The Challenging Diagnosis of Dysferlinopathy – A Case Report

Abstract

Objectives. Dysferlinopathies are a group of rare genetic myopathies characterized by muscle weakness and atrophy with four distinct clinical phenotypes: Miyoshi myopathy, limb girdle muscular dystrophy type 2B, distal myopathy with anterior tibial onset and an intermediate proximo-distal phenotype. We report a case of dysferlinopathy and discuss relevant clinical, pathological and genetic data. Material and methods. We present the case of a 36 years old man with more than ten years history of progressive muscle weakness and atrophies in the distal lower limbs. He had a first clinical evaluation at the age of 24 years and a muscle biopsy was performed but it was inconclusive. On current admission, he presented with clinical suspicion of Charcot-Marie-Tooth disease, but because of increased serum creatine kinase levels and EMG (electromyography) findings of myopathy, another muscle biopsy was recommended. The muscle tissue obtained was analysed by histopathology, immunohistochemistry, and Western blot techniques, and also a genetic confirmation was recommended. Results. Based on morphological findings, electrodiagnostic study results and clinical context, the diagnosis of primary dysferlinopathy was established, supported by genetic data. Conclusions. The diagnosis may be challenging in these rare genetic myopathies, due to the high variability of phenotypes, ranging from asymptomatic hyperCKemia (high serum creatine kinase level) to a severe clinical picture with loss of ambulation. Repeated evaluation, increasing access to genetic testing and a multidisciplinary approach made an accurate diagnosis possible in our case.

The Dysferlinopathies Conundrum: Clinical Spectra, Disease Mechanism and Genetic Approaches for Treatments

“…Misdiagnosis is a concern with dysferlinopathies due to symptomological overlaps with conditions like polymyositis (PM), other limb-girdle muscular dystrophies (LGMDs), and even Charcot–Marie–Tooth disease (CMT) [ 43 , 50 , 58 , 59 ]. The distinction lies in the absence of elevated CK levels and specific sarcolemma upregulation in CMT [ 43 , 59 ]. Electromyographic (EMG) studies, complemented by CT and MRI, aid in differentiating dysferlinopathy from CMT [ 59 ].…”

“…The distinction lies in the absence of elevated CK levels and specific sarcolemma upregulation in CMT [ 43 , 59 ]. Electromyographic (EMG) studies, complemented by CT and MRI, aid in differentiating dysferlinopathy from CMT [ 59 ]. While a Western blot determines the presence or absence of dysferlin protein in tissues, genetic screening, complemented by advanced sequencing, is necessary to pinpoint specific mutations [ 31 , 59 , 60 , 61 , 62 ].…”

“…Electromyographic (EMG) studies, complemented by CT and MRI, aid in differentiating dysferlinopathy from CMT [ 59 ]. While a Western blot determines the presence or absence of dysferlin protein in tissues, genetic screening, complemented by advanced sequencing, is necessary to pinpoint specific mutations [ 31 , 59 , 60 , 61 , 62 ]. In settings with limited resources, polymerase chain reaction (PCR) and array comparative genomic hybridization (CGH) can offer crucial DNA-level diagnostic insights [ 63 ].…”

Portrait of Dysferlinopathy: Diagnosis and Development of Therapy

“…Patients’ creatine kinase (CK) level is also on average 54 times higher than that of control groups [ 31 ], and they start using a cane to walk in their thirties and become wheelchair-bound in their forties or, on average, 21 years after onset [ 33 ]. The phenotype is located in the skeletal muscles, and the heart remains unaffected, with normal results for electrocardiogram and echocardiogram [ 34 ]. However, a 3-year study showed that up to 30% of patients have a reduced forced vital capacity (FVC) and that up to 58% of patients have a cardiac P-wave abnormality, which can be a risk factor for atrial flutter [ 35 ].…”

“…Another possible but rare misdiagnosis for dysferlinopathy can be Charcot–Marie–Tooth disease (CMT), since both diseases involve a distal weakness phenotype [ 34 ]. One way to tell them apart is that CMT does not cause a high creatine kinase level nor the sarcolemma upregulation of major histocompatibility complex class I (MHC I) like dysferlinopathy does.…”