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Biomedical subjects

A E Harding

Publications and source records attributed to A E Harding.

At least 163 records · Page 9Linked to original sources
PubMed1991

Neurological disease and mitochondrial genes.

Mitochondria contain 2-10 copies of a small, double-stranded, circular DNA molecule that is exclusively maternally transmitted. Until recently, the only function of mitochondrial DNA that had any possible significance for clinicians was the fact that the mutation conferring chloramphenicol resistance occurs in one of the mitochondrial ribosomal RNA genes. It is now clear that major deletions and point mutations of mitochondrial DNA cause human diseases, chiefly mitochondrial myopathies and encephalopathies, and Leber's hereditary optic neuropathy.

Amino Acid Sequence↗
PubMed1991

Irish (Donegal) amyloidosis is associated with the transthyretinALA60 (Appalachian) variant.

A cluster of cases of late onset amyloidosis, presenting chiefly with peripheral neuropathy and cardiac failure, has been described in Donegal, north-west Ireland. Molecular genetic and protein analyses show that two new patients from the same region have a mutation in the transthyretin gene previously reported in a family with an Irish ancestor from the Appalachian region of the United States.

Aged↗
PubMed1991

An adult onset hexosaminidase A deficiency syndrome with sensory neuropathy and internuclear ophthalmoplegia.

A 42 year old man presented with a slowly progressive gait disturbance, generalised weakness, dysarthria, clumsiness and tremor of his hands, and involuntary jerks. Hexosaminidase A activity in plasma, leucocytes and fibroblasts was considerably reduced, establishing the diagnosis of GM2 gangliosidosis. Clinical examination showed two previously unreported features, a clinically evident sensory neuropathy and internuclear ophthalmoplegia.

Adult↗
PubMed1991

The relationship between trauma and idiopathic torsion dystonia.

Generalised, multifocal or segmental idiopathic torsion dystonia (ITD), is caused by an autosomal dominant gene with reduced penetrance in about 85% of cases. Of 104 patients with these types of ITD, 17 (16.4%) gave a history which suggested that dystonic movements had been precipitated or exacerbated by trauma. Eight of these 17 patients had affected relatives. If precipitated, dystonia appeared first in the injured part of the body within days or up to 12 months after the trauma and later became more widespread. Peripheral injuries may influence basal ganglia function and provoke the onset of dystonic movements in individuals who are ITD gene carriers.

Chromosome Aberrations↗
PubMed1991

Presymptomatic detection or exclusion of prion protein gene defects in families with inherited prion diseases.

The identification of defects in the prion protein (PrP) gene in families with inherited Creutzfeldt-Jakob disease or Gerstmann-Straussler syndrome allows presymptomatic diagnosis or exclusion of these disorders in subjects at risk. After counseling, PrP gene analysis was performed in three such individuals: two from families with a 144-bp insert and one with a point mutation at codon 102 in the PrP gene. The presence of a PrP gene defect was confirmed in one and excluded in two. Despite the potential problems of using PrP gene analysis in genetic prediction - specifically, uncertainty about penetrance and, generally, problems of presymptomatic testing in any inherited late-onset neurodegenerative disorder - we conclude that it has a role to play in improved genetic counseling for families with inherited prion diseases.

Adult↗
PubMed1991

Mitochondrial disease and mitochondrial DNA.

In the last decade there have been dramatic advances in the understanding of genetic, biochemical and clinical aspects of disorders of the mitochondrial respiratory chain. Neurological manifestations are prominent although involvement of other systems is increasingly recognized. This article reviews current understanding of mitochondrial disease and in particular its genetic basis.

DNA, Mitochondrial↗
PubMed1991

The molecular pathology of human respiratory chain defects.

Deletions of the mitochondrial genome were identified in 21 out of 58 patients (36 percent) with mitochondrial myopathies, 47 of whom had defects in the mitochondrial respiratory chain. In cases with Complex I defects, the deleted regions of mtDNA, were confined to structural genes encoding Complex I subunits but additionally involved the intervening tRNA genes and in one case included the large and small rRNA genes. In cases with more extensive loss of respiratory chain function, the deletions eliminated genes encoding subunits of Complexes I, IV and V, as well as several tRNAs. Complex I and Complex IV polypeptides were usually normal in deleted cases. This was in contrast to 7 out of 22 patients without detectable mtDNA deletions, who showed specific deficiencies of subunits encoded by nuclear genes. Further studies in one of these cases pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The genetic basis of the disease in 15 cases without detectable deletions or specific subunit deficiencies, remains unknown. The multiple biochemical abnormalities encountered in these cases would be consistent with more subtle alterations of the mitochondrial genome.

Chromosome Deletion↗
PubMed1991

Pearson syndrome and mitochondrial encephalomyopathy in a patient with a deletion of mtDNA.

A patient is described who has features of Pearson syndrome and who presented in the neonatal period with a hypoplastic anemia. He later developed hepatic, renal, and exocrine pancreatic dysfunction. At the age of 5 years he developed visual impairment, tremor, ataxia, proximal muscle weakness, external ophthalmoplegia, and a pigmentary retinopathy (Kearns-Sayre syndrome). Muscle biopsy confirmed the diagnosis of mitochondrial myopathy. Analysis of mtDNA from leukocytes and muscle showed mtDNA heteroplasmy in both tissues, with one population of mtDNA deleted by 4.9 kb. The deleted region was bridged by a 13-nucleotide sequence occurring as a direct repeat in normal mtDNA. Both Pearson syndrome and Kearns-Sayre syndrome have been noted to be associated with deletions of mtDNA; they have not previously been described in the same patient. These observations indicate that the two disorders have the same molecular basis; the different phenotypes are probably determined by the initial proportion of deleted mtDNAs and modified by selection against them in different tissues.

Anemia, Sideroblastic↗
PubMed1991

Neuroacanthocytosis. A clinical, haematological and pathological study of 19 cases.

Nineteen cases are described, including 12 cases from three different families and 7 nonfamilial cases, in which multisystem neurological disease was associated with acanthocytosis in peripheral blood and normal plasma lipoproteins. Mild acanthocytosis can easily be overlooked, and scanning electron microscopy may be helpful. Some neurologically asymptomatic relatives with significant acanthocytosis were identified during family screening, including some who were clinically affected. The mean age of onset was 32 (range 8-62) yrs and the clinical course was usually progressive but there was marked phenotypic variation. Cognitive impairment, psychiatric features and organic personality change occurred in over half the cases, and more than one-third had seizures. Orofaciolingual involuntary movements and pseudobulbar disturbance commonly caused dysphagia and dysarthria that was sometimes severe, but biting of the lips or tongue was rarely seen. Chorea was seen in almost all symptomatic cases but dystonia, tics, involuntary vocalizations and akinetic-rigid features also occurred. Two cases had no movement disorder at all. Computerized tomography often demonstrated cerebral atrophy. Caudate atrophy was seen less commonly, and nonspecific focal and symmetric signal abnormalities from the caudate or lentiform nuclei were seen by magnetic resonance imaging in 3 out of 4 cases. Depression or absence of tendon reflexes was noted in 13 cases and neurophysiological abnormalities often indicated an axonal neuropathy. Sural nerve biopsies from 3 cases showed evidence of a chronic axonal neuropathy with prominent regenerative activity, predominantly affecting the large diameter myelinated fibres. Serum creatine kinase activity was increased in 11 cases but without clinical evidence of a myopathy. Postmortem neuropathological examination in 1 case revealed extensive neuronal loss and gliosis affecting the corpus striatum, pallidum, and the substantia nigra, especially the pars reticulata. The cerebral cortex appeared spared and the spinal cord showed no evidence of anterior horn cell loss. Two examples of the McLeod phenotype, an X-linked abnormality of expression of Kell blood group antigens, were identified in a single family and included 1 female. The genetics of neuroacanthocytosis are unclear and probably heterogeneous, but the available pedigree data and the association with the McLeod phenotype suggest that there may be a locus for this disorder on the short arm of the X chromosome.

Acanthocytes↗
PubMed1990

The molecular pathology of respiratory-chain dysfunction in human mitochondrial myopathies.

Some of the different molecular pathologies of respiratory-chain dysfunction in human mitochondrial myopathies will be reviewed in relation to the findings in 58 cases. Deletions of mitochondrial DNA were identified in 21 cases [36%]. There was some correlation between the sites of the deletion and the mitochondrial biochemistry in patients with defects of Complex I but not in cases with more extensive loss of respiratory chain activity. Complex I and Complex IV polypeptides were usually normal in deleted cases. Non-deleted cases, however, often showed specific subunit deficiencies which involved the products of both nuclear and mitochondrial genes. Immunoblots of respiratory-chain polypeptides in one case pointed to defective translocation of the Rieske precursor from the cytosol into the mitochondria. The pathogenic role of circulating autoantibodies to specific matrix proteins and the nature of the target antigens in two patients with mitochondrial encephalomyopathies and respiratory-chain dysfunction will also be discussed.

Autoantibodies↗
PubMed1990

Progressive myoclonic ataxia (the Ramsay Hunt syndrome).

It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned, as its use has led to nosologic confusion, and because, in the light of modern diagnostic techniques, the majority of cases can be allocated to specific disease categories, chiefly, Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome, defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia, showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes, but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.

Adolescent↗
PubMed1990

Hereditary motor and sensory neuropathies and hereditary spastic paraplegia: a magnetic stimulation study.

Central motor conduction to the small hand muscles was investigated in 59 patients with peroneal muscular atrophy and hereditary spastic paraplegia (HSP) by using transcranial magnetic brain stimulation. These comprised 20 patients with type I hereditary motor and sensory neuropathy (HMSN I), 15 with type II (HMSN II), 4 with HMSN I and 10 with HMSN II with associated pyramidal features, and 10 with the "pure" form of HSP. Central motor conduction was usually normal in HMSN I, HMSN II, and HSP. In HMSN I with pyramidal signs, central motor conduction time was greatly prolonged bilaterally. This result may reflect an associated involvement of the central motor pathways in these patients. In HMSN II with accompanying pyramidal features, 6 of the 10 patients had abnormal central motor conduction, although conduction times were only slightly prolonged, suggesting a different pathophysiological pattern.

Adolescent↗
PubMed1990

Movement disorders in mitochondrial myopathies. A study of nine cases with two autopsy studies.

Of 85 consecutive patients with mitochondrial myopathy, 29 had clinically significant central nervous system involvement. Nine of these had movement disorders that included dystonia, chorea, parkinsonism, and myoclonus. Autopsy studies of one patient with ataxia, dementia, and parkinsonism followed by dystonia showed the features of olivopontocerebellar atrophy with additional degenerative changes in the basal ganglia. Postmortem in a further case with myoclonus, deafness, muscle weakness, retinopathy, and ataxia showed symmetrical mineralisation of the striatopallidodentatal system.

Adult↗
PubMed1990

Mitochondrial DNA analysis in Parkinson's disease.

The reduced form of nicotinamide adenine dinucleotide coenzyme Q reductase (complex I) activity has recently been shown to be deficient in the substantia nigra of patients dying with Parkinson's disease. This biochemical defect is identical to that produced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which also produces parkinsonism in humans. Complex I comprises 25 polypeptides, seven of which are encoded by mitochondrial DNA. Restriction fragment analysis of substantia nigra DNA from six patients with Parkinson's disease did not show any major deletion. In two cases, there were different novel polymorphisms that were not observed in control brain (n = 6) or blood (n = 34) samples.

DNA Damage↗
PubMed1990

A genetic study of idiopathic torsion dystonia in the United Kingdom.

The inheritance of idiopathic torsion dystonia (ITD) was investigated in 100 British families containing 107 index cases with generalized, multifocal or segmental dystonia, and 79 secondary cases. Fifty-eight index cases had affected relatives, usually in two or more generations. Nearly half of the secondary cases were asymptomatic. Paternal age was increased among the 49 single cases, parental consanguinity was not increased and there was no evidence of genetic heterogeneity. Eleven cases (10.3%) were Jewish, which exceeded the number expected, but they did not differ clinically or genetically from non-Jewish cases. The most likely explanation for the excess of Jewish cases is a founder effect in Eastern Europe. We conclude that, in the UK, approximately 85% of cases of ITD are due to an autosomal dominant gene with about 40% penetrance and highly variable expression, possibly reflecting environmental influences. Approximately 14% of these inherited cases may represent new mutations. The remaining 15% are probably nongenetic phenocopies, but are not clinically distinguishable. There was no evidence in this study for the existence of autosomal recessive or X-linked forms of ITD. The estimated recurrence risk for first degree relatives of familial cases is 21%; the risk is lower for single cases. Of affected individuals, 75% will have developed symptoms or signs of dystonia by the age of 30 yrs.

Adolescent↗