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Biomedical subjects

P F Chance

Publications and source records attributed to P F Chance.

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

Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A.

BACKGROUND: A general predisposition for vincristine-related neuropathy has been observed in persons with a family history of hereditary neuropathies. METHODS: In a retrospective case series, we investigated the possible association between the DNA rearrangement found in patients with Charcot-Marie-Tooth Disease Type 1A (CMT1A) and susceptibility to the neurotoxicity of vincristine. In selected patients and family members, we performed electrodiagnostic studies and analyzed DNA samples for 17p11.1-12 duplication associated with CMT1A. RESULTS: We describe three families with autosomal dominant CMT1, among whom a family member with a neoplastic disease suffered rapid onset, severe neuropathy after receiving initial doses of vincristine as a part of a routine chemotherapy protocol. All three families had at least one affected family member with 17p11.2-12 duplication. CONCLUSIONS: These cases show that 17p11.2-12 duplication predisposes patients to severe neurotoxicity from vincristine and that this drug should be avoided with patients with CMT1A. It is therefore essential to obtain a detailed family history for all oncology patients to screen for possible hereditary neuropathies. In patients with unexplained or preexisting familial neuropathy, testing for 17p11.2-12 duplication should be carried out prior to initiating vincristine therapy. Patients with other hereditary neuropathies may also be at risk for severe neurotoxic reactions.

Adolescent↗
PubMed1996

Developmental profile in a patient with monosomy 10q and dup(17p) associated with a peripheral neuropathy.

We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed to his severe motor developmental delay.

Abnormalities, Multiple↗
PubMed1996

Myelin protein zero (MPZ) gene mutations in nonduplication type 1 Charcot-Marie-Tooth disease.

The myelin protein zero gene (MPZ) maps to chromosome 1q22-q23 and encodes the most abundant peripheral nerve myelin protein. The Po protein functions as a homophilic adhesion molecule in myelin compaction. Mutations in the MPZ gene are associated with the demyelinating peripheral neuropathies Charcot-Marie-Tooth disease type 1B (CMT1B), and the more severe Dejerine-Sottas syndrome (DSS). We have surveyed a cohort of 70 unrelated patients with demyelinating polyneuropathy for additional mutations in the MPZ gene. The 1.5-Mb DNA duplication on chromosome 17p11.2-p12 associated with CMT type 1A (CMT1A) was not present. By DNA heteroduplex analysis, four base mismatches were detected in three exons of MPZ. Nucleotide sequence analysis identified a de novo mutation in MPZ exon 3 that predicts an Ile(135)Thr substitution in a family with clinically severe early-onset CMT1, and an exon 3 mutation encoding a Gly(137)Ser substitution was identified in a second CMT1 family. Each predicted amino acid substitution resides in the extracellular domain of the Po protein. Heteroduplex analysis did not detect either base change in 104 unrelated controls, indicating that these substitutions are disease-associated mutations rather than common polymorphisms. In addition, two polymorphic mutations were identified in MPZ exon 5 and exon 6, which do not alter the codons for Gly(200) and Ser(228), respectively. These observations provide further confirmation of the role of MPZ in CMT1B and suggest that MPZ coding region mutations may account for a limited percentage of disease-causing mutations in nonduplication CMT1 patients.

Adult↗
PubMed1996

Infantile spasms associated with proximal duplication of chromosome 15q.

We describe a case of infantile spasms associated with a chromosome abnormality (supernumerary inverted duplication of chromosome 15 [47,XX,+inv dup(15)]). The patient was nondysmorphic and presented with mild hypotonia and delay in acquisition of gross motor milestones before the diagnosis of seizures at age 7 months. Additional features included unilateral sensorineural deafness and torticollis. Molecular cytogenetic studies confirmed that the patient has a large inv dup(15). Inv dup(15) chromosomes are variable with respect to the size and genetic composition of the chromosome and in their phenotypic effects. Patients with small inv dup(15s) may have no phenotypic abnormalities, whereas patients with large inv dup(15s) may have multiple abnormalities. ACTH therapy resulted in prompt remission of seizures and resolution of EEG abnormalities. This is the second report of a patient with IS and a supernumerary inv dup(15). Several genes code for neurotransmitter receptor subunits located in the duplicated region of chromosome 15, and abnormal dosage of these genes may be involved in the genesis of seizure activity in carriers of the inv dup(15). Chromosome analysis may lead to a specific diagnosis in infants with unexplained infantile spasms.

Adrenocorticotropic Hormone↗
PubMed1996

Primate origin of the CMT1A-REP repeat and analysis of a putative transposon-associated recombinational hotspot.

The CMT1A-REP repeat on chromosome 17p11.2-12 is proposed to mediate misalignment and meiotic unequal crossover leading to a 1.5 Mb pair duplication associated with Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and a reciprocal deletion associated with hereditary neuropathy with liability to pressure palsies (HNPP). Restriction enzyme endonuclease mapping indicated that the size of the CMT1A-REP repeat is approximately 24 kb and DNA sequence analysis determined that the repeat is flanked by inverted Alu sequences. Full length Alu sequences are present at the centromeric ends of the proximal and distal CMT1A-REP repeats and at the telomeric end of the distal repeat. A truncated Alu sequence is present at the telomeric end of the proximal repeat suggesting that the distal CMT1A-REP repeat is the progenitor copy. The crossover breakpoints for a series of unrelated CMT1A and HNPP patients were mapped using a variant SacI site found only in the proximal CMT1A-REP repeat. Seventy-six percent (66/85) of patients had breakpoints which mapped to a 3.2 kb interval, providing further evidence for a recombinational hotspot within the CMT1A-REP repeat. A mariner-like element was mapped within the CMT1A-REP repeat approximately 700 bp centromeric to the 3.2 kb interval containing the hotspot. Analysis of this sequence suggested that it does not encode a functional transposon. By Northern blot analysis a cloned fragment from the CMT1A-REP repeat containing the mariner-like sequence detected a 2.2 kb transcript only in testis. Two cDNA clones which contain the mariner-like element were isolated from a human testis cDNA library. These clones which are interrupted by Alu and other repeats appear to be non-functional versions of the transposon. The functional relationship of the mariner-like element to the recombinational hotspot remains unknown. The origin of the CMT1A-REP repeat was investigated through an analysis of homologous sequences in non-human primates. Southern blot analysis indicated that the chimpanzee has two copies of a CMT1A-REP-like sequence, whereas gorilla, orangutan, and gibbon have a single copy. A high degree of conservation amongst non-human primates for restriction fragments specific to the human distal CMT1A-REP repeat provides further evidence that the distal repeat is the progenitor copy. The mariner-like sequence was detected in association with the CMT1A-REP sequence in all primates studied suggesting that the mariner-like element was introduced into the progenitor CMT1A-REP sequence prior to emergence of the proximal and distal CMT1A-REP repeats. These observations suggest that CMT1A-REP sequence appeared as a repeat before the divergence of chimpanzee and human, but after gorilla and human around 6 to 7 million years ago.

Animals↗
PubMed1996

Hereditary neuralgic amyotrophy.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features including hypotelorism, long nasal bridge and upslanting palpebral fissures are present in affected people in some pedigrees with this disease. The molecular basis of hereditary neuralgic amyotrophy is unknown and the specific gene which leads to it has not been identified. The feature of brachial neuropathy is shared with hereditary neuropathy with liability to pressure palsies, another autosomal dominant disorder which maps to chromosome 17p11.2-12 and may be clinically confused with hereditary neuralgic amyotrophy. Genetic studies have shown that the two diseases do not map to the same chromosomal region and are, therefore, genetically distinct disorders. Genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees recently localized the hereditary neuralgic amyotrophy gene to the distal long arm of chromosome 17 (17q24-qter).

Adolescent↗
PubMed1996

Comparison of single-strand conformation polymorphism and heteroduplex analysis for detection of mutations in Charcot-Marie-Tooth type 1 disease and related peripheral neuropathies.

To compare the sensitivity of the mutation detection techniques single-strand conformation polymorphism analysis (SSCP) and heteroduplex analysis (HA), we analyzed a cohort of 73 patients with a diagnosis of a demyelinating neuropathy, but without the CMT1A duplication, for mutations in the coding region of the myelin genes PMP22, MPZ and Cx32. In total, 21 samples showed 13 distinct altered migration patterns by one or both methods. Ten altered patterns were detected by both SSCP and HA, two were false negative by HA, and one was false negative by SSCP. Our results suggest that either technique can be useful for mutation detection, but a combination of factors appears to affect the sensitivity of both techniques.

Charcot-Marie-Tooth Disease↗
PubMed1996

Genetic heterogeneity in Charcot-Marie-Tooth neuropathy type 2.

Charcot-Marie-Tooth neuropathy type 2 (CMT2) is a common inherited axonal neuropathy. The locus for one form of CMT2 (CMT2A) is assigned to the short arm of chromosome 1. There is genetic heterogeneity in CMT2 because additional pedigrees do not demonstrate linkage to chromosome 1 and are designated as CMT2B. Further clinical heterogeneity is suggested by CMT2 pedigrees with diaphragm and vocal cord weakness and are designated as CMT2C. To address the possible genetic distinction between CMT2A and CMT2C, we tested markers from the CMT2A locus for linkage in a large CMT2C pedigree. There was no evidence to support linkage of the CMT2C gene to the region of the CMT2A locus on chromosome 1. CMT2C is not an allelic variant of CMT2A. This analysis provides further evidence for genetic heterogeneity within inherited axonal neuropathies.

Charcot-Marie-Tooth Disease↗
PubMed1996

Mapping of hereditary neuralgic amyotrophy (familial brachial plexus neuropathy) to distal chromosome 17q.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus (HNA) is an autosomal dominant disorder associated with recurrent, episodic, painful brachial neuropathies. Mildly dysmorphic facial features, including hypotelorism, long nasal bridge, and upslanting palpebral fissures, are present in affected persons in some pedigrees with HNA. To determine the chromosomal location of the HNA gene, we carried out genetic linkage studies with polymerase chain reaction-based DNA markers in two large pedigrees. Linkage to markers from the distal long arm of chromosome 17 was established.

Adult↗
PubMed1995

A 2D crossover-based map of the human X chromosome as a model for map integration.

We have constructed a two-dimensional map of 243 markers on the X chromosome. The average distance between markers ordered by two recombinants is 5.4 centiMorgans (cM), which is reduced to 3.2 cM using a less stringent criterion of one recombinant. Map resolution is enhanced by replacing the usual reference marker format with a 2D format, and the two-recombinant rule is more conservative than the lod 3.0 criterion for order. Taken together, crossover mapping and the 2D format produces maps with greater reliability and higher resolution than maps constructed using currently accepted standards. This first high-density crossover-based map of an entire human chromosome provides a model for integrating physical and genetic maps.

Chromosome Mapping↗
PubMed1995

Analysis of the CMT1A-REP repeat: mapping crossover breakpoints in CMT1A and HNPP.

The CMT1A-REP repeat sequence flanks a 1.5 megabase pair (Mb) segment of chromosome 17p11.2-12 which is duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A) and deleted in hereditary neuropathy with liability to pressure palsies (HNPP). The CMT1A-REP repeat is proposed to mediate misalignment and unequal crossover resulting in reciprocal chromosomal rearrangements in CMT1A and HNPP. We have constructed a physical map of the proximal and distal CMT1A-REP repeats. Cloned fragments from CMT1A-REP repeat regions are used to determine the size of the repeats and assess regions of homology. The crossover breakpoints were mapped in series of 30 unrelated CMT1A patients and 22 unrelated HNPP patients. The CMT1A-REP repeat spans approximately 27 kilobase pairs and appears to be continuous. Locations of restriction enzyme sites are highly conserved for the proximal and distal CMT1A-REP repeats. All crossovers mapped within the CMT1A-REP repeat sequence and heterogeneity for breakpoint location demonstrated. Seventy-seven percent (40 to 52) of CMT1A and HNPP chromosomes contained breakpoints which mapped within a 7.9 kb interval, suggesting the presence of a possible 'hotspot'for recombination in CMT1A-REP. DNA sequence analysis for 4 kb of the interval containing the majority of crossovers revealed over 98% sequence identity between proximal and distal CMT1A-REP repeat sequences. Probes useful for molecular-based diagnosis of CMT1A and HNPP are described.

Charcot-Marie-Tooth Disease↗
PubMed1995

New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease.

Analysis of the connexin32 gene in patients with X-linked Charcot-Marie-Tooth disease shows mutations distributed throughout the molecule, with all domains affected except the fourth transmembrane domain and the distal carboxy terminus. Sequence analysis of DNA from 19 unrelated patients detected six novel mutations and three previously reported mutations. Identification of additional mutations extends the distribution of connexin32 mutations in X-linked Charcot-Marie-Tooth disease and shows that specific mutations recur in additional families.

Amino Acid Sequence↗
PubMed1994

Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis.

We describe two kindreds with an autosomal dominant inherited disorder characterized by a variable degree of muscle weakness of limbs, vocal cords, and intercostal muscles and by asymptomatic sensory loss, beginning in infancy or childhood in severely affected persons. Life expectancy in severely affected patients is shortened because of respiratory failure. Because nerve conduction velocities are normal and it is an inherited axonal neuropathy, we classify the disorder as a variety of hereditary motor and sensory neuropathy type II (HMSN II) (HMSN IIc). The present report provides further evidence for heterogeneity among the hereditary motor and sensory neuropathy type II disorders. In one large pedigree with the type IIc disorder, no linkage to DNA markers known to map near the HMSN IA locus on chromosome 17p or the HMSN IB locus on chromosome 1q was demonstrated.

Adolescent↗
PubMed1994

Two autosomal dominant neuropathies result from reciprocal DNA duplication/deletion of a region on chromosome 17.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common autosomal dominant demyelinating neuropathy that is associated with a 1.5 megabase (Mb) tandem DNA duplication in chromosome 17p11.2-p12. Hereditary neuropathy with liability to pressure palsies (HNPP, tomaculous neuropathy) is another less frequently diagnosed autosomal dominant neuropathy and is associated with a 1.5 Mb deletion in chromosome 17p11.2-12. Meiotic unequal crossover is a proposed mechanism for the generation of both the duplication in CMT1A and the deletion in HNPP. CMT1A-REP is a repeat that flanks the region which is duplicated/deleted in CMT1A/HNPP. The CMT1A-REP repeat sequence may mediate unequal crossover through misalignment of the homologous, repeated sequences. Three copies of the CMT1A-REP repeat are present on stably inherited CMT1A duplication chromosomes. In this report, molecular analysis in multiple patients detected three copies of the CMT1A-REP sequence on both inherited and de novo CMT1A duplication chromosomes, and one copy of the CMT1A-REP repeat on the deleted chromosome in both inherited and de novo HNPP. These observations support the hypothesis that a reciprocal recombination mechanism involving the CMT1A-REP is responsible for the generation of both the duplicated and deleted chromosomes, and document the first examples in humans of Mendelian syndromes resulting from the reciprocal products of unequal exchange involving large intra-chromosomal segments.

Charcot-Marie-Tooth Disease↗
PubMed1994

Molecular genetics of Charcot-Marie-Tooth disease and related neuropathies.

Collectively, the inherited disorders of peripheral nerves represent a common group of neurologic diseases. Charcot-Marie-Tooth neuropathy type 1 (CMT1) is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX) and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5 megabase (Mb) duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. X-linked Charcot-Marie-Tooth neuropathy (CMTX) is associated with mutations in the connexin32 gene. Charcot-Marie-Tooth neuropathy type II (CMT2) is an axonal neuropathy, also of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine-Sottas disease, also called hereditary motor and sensory neuropathy type III (HMSNIII), is a severe, infantile onset demyelinating polyneuropathy syndrome that may be associated with point mutations in either the PMP22 gene of the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that results in a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5 Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. CMT1A and HNPP are apparent reciprocal duplication/deletion syndromes originating from unequal crossover during germ cell meiosis.

Charcot-Marie-Tooth Disease↗
PubMed1994

Inherited neuropathies.

Charcot-Marie-Tooth neuropathy (CMT) type 1 is a genetically heterogeneous group of chronic demyelinating polyneuropathies with loci mapping to chromosome 17 (CMT1A), chromosome 1 (CMT1B), the X chromosome (CMTX), and to another unknown autosome (CMT1C). CMT1A is most often associated with a tandem 1.5-Mb duplication in chromosome 17p11.2-12, or in rare patients may result from a point mutation in the peripheral myelin protein-22 (PMP22) gene. CMT1B is associated with point mutations in the myelin protein zero (P0) gene. The molecular defect in CMT1C is unknown. CMTX is associated with mutations in the connexin 32 gene. CMT2 is an axonal neuropathy of undetermined cause. One form of CMT2 maps to chromosome 1p36 (CMT2A). Dejerine-Sottas disease is a severe, infantile-onset demyelinating polyneuropathy that may be associated with point mutations in either the PMP22 gene or the P0 gene. Hereditary neuropathy with liability to pressure palsies (HNPP) is a recurrent, episodic demyelinating neuropathy. HNPP is associated with a 1.5-Mb deletion in chromosome 17p11.2-12 and may result from reduced expression of the PMP22 gene. Most examples of CMT1A and HNPP are reciprocal duplication or deletion syndromes originating from unequal crossover during germ cell meiosis. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disorder that classically presents with a sensory peripheral neuropathy and early autonomic involvement. Transthyretin (TTR) is the most common constituent amyloid fibril protein deposited in FAP, and there are now 28 point mutations in the TTR gene described in TTR-related FAP. Liver transplantation looks promising as a treatment for TTR-related FAP.

Amyloid Neuropathies↗
PubMed1994

Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct genetic disorders.

Hereditary neuralgic amyotrophy with predilection for the brachial plexus (HNA) and hereditary neuropathy with liability to pressure palsies (HNPP) are autosomal dominant disorders associated with episodic, recurrent brachial neuropathies. HNPP is associated with a deletion or abnormal structure of the PMP22 gene on chromosome 17p11.2-12. The genetic locus for HNA is unknown. To address the possibility that HNPP and HNA might be identical disorders or allelic variations at the same locus, we investigated three HNA pedigrees with markers from the HNPP region. We did not find the 17p11.2-12 deletion associated with HNPP, nor an abnormality in PMP22 structure with HNA. This analysis provides genetic evidence, in addition to that suggested by the clinical, electrophysiologic, and pathologic differences, that HNA and HNPP are distinct disorders.

Adolescent↗