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Titin mutations - a role still to unriddle

Session Poster Session 4

Speaker Ana Neto

Event : Heart Failure 2019

  • Topic : valvular, myocardial, pericardial, pulmonary, congenital heart disease
  • Sub-topic : Dilative Cardiomyopathy
  • Session type : Poster Session

Authors : A Neto (Penafiel,PT), D Seabra (Penafiel,PT), I Oliveira (Penafiel,PT), A Andrade (Penafiel,PT), P Pinto (Penafiel,PT)

A Neto1 , D Seabra1 , I Oliveira1 , A Andrade1 , P Pinto1 , 1Hospital Centre do Tamega e Sousa, Cardiology - Penafiel - Portugal ,


Titin is the largest protein in the human body. Mutations in the titin gene (TTN) - a sarcomeric protein - cause a broad spectrum of conditions involving the muscle. Dilated cardiomyopathy (CMD) is a primary myocardial disease with a variable natural history and clinical presentation. A genetic aetiology is demonstrated in about 30% of cases with the giant muscle protein TTN being recognized as the major gene causing CMD, mostly by heterozygous truncated mutations.

The present case refers to a 61-year-old female patient (pt) previously followed in Cardiology consultation due to restrictive perimembranous ventricular septal defect with mild left ventricular dysfunction (LVD) and paroxysmal atrial flutter under rhythm control. The pt reported a positive family history of myopathy and sudden death (acknowledged consanguinity among her parents).

She was clinically stable until may 2017; at this time, the pt presented palpitations and decompensated HF having been hospitalized. Echocardiogram showed mild LV dilation, inferoposterior and posterior-septal wall akinesia and hypokinesis of the remaining segments which conditioned severe depression of LVD and new onset right ventricle (RV) dysfunction without dilation. Cardiac catheterization showed angiographically normal coronary arteries; subsequent cardiac MRI revealed extensive septal fibrosis and fibroadipose infiltration suggesting non-ischemic myocardiopathy with severe LVD (but preserved RV function). She was discharged to the HF Clinic for therapeutic optimization and further aetiology workup. Follow-up was marked by difficult drug titration due to bradycardia and hypotension. A switch from ACE inhibitors to ARNI was attempted with clear functional class improvement (despite maintaining a low dose) and a cardio-defibrillator was implanted. Due to myopathy suspicion with persistently high CPK and predominantly proximal muscle weakness at lower limbs level, the pt performed a muscle biopsy that revealed severe changes in the myopathic pattern in which myofibrillar features were prominent. Regarding genetic evaluation, she was submitted to myofibrillar myopathies panel that was negative but mendeleoma identified two variants of uncertain significance in the titin gene (exon 7 and 246). Probable titinopathy with muscular and cardiac manifestations was assumed and the therapeutic and follow-up program were instituted according to.

Some mutations in the TTN gene that predominantly affect the heart muscle, others that affect only the skeletal muscle, and some that affect both. Moreover, truncated variants of the TTN gene are also present in up to 2% of the healthy population. It is suspected that these differences may be related to the location of the mutations in the gene and consequently how they affect the versions of titin that are produced in different muscles. Thus, the actual pathogenic role of these TTN variants remains unknown.

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