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Biomedical subjects

R W Orrell

Publications and source records attributed to R W Orrell.

At least 37 records · Page 2Linked to original sources
PubMed1998

Spontaneous abdominal hematoma in dermatomyositis.

Dermatomyositis is associated with a number of systemic manifestations and diseases. We present 2 patients with dermatomyositis, aged 11 and 50 years, who developed acute abdominal pain, both a result of spontaneous hemorrhage. Hemorrhage was detectable by physical examination in one and on computed tomography scan of the abdomen in the other. Both patients made a full recovery with supportive treatment. While the cause of the hemorrhage was uncertain, in 1 patient massive calcinosis of the abdominal wall was present, and trauma may have been the precipitant. Spontaneous abdominal hematoma is a cause of acute abdominal pain in patients with dermatomyositis, and surgery may be avoided if the diagnosis is recognized.

Abdominal Muscles↗
PubMed1998

Familial cramp due to potassium-aggravated myotonia.

Clinical, electrophysiological, and molecular genetic features were investigated in two patients from a family a with dominantly inherited myotonic disease, characterised by painful cramps, stiffness without weakness, fluctuation of symptoms, and cold sensitivity. A reduction in amplitude of the compound muscle action potential was demonstrated on cooling and administration of potassium, although no clinical exacerbation was seen. A heterozygote mutation Val1589Met was identified in the alpha-subunit of the skeletal muscle sodium channel gene in both patients, consistent with the diagnosis of potassium-aggravated myotonia. The phenotype in this family is much milder than that previously described in another family with a mutation at this site.

Adult↗
PubMed1997

Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser).

Mutations of the SOD1 gene, which encodes the enzyme copper/zinc superoxide dismutase, are associated with familial amyotrophic lateral sclerosis (ALS). SOD1 consists of five exons, and over 50 different mutations have been described involving exons 1,2,4 and 5. The absence of mutations in exon 3 has been attributed to a critical function of this exon, its integrity being necessary for the toxic effect of mutant SOD1, and it has been suggested that such mutations may be lethal rather than leading to adult onset disease. We identified the heterozygote mutation Gly72Ser (exon 3) in a family with two individuals affected by ALS. SOD enzyme activity was reduced by 45% when measured in erythrocytes indicating reduced enzyme activity, or reduced stability of the mutant protein. These findings indicate that exon 3 is not a privileged region from mutation; that all five exons should be investigated when seeking SOD1 mutations in human disease; and may help in a better understanding of the pathogenicity of these mutations in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1997

The relationship of spinal muscular atrophy to motor neuron disease: investigation of SMN and NAIP gene deletions in sporadic and familial ALS.

Amyotrophic lateral sclerosis (ALS) is found in a familial form in around 5-10% of cases. Of these familial cases around 20% are associated with mutations of SOD-1. The genetic basis of the disease in the remaining familial cases, and genetic risk factors in sporadic cases, are unknown. Recently, the common forms of spinal muscular atrophy (SMA) have been associated with mutations of the SMN and NAIP genes on chromosome 5, in the region q11.2-13.3. Some patients with both familial and sporadic motor neuron disease show only lower motor neuron signs, in common with SMA patients, and families containing individuals with phenotypes of both childhood SMA and adult motor neuron disease have been reported. We therefore examined the SMA locus as a candidate for ALS, in 54 patients with sporadic motor neuron disease, and 10 single-generation familial patients (with no evidence of SOD-1 mutations), and in a single patient with Brown-Vialetto-Van Laere syndrome. No mutations of the SMN or NAIP genes were detected. The difficulties of classification of lower motor neuron presentations of motor neuron diseases are discussed. The demonstration that mutations diagnostic of SMA are not found in ALS patients helps distinguish these conditions.

Adult↗
PubMed1997

Clinical and functional investigation of 10 missense mutations and a novel frameshift insertion mutation of the gene for copper-zinc superoxide dismutase in UK families with amyotrophic lateral sclerosis.

Mutations of the gene SOD-1, which encodes the enzyme copper-zinc superoxide dismutase, occur in patients with a familial form of amyotrophic lateral sclerosis (ALS). We investigated 71 families with more than one individual affected by ALS for clinical features and SOD-1 mutations. Mutations were identified in 14 families, indicating the presence of SOD-1 mutations in around 20% of this population. There were 10 different heterozygote missense point mutations in eight different codons, and a novel two-base frameshift insertion (132insTT), which leads to substitution of aspartic acid for glutamic acid at codon 132, and a premature stop codon at 133, with predicted truncation of the protein. SOD enzyme activity was reduced to around 50% of normal in individuals with SOD-1 mutations, and may be a useful predictor for the presence of these mutations. A predilection for disease onset in the lower limbs appears to be a distinguishing feature of familial ALS with SOD-1 mutations, and accords with findings in transgenic mouse models. In general, the finding of an SOD-1 mutation does not accurately predict a prognosis or disease severity.

Adult↗
PubMed1996

Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis.

Mutations of the copper/zinc superoxide dismutase (SOD-1) gene are present in around 20% of patients with a family history of amyotrophic lateral sclerosis. The finding of these mutations in patients with sporadic amyotrophic lateral sclerosis is rare. We describe a family with amyotrophic lateral sclerosis associated with the SOD-1 mutation Asp 101 Asn. This mutation was previously described as occurring in a patient with sporadic disease. We discuss the difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the consequent implications on the neurogenetic advice given to other family members.

Amyotrophic Lateral Sclerosis↗
PubMed1996

Three novel mutations and two variants in the gene for Cu/Zn superoxide dismutase in familial amyotrophic lateral sclerosis.

Autosomal dominant inheritance is exhibited by about 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by the death of motor neurons in the brain and spinal cord. A subgroup of these familial cases are linked to mutations in the gene which codes for Cu/Zn superoxide dismutase (SOD1). We report three additional mutations occurring in the SOD1 gene in ALS patients and two single base pair variant changes. The single base pair change in an ALS family causes a glycine 93 to valine substitution, which is the fifth distinct amino acid change reported for the glycine 93 residue. One missense mutation in exon 5 would substitute neutral valine for the negatively-charged aspartate 124 (aspartate 124 to valine). An individual with an apparently sporadic case of ALS carries a three base pair deletion in exon 5 of the SOD1 gene. These three mutations bring to 38 the total number of distinct SOD1 mutations associated with familial ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Oculomotor function in amyotrophic lateral sclerosis: evidence for frontal impairment.

Saccadic eye movements, fixation, and smooth pursuit were recorded in 17 subjects with amyotrophic lateral sclerosis (ALS) and 11 age-matched controls using a magnetic scleral search coil. Reflexive, remembered and antisaccades, and smooth pursuit at four target velocities were studied. Subjects with ALS showed significantly elevated error rates (distractibility) and latency in the antisaccade and remembered saccade paradigms but no abnormality of reflexive saccades. The frequency of small saccades that intruded on steady fixation (square-wave jerks) was also increased in ALS subjects. Peak velocity gain of smooth pursuit and performance on the Wisconsin Card Sort Test did not differ significantly between the two groups. These findings are consistent with prefrontal dysfunction in ALS and provide an independent source of support for the thesis that the pathology of this condition invades frontal cortex.

Adult↗
PubMed1995

Investigation of a null mutation of the CNTF gene in familial amyotrophic lateral sclerosis.

Neurotrophic factors, such as ciliary neurotrophic factor (CNTF), have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), a human neurodegenerative disease primarily of upper and lower motor neurones. A null mutation of the CNTF gene has recently been described. The mutation is an intronic point mutation (G to A) which generates a new splice acceptor site and a 4 bp insertion within the CNTF coding region, and prevents the expression of the normal protein. We investigated this as a candidate gene in 49 families with ALS, where the genetic component may be expected to be strongest. 65% were normal homozygotes, and 35% were heterozygotes for the mutation. No mutant homozygotes were detected. The absence of CNTF protein expression associated with the homozygote mutation does not appear to be of major significance in the development of ALS.

Adult↗
PubMed1995

Myopathy in acquired partial lipodystrophy.

We describe two women with acquired partial lipodystrophy, one with significant myopathic symptoms and signs. Muscle biopsy of deltoid and quadriceps was performed in each case. The light microscopy findings were of type 1 and type 2 fibre hypertrophy, with an increase in intracytoplasmic fat in both cases. Electron microscopy showed normal fibres, with accumulations of electron-lucent fat droplets between the myofibrils. The cause of the lipodystrophies is uncertain, but myopathy may be a feature, and muscle biopsy studies may help in further defining the syndrome.

Adipose Tissue↗
PubMed1995

Familial amyotrophic lateral sclerosis with a point mutation of SOD-1: intrafamilial heterogeneity of disease duration associated with neurofibrillary tangles.

Mutations of SOD-1 have recently been associated with autosomal dominant familial amyotrophic lateral sclerosis (ALS). A patient is described with a 20 year duration of motor neuron disease, with clinical features of ALS, who was heterozygous for a point mutation ATT to ACT leading to substitution of isoleucine for threonine at codon 113 in exon 4 of SOD-1. This mutation has previously been described in two families with ALS and three apparently sporadic cases of ALS. The patient described here had a family history suggestive of autosomal dominant inheritance of this genetic mutation; other members of the family having a more typical disease duration. Unusual pathological features included neurofibrillary tangles in neurons of the globus pallidus, substantia nigra, locus coeruleus, and inferior olivary nuclei, and absence of ubiquitin immunoreactive inclusions in motor neurons. This may reflect the slow progression of the neurodegeneration associated with the SOD-1 mutation in this patient. The prolonged survival, of over 20 years, with other family members having a more typical survival of two to three years, has important implications for genetic counselling in families with ALS in addition to the fundamental biological questions concerning the influence of these mutations on disease expression.

Amyotrophic Lateral Sclerosis↗
PubMed1995

Cerebral achromatopsia as a presentation of Trousseau's syndrome.

A 67-year-old man developed a sudden onset of achromatopsia. Magnetic resonance imaging showed occipital lobe infarction. Repeated episodes of neurological deficit referable to the posterior circulation initially suggested an embolic source, but subsequently proved to be due to a coagulopathy related to a carcinoma of the bladder. This has implications for the management of patients presenting with achromatopsia, and progressive or recurrent neurological episodes, and in particular the use of anticoagulation in this situation.

Aged↗
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↗