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Biomedical subjects

A E Harding

Publications and source records attributed to A E Harding.

At least 73 records · Page 4Linked to original sources
PubMed1995

Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson's disease.

Mutations in the superoxide dismutase 1 (SOD1) gene have been detected in affected members of some families with familial amyotrophic lateral sclerosis. To evaluate the possibility of a shared genetic defect in amyotrophic lateral sclerosis and Parkinson's disease, the SOD1 gene was sequenced in index patients with familial Parkinson's disease from 23 families. No changes were detected.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome).

We describe an example of a variant of Hallervorden-Spatz disease, characterized by hypoprebeta-lipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome), in an 18-year-old woman who presented with longstanding intellectual subnormality, night blindness, and a 2-year history of orobuccolingual dystonia causing dysarthria and dysphagia. Investigation showed acanthocytosis and hypoprebetalipoproteinemia, and electroretinograms were typical of tapetoretinal degeneration. T2-weighted MRI showed decreased signal intensity in the pallidal nuclei with central hyperintensity, constituting the "eye-of-the-tiger" sign. The patient's sister and mother have a similar lipid disorder but no retinal or neurologic disease. We also report two patients with clinical and radiologic features similar to those of the patient with HARP syndrome but who had normal lipid studies. These various combinations of components of HARP syndrome may be caused by several distinct genetic diseases or may represent variable manifestations of a contiguous gene defect.

Acanthocytes↗
PubMed1995

Pedigree analysis in Leber hereditary optic neuropathy families with a pathogenic mtDNA mutation.

Eighty-nine index patients from 85 families were defined as having Leber hereditary optic neuropathy (LHON) by the presence of one of the mtDNA mutations at positions 11778 (66 families), 3460 (8 families), or 14484 (11 families). There were 62 secondary cases. Overall, 64% of index cases had a history of similarly affected relatives. The ratios of affected males to affected females were 3.7:1 (11778), 4.3:1 (3460), and 7.7:1 (14484). The 95th centile for age at onset of symptoms was close to 50 years in index, secondary, male, and female patients. There were no differences in the distributions of age at onset between different mutation groups, between index and secondary cases, or between males and females, apart from this being slightly later in all female patients than in male 11778 patients. There was no significant correlation between age at onset in index cases and that in their affected siblings or cousins. Heteroplasmy (< 96% mutant mtDNA) was detected in 4% of affected subjects (67%-90% mutant mtDNA) and in 13.6% of 140 unaffected relatives (< 5%-90% mutant mtDNA). Analysis of all pedigrees, excluding sibships < 50 years of age and index cases, indicated recurrence risks of 30%, 8%, 46%, 10%, 31%, and 6%, respectively, to the brothers, sisters, nephews, nieces, and male and female matrilineal first cousins of index cases. Affected females were more likely to have affected children, particularly daughters, than were unaffected female carriers. The pedigree data were entirely compatible with the previously proposed X-linked susceptibility locus, with a gene frequency of .08, penetrance of .11 in heterozygous females, and 40% of affected females being homozygous, the remainder being explained by heterozygosity and disadvantageous X inactivation.

Adolescent↗
PubMed1995

Congenital encephalomyopathy and adult-onset myopathy and diabetes mellitus: different phenotypic associations of a new heteroplasmic mtDNA tRNA glutamic acid mutation.

We report the clinical, biochemical, and molecular genetic findings in a family with an unusual mitochondrial disease phenotype harboring a novel mtDNA tRNA glutamic acid mutation at position 14709. The proband and his sister presented with congenital myopathy and mental retardation and subsequently developed cerebellar ataxia. Other family members had either adult-onset diabetes mellitus with muscle weakness or adult-onset diabetes mellitus alone. Ragged-red and cytochrome c oxidase (COX)-negative fibers were present in muscle biopsies. Biochemical studies of muscle mitochondria showed reduced complex I and IV activities. The mtDNA mutation was heteroplasmic in blood and muscle in all matrilineal relatives analyzed. Primary myoblast, but not fibroblast, cultures containing high proportions of mutant mtDNA exhibited impaired mitochondrial translation. These observations indicate that mtDNA tRNA point mutations should be considered in the differential diagnosis of congenital myopathy. In addition they illustrate the diversity of phenotypes associated with this mutation in the same family and further highlight the association between mtDNA mutations and diabetes mellitus.

Adult↗
PubMed1995

Management of mitochondrial disease on an intensive care unit.

Patients with mitochondrial disease may present to the Intensive Care Unit (ICU) with a variety of neurological and general medical disorders. Eleven patients were admitted to a neurological ICU between 1970 and 1992 because of respiratory insufficiency, status epilepticus and/or metabolic encephalopathy associated with mitochondrial disease. Respiratory impairment occurred in eight patients and was associated with nocturnal hypoventilation due to respiratory muscle weakness, aspiration due to bulbar weakness and abnormalities of central control leading to a reduced CO2 drive, irregular respiratory patterns and sleep apnoea. Seven patients received continuous respiratory support during the acute illness; three were subsequently weaned to domiciliary ventilation, and four died. Five patients had stroke-like episodes, which in two were recurrent. Four patients developed tonic-clonic grand mal epilepsy associated with myoclonic fits (2 patients), absences (2), focal fits (1) and status epilepticus (2). Encephalopathy was associated with recurrent lactic acidosis (2 patients), cardiac failure (2), hyponatraemia (2), renal abnormalities (3) and complete heart block (1). Although rare, mitochondrial disease should be considered in any patient with unexplained respiratory failure, intractable epilepsy, lactic acidosis or recurrent stroke.

Acidosis, Lactic↗
PubMed1995

Molecular genetics of peripheral neuropathies.

Molecular genetic techniques have identified the mutational basis of many inherited neuropathies due to metabolic disorders, including porphyrias, leukodystrophies and other storage diseases. Inherited amyloid neuropathies may be caused by mutations in three different genes: those for gelsolin, apolipoprotein A1 and, most frequently, transthyretin. The classification of hereditary motor and sensory neuropathies has been changed by the identification of underlying mutations encoding myelin proteins, P0 and peripheral myelin protein 22 and connexin 32. Peripheral myelin protein 22 gene defects are also seen in hereditary liability to pressure palsies. There is peripheral sensory nerve involvement in one of the diseases caused by an unstable trinucleotide repeat sequence: X-linked bulbospinal neuronopathy. These advances can be translated into clinical practice, leading to improved diagnosis and genetic counselling.

Adolescent↗
PubMed1994

Mutation analysis in patients with possible but apparently sporadic Huntington's disease.

Until the advent of mutation analysis it was impossible to make a certain diagnosis of Huntington's disease (HD) in the absence of a positive family history, and sporadic cases of possible HD presented a substantial diagnostic dilemma. We have looked for the characteristic expanded trinucleotide (CAG) repeat sequence in the HD gene in 44 patients with probable or possible HD who did not have similarly affected relatives. We used two methods, the traditional widely used method, which estimates both the CAG repeat and the flanking CCG repeat and gives the CAG length by subtraction, and the more precise CAG method, which estimates the repeat length directly. With the CAG method, the HD mutation was detected in 25 (89%) of 28 patients with the typical clinical features of HD and 5 (31%) of 16 in whom the diagnosis was more doubtful. The CAG-CCG method gave results in the borderline abnormal range of repeats for 13 of the 33 patients eventually shown to have an unequivocal repeat expansion by the CAG method. Most of these patients had late onset of symptoms. There was evidence of expansion of an intermediate-length paternal allele in 1 patient and of non-paternity in another. The identification of the mutation causing HD means that it is now possible to confirm or exclude the diagnosis with confidence, even in the absence of a family history, by analysis of DNA from a blood sample. The precise method of measuring the CAG repeat, which is technically more difficult than the traditional method, may be needed to clarify results in a substantial proportion of such patients.

Adult↗
PubMed1994

Nigral dopaminergic cell loss in vitamin E deficient rats.

alpha-Tocopherol concentrations in brain were reduced to 3% of control levels in rats fed a vitamin E deficient diet for 52 weeks. Vitamin E deficiency resulted in a 19-33% loss of tyrosine hydroxylase (TH) immunopositive neurones in the substantia nigra, but not in the adjacent ventral tegmental area, compared with controls. Vitamin E deficiency, however, did not reduce striatal dopamine concentrations or turnover. When antioxidant defence mechanisms are defective, as in chronic vitamin E deficiency, the nigrostriatal pathway may be affected by oxidative damage and this may have implications for Parkinson's disease.

Animals↗
PubMed1994

Nigrostriatal function in vitamin E deficiency: clinical, experimental, and positron emission tomographic studies.

Four patients with vitamin E deficiency and sensory ataxia were studied using [18F]dopa positron emission tomography. The 2 most disabled patients, who had severe and prolonged vitamin E deficiency due to abetalipoproteinemia, showed reduced [18F]dopa uptake in both putamen and caudate. Putaminal uptake was in a similar range to that seen in Parkinson's disease. Studies of [3H]mazindol binding in the striatum of vitamin E--deficient rats indicated a reduced number of dopamine terminals, which was most severe in ventrolateral striatum. These observations suggest that severe and prolonged vitamin E deficiency results in loss of nigrostriatal nerve terminals, and support the hypothesis that oxidative stress may contribute to the etiology of Parkinson's disease.

Adult↗
PubMed1994

Leber's hereditary optic neuropathy mitochondrial DNA mutations in multiple sclerosis.

The observation of a multiple sclerosis (MS)-like illness in patients, particularly women, who carry the most common Leber's hereditary optic neuropathy mitochondrial DNA (mtDNA) mutation may indicate a contributory role for mitochondrial genes in genetic susceptibility to MS. We screened 307 unrelated MS patients, ascertained from population surveys, for the pathogenic Leber's hereditary optic neuropathy mutations at positions 11778 and 3460 of mtDNA, and also studied 20 patients with prominent and early optic nerve involvement. In addition, these 307 patients and 129 control subjects were investigated for the base change at position 13708, which has been suggested to play a role in the pathogenesis of Leber's hereditary optic neuropathy. Neither of the pathogenic mtDNA mutations occurred in the unselected MS patients. The 13708 base change was present in MS patients at a frequency similar to that in healthy control subjects. Three of the patients selected on the basis of severe optic nerve involvement had either the 11778 (one) or 3460 (two) mutations associated with Leber's hereditary optic neuropathy. All were women and none had affected relatives. We conclude that these mutations do not contribute to genetically determined susceptibility in typical MS patients, although a mitochondrial genetic component in the etiology of MS remains possible. A subgroup of MS patients, particularly females with severe bilateral visual failure due to optic neuropathy, may harbor a Leber's hereditary optic neuropathy mutation and we suggest that mtDNA analysis is appropriate in these patients.

Adult↗
PubMed1994

Autosomal-dominant dentatorubropallidoluysian atrophy in the United Kingdom.

Dentatorubropallidoluysian atrophy (DRPLA) has been described chiefly in Japan and appears to be rare in Europe. It is of autosomal dominant inheritance. We report the first British family with DRPLA, which contains four affected individuals in two generations. The diagnosis was made at autopsy in one case. The age of onset of symptoms ranged from 15 to 38 years, and clinical features included ataxia, dementia, chorea, and dystonia; three patients had generalized seizures. The three living patients resemble those with early Huntington's disease clinically. Three main phenotypes of DRPLA have been proposed: an ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epilepsy type. The variation in clinical presentation in our family demonstrates the difficulty in applying such classifications to this and other dominantly inherited disorders with phenotypic variation. DRPLA is likely to be confused with Huntington's disease in European families.

Adult↗
PubMed1994

The neuropathological features of neuroacanthocytosis.

In this article we describe the neuropathological changes in three patients with neuroacanthocytosis and review the neuropathology of the other eight cases reported in the literature. Macroscopically the brains showed enlargement of the lateral ventricles, especially the frontal horns. The most severely and consistently affected brain areas were the caudate nucleus and putamen, which were atrophic and showed by light microscopy marked neuronal loss and gliosis. Small and medium-sized striatal neurons were particularly depleted. The globus pallidus was almost as severely involved as the striatum. In some cases the thalamus, substantia nigra, and anterior horns of the spinal cord showed pathology, mainly neuronal loss and mild gliosis. Brain areas with no pathology included the subthalamic nucleus, cerebral cortex, cerebellum, pons, and medulla. The preservation of these areas may help in the neuropathological distinction of neuroacanthocytosis from Huntington's disease.

Acanthocytes↗
PubMed1994

Tyrosine hydroxylase polymorphism in familial and sporadic Parkinson's disease.

Tyrosine hydroxylase (TH) is a theoretical candidate gene determining susceptibility to Parkinson's disease (PD), and an association between one allele of a polymorphism at the TH locus and sporadic PD has been reported. We investigated TH polymorphism in 44 patients with sporadic PD, 48 patients with familial PD and 89 of their unaffected relatives, and 50 control subjects. No evidence of allelic association was detected in either familial or sporadic PD, and linkage analysis excluded the TH locus, or a closely linked gene, as a major determinant of familial PD.

Alleles↗
PubMed1994

Apo E genotypes in multiple sclerosis, Parkinson's disease, schwannomas and late-onset Alzheimer's disease.

Apolipoprotein E (apo E) exists in three allelic, functionally distinct isoforms (apo E2, E3 and E4). Recent work has suggested that apo-E-dependent uptake of lipoproteins may play important roles in the development and maintenance of the nervous system and in the responses to both peripheral and central nervous system injury. If apo-E-mediated transport of lipids were a rate-limiting step in these processes, one might expect that the functional differences between the alleles would be associated with varying predispositions to neurodegenerative and demyelinating diseases. Thus, we looked for an association between particular apo E genotypes and susceptibility to multiple sclerosis and Parkinson's disease. If apo-E-mediated cholesterol uptake were limiting in neuronal growth, one might also expect that apo E2 alleles would slow CNS tumour growth. Accordingly, apo E genotypes were investigated in individuals with sporadic vestibular schwannomas and neurofibromatosis type 2 (NF-2). No significant alteration in the apo E allele distributions was observed in any of these conditions, nor did the apo E genotypes correlate with disease severity. However, we confirmed the previous findings of an over-representation of the apo E4 allele in autopsy-diagnosed late-onset Alzheimer's disease patients. In addition, our data supported the recent observations that apo E2 may be associated with a protective effect for late-onset Alzheimer's disease. These contrasting risks associated with the apo E2 and E4 alleles strengthen the suggestions that this gene is directly involved in the pathogenesis of Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Mitochondrial gene defects in patients with NIDDM.

Non-insulin-dependent diabetes mellitus (NIDDM) has a strong genetic component and maternal factors have recently been implicated in disease inheritance. The mitochondrial myopathies are a group of diseases which often show maternal inheritance as a result of mtDNA defects; some patients have impaired glucose tolerance. Occasional families with maternally inherited diabetes and deafness associated with a deletion or point mutation of mtDNA have been reported. To assess the importance of mitochondrial gene defects in NIDDM, 150 unrelated diabetic subjects from Wales, UK and 68 unrelated patients with diabetes and at least one affected sibling from England, UK were studied. Southern blot analysis did not show any large mtDNA deletions or duplications. One patient had a mutation in the mitochondrial tRNAleu(UUR) gene at bp 3243. This mutation is commonly associated with the syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS). Study of this patient and his siblings showed a distinct form of late-onset diabetes associated with nerve deafness but no clinical features of the MELAS syndrome. No diabetic subject was shown to have the mtDNA mutation at position 8344 (tRNA(lys)) which has previously been described in the syndrome of mitochondrial encephalomyopathy and red-ragged fibres (MERRF). The role of other mitochondrial gene defects in diabetes and the pathophysiological basis of glucose intolerance in patients with the MELAS mutation requires further elucidation.

Base Sequence↗
PubMed1994

Cortical reflex myoclonus in patients with the mitochondrial DNA transfer RNA(Lys)(8344) (MERRF) mutation.

Five patients from three families with the syndrome of myoclonic epilepsy and ragged red fibres (MERRF), associated with the mitochondrial DNA point mutation at position 8344, were studied neurophysiologically to determine the characteristics of their myoclonus. The findings were those of cortical reflex myoclonus, with enlarged cortical somatosensory evoked potentials and late reflex responses to peripheral nerve stimulation. Electroencephalography showed paroxysmal spike and polyspike and wave discharges, with photic sensitivity. This pattern of electrophysiological abnormalities was uniform, despite considerable variation in severity of myoclonus. Although a consistent finding, cortical reflex myoclonus is not specific to MERRF amongst myoclonic syndromes.

Adult↗