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Biomedical subjects

A E Harding

Publications and source records attributed to A E Harding.

At least 37 records · Page 2Linked to original sources
PubMed1996

Exclusion of the DYT1 locus in familial torticollis.

Clinical-genetic studies of idiopathic torsion dystonia (ITD) indicate that the DYT1 gene on chromosome 9q34 is responsible for most childhood limb-onset disease. The genetic basis of adult-onset ITD is less well studied. In most multiplex adult-onset ITD families, dystonia is limited to the cervical, cranial, or brachial muscles; in a few rare families, dystonia also involves the legs and trunk. Previous linkage studies have excluded the DYT1 locus in these atypical families. We studied two large non-Jewish families with adult-onset ITD limited to the cervical and brachial muscles and excluded the DYT1-containing region. This study further restricts the role of DYT1 to childhood limb-onset ITD and suggests that other genes are responsible for focal adult-onset ITD.

Adolescent↗
PubMed1996

Proton magnetic resonance spectroscopy in Huntington's disease: evidence in favour of the glutamate excitotoxic theory.

The gene responsible for Huntington's disease (HD) has been located, but its action and the pathophysiology of HD remain unclear. Glutamate excitotoxicity may contribute to the striatal neurodegeneration seen in HD. We used localised proton magnetic resonance spectroscopy (MRS) of the brain to investigate five patients with early HD, one symptom-free gene carrier, and 14 healthy volunteers. Peak area ratios of choline-containing compounds (Cho), glutamine and glutamate (Glx), and N-acetyl moieties including N-acetylaspartate (NAx), relative to creatine (Cr), were calculated. Spectra were analysed from the striatum and the occipital and the temporal cortex. The HD patients all had an elevated Glx/Cr in spectra localised to the striatum, compared with healthy controls, and one patient also had an elevated thalamic Glx/Cr. The mean Glx/Cr was unaltered in the cortical spectra of HD patients. The asymptomatic gene carrier displayed no spectral abnormalities. Our findings suggest disordered striatal glutamate metabolism and may support the theory of glutamate excitotoxicity in HD.

Aspartic Acid↗
PubMed1996

HLA class I genotypes in Leber's hereditary optic neuropathy.

There is evidence that mitochondrial DNA (mtDNA) encoded peptides can restrict the immune response in rodents and that these peptides are presented by classical and 'neoclassical' class I major histocompatibility complex (MHC) molecules. We investigated the frequency of HLA-A and two HLA-B genotypes in index cases of 77 families with Leber's hereditary optic neuropathy (LHON), on the basis that there may be an autoimmune component to this disease. There was no association between LHON and any genotype. We conclude that the classical class I MHC loci are not major determinants of the development of blindness in LHON.

Adult↗
PubMed1996

Mitochondrial encephalopathy with multiple mitochondrial DNA deletions: a report of two families and two sporadic cases with unusual clinical and neuropathological features.

A mitochondrial myopathy associated with multiple deletions of mitochondrial DNA has been identified in pedigrees showing an autosomal dominant mode of inheritance. We report the first two British kindreds with this disorder, and two sporadic cases. The families exhibited some unusual clinical features, including pigmentary retinopathy and tremor; the latter was levodopa-responsive and associated with rigidity and micrographia in one family. Members of one pedigree and both sporadic patients had a peripheral neuropathy and nerve biopsy showed marked axonal degeneration. Post-mortem examination of one patient without parkinsonism showed severe neuronal loss in the substantia nigra.

Adult↗
PubMed1996

Associative learning in patients with cerebellar ataxia.

It has been claimed that patients with cerebellar pathology are impaired at associative learning. Patients with cerebellar ataxia (n = 7) were taught a visual-motor associative task. The task was chosen so as to allow comparisons with data currently being collected on the effects of cerebellar lesions on associative learning in monkeys. As a group the patients were as impaired at learning the task as a group of 8 patients with Huntington's disease. When each patient was individually matched with a control of the same age and IQ, some patients with cerebellar ataxia were found to be clearly impaired, but 2 were not. Of the 4 patients who were most clearly impaired, 2 had brainstem pathology and 2 did not. The relevance of these findings is discussed in relation to views concerning the functions of the cerebellum.

Adult↗
PubMed1996

A case-control study of Leber's hereditary optic neuropathy.

Fifty patients with Leber's hereditary optic neuropathy (LHON) with an associated pathogenic mutation of mitochondrial DNA (mtDNA) at base pair (bp) 11778 (35 cases), 14484 (eight cases) or 3460 (seven cases) were matched with 50 controls. The frequency of additional neurological features in LHON and the role of a number of past medical and environmental factors in the development of the disease were investigated using a case-control study. Additional neurological features were reported by 15 patients. Four patients had a multiple sclerosis-like illness; one had focal dystonia. Ten patients had tremor, which occurred at significantly higher frequency in patients than in controls. Alcohol and tobacco consumption were similar in patients with the 11778 mutation and matched controls, but were significantly increased in patients with the 3460 and 14484 mutations. No other associated past medical or environmental factors were identified.

Adult↗
PubMed1996

Dopa-responsive dystonia in British patients: new mutations of the GTP-cyclohydrolase I gene and evidence for genetic heterogeneity.

Dopa-responsive dystonia (DRD) was originally described in a series of Japanese patients, but is now increasingly recognized in other countries. Recently the GTP cyclohydrolase I (GTPCH) gene was isolated as the first causative gene for dopa-responsive dystonia (DRD). Mutations were identified in three Japanese families with autosomal dominantly inherited DRD and in one sporadic Japanese patient. Characterisation of the exon-intron boundaries of this gene has now allowed the analysis of mutations at the level of genomic DNA. Amplifying all six exons, we analyzed the GTPCH gene in nine British families with 33 affected family members and in three sporadic cases and found six new mutations. Only point mutations were found, causing a stop codon in one family and an amino acid change in highly conserved regions of the gene in a further four families and in one sporadic case. None of these mutations were detected more than once and none of the mutations previously described were found in our patients. No mutations were identified in four families and in two sporadic cases.

Dopamine Agents↗
PubMed1996

Autosomal dominant optic atrophy with asymptomatic peripheral neuropathy.

The association between hereditary motor and sensory neuropathy (HMSN) and optic atrophy has been termed HMSN type VI. The autosomal dominant inheritance of this syndrome is reported. Three generations were affected with optic atrophy, which differed in some respects from classic dominant optic atrophy, and an asymptomatic, mainly sensory, neuropathy.

Adult↗
PubMed1996

Anticipation in familial Parkinson's disease: a reanalysis of 13 United Kingdom kindreds.

Several authors reported anticipation for age at onset in familial Parkinson's disease (PD) and postulated the involvement of an unstable trinucleotide repeat gene. We reanalyzed 13 previously reported multiple generation kindreds with familial PD to investigate anticipation and related biases. Although initial review of 33 informative parent-child and aunt/uncle-niece/nephew pairs revealed a mean anticipation interval of 9.3 years (p = 0.0001), exclusion of probands, in an effort to limit referral bias, reduced this to 4.1 years (p = 0.09). This reduced figure is still an overestimate of the true anticipation interval because of residual referral bias and because of incomplete information on the most recent generation. Our analyses did not demonstrate the effects of recall bias or of reduced fertility. We conclude that the observed anticipation in familial PD may partly or completely result from referral and other biases. Caution should be exercised in assuming an unstable trinucleotide repeat gene as the cause of familial PD.

Adolescent↗
PubMed1996

Evidence against an X-linked visual loss susceptibility locus in Leber hereditary optic neuropathy.

Pedigree analysis of British families with Leber hereditary optic neuropathy (LHON) closely fits a model in which a pathogenic mtDNA mutation interacts with an X-linked visual loss susceptibility locus (VLSL). This model predicts that 60% of affected females will show marked skewing of X inactivation. Linkage analysis in British and Italian families with genetically proven LHON has excluded the presence of such a VLSL over 169 cM of the X chromosome both when all families were analyzed together and when only families with the bp 11778 mutation were studied. Further, there was no excess skewing of X inactivation in affected females. There was no evidence for close linkage to three markers in the pseudoautosomal region of the sex chromosomes. The mechanism of incomplete penetrance and male predominance in LHON remains unclear.

DNA, Mitochondrial↗
PubMed1996

The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.

Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II.

Adolescent↗
PubMed1995

Mitochondrial DNA (mtDNA) diseases: correlation of genotype to phenotype.

This study examines the relationship of genotype to phenotype in 14 unselected patients who were found to harbour the A3243G transition in the mitochondrial transfer RNALeu(UUR) gene commonly associated with the syndrome of mitochondrial encephalopathy, lactic acidosis and strokes (MELAS). Only 6 of the 14 cases (43%) had seizures and recurrent strokes, the core clinical features of the MELAS phenotype. Of the remaining cases, four had an encephalomyopathy with deafness, ataxia and dementia, two had syndromes with progressive external ophthalmoplegia and two had limb weakness alone. Even within the MELAS subgroup, the majority of patients had one or more clinical manifestations considered to be atypical of the MELAS syndrome. They included developmental delay, ophthalmoparesis, pigmentary retinopathy and intestinal pseudo-obstruction. The proportion of mutant mitochondrial DNA (mtDNA) in muscle was generally higher in patients with recurrent strokes than in those without strokes, the highest levels being observed in MELAS cases with early onset disease. Studies of isolated muscle mitochondria identified a range of respiratory chain abnormalities mostly involving Complex I; immunoblots of Complex I in 3 of 10 cases showed selective loss of specific subunits encoded by nuclear genes. In the group as a whole, however, no clear correlations were observed between the severity or extent of the respiratory chain abnormality and clinical phenotype or the proportion of mutant mtDNA in biopsied skeletal muscle. These discrepancies suggest that, in patients harbouring the common MELAS3243 mutation, differences in heteroplasmy and the proportions of mutant mtDNA may not be the sole determinants of disease expression and that additional genetic mechanisms are involved in defining the range of clinical and biochemical phenotypes associated with this aberrant mitochondrial genome.

Adolescent↗
PubMed1995

A new mitochondrial DNA mutation associated with progressive dementia and chorea: a clinical, pathological, and molecular genetic study.

A novel mitochondrial DNA transfer RNA mutation at position 5549 was identified in a patient with dementia, chorea, cerebellar ataxia, deafness, and peripheral neuropathy in the absence of clinical myopathy. Muscle biopsy specimens showed ragged red and cytochrome oxidase-negative fibers, and reduced complex I activity on polarography. There was diffuse neuronal loss and gliosis throughout the brain on postmortem examination. The heteroplasmic mutation had a widespread distribution in autopsy tissues.

Adult↗
PubMed1995

A clinical and molecular genetic study of dentatorubropallidoluysian atrophy in four European families.

Dentatorubropallidoluysian atrophy is a neurodegenerative disorder with characteristic pathology, chiefly described in reports from Japan, and is associated with an unstable CAG trinucleotide repeat in a gene on chromosome 12. We describe four European families, three British and one Maltese, with this mutation. All exhibited autosomal dominant inheritance, and there was evidence for anticipation associated with an increase of the expansion with paternal transmission in two families. Affected chromosomes from patients with dentatorubropallidoluysian atrophy had CAG expansions of 58 to 74 repeats, compared to 7 to 26 in control chromosomes, and the size of repeat was significantly inversely correlated with age of onset. The clinical features were diverse, even within individual families, and comprised a combination of a movement disorder (chorea, myoclonus, dystonia, or parkinsonism), cerebellar ataxia, epilepsy, psychosis, and dementia. A clinical diagnosis of Huntington's disease had been made in affected individuals from all families. Neuropathological examination of 2 patients showed no specific abnormality in one and degenerative changes predominantly affecting the spinal cord in the other. Investigation of 55 patients who might represent sporadic examples of dentatorubropallidoluysian atrophy did not detect any expanded alleles. Dentatorubropallidoluysian atrophy is likely to be more common than previously recognized in non-Japanese populations, and should be considered in any patient with a dominantly inherited neurodegenerative disorder with the above-mentioned clinical features.

Adolescent↗
PubMed1995

CYP2D6-debrisoquine hydroxylase gene polymorphism in multiple system atrophy.

Molecular genetic studies of the cytochrome P450 system enzyme CYP2D6, which hydroxylates debrisoquine, have indicated an excess of mutant alleles in large series of patients with Parkinson's disease (PD) when compared with controls. We have investigated CYP2D6 polymorphism in 91 patients with multiple system atrophy (MSA) in order to determine if this finding is specific to PD or if there is similar evidence of genetic susceptibility to neurotoxicity in MSA. The distribution of CYP2D6 alleles was not significantly different between MSA patients and controls, and there were fewer poor metabolisers in the MSA group than in the control group.

Alleles↗
PubMed1995

Mitochondrial DNA diseases: genotype and phenotype in Leber's hereditary optic neuropathy.

We have investigated 107 patients from 79 families with Leber's hereditary optic neuropathy (LHON), defined by the presence of one of the mitochondrial DNA (mtDNA) mutations at positions 11778 (60 families), 3460 (7), or 14484 (12). Only about 60% of the index patients had a history of similarly affected relatives. The ratios of affected male:female patients were 2.5:1 (11778), 2:1 (3460), and 5.7:1 (14484). Visual loss developed between the ages of 11 and 30 years in 69% with a range of 6-62 years, and this was not significantly different between mutation groups or males and females. Retinal microangiopathy was not detected in 36% of patients examined within 3 months of visual loss. A multiple sclerosis-like illness occurred in 45% of females with the 11778 mutation. Prognosis was better in the 14484 than the 3460 or 11778 patients, with useful recovery in 71% of patients. Good visual outcome was positively correlated with early age of onset (before 20 years). Unusual presentations, including young or old age at onset, caused diagnostic difficulties in this series, usually in the absence of a family history, which were resolved by mtDNA analysis. Recurrence risks to relatives could be derived from this series of families with genetically defined LHON.

Adolescent↗