Phenotypical reflection of a patient with a possible pathological variation of the vcp gene and difficulties in neuromuscular differential diagnosis

Abstract

The differential diagnosis of muscle weakness includes a wide spectrum of diseases, from cerebrovascular diseases to motor neuron diseases, peripheral neuropathies, neuromuscular junction diseases and myopathies. Although many methods are used to make a diagnosis, including anamnesis, examination, laboratory, electrophysiological examinations, radiological examinations, biopsy and genetic analysis, there are still many patients who cannot be diagnosed. In this article, we present a case in which it was not possible to differentiate between inclusion body myopathy, amyotrophic lateral sclerosis and hereditary motor neuropathy. A 59-year-old male patient presented with chronic progressive muscle weakness and myalgias. The patient, who had complaints for approximately 8-9 years, had a family history supporting an autosomal dominant inheritance pattern. In the patient’s neurological examination, muscle weakness affecting the distal and proximal parts of the bilateral lower and upper extremities, atrophy in the thenar and hypothenar regions of the upper extremity, and hypoactive deep tendon reflexes were detected. Other neurological examinations were normal. Laboratory tests revealed no pathology other than moderate CK elevation. Electrophysiological findings supporting the association of motor neuropathy and myopathy were detected in electromyography. No pathology was detected in muscle biopsy other than mild inflammatory changes. Genetic examination of the patient revealed a heterozygous mutation (c.365C>G protein Thr122Arg) in the T122R variant of the Valosin-containing protein (VCP) gene. When the literature is reviewed, although there are some variants of VCP gene mutations associated with familial inclusion body myopathy, amyotrophic lateral sclerosis accompanied by frontotemporal dementia, and Charcot-Marie-Tooth (CMT) 2Y, this variant in our patient has not been described before. The patient’s family history of autosomal dominant trait and the presence of both IBM and CMT clinics suggest that these two clinics are phenotypically reflected together as a secondary to the current mutation. In this period when genetic treatments are rapidly developing, it is of great importance to identify genetic muscle diseases and new variants, so such cases should be reported. In patients whom differential diagnosis cannot be made, advanced genetic examinations should be performed even if genetic examinations such as NGS are found negative.