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G A Nicholson

Publications and source records attributed to G A Nicholson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Use of cosH1 probe in hereditary neuropathy with liability to pressure palsies: a reliable genetic test for demonstration of identical size of 17p11.2 deletion in unrelated patients.

We describe pulsed-field gel electrophoresis (PFGE) analysis of 10 unrelated Italian families and seven isolated cases with hereditary neuropathy with liability to pressure palsies (HNPP). Our sample includes patients with different clinical features, varying from classical liability to pressure palsies to ingravescent polyneuropathy. The frequency and the uniformity in size of the 17p11.2 deletion was evaluated by using cosH1 probe from the Charcot-Marie-Tooth neuropathy type 1A (CMT1A)-REP region. The presence of the deletion was demonstrated in all our patients; furthermore, the deletion was of identical size, although our patients had different clinical features. Molecular analysis of the 17p11.2 region by PFGE method proved to be a reliable and non-invasive method of diagnosis in HNPP cases both familial and isolated.

DNA Probes↗
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↗
PubMed1996

The gene for hereditary sensory neuropathy type I (HSN-I) maps to chromosome 9q22.1-q22.3.

Hereditary sensory neuropathy type I (HSN-I, also known as hereditary sensory and autonomic neuropathy type I (HSAN-I), or hereditary sensory radicular neuropathy) is an autosomal dominant disorder that is the most common of a group of degenerative disorders of sensory neurons. HSN-I was initially recognized as a disease that produced mutilating ulceration leading to amputation of digits (Fig. 1). It was given names such as familial ulcers with mutilating lesions of the extremities and perforating ulcers with osseous atrophy. The disease involves a progressive degeneration of dorsal root ganglion and motor neurons, leading to distal sensory loss and later distal muscle wasting and weakness and variable neural deafness. Sensory deficits include loss of all modalities, particularly loss of sensation to pain and temperature. Skin injuries may lead to chronic skin ulcers, osteomyelitis, and extrusion of bone fragments, especially the metatarsals. Onset of symptoms is in the second or later decades. We undertook a genome screen using linkage analysis in four Australian HSN-I kindreds. We now show that the HSN1 gene maps to an 8-centiMorgan (cM) region flanked by D9S318 and D9S176 on chromosome 9q22.1-q22.3. Multipoint linkage analysis suggests a most likely location at D9S287, within a 4.9-cM confidence interval.

Alleles↗
PubMed1996

Apolipoprotein E genotyping in Alzheimer's disease in an Australian sample.

BACKGROUND: Several previous studies have reported an increased frequency of the E4 allele of the gene for Apolipoprotein (APOE4) in both familial and sporadic Alzheimer's disease (AD). We report the results of a study of this association in an Australian clinic-base sample. AIM: To investigate the relationship between APOE4 frequency and AD in an Australian clinic-based sample and compare the results with previous studies. METHODS: Subject DNA was PCR amplified, enzymatically digested with Hha1 and the resulting fragments electrophoretically separated. The genotypes were ascertained according to the resulting fragment sizes and the resulting allele frequencies analysed by calculating a z-statistic for comparison of two proportions. RESULTS: The frequency of the APOE4 allele was 53% in the AD group and 11% in the control group. This difference is statistically significant. There was no significant difference in E4 allele frequencies between AD subjects with a family history and those without. At least one E4 allele was found in 26/30 (87%) of AD patients and 10/50 (20%) of controls. The allele frequencies of the control subjects used in this study were found to be consistent with those of several previous studies. CONCLUSION: The frequency of the APOE4 allele was significantly higher in AD subjects than in unaffected controls. This provides further evidence of an association between APOE4 and both familial and sporadic AD.

Alleles↗
PubMed1996

Prevalence and origin of de novo duplications in Charcot-Marie-Tooth disease type 1A: first report of a de novo duplication with a maternal origin.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Sporadic cases of CMT have been described since the earliest reports of the disease. The most frequent form of the disorder, CMT1A, is associated with a 1.5-Mb DNA duplication on chromosome 17p11.2, which segregates with the disease. In order to investigate the prevalence of de novo CMT1A duplications, this study examined 118 duplication-positive CMT1A families. In 10 of these families it was demonstrated that the disease had arisen as the result of a de novo mutation. By taking into account the ascertainment of families, it can be estimated that > or = 10% of autosomal dominant CMT1 families are due to de novo duplications. The CMT1A duplication is thought to be the product of unequal crossing over between parental chromosome 17 homologues during meiosis. Polymorphic markers from within the duplicated region were used to determine the parental origin of these de novo duplications in eight informative families. Seven were of paternal and one of maternal origin. This study represents the first report of a de novo duplication with a maternal origin and indicates that it is not a phenomenon associated solely with male meioses. Recombination fractions for the region duplicated in CMT1A are larger in females than in males. That suggests that oogenesis may be afforded greater protection from misalignment during synapsis, and/or that there may be lower activity of those factors or mechanisms that lead to unequal crossing over at the CMT1A locus.

Charcot-Marie-Tooth Disease↗
PubMed1995

A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease.

DNA from the probands of seven Australian families with hereditary Alzheimer's disease was screened for the presence of known mutations in the amyloid precursor protein (APP) gene on chromosome 21 using single stranded conformational polymorphism (SSCP) analysis [14]. One subject was found to have a mutation causing a Val-->Ile substitution at position 717. This was confirmed by restriction enzyme digestion and sequencing. The mutation has been found in both the other affected family members available for study and in two at-risk relatives. It was not present in the only living unaffected relative who has passed the usual age of onset in this family. There is so far no evidence that apolipoprotein E (APOE) genotype influences age of onset in this family, though numbers are small. Two other families with autopsy confirmation and age of onset in the fifth decade had no APP mutation and are thought likely to have a mutation on chromosome 14 on the basis of their earlier onset age.

Alzheimer Disease↗
PubMed1995

Déjérine-Sottas neuropathy is associated with a de novo PMP22 mutation.

We identified a de novo mutation in the peripheral myelin protein (PMP22) gene of a patient with Déjérine-Sottas neuropathy. Single-stranded conformation analysis of PCR-amplified DNA fragments showed an additional fragment for exon 1 in the patient, which was absent in the unaffected parents. Sequence analysis showed a de novo point mutation C85-->A that results in an amino acid substitution His12Gln in the first transmembrane domain of PMP22. This provides further evidence that sporadic cases of Déjérine-Sottas neuropathy can be due to dominant single base substitutions.

Amino Acid Sequence↗
PubMed1995

Detection of Charcot-Marie-Tooth type 1A duplication by the polymerase chain reaction.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy with a genetic locus on chromosome 17p11.2. The majority of patients carry a duplicated DNA segment that encompasses the gene PMP22, which encodes a peripheral myelin protein. PMP22 is the crucial gene involved in the pathogenesis of CMT1A. Molecular diagnosis of CMT1A requires detection of this duplicated segment. Existing methods for detection of the duplication are laborious and time consuming. We have developed a set of polymorphic (AC)n repeat markers (contained within the duplication) for use in the polymerase chain reaction, which give a high probability of detecting three unique alleles in affected individuals. This test detected 85% of a panel of 52 CMT1A patients in which the duplication had previously been demonstrated.

Base Sequence↗
PubMed1995

Advances in the genetics of hereditary hypertrophic neuropathy in childhood.

The peripheral neuropathies constitute approximately 30% of cases seen in a pediatric neuromuscular service. Two-thirds of such cases are chronic. Of the latter group roughly 70% are hereditary, 20% indeterminate and 10% acquired. There are definite chromosomal localizations for an increasing number of the hereditary neuropathies: to the region of the centromere of the X chromosome in an X-linked form of Charcot-Marie-Tooth (CMT) disease, to chromosome 17 in the commonest form of CMT, and to the long arm of chromosome 1, close to the Duffy locus, in a few kindreds with a rarer type of CMT. A duplication of DNA on the long arm of chromosome 17 is the commonest abnormality in autosomal dominant CMT. The duplicated region contains the gene for a 22 kDa myelin protein, PMP-22. The gene for PMP-22 is the site of a mutation in the hereditary neuropathy of the Trembler mouse. Some sporadic and inherited cases of chronic hypertrophic demyelinating neuropathy have recently been shown to be associated with specific mutations of the myelin protein P0 and PMP-22 loci. By contrast, a deletion encompassing the PMP-22 locus has been found in tomaculous neuropathy (hereditary liability to pressure palsies). Finally, mutations of the gap junction protein, connexin 32, have been shown to be responsible for X-linked dominant CMT.

Child↗
PubMed1994

Phenotypic expression of benign familial neonatal convulsions linked to chromosome 20.

OBJECTIVES: To determine whether the syndrome of benign familial neonatal convulsions in a large family was linked to markers on chromosome 20q and to study the seizure patterns in affected individuals. DESIGN: A clinical and molecular biologic study of a single large family in which the probands were identical twins with benign familial neonatal convulsions. PATIENTS: Thirteen living affected family members and 27 living unaffected family members were evaluated. RESULTS: Multipoint linkage analysis with use of the chromosome 20q markers CMM6 and RMR6 gave a maximum lod score of 3.13 at theta = 0.063, indicating linkage in this family. Of the 13 affected members, 10 had known neonatal seizures. Four subjects had febrile seizures, of whom only two had known neonatal seizures. Two members had afebrile seizures later, one of whom had not previously suffered neonatal or febrile seizures. CONCLUSION: The phenotypic heterogeneity in this family, with an epilepsy syndrome determined by a single gene, was striking. This suggests that molecular genetic approaches to the common forms of idiopathic epilepsy, involving patients with clinically similar phenotypes from unrelated families, may be inappropriate.

Chromosomes, Human, Pair 20↗
PubMed1994

The gene for Machado-Joseph disease maps to the same 3-cM interval as the spinal cerebellar ataxia 3 gene on chromosome 14q.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder in families of Portuguese-Azorean ancestry. The gene responsible for MJD has been assigned to a 29-cM interval on chromosome 14q. A large Brazilian family with MJD was genotyped with six new microsatellite markers spanning 19 cM on chromosome 14q. Linkage analysis and haplotype reconstruction reduced the MJD candidate region to a 3-cM interval between markers D14S280 and D14S81, permitting positional cloning. This interval also contains the spinal cerebellar ataxia 3 (SCA3) gene, responsible for a genetic subtype of the type I autosomal dominant cerebellar ataxias, clinically related to MJD. This result supports the hypothesis that abnormalities in the same gene may be responsible for both disorders. The minor clinical differences between the two diseases may result from allelic heterogeneity.

Cerebellar Ataxia↗
PubMed1994

A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) has been a associated with a deletion of 1.5 megabases of chromosome 17p. One of four biopsy proven HNPP families that we have studied did not possess this deletion. As the deleted DNA region includes the coding region for a peripheral myelin gene (PMP22), we used single strand conformation analysis to examine this gene for mutations in the non-deleted HNPP family. An abnormal fragment in exon 1 was identified, and sequencing revealed a two base pair deletion in all affected family members. The deletion results in a frame shift, providing strong evidence that this gene has an important role in the pathogenesis of the disease.

Base Sequence↗
PubMed1994

Peroneal muscular atrophy with pyramidal tract features (hereditary motor and sensory neuropathy type V): a clinical, neurophysiological, and pathological study of a large kindred.

A large family with autosomal dominant inheritance of peroneal muscular atrophy, associated with extensor plantar responses in some cases, has been studied. Onset was usually in the first two decades and spasticity was not a feature. Nerve conduction studies in 21 cases and light and electron microscope findings on six sural nerve biopsies were similar to those in hereditary motor and sensory neuropathy type II.

Adolescent↗
PubMed1993

De novo mutation of the myelin P0 gene in Dejerine-Sottas disease (hereditary motor and sensory neuropathy type III).

We have investigated the myelin P0 gene on chromosome 1 as a candidate gene in two sporadic cases with Dejerine-Sottas disease or hereditary motor and sensory neuropathy (HMSN) type III. We found different mutations, a cysteine substitution for serine 63 in the extracellular domain and an arginine substitution for glycine 167 in the transmembrane domain. The patients were genetically heterozygous for the normal allele and the mutant allele, which was absent in their parents and in one hundred unrelated, healthy controls. The results strongly suggest that a de novo dominant mutation of the P0 gene is responsible for at least some sporadic cases of Dejerine-Sottas disease.

Adolescent↗
PubMed1992

Charcot-Marie-Tooth neuropathy type 1A mutation: apparent crossovers with D17S122 are due to a duplication.

A locus for the slow conducting form of Charcot-Marie-Tooth neuropathy (CMT1A) was localised to the proximal short arm of chromosome 17, in band p11.2, distal to D17S58. Linkage studies of CMT1A in 3 large Australian families with the marker loci D17S58, D17S71, and D17S57 suggested the order, pter-CMT1A-D17S71-D17S58-centromere-D17S57. However, the estimate of the recombination fraction between CMT1A and D17S122, also assigned to p11.2, was incompatible with known map distances. The impasse was resolved when the D17S122 genotypes were revised to take into account a dosage effect due to a duplication. After correction of the genotypes, the maximum lod score between CMT1A and D17S122 increased from 0.53 at a recombination fraction of 0.3 to 34.28 at zero recombination. This result emphasizes that genotypes for markers in the p12-p11.2 region should be examined very carefully as ignoring the duplication changes the linkage results dramatically. The fact that no crossovers were found between CMT1A and D17S122 suggests that the duplication may cause the disease phenotype.

Charcot-Marie-Tooth Disease↗