Dear Editor,
We read with interest the article published by Nallamilli and colleagues describing a large limb–girdle muscular dystrophy (LGMD) cohort of patients. 1 In particular, the chapter describing the association of the CAPN3 variant, c.598_612del15 [p.(Phe200_Leu204del)], with an autosomal dominant form of calpainopathy. Indeed, this novel transmission mode for calpainopathies was initially suggested by Vissing and colleagues in 2016 2 and led to the revision of the LGMD classification, introducing the CAPN3 associated limb–girdle muscular dystrophy dominant type 4 (LGMDD4), 3 whereas calpainopathies had until then been considered as restrictively autosomal recessive. Up to the present time, only eight variants are associated with LGMDD4, the initial c.643_663del21 [p.(Ser215_Gly221del)] inframe deletion, 2 , 4 the c.598_612del15 [p.(Phe200_Leu204del)] inframe deletion reported by Nallamilli and colleagues 1 and more recently six additional missenses, c.700G>A [p.(Gly234Arg)], 5 c.1327T>C [p.(Ser443Pro)], 5 c.1333G>A [p.(Gly445Arg)], 5 , 6 c.1661A>C [p.(Tyr554Ser)], 5 c.1706T>C [p.(Phe569Ser)] 5 and c.1715G>C [p.(Arg572Pro)]. 7 While autosomal dominant segregation was confirmed through family analyses for most of these variants, this has not to date been the case for the variant c.598_612del15, identified at a simple heterozygous state in 16 sporadic cases among a large LGMD cohort of more than 4500 patients. 1
We recently identified a family harboring this same c.598_612del15 CAPN3 variant for which familial segregation analysis (Fig. 1A) and phenotypical exploration was performed including creatine kinase (CK) levels measurements.
Figure 1.
(A) Pedigree and familial segregation analysis of the c.598_612del15 [p.(Phe200_Leu204del)] CAPN3 variant. (+) indicates nonmutated allele and (‐) indicates mutated allele for the c.598_612del15 CAPN3 variant; (?) denotes individuals with unknown clinical status and/or ongoing clinical exploration; Black color indicates clinically symptomatic patients; Gray color indicates subjects with isolated hyperCKaemia. (B) Muscle imaging findings for the index case (patient II.2) harboring the c.598_612del15 [p.(Phe200_Leu204del)] CAPN3 variant. MRI shows fatty replacement and atrophy of the posterior thigh compartment of the soleus and medial gastrocnemius muscles (white arrows).
The proband (patient II.2 in Fig. 1A) presented with muscle fatigue of arms associated with weakness and atrophy of the brachioradial muscle. The CK level was about 2000 UI/L.
Western blot also revealed calpain 3 deficiency for the proband.
Moreover, the muscular MRI performed for the proband revealed a mild muscular impairment pattern of the lower limbs (including fatty transformation of the rear thigh, the soleus and medial gastrocnemius muscles) suggestive of autosomal dominant calpainopathy (Fig. 1B) as previously described in the literature. 6
Finally, familial segregation analysis was performed for the mother and the sister of the proband who harbor this same heterozygous CAPN3 variant (Fig.1A), presenting meanwhile with isolated moderate hyperCKaemia (respectively 285 UI/L and 148 UI/L CK levels). This subclinical presentation is consistent with previous descriptions of autosomal dominant calpainopathies associated with the c.643_663del21 and the c.1333G>A CAPN3 variants. 2 , 6
Thus, by describing this additional family harboring the c.598_612del15 CAPN3 variant, we confirm the association of this eighth variant with autosomal dominant calpainopathies (or LGMDD4).
Author Contributions
MC, MK, and AC initiated and directed the study. MC, MB, AS, FR, VB, BLG and MK contributed to data acquisition and analysis. AC conducted clinical phenotyping. MC, AC, AS, FR, MB, MK, and NL contributed to drafting the manuscript.
Conflict of Interest
The authors have no conflict of interest to disclose.
Acknowledgments
We sincerely thank Karine Bertaux, Cécile Mouradian, Pierre Cacciagli, Annachiara De Sandre‐Giovannoli, Jean‐Pierre Desvignes, David Salgado and Christophe Béroud for their contribution to this work. We also wish to thank the patients, and health professionals whose participation made possible this research.
Martin Krahn and Ariane Choumert authors are equal contribution.
Funding Information
This study was supported by Assistance Publique – Hôpitaux de Marseille (APHM), AFM‐Telethon (under grant agreement #19272) and GIPTIS (Genetics Institute for Patients, Therapies Innovation & Science).
References
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