Keywords: Myopathy; Neuromuscular; Non-Compaction; Obscurin; Sarcomere

Letter to the Editor

In an interesting, recent article, Rowland et al. reported a case study of 4 patients carrying variants in the obscurin gene, of whom three presented with Left Ventricular Hypertrabeculation / noncompaction (LVHT) and one with dilated cardiomyopathy [1]. Obscurin plays a key role in myofibrillogenesis and cytoskeletal arrangement through interaction with titin, myomesmin, and obscurin-like-1 to generate a complex important for myofibrillar M-band function. Since the current perception is that contractility of the heart correlates with non-compaction, a relation between obscurin variants and LVHT is not surprising. We have the following comments and concerns.

We do not agree that the association between obscurin variants and LVHT is “strong” [1]. To demonstrate a “strong” association higher levels of evidence are required. Though LVHT has been reported in association with mutations and polymorphisms in >40 genes and with numerous chromosomal defects, a causal relation has never been proven [2]. Arguments against a causal relation are that LVHT can be acquired, that in patients with a dominantly transmitted disease, LVHT may not occur in each generation, that cardiac abnormalities associated with a given mutation can be highly variable within a family, that in families with a Neuromuscular Disorder (NMD), LVHT can be found only in a small number of patients, that the number of mutated genes claimed to be responsible for the occurrence of LVHT is large, and that LVHT may not segregate with a specific mutation [3]. Did other first-degree relatives also carry the obscurin variants and did those carrying the obscurin variants also manifest with LVHT? Arguments in favor of a causal relation, however, are that LVHT is more frequent in patients carrying certain genetic defects (e.g. DMPK, TAZ) compared with mutations in other genes [4] and that LVHT has familial occurrence.

We should be informed whether any of the mutation carriers also had developed myopathy since up to 80% of the patients with an NMD have LVHT and since obscurin mutations have been shown to cause myopathy, at least in mice [5].

Altogether, a causal relation between LVHT and mutations in sarcomeric proteins awaits confirmation and work-up for LVHT must include a neurological investigation and investigation of first degree relatives, even if they are asymptomatic. The reason why obscurin variants were associated with LVHT in 75% of the cases in Roland’s study and previously, awaits an explanation.

1. Rowland TJ, Graw SL, Sweet ME, Gigli M, Taylor MRG, et al. (2016) Obscurin Variants in Patients with Left Ventricular Noncompaction. J Am Coll Cardiol 68: 2237-2238.
2. Finsterer J, Zarrouk-Mahjoub S (2015) Considerations about the genetics of left ventricular hypertrabeculation/non-compaction. Cardiol Young 25: 1435-1437.
3. Finsterer J (2009) Cardiogenetics, neurogenetics, and pathogenetics of left ventricular hypertrabeculation/noncompaction. Pediatr Cardiol 30: 659-681.
4. Finsterer J, Stöllberger C, Towbin JA (2016) Left ventricular noncompaction. cardiomyopathy: cardiac, neuromuscular, and genetic implications. Nat Rev Cardiol 14: 224-237.
5. Lange S, Ouyang K, Meyer G, Cui L, Cheng H, et al. (2009) Obscurin determines the architecture of the longitudinal sarcoplasmic reticulum. J Cell Sci 122: 2640-2650.