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Biomedical subjects

C E Jackson

Publications and source records attributed to C E Jackson.

At least 91 records · Page 5Linked to original sources
PubMed1994

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is a human cancer syndrome characterized by medullary thyroid carcinoma (MTC), pheochromocytomas, mucosal neuromas, ganglioneuromas of the intestinal tract, and skeletal and ophthalmic abnormalities. It appears both as an inherited disorder and as de novo disease. Sequence analysis of germ-line DNA from MEN 2B patients revealed the existence of the same point mutation in the RET protooncogene in 34 unrelated individuals. This sequence difference was not observed in 93 unaffected individuals, including the normal parents of 14 de novo MEN 2B patients. The mutation (ATG-->ACG) results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain. We propose that this amino acid replacement effects substrate interactions and results in dominant oncogenic activity by the RET protein. Missense mutations in the extracellular ligand-binding domain of the RET protooncogene previously have been associated with two other disorders [MEN 2A and familial MTC (FMTC)] in which MTC is observed. MEN 2B represents the third form of heritable MTC known to be an allele of RET. Alterations in two different functional domains of the putative receptor protein tyrosine kinase are implicated in development of MTC.

Alleles↗
PubMed1994

Genetic heterogeneity among craniosynostosis syndromes: mapping the Saethre-Chotzen syndrome locus between D7S513 and D7S516 and exclusion of Jackson-Weiss and Crouzon syndrome loci from 7p.

Saethre-Chotzen, Crouzon, and Jackson-Weiss syndromes are craniosynostotic autosomal dominant conditions with a wide variability in expression. Saethre-Chotzen has been mapped to chromosome 7p by L. A. Brueton et al. (1992, J. Med. Genet. 29: 681-685), the Greig cephalopolysyndactyly gene was identified at 7p13 by A. Vortkamp et al. (1991, Nature 352: 539-540), and many cases of craniosynostosis have been associated with 7p deletions. We confirmed linkage of the Saethre-Chotzen syndrome locus to chromosome 7p. The tightest linkage was to locus D7S493 (Z = 5.04, theta = 0.00), and linkage and haplotype analyses refined the location of the gene to the region between D7S513 and D7S516. Jackson-Weiss and Crouzon syndrome loci were analyzed using markers spanning the entire 7p arm and were excluded, proving that they are nonallelic to Saethre-Chotzen, Greig cephalopolysyndactyly, and the del(7p) syndromes.

Abnormalities, Multiple↗
PubMed1994

Immunosuppressive treatment of motor neuron syndromes. Attempts to distinguish a treatable disorder.

OBJECTIVE: To determine if response to immunosuppressive treatment in motor neuron syndromes could be predicted on the basis of clinical features, anti-GM1 antibodies, or conduction block. DESIGN: Prospective, uncontrolled, treatment trial using prednisone for 4 months followed by intravenous cyclophosphamide (3 g/m2) continued orally for 6 months. SETTING: All patients were referred to university hospital medical centers. PATIENTS: Sixty-five patients with motor neuron syndromes were treated with prednisone; 11 patients had elevated GM1 antibody titers, and 11 patients had conduction block. Forty-five patients received cyclophosphamide, eight of whom had elevated GM1 antibodies and 10 had conduction block. RESULTS: One patient responded to prednisone, and five patients responded to cyclophosphamide treatment. Only patients with a lower motor neuron syndrome and conduction block improved with either treatment. Response to treatment did not correlate with GM1 antibodies. CONCLUSIONS: GM1 antibodies did not serve as a marker for improvement in patients with motor neuron syndrome treated with immunosuppressive drugs. Patients with amyotrophic lateral sclerosis failed to improve irrespective of laboratory findings.

Adult↗
PubMed1994

Prolonged paralysis due to nondepolarizing neuromuscular blocking agents and corticosteroids.

The long-term use of nondepolarizing neuromuscular blocking agents (ND-NMBA) has recently been implicated as a cause of prolonged muscle weakness, although the site of the lesion and the predisposing factors have been unclear. We report 3 patients (age 37-52 years) with acute respiratory insufficiency who developed prolonged weakness following the discontinuation of ND-NMBAs. Two patients also received intravenous corticosteroids. Renal function was normal but hepatic function was impaired in all patients, and all had acidosis. Electrophysiologic studies revealed low amplitude compound motor action potentials, normal sensory studies, and fibrillations. Repetitive stimulation at 2 Hz showed a decremental response in 2 patients. The serum vecuronium level measured in 1 patient 14 days after the drug had been discontinued was 172 ng/mL. A muscle biopsy in this patient showed loss of thick, myosin filaments. The weakness in these patients is due to pathology at both the neuromuscular junction (most likely due to ND-NMBA) and muscle (most likely due to corticosteroids). Hepatic dysfunction and acidosis are contributing risk factors.

Adrenal Cortex Hormones↗
PubMed1994

Paramyotonia congenita: abnormal short exercise test, and improvement after mexiletine therapy.

The diagnosis of paramyotonia congenita (PC) can be aided by demonstrating a decrease in compound motor action potential amplitude after exercise and a decrement on repetitive stimulation, following cold exposure. We report a patient with PC who presented with complaints of cold-induced hand and jaw stiffening, in the absence of any episodes of weakness. Treatment with mexiletine led to resolution of the abnormalities exhibited during a short exercise test and repetitive stimulation following ice bath immersion. Molecular genetic analysis revealed a missense mutation (cytosine to thymidine) on chromosome 17 in the alpha-subunit of the skeletal muscle sodium channel gene that results in the replacement of threonine with methionine. This case demonstrates that, despite the absence of weakness, the short exercise test following cold exposure can be used to confirm the diagnosis of PC in patients without episodic weakness. Furthermore, improvement of the electrophysiologic abnormalities with mexiletine was documented, corresponding with clinical improvement.

Cold Temperature↗
PubMed1994

Evaluation of myosin-reactive antibodies from a panel of myasthenia gravis patients.

In the study described below, 97 myasthenia gravis (MG) patients have been evaluated for antibody reactivity against muscle myosin. With few exceptions, we could clearly observe a positive correlation between the presence of circulating serum anti-myosin antibodies and disease severity. Unlike some studies of anti-striational antibodies in MG patients, no association with thymoma was apparent. Moreover, no relationships were revealed between the severity of disease symptoms demonstrated and absolute anti-myosin antibody titers or prominent IgG subclasses. Therefore, we suggest that expression of myosin reactivity may be one useful parameter for predicting disease severity in those patients, but it is not prerequisite for induction of MG.

Antibodies↗
PubMed1994

Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC.

We have analysed 118 families with inherited medullary thyroid carcinoma (MTC) for mutations of the RET proto-oncogene. These included cases of multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial MTC (FMTC). Mutations at one of 5 cysteines in the extracellular domain were found in 97% of patients with MEN 2A and 86% with FMTC but not in MEN 2B patients or normal controls. 84% of the MEN2A mutations affected codon 634. MEN 2A patients with a Cys634 to Arg substitution had a greater risk of developing parathyroid disease than those with other codon 634 mutations. Our data show a strong correlation between disease phenotype and the nature and position of the RET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.

Base Sequence↗
PubMed1994

Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.

Jackson-Weiss syndrome is an autosomal dominant condition characterized by craniosynostosis, foot anomalies and great phenotypic variability. Recently mutations in fibroblast growth factor receptor 2 (FGFR2) have been found in patients with another craniosynostotic syndrome, Crouzon syndrome. FGFR2 is a member of the tyrosine kinase receptor superfamily, having a high affinity for peptides that signal the transduction pathways for mitogenesis, cellular differentiation and embryogenesis. We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. In addition, in four of 12 Crouzon syndrome cases, we identified two new mutations and found two previously described mutations in the same region.

Alleles↗
PubMed1994

Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1.

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.

Amino Acid Sequence↗
PubMed1994

Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours.

The susceptibility loci for the three multiple endocrine neoplasia (MEN) type 2 syndromes have been mapped to the region of chromosome 10q11.2 containing the RET proto-oncogene, which codes for a receptor tyrosine kinase. The majority of MEN 2A and familial medullary thyroid carcinoma results from missense mutations within one of five cysteine codons in the extracellular domain of the RET proto-oncogene. We now report a missense mutation, resulting in the substitution of a threonine for a methionine at codon 918 in the tyrosine kinase catalytic domain, in the germline of 26 of 28 apparently distinct families with MEN 2B. DNA from five of 13 apparently sporadic MTC and one of 12 apparently sporadic phaeochromocytomas harboured a similar mutation, but the corresponding germline DNA was wildtype in each case.

Adenoma↗
PubMed1994

Genetic heterogeneity in hereditary haemorrhagic telangiectasia: possible correlation with clinical phenotype.

Hereditary haemorrhagic telangiectasia (HHT) or Osler-Weber-Rendu syndrome is an autosomal dominant vascular dysplasia characterised by recurrent haemorrhage. Our initial linkage studies found an HHT gene to be localised to 9q3 in two large kindreds. In the present study, we examine an additional five unrelated HHT families. Linkage analysis in this region resulted in a peak multipoint location score of 13.03, 10 cM proximal of D9S60. We found significant evidence for heterogeneity of HHT. Multipoint analysis supports the family specific two point studies with odds of 3,000,000:1 showing linkage and heterogeneity over linkage and homogeneity. Four of the seven families give a posterior probability of > 99% of being of the linked type, and three families appear unlinked to this region of 9q, and by multipoint analysis completely exclude the candidate region for HHT. Two new crossovers in affected persons in one of the linked families further define the proximal border of the candidate region on 9q3. A possible correlation in clinical phenotype between the 9q3 linked families and unlinked families is described. Although six of the seven families clearly meet the clinical criteria for HHT diagnosis, a significant absence of pulmonary arteriovenous malformations is seen in all three 9q3 unlinked families. Genetic heterogeneity of HHT and its potential correlation with a clinical phenotype may have a significant impact on the clinical management and treatment of HHT patients.

Chromosomes, Human, Pair 9↗
PubMed1994

Inclusion body myositis: treatment with intravenous immunoglobulin.

We report the results of nine patients with inclusion body myositis treated with intravenous immunoglobulin in an open-label uncontrolled study. None of our patients improved on objective manual muscle testing or functional disability scores. One patient developed mild neutropenia, complicating the intravenous immunoglobulin treatment. Our results do not exclude the possibility that intravenous immunoglobulin could be beneficial in some patients by slowing the rate of deterioration or perhaps stabilizing the disease. However, given the lack of objective improvement and high cost of treatment, we would not recommend intravenous immunoglobulin in the treatment of inclusion body myositis unless a blinded, controlled trial demonstrates clear benefit.

Aged↗
PubMed1994

Parent-of-origin effects in multiple endocrine neoplasia type 2B.

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medullary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglioneuromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases arising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in order to determine the parental origin of the mutated RET allele. In all cases the new mutation was of paternal origin. We observe a distortion of the sex ratio in both de novo MEN 2B patients and the affected offspring of MEN 2B transmitting males. These results suggests a differential susceptibility of RET to mutation in paternally and maternally derived DNA and a possible role for imprinting of RET during development.

Chromosomes, Human, Pair 10↗
PubMed1994

Clinical value of direct DNA analysis of the RET proto-oncogene in families with multiple endocrine neoplasia type 2A.

BACKGROUND: The multiple endocrine neoplasia type 2A gene is the RET proto-oncogene located on the long arm of chromosome 10, and many mutations within this gene have been reported. METHODS: Peripheral blood DNA was analyzed from 95 members of twelve families with multiple endocrine neoplasia type 2A and known mutations in codon 634 (of exon 11) of the RET proto-oncogene. This region was amplified by the polymerase chain reaction, followed by digestion with Cfo I, which detects restriction sites created by the most common TGC- > CGC mutation and by a TGC- > TGG mutation or with Rsa I, which detects a restriction site created by a TGC- > TAC mutation. RESULTS: Diagnoses were confirmed in 39 patients; 15 of 56 at-risk persons were gene carriers and 41 were noncarriers. The noncarriers included seven persons who had previously undergone thyroidectomies for suspected C-cell hyperplasia but were negative for the RET mutation present in affected members of their families. CONCLUSIONS: Identification of the specific gene alterations within families permits direct DNA diagnosis of at-risk family members. The 41 noncarriers will not require further testing nor need to be concerned about transmitting multiple endocrine neoplasia type 2A to their descendants. The normal DNA findings in seven of these persons emphasize the importance of DNA studies in patients with C-cell hyperplasia but no medullary thyroid cancer at operation.

DNA↗
PubMed1993

Acute paralytic syndrome in three American men. Comparison with Chinese cases.

OBJECTIVE: To define clinically an unusual acute paralytic syndrome with features distinctive from those of the Guillain-Barré syndrome and similar to those described in Chinese children and young adults. DESIGN: Case series. SETTING: University medical centers. PATIENTS: Three North American men (mean age, 29 years) who presented with acute symmetric weakness and muscle cramps after a preceding gastrointestinal tract illness. These patients had no sensory symptoms, developed no respiratory insufficiency or facial weakness, and had normal to brisk muscle stretch reflexes. RESULTS: Results of serial nerve conduction studies were normal except for low-amplitude motor potentials. Needle electromyography revealed diffuse denervation potentials. Cerebrospinal fluid showed an elevated protein level and, in one case, a mild pleocytosis. A sural nerve biopsy specimen in one patient was normal; muscle biopsy specimens showed denervation atrophy. CONCLUSION: These cases resemble those described in Chinese children and young adults and may represent a postviral monophasic process affecting the anterior horn cell or distal motor nerve terminal. Further pathologic correlation will be required to identify the exact site of the lesion. Differentiation is important when considering modes of treatment.

Action Potentials↗
PubMed1993

Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2.

We have carried out genetic linkage analyses using fifteen polymorphic loci in the pericentromeric region of chromosome 10 in families with the inherited cancer syndromes multiple endocrine neoplasia (MEN) type 2A or 2B. A highly polymorphic microsatellite from the locus D10S141 in q11.2 was found to be recombinant with respect to the disease locus in two individuals and defines a new proximal flanking marker for both MEN2A and 2B. An additional recombination provides evidence that the locus D10S94, also in q11.2, is the closet distal flanking marker for MEN2A. This localises the MEN2A gene to a small region of 10q11.2 flanked by the loci D10S141 and D10S94, which are separated by a sex-averaged genetic distance of 0.55 cM. The MEN2B gene maps to a larger region, flanked by D10S141 and RBP3.

Chromosome Mapping↗