Hereditary transthyretin amyloidosis presenting with carpal tunnel syndrome

Key Information
Year
2024
summary/abstract

KEY POINTS

  • Transthyretin amyloidosis typically presents with entrapment neuropathy, polyneuropathy or heart failure; some patients may experience autonomic dysfunction or symptoms of central nervous system pathology.

  • While signs of transthyretin amyloidosis (e.g., bilateral carpal tunnel syndrome, autonomic and length-dependent neuropathies, heart failure, atrial fibrillation) are common among those without the condition, a high level of suspicion is warranted when patients present with more than 1 classic feature, especially when refractory to treatment, as well as with a family history.

  • The diagnosis of transthyretin amyloidosis is made by Congo red stain of tissue biopsies or genetic testing.

  • Inotersen and tafamidis are new treatments that may slow the progression of cardiac and neurologic disease and improve quality of life.

We admitted a 65-year-old right-handed man to the general internal medicine service with decompensated heart failure and gastrointestinal bleeding. Seven years previously, he had presented to his family physician with intermittent, nocturnal numbness and paresthesias of the first 3 digits of his right hand, which progressively worsened and later involved the left hand. He was diagnosed clinically with bilateral carpal tunnel syndrome and was treated unsuccessfully with wrist splints. Two years later he noted tingling in both feet and was diagnosed with atrial fibrillation. Four years after his initial presentation he reported progressive ascending numbness causing gait instability. Nerve conduction studies and electromyography showed bilateral median neuropathy at the wrist (severe on the right, moderate on the left), and length-dependent symmetric axonal sensorimotor polyneuropathy. Despite right carpal tunnel release, his symptoms persisted.

The patient was referred to a neurologist; on physical examination he had a positive Romberg test, absent proprioceptive sensation in the toes, stocking gradient sensory loss to the midshins, absent lower-extremity reflexes, 5/5 proximal strength and 4/5 distal strength. Investigations for acquired axonal neuropathy (Table 1external link, opens in a new tab) were unremarkable. A year later, his neuropathy had worsened to the point where he required a walker to ambulate. He also developed non-bloody watery stools alternating with constipation.

Genetic testing for inherited neuropathy found a pathogenic variant consistent with hereditary transthyretin amyloidosis. The patient was started on inotersen (an antisense oligonucleotide inhibitor of hepatic transthyretin production) to treat the polyneuropathy. He noted improvement in his neuropathy and balance, but neurologic examination was unchanged. He was seen by a geneticist who elicited a history of neurologic and cardiac disease in his father and uncle.

Screening cardiac magnetic resonance imaging (MRI) suggested cardiac amyloidosis with an ejection fraction of 38%, asymmetric septal hypertrophy and diffuse delayed enhancement (Figure 1external link, opens in a new tab). The patient was seen by a cardiologist, who did not recommend any treatment specific for cardiac amyloidosis. Six months after the diagnosis of hereditary transthyretin amyloidosis, he developed progressive orthopnea and dyspnea on exertion, and months later we admitted him under our care with anasarca secondary to decompensated heart failure, gastrointestinal bleeding and marked functional decline.

The patient’s hemoglobin level was 49 g/L on admission. We found severe portal hypertensive gastropathy and severe esophagitis in the distal esophagus on upper endoscopy. We treated him with intravenous pantoprazole twice daily and with transfusions, with no further bleeding during his admission.

Electrocardiography showed low voltage on the limb leads (Figure 2external link, opens in a new tab), and transthoracic echocardiography showed increased septal thickening (Figure 3external link, opens in a new tab). A pyrophosphate scan showed mild diffuse myocardial tracer uptake suggestive of cardiac amyloidosis. During admission, the cardiology service thought that because of the patient’s New York Heart Association (NYHA) class IV symptoms he was unlikely to benefit from tafamidis. We treated him with diuretics and discharged him on standard heart failure therapy. Repeat MRI showed a poorer ejection fraction of 24%. We started him on topical sildenafil for vasomotor neuropathic symptoms, which has provided relief. He continues to live independently despite his NYHA class III symptoms.

Authors
Nicole Zaki, Nicholas J. Miller, Patrick Frosk and Aditya Sharma