Immune-mediated rippling muscle disease in a patient with treated hypothyroidism (original) (raw)

2017, Journal of the neurological sciences

Rippling muscle disease (RMD) is a myopathy with symptoms and signs of muscular hyperirritability [1]. Hereditary RMD is caused by caveolin-3 deficiency due to mutations in the CAV-3 gene and in PTRF gene coding for cavin-1 [1-3]. The rare cases of acquired RMD are usually associated with myasthenia gravis (MG). In these situations, RMD has been named as "immune-mediated RMD (iRMD)" [4-7]. There are also descriptions of RMD preceding malignant lymphoma [8] and breast cancer [9]. We describe a 17-year-old girl who has been treated for hypothyroidism for 10 years, and at moment she is asymptomatic. In the last two years, she started with brief muscle contractions followed by intense muscle pain in the limbs, abdomen and back. Symptoms appeared at rest, during exercise and during sleep. Clinical features included muscle hypertrophy in the lower limbs and local mounding and rippling phenomenon after skeletal muscle percussion and sudden stretching of the quadriceps femoris muscle. Needle electromyography showed electrical silence during the rippling phenomenon. Repetitive nerve stimulations were normal. Laboratory tests showed that free T4, TSH and thyroid peroxidase autoantibodies were normal, the CK level was 647 U/L (normal < 145 U/L) and anti-AChR antibodies were not detectable. Whole-body FDG-PET/CT was normal. The muscle biopsy was compatible with nonspecific myopathic features with rare infiltration of inflammatory cells in endomysial tissue along with type 1 and 2 fiber atrophy (Fig. 1). Immunohistochemical analysis of sarcolemmal proteins showed moderate reduction in the mosaic pattern in caveolin-3 and partial reduction in dysferlin (Fig. 1). Molecular investigation using a next generation exome sequencing customized panel for 88 genes involved in genetic neuromuscular disorders (http://laboratorio.genoma. ib.usp.br), including the CAV-3 and DYSF genes, did not find any significant pathogenic variant in the coding region of these genes that could explain the phenotype. There was significant improvement in her symptoms during corticosteroids and azathioprine therapies, but she returned to having symptoms after withdrawal, in two different occasions, suggesting an autoimmune etiological role in this case. iRMD is usually described to be associated with MG, with or without thymoma, particularly after the third decade of life [4-7]. Hypothyroidism was only recently described in one patient with iRMD associated with MG [4] and few cases of iRMD without MG are described to date [10]. Muscle biopsy features in iRMD were described with inflammatory changes or as nonspecific myopathy. The most frequent features consisted of rare interstitial and perivascular lymphocytic infiltrates in addition to scattered atrophic type I and II muscle fibers, as seen in our patient [7]. A different feature seen in RMD patients with CAV-3 mutations is that caveolin-3 in the muscle biopsies of iRMD patients were moderately reduced as a mosaic pattern [4-8,10]. Ultrastructural studies showed a loss of caveolae and alterations of the T tubules in iRMD [7]. It is possible that the mosaic pattern of the caveolin-3 in the muscle biopsy is a hallmark of iRMD, but the precise mechanism leading to that mosaic finding in iRMD is unknown. Similar to our case, mild deficiency of dysferlin was also reported in iRMD [6,7,10]. Therapy of iRMD was immunosuppressant drugs, such as steroids, azathioprine and cyclosporine, in several cases [4,6,10]. Phasmapheresis [10] and intravenous immunoglobulin [9] were also reported. Our report also highlights that it is extremely important to distinguish between hereditary RMD and iRMD because iRMD can respond to immunosuppressive therapy.