genetic counselling in these disorders.

Adolescent↗
PubMed1995

Persistent functional deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss.

Proton magnetic resonance spectroscopy (MRS) and MRI were carried out in 11 patients with multiple sclerosis who had clinical evidence of severe cerebellar involvement, 11 multiple sclerosis patients (of similar age and disease duration) who had minimal or no signs of cerebellar disease, eight patients with autosomal dominant cerebellar ataxia (ADCA) and 11 healthy controls. In all subjects MRS was localized to cerebellar white matter (volumes of interest 3-6 ml). Apparent metabolite concentrations were calculated using the fully relaxed water spectrum as an internal standard of reference. The patients also underwent MRI to assess cerebellar volume and (in the two multiple sclerosis groups) lesion volume within the posterior fossa. Magnetic resonance spectroscopy from cerebellar white matter showed a highly significant reduction in the concentration of N-acetyl groups (NA) [which consists predominantly of N-acetylaspartate (NAA), a neuronal marker] in the multiple sclerosis group with cerebellar deficit compared with the multiple sclerosis group with minimal or no signs of cerebellar involvement, and healthy controls. Follow-up MRS performed in six of the multiple sclerosis patients 9 months later showed no change in the median NA concentration. The ADCA group showed a significant reduction of NA from a region of cerebellar white matter and also a reduction in the concentration of choline-containing compounds. The multiple sclerosis group with severe cerebellar deficit and the ADCA group both had significant cerebellar atrophy (suggesting nerve cell body and axon loss) compared with the multiple sclerosis patients with minimal or no signs of cerebellar deficit and healthy controls. The multiple sclerosis patients with cerebellar deficit had a significantly greater lesion volume in the posterior fossa, although the proportion of the spectroscopic voxel occupied by lesions was small, suggesting that axonal loss from normal appearing white matter also contributes to the observed reduction in NA. These results support the hypothesis that axonal loss is important in the development of persistent clinical disability in multiple sclerosis.

Adult↗
PubMed1995

Bilateral simultaneous optic neuropathy in adults: clinical, imaging, serological, and genetic studies.

To elucidate the cause(s) of acute or subacute bilateral simultaneous optic neuropathy (BSON) in adult life, a follow up study of 23 patients was performed with clinical assessment, brain MRI, HLA typing, and mitochondrial DNA analysis. The results of CSF electrophoresis were available from previous investigations in 11 patients. At follow up, five (22%) had developed clinically definite multiple sclerosis, four (17%) had mitochondrial DNA point mutations indicating a diagnosis of Leber's hereditary optic neuropathy (LHON). The remaining 14 patients (61%) still had clinically isolated BSON a mean of 50 months after the onset of visual symptoms: three of 14 (21%) had multiple MRI white matter lesions compatible with multiple sclerosis, three of 14 (21%) had the multiple sclerosis associated HLA-DR15/DQw6 haplotype, and one of seven tested had CSF oligoclonal IgG bands; in total only five (36%) had one or more of these risk factors. The low frequency of risk factors for the development of multiple sclerosis in these 14 patients suggests that few will develop multiple sclerosis with more prolonged follow up. It is concluded that: (a) about 20% of cases of BSON without affected relatives are due to LHON; (b) multiple sclerosis develops after BSON in at least 20% of cases, but the long term conversion rate is likely to be considerably less than the rate of over 70% seen after an episode of acute unilateral optic neuritis in adult life.

Adolescent↗
PubMed1995

Loss of heterozygosity for DNA polymorphisms mapping to chromosomes 10 and 17 and prognosis in patients with gliomas.

Twenty nine patients with gliomas were investigated for loss of heterozygosity for 40 DNA polymorphisms in tumour DNA, particularly concentrating on those mapping to chromosomes 10 and 17. Eight of 18 grade IV gliomas showed loss of sequences from chromosomes 10, 17, or both. The data suggested total loss of one copy of chromosome 10, but there were interstitial deletions of the short arm of chromosome 17 in three of five tumours. Heterogeneous interstitial deletions of chromosome 17 were also found in two lower grade astrocytomas and one benign oligodendroglioma. The striking finding of this study was that patients with high grade gliomas whose tumours exhibited loss of heterozygosity for chromosomes 10, 17, or both survived significantly longer after surgery (median 17.4 months) than those whose tumours did not show loss of these chromosomes (median 6.7 months). These findings suggest that there is a subset of particularly aggressive high grade gliomas with no currently known molecular genetic abnormalities.

Adult↗
PubMed1995

Progressive neuronal degeneration of childhood with liver disease (Alpers' disease) presenting in young adults.

Two unrelated and previously healthy girls, aged 17 and 18, presented with a subacute encephalopathy, visual and sensory symptoms and signs, and prominent seizures that were difficult to control. Brain MRI showed lesions (high signal on T2 weighted images) in the occipital lobes and thalamus; EEG showed slow wave activity with superimposed polyspikes. Inexorable downhill progression led to death in hepatic failure within eight months of onset. Histopathological findings in both patients ((a) chronic hepatitis with prominent bile duct proliferation, fatty change, and fibrosis; (b) in the brain a patchy destruction of the cerebral cortex, predominantly involving striate cortex) were characteristic of progressive neuronal degeneration of childhood with liver disease--Alpers-Huttenlocher syndrome--a rare autosomal recessive disorder usually seen in infants and young children.

Adolescent↗
PubMed1995

Familial amyloid polyneuropathy (TTR ala 60) in north west Ireland: a clinical, genetic, and epidemiological study.

A cluster of cases of familial amyloid polyneuropathy has been described in Donegal, north west Ireland. Two patients from this region have been shown to have the ala 60 mutation in the transthyretin gene. Three kindreds with this mutation have also been described in the United States. Genealogical and haplotype studies indicate that all known patients with this mutation are related and are descended from a founder in north west Ireland. There is evidence for reduced penetrance of this disorder. A population based study showed that 1.1% of the population in this area in north west Ireland carry the mutation. This has implications in terms of diagnosis, genetic counselling, and treatment in the future.

Aged↗