New deletion in LAMP2 causing familial Danon disease. Effect of the X-chromosome inactivation.

Danon disease (DD), a rare X-linked genetic illness with a poor prognosis, is caused by a mutation in the lysosome-associated membrane protein 2 gene (LAMP2). Three main clinical features of this pathology are cardiomyopathy, skeletal myopathy, and mental retardation. Most Danon disease mutations create premature stop codons resulting in the decrease or absence of LAMP2 protein.

Novel desmoplakin mutations in familial Carvajal syndrome.

Desmoplakin is encoded by DSP gene, whose altered function leads to skin and hair abnormalities, and heart diseases. The whole triad of these traits characterizes the Carvajal syndrome (CS). CS is an autosomal recessive genetic disorder, mapping on chromosome 6q24 and caused by mutations in DSP gene. We report a patient with CS caused by two novel mutations in DSP gene, inherited from his parents, both asymptomatic. The same phenotype was present in his younger sister who showed skin abnormality and woolly hairs. The segregation analysis of the known loci in DSP gene performed by genetic testing, was able to established the trans position of the two mutations (c.6986T > C and c.7123G > C) in the patient and his sister. The first mutation has been inherited from the mother, the other one from the father. The resulting compound heterozygous mutation in the siblings, is likely the cause of the disease.

Three new cases of dilated cardiomyopathy caused by mutations in LMNA gene.

Three cases of delated cardiomyopathy (DCM) with conduction defects (OMIM 115200), limb girdle muscular dystrophy 1B (OMIM 159001) and autosomal dominant Emery-Dreifuss muscular dystrophy 2 (OMIM 181350), all associated with different LMNA mutations are presented. Three heterozygous missense mutations were identified in unrelated patients - p.W520R (c.1558T > C), p.T528R (с.1583С > G) and p.R190P (c.569G > C). We consider these variants as pathogenic, leading to isolated DCM with conduction defects or syndromic DCM forms with limb-girdle muscular dystrophy and Emery-Dreifuss muscular dystrophy. The mutations were not detected in the ethnically matched control group and publicly available population databases. Their de novo occurrence led to the development of the disease that was not previously detected in the extended families. Mutations at the same codons associated with laminopathies have been already reported. Differences in the clinical phenotype for p.R190P and p.T528R carrier patients are shown and compared to previous reports.

LMNA-related dilated cardiomyopathy.

A case of idiopathic dilated cardiomyopathy (DCM) that is likely to be associated with LMNA mutation Arg190Pro in a heterozygote is described. The features of DCM in the patient were conduction disorders, cardiac arrhythmias, progressive heart failure and minor musculoskeletal disturbances. We consider that the mutation Arg190Pro contributes to the formation of a weak nuclear lamina and diminishes muscle mechanical stability which is critical during cardiac contraction. The case report illustrates in detail the phenotypic manifestations of the novel LMNA mutation and difficulties in management related to it.