Do cypher gene mutations cause left ventricular noncompaction with subclinical myopathy?

n their article, Vatta et al. (1) showed that dilative cardioyopathy (DCM) is associated with cypher (Z-band lternatively-spliced PDZ-motif-protein) gene mutations in xons 4, 6, and 10 in 6% of the cases. Additionally, mutant ypher-gene-transfected myoblasts developed cytoskeletal disrray (1). Their findings raise the following concerns: It is not entioned which clinical and echocardiographic criteria for CM were applied. Were patients with DCM due to coroary heart disease also included, or did all patients have normal oronary angiograms? It remains unclear according to which riteria left ventricular hypertrabeculation/noncompaction LVHT/NC) was diagnosed (2,3). It is not indicated whether atients with DCM were consecutively or selectively included nd how many centers recruited the patients during which eriod. Did relatives of all 100 patients or only those of ypher-gene mutation carriers undergo clinical cardiologic and eurologic examination, creatine-kinase determination, and enetic studies? How was cardiac affection defined? It is nclear why patient II:1 (family 065) was classified as cardioogically normal, although, according to their Table 3, no chocardiographic examinations were performed. Furtherore, the description of a “mildly dilated left ventricle” in atient III:1 does not match Table 3, indicating that echocariography was not carried out at all in this patient. Concerning he authors’ speculations that mutations in the skeletal muscle ypher-isoform may go along with fatigue and exercise intolrance, it would be interesting to know whether any of the utation carriers complained about symptoms suggestive of a euromuscular disorder. How do the authors explain that ypher knock-out mice develop severe myopathy, whereas umans with cypher-mutations were neurologically normal? ormal clinical neurologic examination and normal creatine inase, however, do not rule out myopathy. It is not clear hether the skeletal muscle cypher-isoform was regularly xpressed in the skeletal muscle. Did any of the patients ndergo muscle biopsy? It appears as if the 200 control subjects ad not undergone clinical cardiologic or neurologic investigaions. Did any of these probands have DCM or LVHT/NC? t remains unclear how mutations in exon 4 were exclusively ssociated with LVHT/NC although the inclusion criterion as DCM. Did the authors find mutation carriers without linical affection? It is not mentioned how many of the patients ith cypher mutations also had LVHT/NC. Concerning their able 3, the title is misleading because not all patients had ypher-mutations. It also is not explained from which meaurements the standard deviation was calculated. Were patients epeatedly investigated or does it derive from a non-described ontrol group? Figure 1B erroneously shows a 352M instead of I352M mutation. The authors do not mention that e VHT/NC may be also associated with mutations in the MPK, DMD, AMPD1, and mitochondrial gene(s) (4–6). verall, the study lacks proper characterization of the phenoype and control group. Criteria for cardiac affection are mbiguous. Although the study nicely shows cypher-mutations o be associated with LVHT/NC, the prevalence of this ssociation remains uncertain. To further clarify the pathogeetic background of LVHT/NC, we suggest that patients with VHT/NC should undergo thorough investigation of the keletal muscle in the light of previous findings, according to hich LVHT/NC is associated with myopathies in up to our-fifths of these patients (3).