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Characterisation of a novel cardiac phenotype in patients with GFPT1 or DPAGT1 mutations

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Journal of Cardiovascular Magnetic Resonance201416 (Suppl 1) :P332

https://doi.org/10.1186/1532-429X-16-S1-P332

  • Published:

Keywords

  • Cardiovascular Magnetic Resonance
  • Diastolic Dysfunction
  • Late Gadolinium Enhancement
  • Myocardial Fibrosis
  • Cardiac Phenotype

Background

Mutations in the GFPT1 and DPAGT1 genes, which encode enzymes associated with roles in protein N-linked glycosylation, have been recently identified in a rare subgroup of patients with congenital myasthenic syndromes (CMSs). These mutations are inherited in an autosomal recessive pattern, and the mechanism of impaired neuromuscular transmission may be acetylcholine receptor (AChR) deficiency due to impaired (AChR) subunit glycosylation. Aberrant protein glycosylation is also implicated in the development of severe cardiomyopathies in the congenital disorders of glycosylation, although the mechanisms responsible for cardiac involvement are unknown. We investigated whether patients with CMS and GFPT1 or DPAGT1 mutations also had evidence of a cardiac phenotype.

Methods

We performed comprehensive cardiovascular magnetic resonance (CMR) imaging at 1.5T (Avanto, Siemens), 31P spectroscopy at 3T (Tim Trio, Siemens) and echocardiography to evaluate cardiac structure and function in patients with GFPT1 (n = 2) and DPAGT1 (n = 2) mutations. The mean age of the participants was 45 (range 25-57) and two were male.

Results

Electrocardiography was abnormal in all, with abnormal repolarisation and deep S waves (n = 3) or marked left ventricular hypertrophy by voltage criteria (n = 1). Despite normal biventricular volumes and systolic function, GFPT1/DPAGT1 patients demonstrated late gadolinium enhancement suggestive of myocardial fibrosis (n = 4, mean proportion of enhanced myocardium > 5 SD above individual reference regions 3.2% +/-1.6, Figure 1), impaired energetics (n = 2) and diastolic dysfunction (n = 3). No patient had symptoms attributable to cardiovascular disease on structured interview.
Figure 1
Figure 1

Representative electrocardiograph demonstrating repolarization abnormalities with inversion of T-waves in inferolateral leads and deep S waves.

Conclusions

Patients with GFPT1 or DPAGT1 mutations demonstrate a cardiac phenotype including abnormal electrocardiography, myocardial fibrosis, diastolic dysfunction and impaired energetics, despite normal systolic function. These findings may reflect incipient cardiomyopathy due to aberrant cardiac glycoprotein function. The reason for the milder phenotype than is seen many congenital disorders of glycosylation may be greater residual enzyme function as a consequence of a less pathogenic mutation. This study highlights the utility of CMR for the assessment of rare cardiac phenotypes and reinforces the need for cardiac surveillance in patients with undefined or uncharacterised neuromuscular disorders due to glycosylation pathway defects.

Funding

British Heart Foundation.

Table 1

 

Patient 1

Patient 2

Patient 3

Patient 4

Reference range

Age/years

57

58

38

25

 

Gender

Female

Female

Male

Male

 

Mutation

DPAGT1

DPAGT1

GFPT1

GFPT1

 

Nucleotide change

c.349G > A

c.699dup

c.478G > A

c.574G > A

c.44C > T

c.1486C > T

c.1154G > A

c.1301G > A

 

Effect on protein

p.Val117Ile

p.Thr234Hisfs*116

p.Gly160Ser

p.Gly192Ser

p.Thr15Met

p.Arg496Trp

p.Arg385His

p.Arg434His

 

LVEDV/ml

104

142

124

144

102-218 ml (male)

83-187 (female

LVESV/ml

29

53

41

46

18-82 ml (male)

18-66 ml (female)

LVEF

72

63

67

68

57-81%

(male and female)

RVEF

75

64

66

70

47-71% (male)

53-73% (female)

LV mass/g

120

115

134

124

81-165 g (male)

42-150 g (female)

LGE regions

Anterior septum and inferior LV/RV junction

Basal inferolateral wall

Basal inferolateral wall

Inferior and inferolateral wall

 

LGE > 5SD/%

1.6

2.3

5.1

3.9

 

Stress perfusion CMR (visual assessment)

Normal

Not performed

Normal

Normal

 

PCr/ATP ratio

1.19

1.01

2.23

2.25

 

Diastolic function

Grade 1 dysfunction

Grade 2 dysfunction

Grade 1 dysfunction

Normal

 

Baseline characteristics and CMR and echo indices including left ventricular end diastolic volume (LVEDV), left ventricular end systolic volume (LVESV), left ventricular ejection fraction (LVEF), right ventricular ejection fraction (RVEF), late gadolinium enhancement (LGE) and phosphocreatine to adenosine triphosphate ratio (PCrR/ATP).

Authors’ Affiliations

(1)
University of Oxford, Oxford, UK

Copyright

© Lewis et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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