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ATTR Amyloidosis Complicated by Phrenic Nerve Palsy

Amyloidoses are groups of protein misfolding and deposition diseases, and many proteins are known to form amyloid fibrils. Mutated transthyretin (TTR) can cause familial amyloid polyneuropathy (FAP), which is associated with systemic disorders including neuropathy and cardiac diseases. Here we report a rare case of ATTR amyloidosis presenting with fatal hypoventilation accompanied by bilateral phrenic nerve palsy. A woman began to suffer from numbness in her hands and soles when she was 69-years-old. Her past history was unremarkable. She was born in Yokosuka city, away from the endemic foci of FAP in Japan, and had no family history of any neurological diseases. She was diagnosed as carpal tunnel syndrome, but surgery did not improve her symptoms. She came to our clinic one year later. neurologic examination revealed muscle weakness, atrophy, and sensory loss, predominantly in the distal limbs. Deep tendon reflexes were all absent. Conventional nerve conduction studies (nCSs) in limbs showed severely decreased amplitudes of the compound muscle action potentials (CMAPs) and the sensory nerve action potentials (SnAPs). Conduction velocities were almost normal. A left sural nerve biopsy showed axonal loss, but Congo-red staining did not disclose amyloid deposits at that time. Her symptoms further progressed and she became bedridden at the age of 72. At the same time, she was also suffering from syncope and alternating diarrhea and constipation, suggesting complication of autonomic dysfunction. At the age of 74 she began to suffer from dyspnea. Physical examination revealed pitting edema in her legs. Blood tests were unremarkable, but plasma brain natriuretic peptide was elevated to 264 pg/mL (normal: <20 pg/mL). An arterial blood gas under inhalation of 2 L/min oxygen showed chronic hypoventilation (pH: 7.34; PaCO2: 66.0 Torr; PaO2: 85.9 Torr; HCO3: 34.5 mM). Spirometry revealed reduced vital capacity (53% of predicted) and forced expiratory volume in 1 s (56%). Chest X-ray and high-resolution computed tomography of the lung indicated cardiomegaly and mild pleural effusion without any pulmonary lesions. Electrocardiogram was normal, though coefficient of variation of R-R intervals was markedly low (0.37%). Ejection fraction was preserved (66.7%), but concentric hypertrophy, diastolic dysfunction and granular sparkling pattern in the ventricular walls were demonstrated by cardiac ultrasonography (left ventricular end-diastolic dimension: 36 mm; inter-ventricular septum thickness: 12 mm; E/A ratio: 0.78). Even after oral diuretics decreased the pleural effusion and edema, her dyspnea scarcely improved. Phrenic nCSs performed using Bolton's method1 showed low negativepeak-amplitudes of CMAPs (left: 0.051 mV, right: 0.079 mV; normal: >0.3 mV) and prolonged latencies (left: 12.4 ms, right: 11.5 ms; normal: <8 ms) (Figure 1). The patient rejected tracheostomy and she was treated with non-invasive positive pressure ventilation (nIPPV). However, she could hardly adapt to nIPPV and finally died from respiratory failure. Her DnA could not be analyzed, but Congo-red staining of her right sural nerve necropsy specimen revealed amyloid deposits that were positively immunostained with an anti-TTR antibody (Figure 2), which was prepared against the peptide “SYSTTAVVTn” corresponding to the TTR#115-TTR#124. Our patient presented with chronic progressive polyneuropathy, cardiomyopathy, and finally died of respiratory failure resistant to diuretics. Postmortem pathology revealed ATTR amyloidosis. Although no gene study was performed, she suffered from typical complications of sporadic familial amyloid polyneuropathy, a group of systemic disorders that includes symptoms of polyneuropathy and cardiomyopathy. Mutations in the transthyretin gene can be proven even in sporadic cases.