A 20-year-old man suddenly collapses while walking on a college campus. He is found to be unresponsive and pulseless by a bystander. Despite efforts by emergency medical personnel, the man is unable to be resuscitated. His friends say he appeared fatigued and described palpitations and dyspnea with exertion in the weeks leading up to the event. He had no known medical history and did not use tobacco, alcohol, or illicit drugs. The man's 3 younger siblings are healthy. His parents confirm a history of "early heart disease" in a paternal grandfather and request an autopsy and genetic testing for further evaluation. Genetic studies reveal a defect in a TTN gene exon resulting in a truncated titin protein. Autopsy findings are most likely to show which of the following phenotypes?

Question

A 20-year-old man suddenly collapses while walking on a college campus.  He is found to be unresponsive and pulseless by a bystander.  Despite efforts by emergency medical personnel, the man is unable to be resuscitated.  His friends say he appeared fatigued and described palpitations and dyspnea with exertion in the weeks leading up to the event.  He had no known medical history and did not use tobacco, alcohol, or illicit drugs.  The man's 3 younger siblings are healthy.  His parents confirm a history of "early heart disease" in a paternal grandfather and request an autopsy and genetic testing for further evaluation.  Genetic studies reveal a defect in a TTN gene exon resulting in a truncated titin protein.  Autopsy findings are most likely to show which of the following phenotypes?

Quizplus · Accepted Answer

11ec160b_3754_85ac_9249_6bafa3ee0d9f_MD0001_00 Dilated cardiomyopathy (DCM) occurs due to a direct insult to the myocardium that leads to a decrease in contractile function of one or both ventricles with a consequent increase in ventricular cavity size. It can result from a variety of causes, including viral infection, chemical toxicity (eg, doxorubicin, alcohol, cocaine), and infiltrative disease (late manifestation). Patients typically have symptoms of decompensated heart failure (eg, fatigue, dyspnea, orthopnea). In addition, the left ventricular structural changes place these patients at risk for sudden cardiac death due to ventricular arrhythmia. Patients are classified as having idiopathic DCM when no apparent cause of DCM is identified on routine clinical evaluation. A large percentage of these patients likely have a familial (inherited) cause. Familial DCM can result from a variety of genetic mutations affecting either sarcomere (ie, the contractile apparatus) or nonsarcomere proteins. Truncating mutations (usually nonsense mutations) affecting the TTN gene, which encodes for the sarcomere protein titin, are the most common cause of familial DCM. Titin is an elastic protein that anchors the beta-myosin heavy chain to the Z-discs and likely contributes to passive myocardial tension; absence of complete titin proteins leads to myocardial dysfunction. TTN gene mutations follow autosomal dominant inheritance; however, they have incomplete penetrance, leading to delayed or absent clinical manifestations in some family members. (Choice A) Arrhythmogenic right ventricular cardiomyopathy is characterized by fibrosis and scarring of right ventricular myocardium, which predisposes to ventricular arrhythmias and sudden cardiac death. The disease results from impaired desmosome function due to mutations in genes encoding desmosomal proteins (eg, plakoglobin, desmoplakin). (Choice B) Familial bicuspid aortic valve disease has been associated with a mutation affecting the NOTCH1 gene that encodes transcription regulatory proteins. (Choice D) Hypertrophic cardiomyopathy is a common cause of sudden cardiac death in young patients. It is inherited in an autosomal dominant pattern and most commonly involves mutations in the genes encoding beta-myosin heavy chain or myosin-binding protein C. (Choice E) Restrictive cardiomyopathy most commonly results from infiltrative disease (eg, amyloidosis, hemochromatosis, sarcoidosis); however, familial disease does occur. Familial restrictive cardiomyopathy typically involves mutations in genes encoding one of several sarcomere or cytoskeletal proteins, but mutations of the TTN gene are not a well-established cause. Educational objective: Autosomal dominant mutations in the TTN gene, which encodes for the sarcomere protein titin, are the most common cause of familial dilated cardiomyopathy. __________ References: Dilated cardiomyopathy: the complexity of a diverse genetic architecture. (http://www.ncbi.nlm.nih.gov/pubmed/23900355) Truncations of titin causing dilated cardiomyopathy. (http://www.ncbi.nlm.nih.gov/pubmed/22335739)

A 20-Year-Old Man Suddenly Collapses While Walking on a College