An Indian family with an Emery-Dreifuss myopathy and familial dilated cardiomyopathy due to a novel LMNA mutation
A 53-year-old man was admitted to the neurology intensive care unit with an acute ischemic stroke of 2 h duration. On examination, he had a dense right hemiplegia and global aphasia. Computed tomography (CT) brain was normal. He was started on IV thrombolysis with 20 mg of Recombinant Tissue Plasminogen Activator (rtPA) and taken up for intra-arterial thrombolysis. Four-vessel digital subtraction angiography (DSA) revealed a left internal carotid artery (ICA) dissection with flame-shaped occlusion at the carotid bifurcation. Despite multiple attempts, the artery could not be recanalized and the procedure was abandoned. He remained densely hemiplegic and aphasic after the procedure. On detailed questioning, his brother revealed that 10 members of his extended family had undergone cardiac permanent pacemaker implantations (PPI) in the past 15 years []. The youngest brother of the proband had developed difficulty in walking and had been diagnosed with a possible myopathy or spinal muscular atrophy 5 years earlier. He had undergone a PPI 2 years earlier. Another cousin reported a stiff back and had restricted spinal flexion as well as a mild myopathy and a PPI. The possibility of a familial cardiac conduction defect with skeletal myopathy was considered and further detailed evaluation was undertaken. Further evaluation of the proband revealed wasting of the shoulder girdle, enlarged forearms (Popeye forearms), wasting of the peroneal muscles and high arched feet []. Examination of his sibling with the myopathy and the cousin with a stiff back showed the same muscular phenotype. Echocardiogram showed a dilated left ventricle with an ejection fraction of 39%, suggesting a dilated cardiomyopathy (DCM). A CT chest revealed calcification of the A-V node as well as the proximal bundle of His []. Ultrasound abdomen revealed small liver (8 cm) with coarse echotexture, portal vein dilatation and mild splenomegaly (suggestive of cirrhosis). Three weeks after admission, the patient developed massive hematemesis and expired. After discussion with the family and obtaining informed consent, blood was sampled from the patient as well as from a first cousin and dispatched to Diagenos Lab (Germany) for genetic sequencing. The entire coding region of the LMNA gene was sequenced by polymerase chain reaction (PCR). PCR products were analyzed by direct sequencing. This revealed a heretofore undescribed heterozygous mutation in the LMNA gene: c.1059_1060 delGC insCT (p.[Gln353His];[Gln354Term]). This mutation resulted in two amino acid changes. The amino acid change p.Gln354Termn resulted in a premature termination signal.