Scapuloperoneal syndrome type Kaeser and a wide phenotypic spectrum of adult-onset, dominant myopathies are associated with the desmin mutation R350P

Abstract

In 1965, an adult-onset, autosomal dominant disorder with a peculiar scapuloperoneal distribution of weakness and atrophy was described in a large, multi-generation kindred and named 'scapuloperoneal syndrome type Kaeser' (OMIM #181400). By genetic analysis of the original kindred, we discovered a heterozygous missense mutation of the desmin gene (R350P) cosegregating with the disorder. Moreover, we detected DES R350P in four unrelated German families allowing for genotype-phenotype correlations in a total of 15 patients carrying the same mutation. Large clinical variability was recognized, even within the same family, ranging from scapuloperoneal (n = 2, 12%), limb girdle (n = 10, 60%) and distal phenotypes (n = 3, 18%) with variable cardiac (n = 7, 41%) or respiratory involvement (n = 7, 41%). Facial weakness, dysphagia and gynaecomastia were frequent additional symptoms. Overall and within each family, affected men seemingly bear a higher risk of sudden, cardiac death as compared to affected women. Moreover, histological and immunohistochemical examination of muscle biopsy specimens revealed a wide spectrum of findings ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin. This study reveals that the clinical and pathological variability generally observed in desminopathies may not be attributed to the nature of the DES mutation alone, but may be influenced by additional genetic and epigenetic factors such as gender. In addition, mutations of the desmin gene should be considered early in the diagnostic work-up of any adult-onset, dominant myopathy, even if specific myofibrillar pathology is absent.

How much mutant protein is needed to cause a protein aggregate myopathy in vivo? Lessons from an exceptional desminopathy

“…In this context, it is tempting to speculate that the interindividual phenotypic variability may be due to differences in splicing of the desmin mRNA. However, since previously reported desmin missense mutations are also associated with different clinical presentations (Bär et al, 2005a;Walter et al, 2007), this hypothesis seems rather unlikely. As an alternative explanation interindividual differences in the regulation of genes which are involved in desmin mRNA editing and desmin filament assembly and formation may modify the individual clinical presentation of the desminopathy.…”

“…From the clinical point of view it is remarkable, that the oldest offspring of the index patient carrying the mutation was clinically asymptomatic and that the muscle biopsy of one affected son displayed the classical myopathological features of a myofibrillar myopathy. In analogy to p.Arg350Pro (Bär et al, 2005a;Walter et al, 2007), the heterozygous c.735G>C desmin mutation does neither correlate to the myopathological phenotype, the age of disease onset nor the clinical phenotype.…”

“…The majority of cases exhibits an autosomal-dominant inheritance Selcen et al, 2004;Walter et al, 2007). The disease usually manifests in the second to third decade of life with distal weakness of the lower extremities.…”

Cardiac Myocytes and Mechanosensation

“…In cardiac myocytes desmin connects desmosomes with other organelles such as the Z-disc or the nucleus. Mutations in this gene result in a variety of different cardiac diseases such as desmin related myopathy [17][18], limb girdle muscular dystrophy [19], dilated cardiomyopathy (DCM) [20], arrhythmogenic right ventricular cardiomyopathy (ARVC) [21], cardiomyopathy with advanced AV block and arrhythmia [22], familial restrictive cardiomyopathy [23] and DCM with conduction system defects [24]. IFs interact with a variety of different proteins and because of their elasticity they are able to sense any deformation of cellular structure.…”

156th ENMC International Workshop: Desmin and protein aggregate myopathies, 9–11 November 2007, Naarden, The Netherlands

“…Usually, desminopathies are diagnosed through muscle histology. Interestingly, histopathological examination of the biceps brachii muscle of the index patient from the original Kaeser family showed very limited myofibrillar changes or protein aggregation which was hardly demonstrated by desmin and filamin-c immunohistochemistry [26]. Therefore, there is a wide morphologic spectrum of findings, ranging from near normal or unspecific pathology to typical, myofibrillar changes with accumulation of desmin.…”