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Rasmussen T.,Research Unit for Molecular Medicine | Hansen J.,Research Unit for Molecular Medicine | Palmfeldt J.,Research Unit for Molecular Medicine | Dalager S.,Institute of Pathology | And 3 more authors.
Clinical Genetics | Year: 2013

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans. © 2012 John Wiley & Sons A/S.

Evans M.,Royal Melbourne Hospital | Andresen B.S.,Research Unit for Molecular Medicine | Andresen B.S.,University of Southern Denmark | Nation J.,Royal Melbourne Hospital | And 3 more authors.
Molecular Genetics and Metabolism | Year: 2016

Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is an inherited metabolic disorder of fatty acid oxidation. Treatment practices of the disorder have changed over the past 10-15. years since this disorder was included in newborn screening programs and patients were diagnosed pre-symptomatically. A genotype-phenotype correlation has been suggested but the discovery of novel mutations make this knowledge limited.Herein, we describe our experience in treating patients (n = 22) diagnosed through newborn screening and mutational confirmation and followed up over a median period of 104. months. We report five novel mutations. In 2013 we formalised our treatment protocol, which essentially follows a European consensus paper from 2009 and our own experience. The prescribed low natural fat diet is relaxed for patients who are asymptomatic when reaching age 5. years but medium-chain triglyceride oil is recommended before and after physical activity regardless of age. Metabolic stability, growth, development and cardiac function are satisfactory in all patients. There were no episodes of encephalopathy or hypoglycaemia but three patients had episodes of muscle pain with our without rhabdomyolysis. Body composition studies showed a negative association between dietary protein intake and percent body fat.Larger patient cohort and longer follow up time are required for further elucidation of genotype-phenotype correlations and for establishing the role of dietary protein in metabolic stability and long-term healthier body composition in patients with VLCAD deficiency. © 2016 Elsevier Inc.

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