Case report

An 83 year old white man was admitted in July 1997 with left sided weakness. He was in atrial fibrillation and had a left hemiparesis; computed tomography of the brain confirmed a right cerebral infarct. As well as atrial fibrillation, the electrocardiogram showed left axis deviation and pathological Q waves in leads V1–V4. Echocardiography revealed biventricular hypertrophy and a speckled myocardium characteristic of amyloid infiltration. Chest radiography and routine biochemistry were normal. The patient was given warfarin and made a good recovery returning to full mobility over the following weeks. Three months later he was well without signs of systemic amyloidosis and complained only of minimal breathlessness on exertion and mild residual left sided weakness. There was no known family history of amyloidosis or African ancestry. There was no evidence of a monoclonal gammopathy and serum amyloid P component scintigraphy did not show significant extracardiac amyloid deposits; a rectal biopsy, stained positively with Congo red, confirmed the diagnosis of amyloidosis.5 Immunohistochemical staining of the biopsy tissue with anti-TTR was positive, which confirmed that TTR was the major amyloid fibril constituent. Amplification and sequencing of the patient’s TTR gene revealed heterozygosity for the Ile122 mutation (fig 1), which had been described previously only in patients of African descent. Subsequent TTR genotyping of the patient’s family is shown in fig 2. The caucasian Ile122 mutation was on haplotype III, as is the African Ile122 mutation.

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Figure 1

Nucleotide sequence of part of exon 4 of the transthyretin gene from the patient (right) compared with a healthy subject (left). The patient was heterozygous for a single base change, a transition from C to T (arrowed), which alters codon 122 to code for isoleucine instead of valine (antisense strand shown).

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Figure 2

Transthyretin (TTR) genotyping of the present kindred. The arrow indicates the patient. Black symbols, individuals heterozygous for the Ile122 mutation; grey symbols, individuals with wild-type sequence; open symbols, not tested. The two children of the patient who are heterozygous for the TTR Ile122 mutation are currently asymptomatic aged 42 and 40.

Discussion

This is the first reported case of familial amyloid cardiomyopathy associated with TTR Ile122 in a white patient. The Ile122 mutation is present in 4% of African Americans and usually results in isolated cardiac amyloidosis from age 60 years onwards, presenting with cardiac failure and/or arrhythmia. Occasionally, there is associated carpal tunnel syndrome, and peripheral polyneuropathy has been reported.3

Amyloid deposits of wild-type TTR are found in 25% of hearts from people over 80 years old, examined after death.6 These deposits do not always cause clinical symptoms but the possibility of amyloidosis should be considered when treating elderly patients with heart failure, particularly in cases resistant to conventional treatment with diuretics and ACE inhibitors. The diagnosis of cardiac amyloidosis is suggested by an ECG showing small complexes and/or anterior Q waves in association with concentric left ventricular hypertrophy or restrictive physiology and occasionally a speckled myocardium on the echocardiogram.7 However, confirmation of the diagnosis requires biopsy of either the endomyocardium or another affected organ. Once the diagnosis is confirmed, the use of digoxin, which binds to amyloid fibrils, is contraindicated and overzealous use of diuretics and angiotensin converting enzyme inhibitors should be avoided.8

Precise characterisation of amyloid type is important for a number of reasons. Cardiac involvement in AL amyloidosis is associated with a much poorer prognosis than cardiac TTR amyloidosis: the median survival of a patient with significant cardiac AL amyloidosis is 4–6 months; patients with TTR cardiac amyloidosis usually survive for several years after diagnosis.9 ,10 Furthermore, although elderly patients are usually deemed ineligible for liver transplantation or chemotherapy regimens, which are the standard treatments for hereditary TTR and AL amyloidosis respectively, they may be eligible for experimental treatment aimed at reducing circulating TTR levels.

The identification of a mutation of the TTR gene in a patient with TTR cardiac amyloidosis has implications for other family members—for example, in an affected relative, early identification of arrhythmias such as atrial fibrillation may lead to treatment with warfarin and avoidance of digoxin; these measures could prevent complications such as cerebral infarction or sudden death. In addition, at present the age at which cardiac amyloid deposition starts among patients with the Ile122 mutation is unknown.

Finally, the prevalence of the Ile122 mutation in white people is unknown. An estimated 1.2 million African Americans are heterozygous for the mutation, together with an estimated 12 000 homozygotes,3 and although likely to be less prevalent, it may be a significant, as yet unrecognised, cause of heart failure in elderly white people. As the caucasian and African Ile122 mutations are on the same haplotype, the possibility of an ancient common founder cannot be excluded.