Journal of Cardiovascular Translational Research

https://doi.org/10.1007/s12265-018-9859-0

ORIGINAL ARTICLE

Amyloid Cardiomyopathy in the Rare Transthyretin

Tyr78Phe Mutation
Giacomo Tini 1 & Pier Filippo Vianello 1 & Chiara Gemelli 2 & Marina Grandis 2 & Marco Canepa 1

Received: 30 July 2018 / Accepted: 12 December 2018

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Tyr78Phe is a rare pathogenic transthyretin (TTR) mutation. Few previous reports described a late-onset hereditary transthyretin-
related amyloidosis (ATTR-m) form with a variable phenotype, mainly dominated by neurological manifestations. We describe
the case of a 69-year-old male with massive but asymptomatic cardiac infiltration and only subclinical neurological involvement,
and review the literature to depict characteristics of the Tyr78Phe TTR mutation.

Keywords Transthyretin . Amyloidosis . Amyloid cardiomyopathy . Tyr78Phe . Transthyretin familial amyloid polyneuropathy

More than 120 mutations in the transthyretin (TTR) gene have abnormalities (Fig. 1a). TTE was repeated demonstrating sig-
been reported to cause hereditary transthyretin-related amy- nificant symmetric LVH (24 mm in the basal septum and
loidosis (ATTR-m), with a variable clinical expression of the 19 mm in the posterior wall), normal systolic function,
disease [1]. Tyr78Phe is a rare mutation whose clinical phe- grade-I diastolic dysfunction, significant thickening of atrio-
notype has not been previously completely elucidated. ventricular valves and of the interatrial septum, slight bi-atrial
We report the case of an asymptomatic 69-year-old man enlargement, right ventricular hypertrophy (9 mm), and no
with no family history of cardiomyopathy, no cardiovascular pulmonary hypertension nor pericardial effusion (Fig. 1b).
risk factors, who had always been an active person, at that Given the suspicion of an amyloidotic infiltrative disease, fur-
time regularly playing tennis. At the age of 55, he had surgery ther testing was pursued. A light-chain etiology was excluded
for bilateral carpal tunnel syndrome (CTS). Due to his recre- due to a lack of abnormal findings (protein electrophoresis,
ational sport activity, he has undergone periodical clinical as- serum-free light-chain assay and immunofixation, urine
sessment since 2006. In 2015, a transthoracic echocardiogram Bence-Jones protein research). Cardiac magnetic resonance
(TTE) demonstrated left ventricular hypertrophy (LVH) confirmed LVH (Fig. 1c) with patchy non-specific late gado-
(23 mm in the basal interventricular septum), interpreted as linium enhancement in the interventricular septum. Finally, a
Bathlete’s heart.^ No other investigation was performed until bone scintigraphy with (99 m)technetium-hydroxymethylene
May 2017, when hypertrophic cardiomyopathy (HCM) was diphosphonate showed low-to-moderate uptake of the radio-
for the first time suspected. The first visit to our clinic was in nuclide in the myocardium (reported Perugini score 2) (Fig.
October 2017. Electrocardiogram showed sinus rhythm, first- 1d). DNA sequencing found the Tyr78Phe mutation in the
degree atrio-ventricular block, and diffuse ST-T segment TTR gene. A neurological evaluation highlighted a mild
weakness involving the dorsal and plantar flexion of halluces
and a distal sensory impairment to vibration. No signs of au-
Associate Editor Mazen Hanna oversaw the review of this article
tonomic involvement were identified. An electromyography
* Marco Canepa
study showed an axonal sensory neuropathy with a decrease
marco.canepa@unige.it of both sensory nerve action potentials recorded by antidromic
technique (left 2.2 μV, right 4.3 μV; n.v. > 5 μV). To date,
1
Cardiovascular Unit, Department of Internal Medicine, University of Tyr78Phe has been reported in four cases, after the recognition
Genova and San Martino Hospital, Viale Benedetto XV, 6, of its pathological potential in an in vitro model [2]. It was
16132 Genoa, Italy
firstly reported by Anesi et al. [3] in a 70-year-old male with
2
Department of Neuroscience, Rehabilitation, Ophthalmology, both severe cardiac and neurological symptoms, preceded by
Genetics, Maternal and Child Health (DINOGMI), University of
Genova and San Martino Hospital, Genoa, Italy
a history of bilateral CTS 10 years before.
 J. of Cardiovasc. Trans. Res.

Fig. 1 Electrocardiogram (ECG) showing sinus rhythm, first-degree septum, as well as right ventricular hypertrophy. (99 m)technetium-
atrio-ventricular block, and diffuse ST-T segment abnormalities (a). hydroxymethylene diphosponate bone scintigraphy (d) shows low-to-
Transthoracic echocardiogram (TTE) (b) and cardiac magnetic moderate radionuclide uptake in the myocardium (reported as Perugini
resonance study (c) show symmetric left ventricular hypertrophy, score 2)
significant thickening of the atrio-ventricular valves and interatrial
J. of Cardiovasc. Trans. Res.

The patient suffered also from macroglossia, hepatomega- Unfortunately, no information regarding age or clinical condi-
ly, proteinuria, weight loss, and gastrointestinal symptoms. In tions of the mutation-positive siblings was given.
2009, Magy et al. [4] described the mutation in a 78-year-old Nonetheless, the fact that among 4 carriers only one had an
man, who presented with a 5-year history of lower limbs par- overt phenotypical manifestation of the disease is in line with
aesthesia and a surgery for bilateral CTS 15 years before. the subclinical presentation of our patient.
Clinical conditions were characterized by an axonal sensory-
motor neuropathy of the lower extremities and by skin infil-
tration, with no evidence of cardiac involvement. Riboldi et al. Compliance with Ethical Standards
[5] in 2011 reported the mutation in a case with only neuro-
This study complied with all ethical standards involving human subjects.
logical manifestations. The 63-year-old male patient presented
The patient consented to participation into clinical surveys by signing an
with dysphagia and lower limbs weakness which began informed consent.
4 years before, and had had a history of bilateral CTS, treated
surgically at the age of 44 and 55 years. He had a severe and Conflict of Interest The authors declare that they have no conflict of
rapid neurological progression with mainly motor involve- interest.
ment and only minimal sensory signs. Finally, in a contempo-
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
rary Italian series of 186 ATTR-m patients, only one Tyr78Phe
tional claims in published maps and institutional affiliations.
subject was identified, with isolated cardiac involvement [1].
In our case, the patient has subclinical cardiac and neuro-
logical involvement. Neurological findings are mild, while
cardiac infiltration had been present for at least 2 years (with- References
out symptoms) before the suspicion of an underlying patho-
1. Rapezzi, C., Quarta, C. C., Obici, L., et al. (2013). Disease profile
logical condition was raised. Nevertheless, cardiac findings and differential diagnosis of hereditary transthyretin-related amyloid-
led to the recognition of neurological involvement. This early osis with exclusively cardiac phenotype: an Italian perspective.
diagnosis may significantly impact the prognosis of our pa- European Heart Journal, 34(7), 520–528. https://doi.org/10.1093/
eurheartj/ehs123.
tient, having allowed the initiation of an etiological treatment.
2. Redondo, C., Damas, A. M., Olofsson, A., et al. (2000). Search for
Tyr78Phe probably presents with late-onset intermediate clin- intermediate structures in transthyretin fibrillogenesis: soluble tetra-
ical manifestations, with neurological involvement likely to be meric Tyr78Phe TTR expresses a specific epitope present only in
dominant and cardiac manifestations of less importance. amyloid fibrils. Journal of Molecular Biology, 304(3), 461–470.
However, it carries a significant phenotypical heterogeneity. https://doi.org/10.1006/jmbi.2000.4220.
3. Anesi, E., Palladini, G., Perfetti, V., et al. (2001). Therapeutic ad-
The mutation appears to have a definite Italian geographical
vances demand accurate typing of amyloid deposits. The American
context. Beyond the patient in the Italian registry and the one Journal of Medicine, 111(3), 243–244.
herein described, one subject was a French man of Italian 4. Magy, N., Liepnieks, J. J., Gil, H., et al. (2003). A transthyretin
origin [4], whereas the two others reported by Italian investi- mutation (Tyr78Phe) associated with peripheral neuropathy, carpal
gators may be assumed to be Italian [3, 5]. Family history is tunnel syndrome and skin amyloidosis. Amyloid, 10(1), 29–33.
5. Riboldi, G., Del Bo, R., Ranieri, M., et al. (2011). Tyr78Phe
reported only in the case by Magy: among 9 siblings (one transthyretin mutation with predominant motor neuropathy as the
dead), the mutation was found in 4 of them, with only one initial presentation. Case Report in Neurology, 3(1), 62–68. https://
reported to have phenotypic evidence of the disease [4]. doi.org/10.1159/000324925.