Cardiac involvement in proximal myotonic myopathy

Mühlen, Friederike von zur; Klass, Carmen M.; Kreuzer, H; Mall, Gerhard; Giese, Alf; Reimers, Carl D.

doi:10.1136/hrt.79.6.619

Cited by 31 publications

(16 citation statements)

References 9 publications

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“…[1][2][3][4][5][6][7][8] However, the affected family members described in this study demonstrated a remarkably benign clinical pattern. They have a structurally normal heart, asymptomatic bradycardia, and excellent exercise tolerance; therefore, no pacemaker implantation was required in this family.…”

Section: Discussionmentioning

confidence: 99%

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Nof

Luria²,

Brass³

et al. 2007

Circulation

166

116

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Background-The hyperpolarization-activated nucleotide-gated channel-HCN4 plays a major role in the diastolic depolarization of sinus atrial node cells. Mutant HCN4 channels have been found to be associated with inherited sinus bradycardia. Methods and Results-Sixteen members of a family with sinus bradycardia were evaluated. Evaluation included a clinical questionnaire, 12-lead ECGs, Holter monitoring, echocardiography, and treadmill exercise testing. Eight family members (5 males) were classified as affected. All affected family members were asymptomatic with normal exercise capacity during long-term follow-up. Electrophysiological testing performed on 2 affected family members confirmed significant isolated sinus node dysfunction. Segregation analysis suggested autosomal-dominant inheritance. Direct sequencing of the exons encoding HCN4 revealed a missense mutation, G480R, in the ion channel pore domain in all affected family members. Function analysis, including expression of HCN4 wild-type and G480R in Xenopus oocytes and human embryonic kidney 293 cells, revealed that mutant channels were activated at more negative voltages compared with wild-type channels. Synthesis and expression of the wild-type and mutant HCN4 channel on the plasma membrane tested in human embryonic kidney 293 cells using biotinylation and Western blot analysis demonstrated a reduction in synthesis and a trafficking defect in mutant compared with wild-type channels. Conclusions-We describe an inherited, autosomal-dominant form of sinus node dysfunction caused by a missense mutation in the HCN4 ion channel pore. Despite its critical location, this mutation carries a favorable prognosis without the need for pacemaker implantation during long-term follow-up.

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Section: Discussionmentioning

confidence: 99%

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Nof

Luria²,

Brass³

et al. 2007

Circulation

166

116

View full text Add to dashboard Cite

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“…Involvement of cardiac conduction may also occur in atypical cases [64] as well atypical cases with PROMM and primary hyperparathyroidism have been reported [50].…”

Section: Progressive Myotonic Myopathies With Multiorgan Dysfunction mentioning

confidence: 97%

“…Reports have also described atypical cases of PROMM in which the DM2 mutation analysis was not performed [4,9,13,44,46,50,52,55,64]. DM2 represents a spectrum of clinical manifestations.…”

mentioning

confidence: 93%

Myotonic dystrophy type 2 and related myotonic disorders

Meola

Moxley

2004

J Neurol

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The myotonic dystrophies are a group of dominantly inherited disorders characterized by muscle wasting, myotonia, cataracts, hypogonadism and other system manifestations. Myotonic dystrophy type 1 (DM1) results from an unstable expansion of a CTG repeat in 3' UTR of the DM protein kinase (DMPK) gene on chromosome 19q 13.3. Myotonic dystrophy type 2 (DM2) is caused by an unstable expansion of a CCTG tetraplet repeat in intron 1 of the zinc finger 9 (ZFN9 gene) on chromosome 3q 21.3. However, the clinical diagnosis of DM2 is more complex than that of DM1, and conventional molecular genetic methods used for diagnosis of DM1 are not helpful for DM2. We here describe the detailed clinical, laboratory and biomolecular tests to identify DM2 and related myotonic disorders. At present, foci of accumulated noncoding CCTG repeat RNA (ribonuclear inclusions) in the cell nuclei are thought to interfere with the regulation and expression of several genes at the basis of multisystemic aspects of myotonic dystrophy type 2.

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“…In a recent prospective study, 51% of 49 DM1 patients with a prophylactic pacemaker implant developed complete atrioventricular conduction block during a follow‐up of 51 months 20. In DM2/PROMM, involvement of the cardiac conduction system usually seems more benign,23 but severe forms of cardiomyopathy have been reported 38…”

mentioning

confidence: 99%

Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): A quantitative ³¹P‐MRS and MRI study

et al. 2004

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In myotonic dystrophy type 2 (DM2/PROMM), cardiac muscle involvement is usually more benign than in DM1, but clinically severe cardiomyopathy has been reported in some patients. Using a novel method of magnetic resonance spectroscopy (MRS), we examined the left ventricular myocardium and the left gastrocnemius muscle in 11 unselected DM2/PROMM patients without overt cardiac disease. Data on cardiac morphology and function were obtained by gradient echo two-dimensional cine magnetic resonance imaging (MRI); no significant differences were found between DM2 patients and healthy controls, but using a median split approach older patients showed mildly increased left ventricular (LV) volumes, i.e., 59% increase of end-systolic volume index (ESVI) and 35% increase of end-diastolic volume index (EDVI), and an increase of LV mass (26%). On cardiac MRS, DM2/PROMM patients showed a reduction of phosphocreatine (PCr) and adenosine triphosphate (ATP) by 25 and 20% compared to matched healthy controls. No significant differences were found between younger and older patients. In skeletal muscle of the DM2 patients, no significant decrease of PCr and ATP concentrations was found. However, in older patients, who commonly show overt hip flexor muscle weakness, we observed reduced values for PCr and ATP. Our MRS and MRI findings reveal evidence for subclinical cardiomyopathy in DM2/PROMM patients without overt heart disease. Future prospective studies are needed to clarify the risk of developing overt cardiac disease in DM2 and to define prognostic factors.

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Cardiac involvement in proximal myotonic myopathy

Cited by 31 publications

References 9 publications

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Myotonic dystrophy type 2 and related myotonic disorders

Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): A quantitative ³¹P‐MRS and MRI study

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Cardiac involvement in proximal myotonic myopathy

Cited by 31 publications

References 9 publications

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Point Mutation in the HCN4 Cardiac Ion Channel Pore Affecting Synthesis, Trafficking, and Functional Expression Is Associated With Familial Asymptomatic Sinus Bradycardia

Myotonic dystrophy type 2 and related myotonic disorders

Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): A quantitative 31P‐MRS and MRI study

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Cardiac and skeletal muscle involvement in myotonic dystrophy type 2 (DM2): A quantitative ³¹P‐MRS and MRI study