Abstract
Calpainopathy is mainly characterized by symmetric and progressive weakness of proximal muscles. Several reports showed that the most common LGMD subtype is LGMDR1 or calpainopathy, which had previously been defined as LGMD2A. Until now, more than 500 likely pathogenic/pathogenic variants in the CAPN3 gene have been reported. However, a clear genotype–phenotype association had not yet been established and this causes major difficulties in predicting the prognosis in asymptomatic patients and in providing genetic counseling for prenatal diagnosis. In this report, we aimed to add new data to the literature by evaluating 37 patients with likely pathogenic/pathogenic variants for the detected variants’ nature, patients’ phenotypes, and histopathological features. As a result, the general clinical presentation of the 23 different variants was presented, the high frequency of NM_000070.3:c.550delA mutation in Exon 4 was discussed, and some novel genotype–phenotype associations were suggested. We have underlined that calpainopathy can be misdiagnosed with inflammatory myopathies histopathologically. We have also emphasized that, in young or adult patients with mild to moderate proximal muscle weakness and elevated CK levels, calpainopathy should be the first suspected diagnosis.
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Remarks
• In young or adult patients with mild to moderate proximal muscle weakness and elevated CK levels, calpainopathy should be the first suspected diagnosis.
• Histopathology of calpainopathy may be accompanied by inflammatory findings. Thus, we suggest that calpainopathies should be kept in mind in both differential diagnosis and molecular genetic test planning in patients with suspected inflammatory myopathy.
• Among 359 patients, we have evaluated for the diagnosis of muscular dystrophy; 37 (10.3%) had one or more pathogenic/likely pathogenic variants in the CAPN3 gene. Three of the variants were not found in databases and literature; thus, they were interpreted as novel pathogenic variants.
• The NM_000070.3:c.550delA variant at exon 4, was the most frequent variant (5 homozygous patients, 10 alleles) in this report. c.550delA variant is usually associated with moderate phenotype progressing to loss of ambulation in later decades.
• The NM_000070.3:c.597_611delGTTCTGGAGTGCTCT variant was recently associated with autosomal dominant inheritance; however, with the data we acquired in this study, we suggest that it may be associated with both autosomal recessive and autosomal dominant forms of calpainopathy.
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Ozyilmaz, B., Kirbiyik, O., Ozdemir, T.R. et al. Experiences in the molecular genetic and histopathological evaluation of calpainopathies. Neurogenetics 23, 103–114 (2022). https://doi.org/10.1007/s10048-022-00687-4
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DOI: https://doi.org/10.1007/s10048-022-00687-4