Limb‐Girdle Muscular Dystrophy Type 2 Caused by a Novel Homozygous Mutation in <scp>DYSF</scp> in a Consanguineous Family

A 40-year-old man was referred to our clinic due to limb weakness. Around the age of 30, he started experiencing limb muscle soreness and weakness. Over time, his bilateral lower extremities had visibly thinned, and this manifestation had exacerbated in the last 4 months. On physical examination, atrophy was detected in the bilateral biceps brachii, quadriceps, and calves, as well as in the left pectoralis major (Figure 1A,B). The patient denied having a rash, shortness of breath, or cough. He had been diagnosed with dermatomyositis positive for antimelanoma differentiation-associated gene 5 (anti-MDA5) antibody by immunoblot assay in another hospital based on a weak positive anti-MDA5 antibody result. He was treated with glucocorticoids, intravenous immunoglobulin, and tacrolimus, but no clinical or biochemical improvement was observed. Hematological examinations indicated that the serum creatine kinase level increased markedly, reaching 3273 U/L (normal range, 21–190 U/L). Upon re-examination, the anti-MDA5 antibody retesting by immunoblot yielded a negative result. Electromyography demonstrated a myopathic pattern. Muscle biopsy revealed scattered necrosis of muscle fibers with occasional signs of muscle fiber regeneration (Figure 1C). Immunohistochemical analysis indicated that the major histocompatibility complex-1 was partially expressed on the membranes of a few muscle fibers. The expression of dystrophin remained normal. In contrast, a partial reduction in the expression of dysferlin was observed (Figure 1D–F). A deeper look into the patient's family history showed that the patient's parents are first cousins, having a third-degree consanguineous relationship. The patient also has two asymptomatic younger brothers. Whole exome sequencing identified a novel homozygous mutation in the DYSF gene (c.1256G>C, [p.Arg419Pro]) (Figure 1G). Although the variant is present in gnomAD at a very low frequency (1.24e-6), its absence in HGMD and homozygous states in population databases supports its novelty in the context of limb-girdle muscular dystrophy type R2 (LGMDR2). Consequently, a diagnosis of LGMDR2 was established [1]. This particular case underscores the crucial importance of adopting a comprehensive diagnostic methodology, incorporating genetic testing and muscle biopsy, for patients suspected of having muscle disorders. Additionally, mild anti-MDA5 antibody positivity on immunoblot should be interpreted with caution, especially in the absence of characteristic clinical features of dermatomyositis. Zhen He collected data and wrote the manuscript. Zhen He, Sheng-Ming Dai, and Zhiyong Chen revised the manuscript. Zhiyong Chen managed this patient and conceived this work. All authors have read and approved the final version of the manuscript. The informed consent was obtained from the patient. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.