Biomedical subjects
Publications and source records attributed to A E Harding.
We describe a family with distal spinal muscular atrophy and vocal cord paralysis, similar to the condition reported by Young and Harper in 1980. Both pedigrees are consistent with autosomal dominant inheritance.
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We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.
The Portuguese type of familial amyloid polyneuropathy (FAP type I) is a disabling autosomic dominant disorder, which is caused by a point mutation in the transthyretin (TTR) gene. Other TTR gene mutations have been reported recently in other FAP. In the absence of monoclonal gammopathy, sporadic amyloid neuropathies raise a problem for their pathogenicity. In this study, we have looked for TTR gene mutations in apparently sporadic cases of amyloid polyneuropathy by Southern's technique. All the patients were of french origin. None had monoclonal gammopathy. The mean age at onset was 64 (50 to 79 years). Most of the patients (9/1) were male. Five patients were found to carry FAP type 1 mutation, and 2 the tyr 77 (German) mutation. This study suggests that investigations in amyloid polyneuropathy with no overt family history should include systematic DNA analysis.
Rapid progress has been made in elucidating the molecular genetic basis of several neuromuscular disorders in the past year. Candidate genes have been identified or analysed in hereditary motor and sensory neuropathy (HMSN) type I, X-linked bulbospinal neuronopathy and non-dystrophic myotonic disorders, and further mutations causing amyloidosis have been identified. A familial amyotrophic lateral sclerosis (ALS) locus maps to chromosome 21 in some families, and the chronic childhood spinal muscular atrophy (SMA), facioscapulohumeral muscular dystrophy (FSHD) and malignant hyperthermia loci have been localized more precisely.
Leber hereditary optic neuropathy (LHON) is associated with mutations of mtDNA, but two features of LHON pedigrees are not explicable solely on the basis of mitochondrial inheritance. There is a large excess of affected males, and not all males at risk develop the disease. These observations could be explained by the existence of an X-linked visual loss susceptibility gene. This hypothesis was supported by linkage studies in Finland, placing the susceptibility locus at DXS7, with a maximum lod score of 2.48 at a recombination fraction of 0. Linkage studies in 1 Italian and 12 British families with LHON, analyzed either together or separately depending on the associated mtDNA mutation, have excluded the presence of such a locus from an interval of about 30 cM around DXS7 in these kindreds, with a total lod score of -26.51 at a recombination fraction of 0.
We have previously described a family with a neurological syndrome comprising neurogenic muscle weakness, ataxia, retinitis pigmentosa, and variable sensory neuropathy, seizures, and mental retardation or dementia. This is associated with a heteroplasmic point mutation of mtDNA at bp 8993. The mother of a severely affected child underwent prenatal diagnosis in two further pregnancies. Analysis of chorionic villus samples showed a higher proportion of mutant mtDNA on both occasions, and this was reflected in the majority of fetal tissues, including brain and muscle. Prenatal diagnosis is a rational approach to the prevention of severe diseases caused by point mutations of mtDNA but is currently hampered by incomplete knowledge concerning the proportion of mutant mtDNA: its relationship to disease severity, how it may change during fetal and postnatal development, and its tissue distribution.
X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.
Point mutations of mitochondrial DNA have been described in the muscle of patients with syndromes of myoclonic epilepsy and ragged red fibres (MERRF) and of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). We have found the MERRF mutation in members of 6 British kindreds; 2 of these had unusual phenotypes but all index patients had myoclonus. The MELAS mutation was detected in 17 patients from 16 families, who had a wide range of clinical features that particularly affected the central nervous system; stroke-like episodes were observed in 10.3 patients with mitochondrial DNA mutations did not have ragged red fibres on muscle biopsy, generally considered to be the morphological hallmark of mitochondrial diseases. In all 6 patients with the MERRF mutation, and 10 of 11 with the MELAS mutation, the genetic defect was easily detected in blood cells as well as muscle (blood samples were not available in 6 patients with MELAS mutations in muscle). Molecular genetic analysis of blood samples represents an inexpensive and reliable screening test for mitochondrial encephalopathies, and use of such techniques could influence diagnosis and genetic counselling in patients with seizure disorders and young-onset stroke.
A genetic study of idiopathic focal dystonias was undertaken by examining 153 first-degree relatives of 40 index patients with torticollis (14 patients), other focal cranial dystonias (16 patients), and writer's cramp (10 patients). Nine relatives with dystonia were identified in 6 families; 8 of these had symptoms such as clumsiness or tremor, but none were aware of any dystonia. A further 4 relatives, now decreased, were affected by history. Overall, 25% of index patients had relatives with dystonia. The results of segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrance as a common cause for focal dystonia. Segregation ratios were not significantly different from those ratios observed in generalized or segmental dystonia in the United Kingdom, and it is possible that a single autosomal dominant gene mutation is responsible for inherited dystonia in the majority of patients irrespective of distribution or severity.
Using [18F]dopa, [11C]raclopride, C15O2, and positron emission tomography, we have assessed striatal dopamine storage capacity, dopamine D2-receptor integrity, and regional cerebral blood flow, respectively, of 6 patients with neuroacanthocytosis. The patients with neurocanthocytosis all had chorea and variable combinations of seizures, dementia, axonal neuropathy, and orolingual self-multiation. [18F]dopa positron emmission tomographic findings were compared with 30 normal controls and 16 patients with sporadic, L-dopa-responsive, Parkinson's disease. Caudate and anterior putamen [18F]dopa uptake were normal in patients with neuroacanthocytosis, but mean posterior putamen [18F]dopa uptake was reduced to 42% of normal, similar to that in patients with Parkinson's disease. In patients with neuroacanthocytosis, mean equilibrium caudate: cerebellum and putamen: cerebellum [11C]raclopride uptake ratios were reduced to 54% and 62% of normal, compatible with a 65% and 53% loss of caudate and putamen D2-receptor-binding sites, respectively. Striatal and frontal blood flow was also depressed. The severe loss of D2-receptor-bearing striatal neuron, with concomitant loss of dopaminergic projections from the nigra to the posterior putamen, is consistent with both chorea and extrapyramidal rigidity being features of patients with neuroacanthocytosis.
The clinical features of familial Parkinson's disease (PD) were investigated by examining the families of 20 British probands who were selected on the basis of having clinically typical PD and at least one affected relative. Forty-nine secondary cases were identified. These subjects were clinically indistinguishable from sporadic cases of idiopathic PD. If it is assumed that familial PD has a genetic basis, pedigree and segregation analysis suggested autosomal dominant inheritance of a gene or genes with reduced penetrance as the most likely explanation. The data did not support the possibilities of either mitochondrial or polygenic inheritance, although the latter cannot be excluded. The role of genetic factors in sporadic cases of PD remains unclear.
A study of 71 patients with idiopathic torsion dystonia (ITD) and 71 matched controls was performed to investigate the range of possible clinical expression of ITD and the role of environmental factors in the development of the disease. A family history of tremor and stuttering were the only factors significantly associated with ITD. No associated environmental factor was identified.
Age of onset and severity of idiopathic torsion dystonia (ITD) were studied in 100 British families containing 107 index cases and 79 secondary cases. Analysis of variance of these clinical features did not suggest that ITD is genetically heterogenous, and they were similar in Jewish and non-Jewish patients. Intrafamilial correlation for age of onset was low, particularly between parents and their offspring, suggesting that the ITD phenotype may be determined in part by nongenetic factors or an allelic modifying gene.
The clinical features of a brother and sister with the Chediak-Higashi syndrome (CHS) are reported. Both showed evidence of a sensory neuropathy associated with central nervous system involvement. Nerve conduction studies indicated an "axonal" neuropathy. Sural nerve biopsy in the brother demonstrated a loss of myelinated nerve fibres, particularly those of larger size, and of unmyelinated axons. In contradistinction to some previous reports, giant lysosomes in Schwann cells were not observed and there were no inflammatory changes. Electron microscopy and teased-fibre studies showed no evidence of demyelination. It is concluded that the neuropathy of CHS is of axonal type. Its mechanism remains obscure.
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A number of mutations have been demonstrated in the open reading frame (ORF) of the prion protein (PrP) gene in patients with familial Creutzfeldt-Jakob disease or Gerstmann-Sträussler syndrome. On the basis of detecting an insertion in the ORF of the PrP gene in a patient originally suspected to be suffering from familial Alzheimer-type dementia, we screened 101 individuals with atypical dementias for the known PrP gene mutations. Insertions were found in five individuals, whereas none of the other reported mutations in the PrP gene was detected in the present study. One of the five insertions was larger than that described previously, suggesting that the individuals with these mutations are unlikely to be all lineally related and that insertions in the PrP gene may not be uncommon in prion diseases.