0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Hereditary Motor and Sensory Neuropathy Type 2C Is Genetically Distinct From Types 2B and 2D FREE

Masaaki Nagamatsu, MD; Robert B. Jenkins, MD, PhD; Daniel J. Schaid, PhD; Diane M. Klein, MT(ASCP); Peter James Dyck, MD
[+] Author Affiliations

From the Peripheral Neuropathy Research Center (Drs Nagamatsu and Dyck and Ms Klein) and the Departments of Laboratory Medicine and Pathology (Dr Jenkins) and Health Science Research (Dr Schaid), Mayo Clinic and Mayo Foundation, Rochester, Minn.


Arch Neurol. 2000;57(5):669-672. doi:10.1001/archneur.57.5.669.
Text Size: A A A
Published online

Background  Linkage analysis studies have identified 3 genetically different varieties of hereditary motor and sensory neuropathy type 2 (HMSN 2, also called Charcot-Marie-Tooth disease type 2, or CMT 2): HMSN 2A (linked to 1p35-p36), 2B (to 3q13-q22), and 2D (to 7p14). Hereditary motor and sensory neuropathy type 2C is characterized by diaphragmatic and vocal cord paresis; its disease locus has not been mapped.

Objective  To determine whether the HMSN 2C phenotype, previously shown not to be linked to the HMSN 2A locus, is linked to the HMSN 2B or HMSN 2D loci.

Design  Linkage analysis.

Setting and Patients  Thirty-three subjects, including 12 affected individuals and 11 individuals at risk, in a large family with HMSN 2C.

Results  Evidence was found against linkage of HMSN 2C phenotype to either the HMSN 2B or the 2D loci.

Conclusions  HMSN 2C is genetically distinct from HMSN 2A, 2B, and 2D. We think that at least 4 genetically distinct varieties of autosomal dominant HMSN 2 exist.

Figures in this Article

HEREDITARY MOTOR and sensory neuropathy (HMSN; also called Charcot-Marie-Tooth disease, or CMT) comprises a group of phenotypically similar inherited disorders of the peripheral nervous system.1 HMSN type 1 (HMSN 1) represents a genetically heterogeneous group of autosomal-dominant demyelinating hypertrophic neuropathies with characteristically low peripheral nerve conduction velocities. The HMSN 1 loci have been mapped to chromosome region 17p11.2-p12 (HMSN 1A) and 1q22-q23 (HMSN 1B).

Hereditary motor and sensory neuropathy type 2 (HMSN 2) is a genetically heterogeneous group of axonal (neuronal) neuropathies with normal or slightly low nerve conduction velocities, also usually inherited as autosomal dominant traits. Hentati et al2 and Loprest et al3 have demonstrated that the autosomal dominant HMSN 2 families that they studied did not have abnormal alleles at the HMSN 1A or HMSN 1B loci. Othmane et al4 have reported 3 families with dominantly inherited HMSN 2 linked to chromosome region 1p35-p36 (HMSN 2A) and also 3 other pedigrees with HMSN 2 that did not link to these loci, demonstrating genetic heterogeneity within HMSN 2. Subsequently, Kwon et al5 have reported a family with dominantly inherited HMSN 2 linked to markers mapped to chromosome region 3q13-q22 (HMSN 2B). Then Ionasescu et al6 described a family with dominantly inherited HMSN 2 linked to 7p14 (HMSN 2D).

Hereditary motor and sensory neuropathy type 2C is a clinical variety of HMSN 2 characterized by motor and sensory involvement of the limbs and progressive weakness of the vocal cords, diaphragm, and intercostal muscles.7 We have reported 2 unrelated HMSN 2C families7; the larger of these kindred was genetically distinct from HMSN 2A.8 In the present study we tested whether the HMSN 2C phenotype in this family is linked to the HMSN 2B or HMSN 2D loci.

KINSHIP

The clinical and electrophysiologic features of the kinship studied here have been described.7 Autosomal dominant inheritance was evident from at least 1 occurrence of male-to-male transmission based on the clinical examination. Affected persons had weakness and atrophy of peroneal and hand muscles, and decreased or absent deep tendon reflexes of the limbs. Their motor nerve conduction velocities in the median nerve were within the normal range. Sensory involvement of the feet and absent or decreased sensory nerve action potentials occurred in severely affected persons. Of 12 affected subjects, 9 had clinical evidence of diaphragmatic or vocal-cord paresis or paralysis. The severity of clinical symptoms in affected persons was variable; phenotypes did not differ by sex.

In the present study, the neuropathic status of 33 subjects in the larger kinship, including 12 affected individuals and 11 individuals at risk, were investigated (Figure 1). Clinically unaffected offspring who were at risk but younger than 26 years were excluded. After informed consent was given, 20 mL of blood was obtained by venipuncture from the family members. Continuing lymphoblast cell lines were established by Epstein-Barr virus transformation,9 and genomic DNA was isolated using a nucleic acid extraction kit (Isoquick; Microprobe, Bothell, Wash).

Place holder to copy figure label and caption
Figure 1.

Pedigree of the kindred with hereditary motor and sensory neuropathy type 2C in the present study. Squares represent male subjects; circles, female; black and white symbols, affected by history; solid black symbols, affected by clinical examination; white symbols, unaffected; plus sign, genotype checked; and diagonal slash, deceased. Numbering used is the same as in our previous publication.7

Graphic Jump Location
GENETIC STUDIES

Genotyping was performed for DNA microsatellite markers D3S1558, D3S1769, GGAA8B03, D3S1267, D3S1551, D3S1290, GATA4A10, and D3S1744. These markers map to the chromosome region 3q13-q22 and are linked to the HMSN 2B phenotype.5 Genotyping also was performed for microsatellite markers mapped to 7p14 (D7S1808, D7S1869, D7S435, and D7S1806), linked to the HMSN 2D phenotype,6 and for markers situated proximally (D7S2201) and distally (D7S526 and D7S1830) to 7p14. The markers (Research Genetics, Huntsville, Ala) were amplified by polymerase chain reaction in a final volume of 15 µL containing 50 ng of genomic template DNA, 2 pmol of each oligonucleotide microsatellite primer, 200 µM concentrations of dATP, dGTP, and dTTP, 50 mM of dCTP (Boehringer Mannheim, Indianapolis, Ind), 0.5 µCi of α-32P dCTP (Amersham Life Science, Arlington Heights, Ill), and 0.5 U of Taq DNA polymerase (Boehringer Mannheim) in a 1 × Taq buffer containing 10-mmol/L Trishydrochloride (pH 8.3 at 20°C), 50-mmol/L potassium chloride, and 1.5-mmol/L magnesium chloride. Amplification was performed for 35 cycles of denaturation at 94°C for 15 seconds, annealing at 55°C for 1 minute, and extension at 72°C for 15 seconds, with a final elongation cycle at 72°C for 10 minutes. After 10 µL of loading buffer (95% formamide, 10-mmol/L EDTA, 0.1% bromophenol blue, and 0.1% xylene cyanol) was added, the amplified products were denatured at 94°C for 10 minutes and then cooled rapidly to 4°C and placed on ice. Three microliters of each sample was electrophoresed on 6% denaturing polyacrylamide sequencing gels at 75 W for 2 to 3 hours. Gels were vacuum dried and autoradiographed overnight at −70°C. Base-pair sizes of the polymerase chain reaction products were calculated using a double-strand DNA cycle sequencing system (Gibco BRL, Grand Island, NY).

LINKAGE ANALYSIS

A linkage analysis was carried out between chromosome 3q13-q22 markers and the HMSN 2C phenotype in the large kinship described above. A linkage analysis was also performed between 7p14 markers and the HMSN 2C phenotype. Pairwise limit of detection (LOD) scores (Z values) were calculated, under the assumption of single-gene autosomal-dominant inheritance, using the MLINK option of the computer program LINKAGE (version 5.1; http://linkage.rockefeller.edu/soft/list.html) as described by Lathrop et al.10,11 A gene frequency of 0.0001 was assumed for the mutant HMSN 2C allele; no phenocopies were assumed, and penetrance was assumed to be 0.99 for heterozygotes and 1.0 for homozygotes. Male and female recombination fractions were assumed to be equal. Marker allele frequencies for white populations were obtained from the Genome Data Base (accessed June 1999; http://gdbwww.gdb.org/).

Multipoint location scores for the HMSN 2B locus were determined for the chromosome region 3q13-q22 using the LINKMAP option of LINKAGE, using published genetic map information from the Cooperative Human Linkage Center 12,13 and Généthon14 as in a previous report.5 Multipoint location scores for the HMSN 2D locus were determined for the chromosome region 7p14 using the same computer program, employing published genetic map information from the Genome Data Base. Haldane's mapping function was used to convert recombination fractions (θ) to genetic distances (centimorgan [cM]). Multipoint LOD scores were computed as the logarithm of the ratio of the likelihood with the disease locus at a specific recombination fraction from the test locus (θ=0.00-0.49) and the likelihood with the disease locus placed in an unlinked state (θ=0.50).

To assess how informative the data of our kindred were for linkage studies, simulation calculations were carried out by the computer program SIMLINK.15 The maximum attainable LOD score at a recombination fraction of 0 with fully informative linkage markers including all persons at risk was 7.7 (average LOD score, 6.1).

The results of pairwise analyses between HMSN 2C phenotype and 8 markers from the region of the HMSN 2B locus are given in Table 1: all of the 2-point LOD scores were negative. A multipoint linkage analysis testing with the HMSN 2C locus against the fixed genetic map of chromosome region 3q13-q22 markers is presented in Figure 2. The multipoint LOD scores in the region of these markers were less than −2, excluding the HMSN 2C locus from this region.

Table Graphic Jump LocationTwo-Point LOD Scores Between CMT 2C Phenotype and HMSN 2B and 2D Markers*
Place holder to copy figure label and caption
Figure 2.

Multipoint linkage analysis with markers spanning chromosome 3q13-q22. Limit of detection (LOD) scores are shown on the y-axis and genetic distances (centimorgans [cM]) are shown on the x-axis. Distances between markers are based on maps from the Cooperative Human Linkage Center and Généthon.5 The points with an LOD score of −2 are 20.7 cM proximal to D3S1558 and 27.8 cM distal to D3S1744. No evidence mapping the HMSN 2C gene to the studied region of chromosome 3 was found. Abbreviation q ter indicates q terminus; cen, centromere.

Graphic Jump Location

Ionasescu et al6 have reported that the HMSN 2D family showed the highest 2-point LOD score (4.83) at D7S435, and the highest multipoint LOD score (6.89) at the point 0.5 cM proximal from D7S435 and 4.6 cM distal to D7S1808. The results of pairwise analysis with 7 markers near the HMSN 2D locus are given in Table 1. No evidence for linkage was seen in this region. The results of multipoint linkage analysis with the HMSN 2C locus tested against a fixed genetic map of these markers are presented in Figure 3; the multipoint LOD scores in the region of these markers were less than −2 between points 9.7 cM proximal to D7S1801 and 10.1 cM distal to D7S435, which excludes the HMSN 2C locus from this region.

Place holder to copy figure label and caption
Figure 3.

Multipoint linkage analysis with markers spanning chromosome 7p14. Ionasescu et al6 have shown that the hereditary motor and sensory neuropathy (HMSN) type 2D locus is just proximal to D7S435. Limit of detection (LOD) scores are shown on the y-axis and genetic distances (centimorgans [cM]) are shown on the x-axis. Distances between markers are based on maps from the Genome Data Base (accessed June 1999; http://gdbwww.gdb.org/). The points with an LOD score of −2 are 9.7 cM proximal to D7S1801 and 10.1 cM distal to D7S435. No evidence supported mapping of the HMSN 2C gene to the studied region of chromosome 7. Abbreviation cen indicates centromere; p ter, p terminus.

Graphic Jump Location

Three different disease loci have been established for autosomal dominant HMSN 2. Three families in the United States and 2 Japanese families with HMSN 2 have shown linkage with chromosome region 1p35-p36 (HMSN 2A),4,16 and an Italian family also has shown evidence suggestive of linkage to this locus.17 On the other hand, 3 of 6 families in the United States with HMSN 2 and 10 of 11 European families with HMSN 2 have been shown to lack linkage to the HMSN 2A locus4,17; in the aggregate these findings demonstrated genetic heterogeneity in HMSN 2. Subsequently, the disease locus in a family with HMSN 2 in the United States has been mapped to chromosome region 3q13-q22 (HMSN 2B),5 and then a European family with HMSN 2 has shown suggestive evidence for linkage to the same locus.18 The third disease locus for HMSN 2 has been mapped to chromosome region 7p14 (HMSN 2D) in a single family in the United States.6 Clinically HMSN 2A shows a motor-dominant pattern with more pronounced weakness in the lower than the upper extremities.11 Hereditary motor and sensory neuropathy type 2B is characterized by a marked sensory disturbance in the distal lower extremities resulting in ulceration in the feet,18,19 while HMSN 2D shows more severe motor and sensory disturbance in the upper than in the lower extremities.6

In comparison with other forms of HMSN 2, the HMSN 2C family we studied here had unique clinical features in addition to motor and sensory involvement of the limbs, including progressive paresis of the vocal cords, diaphragm, and intercostal muscles. Yoshioka et al8 have shown this family's abnormality to be genetically distinct from HMSN 2A. In the present study, we found no evidence to support linkage of the HMSN 2C phenotype to either the HMSN 2B locus on chromosome 3 or the HMSN 2D locus on chromosome 7.

Our results provide further evidence of genetic heterogeneity in HMSN 2. At least 4 genetic varieties of HMSN 2 seem to have been confirmed: HMSN 2A (1p35-p36), HMSN 2B (3q13-q22), HMSN 2D (7p14), and HMSN 2C (not linked to any of these loci). A linkage study employing DNA markers from multiple autosomes will be needed to map the HMSN 2C locus.

Accepted for publication April 12, 1999.

This study was supported in part by research grants obtained from the Muscular Dystrophy Association of America, Tucson, Ariz (grant 12), the National Institute of Neurological Disorders and Stroke (grant 14304), and the Kawamura fund, Gifu City, Japan. We thank Amie Bissonnett, BS, for her expert assistance in computer programming.

Reprints: Peter James Dyck, MD, Peripheral Neuropathy Research Center, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: dyck.peter@mayo.edu).

Dyck  PJChance  PLebo  RCarney  JA Hereditary motor and sensory neuropathies. Dyck  PJThomas  PKGriffin  JWLow  PAPoduslo  JFeds.Peripheral Neuropathy. 3rd ed. Philadelphia, Pa WB Saunders Co1993;1094- 1136
Hentati  ALamy  CMelki  JZuber  MMunnich  Ade Recondo  J Clinical and genetic heterogeneity of Charcot-Marie-Tooth disease. Genomics. 1992;12155- 157
Link to Article
Loprest  LJPericak-Vance  MAStajich  J  et al.  Linkage studies in Charcot-Marie-Tooth disease type 2: evidence that CMT types 1 and 2 are distinct genetic entities. Neurology. 1992;42597- 601
Link to Article
Othmane  KBMiddleton  LTLoprest  LJ  et al.  Localization of a gene (CMT 2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics. 1993;17370- 375
Link to Article
Kwon  JMElliott  JLYee  WC  et al.  Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet. 1995;57853- 858
Ionasescu  VSearby  CSheffield  VCRoklina  TNishimura  DIonasescu  R Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped to chromosome 7p (CMT2D). Hum Mol Genet. 1996;51373- 1375
Link to Article
Dyck  PJLitchy  WJMinnerath  S  et al.  Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35608- 615
Link to Article
Yoshioka  RDyck  PJChance  PF Genetic heterogeneity in Charcot-Marie-Tooth neuropathy type 2. Neurology. 1996;46569- 571
Link to Article
Neitzel  H A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet. 1986;73320- 326
Link to Article
Lathrop  GMLalouel  JMJulier  COtt  J Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984;813443- 3446
Link to Article
Lathrop  GMLalouel  JMJulier  COtt  J Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985;37482- 498
Buetow  KHLudwigsen  SSchepbier-Heddema  T  et al.  Human genetic map. Genome maps V: a wall chart. Science. 1994;2652055- 2070
Link to Article
Murray  JCBuetow  KHWeber  JL  et al.  A comprehensive human linkage map with centimorgan density. Science. 1994;2652049- 2050
Link to Article
Gyapay  GMorissette  JVignal  A  et al.  The 1993-1994 Généthon human genetic linkage map. Nat Genet. 1994;7246- 339
Link to Article
Ploughman  LMBoehnke  M Estimating the power of a proposed linkage study for a complex genetic trait. Am J Hum Genet. 1989;44543- 551
Saito  MHayashi  YSuzuki  TTanaka  HHozumi  ITsuji  S Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A. Neurology. 1997;491630- 1635
Link to Article
Timmerman  VDe Jonghe  PSpoelders  P  et al.  Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13. Neurology. 1996;461311- 1318
Link to Article
De Jonghe  PTimmerman  VPatrick  DFSpoelders  PMartin  JJBroeckhoven  V Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J Neurol Neurosurg Psychiatry. 1997;62570- 573
Link to Article
Elliott  JLKwon  JMGoodfellow  PJYee  WC Hereditary motor and sensory neuropathy IIB: clinical and electrophysiologic characteristics. Neurology. 1997;4823- 28
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Pedigree of the kindred with hereditary motor and sensory neuropathy type 2C in the present study. Squares represent male subjects; circles, female; black and white symbols, affected by history; solid black symbols, affected by clinical examination; white symbols, unaffected; plus sign, genotype checked; and diagonal slash, deceased. Numbering used is the same as in our previous publication.7

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Multipoint linkage analysis with markers spanning chromosome 3q13-q22. Limit of detection (LOD) scores are shown on the y-axis and genetic distances (centimorgans [cM]) are shown on the x-axis. Distances between markers are based on maps from the Cooperative Human Linkage Center and Généthon.5 The points with an LOD score of −2 are 20.7 cM proximal to D3S1558 and 27.8 cM distal to D3S1744. No evidence mapping the HMSN 2C gene to the studied region of chromosome 3 was found. Abbreviation q ter indicates q terminus; cen, centromere.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Multipoint linkage analysis with markers spanning chromosome 7p14. Ionasescu et al6 have shown that the hereditary motor and sensory neuropathy (HMSN) type 2D locus is just proximal to D7S435. Limit of detection (LOD) scores are shown on the y-axis and genetic distances (centimorgans [cM]) are shown on the x-axis. Distances between markers are based on maps from the Genome Data Base (accessed June 1999; http://gdbwww.gdb.org/). The points with an LOD score of −2 are 9.7 cM proximal to D7S1801 and 10.1 cM distal to D7S435. No evidence supported mapping of the HMSN 2C gene to the studied region of chromosome 7. Abbreviation cen indicates centromere; p ter, p terminus.

Graphic Jump Location

Tables

Table Graphic Jump LocationTwo-Point LOD Scores Between CMT 2C Phenotype and HMSN 2B and 2D Markers*

References

Dyck  PJChance  PLebo  RCarney  JA Hereditary motor and sensory neuropathies. Dyck  PJThomas  PKGriffin  JWLow  PAPoduslo  JFeds.Peripheral Neuropathy. 3rd ed. Philadelphia, Pa WB Saunders Co1993;1094- 1136
Hentati  ALamy  CMelki  JZuber  MMunnich  Ade Recondo  J Clinical and genetic heterogeneity of Charcot-Marie-Tooth disease. Genomics. 1992;12155- 157
Link to Article
Loprest  LJPericak-Vance  MAStajich  J  et al.  Linkage studies in Charcot-Marie-Tooth disease type 2: evidence that CMT types 1 and 2 are distinct genetic entities. Neurology. 1992;42597- 601
Link to Article
Othmane  KBMiddleton  LTLoprest  LJ  et al.  Localization of a gene (CMT 2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity. Genomics. 1993;17370- 375
Link to Article
Kwon  JMElliott  JLYee  WC  et al.  Assignment of a second Charcot-Marie-Tooth type II locus to chromosome 3q. Am J Hum Genet. 1995;57853- 858
Ionasescu  VSearby  CSheffield  VCRoklina  TNishimura  DIonasescu  R Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped to chromosome 7p (CMT2D). Hum Mol Genet. 1996;51373- 1375
Link to Article
Dyck  PJLitchy  WJMinnerath  S  et al.  Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35608- 615
Link to Article
Yoshioka  RDyck  PJChance  PF Genetic heterogeneity in Charcot-Marie-Tooth neuropathy type 2. Neurology. 1996;46569- 571
Link to Article
Neitzel  H A routine method for the establishment of permanent growing lymphoblastoid cell lines. Hum Genet. 1986;73320- 326
Link to Article
Lathrop  GMLalouel  JMJulier  COtt  J Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984;813443- 3446
Link to Article
Lathrop  GMLalouel  JMJulier  COtt  J Multilocus linkage analysis in humans: detection of linkage and estimation of recombination. Am J Hum Genet. 1985;37482- 498
Buetow  KHLudwigsen  SSchepbier-Heddema  T  et al.  Human genetic map. Genome maps V: a wall chart. Science. 1994;2652055- 2070
Link to Article
Murray  JCBuetow  KHWeber  JL  et al.  A comprehensive human linkage map with centimorgan density. Science. 1994;2652049- 2050
Link to Article
Gyapay  GMorissette  JVignal  A  et al.  The 1993-1994 Généthon human genetic linkage map. Nat Genet. 1994;7246- 339
Link to Article
Ploughman  LMBoehnke  M Estimating the power of a proposed linkage study for a complex genetic trait. Am J Hum Genet. 1989;44543- 551
Saito  MHayashi  YSuzuki  TTanaka  HHozumi  ITsuji  S Linkage mapping of the gene for Charcot-Marie-Tooth disease type 2 to chromosome 1p (CMT2A) and the clinical features of CMT2A. Neurology. 1997;491630- 1635
Link to Article
Timmerman  VDe Jonghe  PSpoelders  P  et al.  Linkage and mutation analysis of Charcot-Marie-Tooth neuropathy type 2 families with chromosomes 1p35-p36 and Xq13. Neurology. 1996;461311- 1318
Link to Article
De Jonghe  PTimmerman  VPatrick  DFSpoelders  PMartin  JJBroeckhoven  V Mutilating neuropathic ulcerations in a chromosome 3q13-q22 linked Charcot-Marie-Tooth disease type 2B family. J Neurol Neurosurg Psychiatry. 1997;62570- 573
Link to Article
Elliott  JLKwon  JMGoodfellow  PJYee  WC Hereditary motor and sensory neuropathy IIB: clinical and electrophysiologic characteristics. Neurology. 1997;4823- 28
Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Please click the checkbox indicating that you have read the full article in order to submit your answers.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 9

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles