1516 - Novel Titin Mutation in a 51-Year-Old Male with Muscle Cramping and Dilated Cardiomyopathy

51 year old male presented with severe muscle cramping/spasms, “locking up” for 5 to 30 minutes with visible contraction and excruciating pain. Episodes involved extremities, torso, and jaw muscles, both bilateral and unilateral. Episodes occurred after exertion and more frequent when cold or at night, waking him from sleep.  Endorsed decreased grip strength, fatigability and inability to complete farm work. Previously had intermittent muscle cramps that were tolerated and related to the intensity of labor but no history of impaired muscle relaxation. Acute worsening of spasms, difficulty swallowing and chest pain lead to hospitalization. Workup revealed non-ischemic dilated cardiomyopathy with decreased EF different from a normal TTE one year prior.

 

Case Description:

Genetic testing via next generation sequencing was completed and revealed a novel heterozygous TTN gene mutation located in the A-band (c.69234_69238del), resulting in a premature translocation stop signal in the sequence creating a truncated TTN protein. This was also the only mutation found on whole exome sequencing. Muscle biopsy demonstrated both denervation/reinnervation changes, scattered degeneration/regeneration and myofiber necrosis suggesting myopathic changes. EMG negative for large-fiber polyneuropathy and myopathy.

Discussions:

TTN gene mutations have been implicated in both cardiac and neuromuscular disease, including common mutations in the DNA sequence that result in a truncated protein by introducing an early stop codon. TTN mutations are present in 25% of patients with dilated cardiomyopathy, associated predominantly with mutation of exons located the A-band, as is the case in this patient. 

Conclusions:

Given his skeletal muscle symptoms and biopsy findings, which have been reported in TTN-related myopathies, it is suspected that his skeletal muscle symptoms are also related to his TTN mutation, though represents a unique phenotype not previously reported. This case raises awareness of the potential concurrent involvement of skeletal muscle and cardiac muscle in TTN mutations which may have implications for future treatments.