We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.

Cloned coding sequences for rat and human ornithine transcarbamylase (OXC) were obtained by screening a rat and a human cDNA library respectively with a synthetic oligonucleotide corresponding to 27 bases of the rat sequence. These clones, 1100 bp long for the rat clone and 1300 bp for the human, contain approximately 80% of the human OTC coding sequence. The OTC mRNA length determined by Northern blot analysis is 1700bp. The human OTC sequence was shown to be localised Xpt1 j-Xp,, using somatic cell hybrids. There is a frequent RFLP revealed with the restriction enzyme Mspl. OTC is located more closely to the Duchenne muscular dystrophy mutation than previously reported markers such as RC8 and LI.28, and therefore should prove useful in carrier detection and haplotype analysis of families carrying the mutation causing the disease.

Charcot-Marie-Tooth (CMT) disease is a progressive neuropathy of the peripheral nervous system, typically characterized by muscle weakness of the distal limbs. CMT is noted for its genetic heterogeneity, with four distinct loci already identified for the axonal form of the disease (CMT2). In 1996, linkage analysis of a single large family revealed the presence of a CMT2 locus on chromosome 7p14 (designated CMT2D). Additional families have been linked subsequently to the same genomic region, including one with distal spinal muscular atrophy (dSMA) and one with mixed features of dSMA and CMT2; symptoms in both of these latter families closely resemble those seen in the original CMT2D family. There is thus a distinct possibility that CMT2 and dSMA encountered in these families reflect allelic heterogeneity at a single chromosome 7 locus. In the study reported here, we have performed more detailed linkage analysis of the original CMT2D family based on new knowledge of the physical locations of various genetic markers. The region containing the CMT2D gene, as defined by the original family, overlaps with those defined by at least two other families with CMT2 and/or dSMA symptoms. Both yeast artificial chromosome (YAC) and bacterial clone-based [bacterial artificial chromosome (BAC) and P1-derived artificial chromosome (PAC)] contig maps spanning approximately 3.4 Mb have been assembled across the combined CMT2D critical region, with the latter providing suitable clones for systematic sequencing of the interval. Preliminary analyses have already revealed at least 28 candidate genes and expressed-sequence tags (ESTs). The mapping information reported here in conjunction with the evolving sequence data should expedite the identification of the CMT2D/dSMA gene or genes.

Clinical, electrophysiological and genetic linkage studies were performed on a large autosomal dominant family with Charcot-Marie-Tooth axonal neuropathy type 2 (CMT2) with 38 members of which 14 were affected. Onset of the disease was between 16 and 30 years of age with weakness and atrophy of the hands more severe than of the feet with slow progressive course in 12 patients. Deep tendon reflexes were absent in the upper extremities and decreased in the lower extremities. There was distal hypesthesia for touch, proprioception and vibration sense for the hands more than for the feet. Motor nerve conduction velocities showed normal values (48-53 M/s) with normal latencies (2-3 msec) and electromyography revealed signs of denervation. Genetic linkage analysis used 167 short tandem repeat markers (STRPs) spaced throughout the 22 autosomes. Linkage to the short arm of chromosome 7 at 7p14 was found using the marker D7S435 (Z = 4.83 at theta = 0). Flanking markers were D7S1808 and D7S1806 and the genetic distance between them was 6.8 cM. The multipoint linkage analysis gave a peek multipoint lod score of 6.89 between the markers D7S1808 and D7S435. Linkage analysis showed significantly negative lod scores (with values less than -2) with markers of chromosomes 1 and 3 where CMT axonal forms have been previously mapped. PFGE analysis indicated the absence of the CMT1A duplication. Our findings are consistent with a new genetic type of axonal CMT neuropathy designated by us as CMT2D. Potential candidate genes are multiple T-cell gamma receptor genes which map to the same cytogenetic interval as CMT2D neuropathy.

We studied the relationship between the genotype and clinical phenotype in 27 families with dominant X-linked Charcot-Marie-Tooth (CMTX1) neuropathy. Twenty-two families showed mutations in the coding region of the connexin32 (cx32) gene. The mutations include four nonsense mutations, eight missense mutations, two medium size deletions, and one insertion. Most missense mutations showed a mild clinical phenotype (five out of eight), whereas all nonsense mutations, the larger of the two deletions, and the insertion that produced frameshifts showed severe phenotypes. Five CMTX1 families with mild clinical phenotype showed no point mutations of the cx32 gene coding region. Three of these families showed positive genetic linkage with the markers of the Xq13.1 region. The genetic linkage of the remaining two families could not be evaluated because of their small size.

The purpose of this study was the identification of new mutations of the connexin 32 (CX32) gene in CMTX families. We report six new mutations of the CX32 gene including two medium sized (29 and 18 bp) deletions. The clinical phenotype is consistent with CMT peripheral neuropathy in all patients. Four families show both male and female patients, with more severe symptoms in males. The disease is asymptomatic in females in two families. The clinical deficit in CMTX families Nos 1, 2 and 4 with missense mutations of the CX32 gene was mild or moderate. Severe weakness of the feet and hands was present in CMTX family No. 5 with a G insertion and family No. 6 with a 29 bp deletion in the carboxyl terminal region of the CX32 gene. Most likely the severe clinical impact in those families was related to frame shift and premature termination of the protein.

Ten families with X-linked dominant CMT neuropathy (CMTX1) were screened for point mutations of the connexin32 (Cx32, GJB1) gene. Two families showed missense mutations, respectively an A-->G transition at amino acid 102 (glutamate to glycine) and a C-->T transition at amino acid 142 (arginine to tryptophan). Three families showed nonsense mutations, respectively a C-->T transition at amino acid 22 (arginine to stop) a G-->T transversion at amino acid 186 (glutamate to stop), and a T-->A transversion at amino acid 217 (cysteine to stop). Five CMTX1 neuropathy families showed no evidence of point mutations of the connexin32 coding sequence. These findings suggest that the CMTX1 neuropathy genotype is heterogeneous or the result of promoter mutations, 3'-untranslated region mutations or exon/intron splice site mutations. Four of the reported mutations created or destroyed restriction enzyme sites: a HaeIII restriction enzyme site was destroyed by the mutation at amino acid position 22, a HpaII site was eliminated at amino acid position 142, a Bfal restriction site was created by the mutation at amino acid 186 and a Ddel restriction site was created by the mutation at amino acid 217. These changes allowed us to test family members for the mutations and observe the segregation of the disease with the mutations.

A 42‐Year‐old woman sith negative family history had the insidious onset of weakness in her lower extremities 8 years before, in 1983. The disorder slowly progressed to include cramps and muscle twitches. The diagnosis of adult spinal muscular atrophy (SMA) was made when electromyography showed large rapidly firing motor unit potentials, positive waves, and fibrillation potentials, and when muscle biopsy of the quadriceps revealed severe alterations consistent with neurogenic atrophy. The patient also had severe chronic constipation for many years. More recently she had developed unremitting diarrhea. Gastrointestinal studies showed no evidence of peristaltic contractions in the rectum, delayed gastric emptying, and abnormal jejunal manometry with altered propagation of the migrating myoelectrical complex. © 1994 John Wiley & Sons, Inc.

We studied a family with nine of twenty members affected with Charcot-Marie-Tooth disease type 1A (CMT1A). The proband and her four affected sibs showed no duplication of the 17p11.2-17p12 (CMT region). Two of the proband's affected daughters three affected grandchildren showed duplication of the PMB-22 gene and of the marker VAW409R3 but not of the markers VAW412B3 and EW401. Pulsed field gel electrophoresis (PFGE) revealed a 220 kb SacII fragment in one CMTIA patient with duplication instead of a 500 kb SacII fragment as previously reported. Our findings suggest a smaller size of the duplication in this CMT1A family. The disease segregates with the same haplotype in both duplicated and nonduplicated CMT1A patients. The clinical phenotype showed more severe weakness with earlier onset and motor nerve conduction velocities were characterized by more significant slowing in the patients with duplication than in the patients who did not show duplication.

Two identical twins with becker Muscular Dystrophy are reported. Both twins had the same red cell types for ABO, Rh, CDE, MNSs, Kelly, Lewis, Duffy, and Kidd. HLA typing detected the same antigens in both twins: A1, A26, B8, B17, DR3, DR7. Family history was negative. The twin patients showed identical haplotypes that were different from the haplotypes of the normal male members of the family. The sister of the twins showed a recombinant X chromosome. The informative haplotype with respect to the gene of BMD, present in the twins, was ascertained in their mother as well. Our findings strongly suggest that a mutation has occurred either in the mother or in the twins.

A recombinant DNA study was performed in a three-generation family with 8 typical cases of late onset myotonic dystrophy (DM) and with one case of Duchenne muscular dystrophy (DMD). The study with DNA markers for chromosome 19 showed linkage of DM locus to the 3.8 Kb allele of apolipoprotein C2 (APOC2) probe and to 9 Kb allele of pSC11 probe (APOC2 lod score = 0.69 at theta = 0). The 21-year-old DMD patient showed no myotonic signs. His clinical history revealed onset with weakness around 4 years of age, progressive course with wheelchair confinement at 11, and cardiomyopathy. His karyotype was normal (46, XY). The study with 10 DNA markers for the chromosome X found a deletion limited to XJ 1.1, XJ 1.2, and XJ 2.3 probes. His 22-year-old sister with typical clinical, EMG and recombinant DNA findings characteristic for myotonic dystrophy was also a carrier of DMD deletion.

Research Articles| May 09 2008 Linkage between the loci for autosomal dominant Charcot-Marie-Tooth neuropathy type 1 and human glucocerebrosidase Subject Area: Genetics V. Ionasescu; V. Ionasescu aDivision of Genetics, Department of Pediatrics, Search for other works by this author on: This Site PubMed Google Scholar T. Burns; T. Burns bDepartment of Preventive Medicine, University of Iowa Hospitals, Iowa City, IA, and Search for other works by this author on: This Site PubMed Google Scholar R. Ionasescu; R. Ionasescu aDivision of Genetics, Department of Pediatrics, Search for other works by this author on: This Site PubMed Google Scholar C. Searby; C. Searby aDivision of Genetics, Department of Pediatrics, Search for other works by this author on: This Site PubMed Google Scholar E. Ginns E. Ginns cMolecular and Medical Genetics Section, National Institute of Neurological and Communicative Disorders and Stroke, NIH, Bethesda, MD Search for other works by this author on: This Site PubMed Google Scholar Cytogenetics and Cell Genetics (1988) 47 (3): 173–174. https://doi.org/10.1159/000132539 Article history Accepted: August 13 1987 Published Online: May 09 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation V. Ionasescu, T. Burns, R. Ionasescu, C. Searby, E. Ginns; Linkage between the loci for autosomal dominant Charcot-Marie-Tooth neuropathy type 1 and human glucocerebrosidase. Cytogenetics and Cell Genetics 1 March 1988; 47 (3): 173–174. https://doi.org/10.1159/000132539 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsCytogenetic and Genome Research Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. 1988Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

We studied 169 members of 15 families with Charcot-Marie-Tooth neuropathy (CMT1) showing male-to-male transmission and slow motor-nerve conduction velocities. Four of these families were informative for linkage to apolipoprotein A2 on chromosome 1 (1q21-23) with an overall lod score of 2.45 at theta = .001. There was no statistical evidence of genetic heterogeneity.