A Symptomatic Female Patient with Duchenne Muscular Dystrophy Gene Mutation Showing Rimmed Vacuoles in Muscle Biopsy
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.284351
Source of Support: None, Conflict of Interest: None
Myopathies with rimmed vacuoles (RVs) constitute a clinically and genetically heterogeneous group of muscle diseases, comprising distal myopathy with rimmed vacuoles, sporadic inclusion body myositis, myofibrillar myopathies, and lysosomal myopathies.,,
Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive disorders that are caused by mutations of the DMD gene located at Xp21. They affect approximately 1 in 3500 boys and cause progressive muscle weakness. DMD patients generally carry frame-shift dystrophin mutations, whereas BMD (a milder form) is due to in-frame mutations. Deletions of one or more exons occur in approximately 60-70% of individuals with DMD/BMD and duplications are found in approximately 5-10%. The remaining 25-35% of DMD cases and 10-20% of BMD cases are caused by point mutations or other subtle changes in the dystrophin gene. Although DMD and BMD predominantly affect males, a significant proportion of females with clinical symptoms have also been reported. They represent a heterogeneous group characterized by variable degrees of muscle weakness and/or cardiac involvement. de Visser et al. had discovered an unusual variant of dystrophinopathies that showed RVs in the muscles; Momma et al. reported 12 cases with RVs among 65 BMD patients. Yet, RVs are rarely reported in symptomatic (or asymptomatic) female DMD/BMD patients. Herein, we report a symptomatic Chinese female patient with DMD gene mutation who showed RV in muscle biopsy.
A 34-year-old female patient developed progressive muscle weakness over a period of 30 years. As a child, she had weaker motor ability than peers and could not lift heavy things with her arms. She had difficulty in climbing stairs and doing leg squats. She started walking on tiptoes since she was unable to walk on heels. She was referred to our hospital at the age of 34 years, with motor power of the body rated by the Medical Research Council Scale as follows: proximal left upper limb 4/5, proximal right upper limb 5/5, bilateral distal upper limbs 5/5, proximal left lower limb 3/5, proximal right lower limb 4/5, bilateral distal lower limbs 4/5. The winging scapula was obvious on the right side of the body. She also exhibited bilateral calf muscle hypertrophy. There was no pain, sensory disturbance, muscle cramps, or any scoliosis, with normal muscle tension and coordination movement. The Babinski signs were negative. Her family members did not show any signs of weakness. The blood test showed high serum creatine kinase (CK) levels [CK 984 U/L (normal range: 24-194 U/L)] and mildly elevated lactic dehydrogenase (LDH) levels [LDH 329 U/L (normal range: 100–240 U/L)]. Electromyography (EMG) showed a myopathic change.
Muscle biopsy of the left quadriceps femoris muscle revealed atrophied muscle fibers of different sizes, with the appearance of small circular and irregular shapes. Rimmed vacuoles (RVs) were found in many atrophic or necrotic myofibers, which contained basophilic materials, accompanied by muscle fiber hypertrophy, internal nuclei, and fiber splitting. Materials in RVs were red-stained in Gomori trichrome stain [Figure 1]. ATP staining showed a predominance of type 1 fibers. Immunohistochemistry was also conducted, which showed a mosaic reduction for dystrophin (R, C, N) staining, while CD4, CD8, CD68, C5B9, MHC-1, and SRP19 were all negative [Figure 2]. The patient was thus suspected with BMD and/or inclusion body myopathy.
The genetic analysis of targeted next-generation showed a heterozygous mutation c.583C>T (NM004006.2) in the DMD gene (chrX:g.32827676) [Figure 3], causing p.R195X. This premature stop mutation was reported as DMD's pathogenic gene in the HGMD pro database. Her mother was also detected to carry the same mutation but without any symptoms [Figure 3]. This result correlated with the clinical presentation and muscle biopsy, indicating that the patient was a symptomatic female DMD gene carrier with RVs.
DMD is a serious disease with apparent muscle weakness at 4-5 years of age, which subsequently progresses until patients are unable to walk by the age of 12 years and die in their 20s or 30s for cardiac or respiratory failure. In contrast, BMD has a slower rate of progression and some affected individuals may lead near-normal lives.
The dystrophin gene is the largest of the identified human genes, spanning 2.4 Mb and corresponding to about 0.1% of the total human genome., The majority of identified mutations are deletions, accounting for approximately 60-65% of DMD and 85% of BMD mutations, and duplications are found in approximately 5-15% of patients.,,
Both DMD and BMD usually affect males, with the majority of female carriers of DMD mutations being asymptomatic and presenting with high serum CK levels as the only clinical sign. Nevertheless, certain female carriers, defined as “manifesting” or “symptomatic,” develop symptoms that vary from mild muscle weakness to a DMD-like clinical course. The muscle weakness is generally asymmetric and proximally distributed, and the age of onset is extremely variable., Manifesting carriers may also present cardiac pathology (dilated cardiomyopathy), either alone or accompanied by muscle weakness., Approximately, 8% of female carriers suffer from some degree of muscle weakness.,, A study from the Netherlands even revealed a higher proportion (22%) of carriers manifesting symptoms.
Our female patient who presented clinical manifestations of symptomatic DMD carriers had revealed a mosaic pattern with positive and negative dystrophin fibers, which is coincident with previous report. In the study of Simona et al., both symptomatic and asymptomatic females DMD carriers, immunostaining of muscle biopsy tissue revealed a mosaic pattern of dystrophin-positive and dystrophin-negative fibers, in addition to fibers with reduced dystrophin labeling. There is no correlation between the percentage of negative fibers and clinical phenotype according to other groups' report.,,, In the series of Momma et al., the deletion in exons 45-47 or 45-48 in the DMD gene was frequently found in the patients with RV. The authors suggested that a milder clinical course and longer disease duration in dystrophinopathy could contribute to the formation of RVs in muscles. Moreover, RV formation may be a phenotype of the disease spectrum of a mild myopathic process.
In conclusion, we reported a symptomatic Chinese female DMD gene carrier with RV in muscle biopsy.
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The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
This work was supported by National Natural Science Foundation of China (No. 81501083 and 81671236).
Conflicts of interest
There are no conflicts of interest.
[Figure 1], [Figure 2], [Figure 3]