Familial Transthyretin Amyloidosis with Variant Asp38Ala Presenting with Orthostatic Hypotension and Chronic Diarrhea
In July 2010, a 53-year-old man was admitted to our neurology clinic for the evaluation of dizziness and headache of three years duration. He had not been diagnosed with hypertension, diabetes, or pulmonary disease. The patient presented with chronic diarrhea and a residual urine sensation of several years duration, and reported taking an alpha-blocker to treat the latter. In addition, he complained of non-rotating dizziness aggravated by abrupt standing for 1 years. However, despite of the cessation of alpha-blocker treatment, which could have been responsible for the orthostatic hypotension, the non-rotating dizziness did not improve. On physical examination, blood pressure was 108/65 mmHg and his pulse rate was regular at 60 beats/min in the supine position. However, when the patient changed posture from supine to standing, his blood pressure fell below 80/45 mmHg. Nerve-conduction velocity testing revealed peripheral sensory-motor polyneuropathy combined with bilateral carpal tunnel syndrome. He also showed autonomic dysfunction. At admission, he presented atypical chest pain of four months duration, and was referred to the cardiology department. No abnormal findings were found by 12-lead standard electrocardiography, and laboratory studies revealed normal liver and renal functions. In addition, his erythrocyte sedimentation rate (4.0 mm/hr: normal < 10 mm/hr) and C-reactive protein (0.15 mL/dL: normal < 0.5 mL/dL) were also normal. However, two-dimensional transthoracic echocardiography revealed a thickened left ventricle (interventricular septal dimension 1.19 cm, left ventricle posterior wall dimension 1.28 cm), and that the right ventricle and interatrial septum had a granular "sparkling" appearance (). Left ventricular systolic function was preserved (ejection fraction = 54% by the modified Simpson' method) but diastolic dysfunction was present. Pulsed-wave Doppler recording of mitral inflow showed a normal diastolic filling pattern, with an E/A ratio of 1.1 (), but early diastolic mitral annulus tissue Doppler velocity (Ea) and the E/Ea index were 4 cm/s and 20.3, respectively, indicating a pseudonormal pattern (). These findings were compatible with infiltrative cardiomyopathy. Coronary angiography showed normal coronary arteries and an endomyocardial biopsy revealed lesions consistent with cardiac amyloidosis. Light microscopic findings (haematoxylin and eosin staining) revealed amyloid appearing as pink-hyaline extracellular deposits between myocytes and in blood vessels (). Electron microscopic findings demonstrated amyloid fibrils at the edge of a myocytes ().\nIn addition, a colonoscopic biopsy was performed to identify the cause of the chronic watery diarrhea, and histopathological findings of a colon mucosal biopsy specimen showed chronic colitis and amyloid fibril depositions.\nGene analysis of the TTR exons found a heterozygous mutation at 173 A > C, and thus, a diagnosis of ATTR with variant Asp38Ala (aspartate to alanine mutation at amino acid 38) (). Family screening for ATTR revealed that his son had the same mutation but that his three daughters did not (); his son had no symptoms and normal echocardiographic findings. The patient is being treated by continued symptomatic care and is being regularly followed.