Highlights
- •The most frequent cause of death in Friedreich ataxia is cardiomyopathy.
- •Abnormal intercalated discs contribute to Friedreich cardiomyopathy.
- •Intercalated discs and gap junctions are normal in long-surviving patients.
Abstract
Friedreich ataxia (FRDA) is an autosomal recessive disorder with a complex clinical
and neuropathological phenotype, but the most frequent cause of death is cardiomyopathy.
The principal autopsy findings in FRDA hearts are concentric hypertrophy, enlargement
of cardiomyocytes, myofiber necrosis, inflammatory infiltration, scarring, and random
accumulation of iron. In addition, the myocardium shows generalized disorganization
of intercalated discs (ICD), the Velcro-like end-to-end connections of heart fibers
that provide mechanical cohesion and ionic coupling. The principal components of ICD
are fascia adherens junctions (FAJ), desmosomes, and gap junctions. Frataxin deficiency
in FRDA may cause improper assembly of ICD early in life, making hearts vulnerable
to mechanical stress in childhood and adolescence. We studied the ICD in the myocardium
of left ventricular wall (LVW), right ventricular wall, and ventricular septum in
18 genetically confirmed FRDA patients (age of death, 10 to 87 years) and 12 normal controls (age of death, 13 to 69 years). In cases with juvenile onset, electron microscopy and immunohistochemistry
of N-cadherin and vinculin, two abundant FAJ proteins, showed enlargement of ICD,
discontinuity, and hyperconvolution. Reaction product of the desmosomal protein desmoglein
2 was similar. The distribution of the gap junction protein connexin 43 at ICD was
also irregular and displayed abnormal lateralization to the plasma membranes of cardiomyocytes.
Confocal immunofluorescence microscopy of α-actinin, affinity fluorescence microscopy
of actin with rhodamine-labeled phalloidin, and electron microscopy, revealed the
principal integrity of sarcomeres of the myocardium in FRDA. In two late-onset long-surviving
FRDA patients (ages 79 and 87), clinical cardiomyopathy was absent, and ICD were normal.
The described observations in patients with a broad range of disease onset and duration
allow us to conclude that faulty assembly of ICD interferes with proper end-to-end
adhesion of cardiomyocytes of the growing heart and contributes to the pathogenesis
of FRDA cardiomyopathy.
Keywords
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References
- Compound heterozygous FXN mutations and clinical outcome in Friedreich ataxia.Ann. Neurol. 2016; 79: 485-495
- Friedreich's ataxia: pathology, pathogenesis, and molecular genetics.J. Neurol. Sci. 2011; 303: 1-12
- The pathogenesis of cardiomyopathy in Friedreich ataxia.PLoS One. 2015; 10e0116396
- Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia.Nat. Genet. 1997; 17: 215-217
- Myocarditis in Friedreich's ataxia.J. Pathol. Bacteriol. 1946; 58: 739-748
- Pathology of intercalated discs in Friedreich cardiomyopathy.J. Am. Coll. Cardiol. 2015; 66: 1739-1740
- A pool of extramitochondrial frataxin that promotes cell survival.J. Biol. Chem. 2006; 281: 16750-16756
- Nucleic Acids Res. 2015; 43: D204-D212
- A sensitive mass spectrometric method for hypothesis-driven detection of peptide post-translational modifications: multiple reaction monitoring-initiated detection and sequencing (MIDAS).Nat. Protoc. 2009; 4: 870-877
- Intercalated discs of mammalian heart: a review of structure and function.Tissue Cell. 1985; 17: 605-648
- Ultrastructure of intercellular junctions in adult and developing cardiac muscle.Am. J. Cardiol. 1970; 25: 169-183
- Spatiotemporal relation between gap junctions and fascia adherens junctions during postnatal development of human ventricular myocardium.Circulation. 1994; 90: 713-725
- Cell-cell connection to cardiac disease.Trends Cardiovasc. Med. 2009; 19: 182-190
- Establishment of cardiac cytoarchitecture in the developing mouse heart.Dev. Biol. 2006; 289: 430-441
- Development and proliferative capacity of cardiac muscle cells.Circ. Res. 1974; 35: 17-26
- Ultrastructure of hypertrophied heart muscle in relation to adaptive tissue growth.Circ. Res. 1974; 35: 27-32
- Neurons and cardiomyocytes derived from induced pluripotent stem cells as a model for mitochondrial defects in Friedreich's ataxia.Dis. Models Mech. 2013; 6: 608-621
- The involvement of adherens junction components in myofibrillogenesis in cultured cardiac myocytes.Development. 1992; 114: 173-183
- Structural and molecular pathology of the heart in Carvajal syndrome.Cardiovasc. Pathol. 2004; 13: 26-32
- Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease).Heart Rhythm. 2004; 1: 3-11
- Remodelling of gap junctions and connexin expression in diseased myocardium.Cardiovasc. Res. 2008; 80: 9-19
Article info
Publication history
Published online: June 03, 2016
Accepted:
June 2,
2016
Received in revised form:
May 18,
2016
Received:
March 17,
2016
Identification
Copyright
Published by Elsevier B.V.
