Role of desmoplakin mutations in the pathogenesis of non-compaction

With interest we read the article by Lopez-Ayala et al.¹ about 3 families (49 probands) in which 3 unrelated heterozygote probands and 15 asymptomatic relatives carried a novel desmoplakin mutation. In six of the mutation carriers, left ventricular hypertrabeculation/non-compaction (LVHT) was diagnosed.¹ We have the following comments and concerns.

There is some confusion concerning numbers provided at different locations in the text. The result section mentions that altogether six patients were diagnosed with LVHT.¹ However, in the discussion the authors mention that only five had LVHT.¹ In Table 1, 18 mutation carriers are listed. In Figure 2, however, only 15 mutation carriers are shown. How to explain these discrepancies?

According to the result section, LVHT was diagnosed in only three patients echocardiographically.¹ Was LVHT diagnosed in the other three only upon cardiac magnetic resonance imaging (MRI)? It is well known that echocardiography as well as cardiac MRI produce false-negative results.² However, echocardiography is the investigation of choice to diagnose LVHT. Which was the reason why LVHT was missed on echocardiography in half of the patients?

Left ventricular hypertrabeculation/non-compaction was diagnosed in proband CII.1.¹ However, in Table 1 it is mentioned that cardiac MRI was not available in proband CII.1. Was LVHT diagnosed only by echocardiography in this patient? Table 1 indicates that LVHT was confirmed in five of six patients by cardiac MRI.¹ Which criteria were applied to diagnose LVHT on cardiac MRI? Jenni's criteria are applicable only to echocardiography.

Left ventricular hypertrabeculation/non-compaction is frequently associated with neuromuscular disorders (NMDs).³ In addition, a desmoplakin isoform is also expressed in the sarcolemma.⁴ and loss of plektin was associated with muscular dystrophy. Did any of the six probands with LVHT present with clinical or subclinical manifestations of a NMD? Was the history positive for NMD in any of the other mutation carriers or relatives with unknown mutation status?

Interestingly, three of six patients' LVHT showed late gadolinium enhancement (LGE). Do the authors assume any association between LGE and LVHT? Do they attribute LGE to fibrosis within the trabeculations?

Since 49 patients had undergone echocardiography it would be interesting to know if LVHT was found in any of the investigated probands without the desmoplakin mutation. Left ventricular hypertrabeculation/non-compaction in probands not carrying the mutation would suggest that there is no causal relation between LVHT and the desmoplakin mutation.

Desmoplakin mutations have been previously described in association with LVHT.⁵ In two affected boys from consanguineous parents carrying the deletion 5208_5209delAG, Carvajal syndrome was diagnosed. Did any patient of the presented study present with this phenotype?

Left ventricular hypertrabeculation/non-compaction is frequently associated with severe complications, such as heart failure, ventricular arrhythmias, sudden cardiac death (SCD), or embolism. In how many of those with a history of heart failure or SCD was LVHT detected? Was the history in any of the 49 patients positive for stroke/embolism?

Overall, some inconsistencies concerning this interesting study need to be clarified and the family screening should be intensified. The reason why some patients carrying a desmoplakin mutation develop LVHT and others do not needs to be elucidated. Possibly, the mutation is not causative and other factors are responsible that LVHT evolves.

Conflict of interest: none declared.

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