Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology

Figures & data

Table 1. Current symptoms for polyneuropathy and cardiomyopathy of undetermined aetiology.

Does the patient have any of the following?	Number of patients with information	Present n (%)
Reduced ability to sense temperature	4016	1090 (27.1)
Numbness	4017	2177 (54.2)
Tingling	4016	2041 (50.8)
“Burning feet”	4017	1410 (35.1)
Pain	4016	1912 (47.6)
Muscle atrophy in the leg	4017	775 (19.3)
History of carpal tunnel syndrome	4016	704 (17.5)
Allodynia	4017	527 (13.1)
Muscle weakness in the leg	4017	1470 (36.6)
Difficulty urinating or holding the urine	4016	638 (15.9)
Dizziness or fainting upon standing	4015	1468 (36.6)
Inability to obtain or maintain an erection	2514 males	515 (20.5)
Bouts of constipation that alternate with diarrhoea	4017	312 (7.8)
Unintentional weight loss	4017	435 (10.8)
Anaemia	4017	287 (7.1)
Diarrhoea	4017	481 (12.0)
Constipation	4016	583 (14.5)
Shortness of breath	4017	1551 (38.6)
Water accumulation in the ancles and lower limbs	4017	1209 (30.1)
Dyshidrosis	4017	662 (16.5)
Chest pain	4015	652 (16.2)
Palpitation	4016	1122 (27.9)
Arrhythmia	4015	1014 (25.3)
Enlargement of heart cavities	4015	830 (20.7)
Enlargement of heart muscle	4017	1025 (25.5)
Abnormal (fluttering) heartbeat	4015	1011 (25.2)

Figure 1. TTR variants as identified by the present study. (A) Fraction of the three relevant classes amongst patients (A’) and variants (A”). Absolute numbers are provided within the charts. (B) Number of observations of individual variants. Colour shade-coding as in (A).

Table 2. TTR heterozygous variants in patients with PNP and/or CM.

	Literature		TRAM study
Variant name	Phenotype	Ethnicity	n	m/f	Age of onset, years	Phenotype	Ethnicity
NM_000371.3:
c.148G > A (p.Val50Met)	AN E LM PNP	AM CN JP EUR DE ES FR IT PT SE AT	17	11/6	15–78	CM-2 PNP-10	DE
						CM/PNP-5
c.424G > A (p.Val142Ile)	H	AFR AM FR PT IT AT	8	8/0	30–78	CM-5 PNP-1	DE AT
						CM/PNP-2
c.233T > A (p.Leu78His)	H CTS	AM DE	3	3/0	57, 62, 63	PNP-3	DE
c.179C > A (p.Thr60Asn)	H AN PNP	DE	2	1/1	71, 75	CM/PNP-2	DE
c.238A > G (p.Thr80Ala)	CTS H PNP	AT DE IE DON BR AM AP SE	2	1/1	68, 72	CM-1 PNP-1	DE
c.311T > C (p.Ile104Thr)	H PNP	DE BR	2	1/1	59, 68	CM/PNP-2	DE
c.377C > A (p.Thr126Asn)	–	–	2	1/1	66, 73	CM-1 CM/PNP-1	DE
c.379A > G (p.Ile127Val)	CTS H PNP	DE AM	2	2/0	55, 70	PNP-2	DE
c.88T > C (p.Cys30Arg)	AN E H PNP	AM HU	2	1/1	76, 78	PNP-1 CM-1	DE
c.206C > T (p.Thr69Ile)	H PNP	JP	1	1/0	58	CM/PNP	AT
c.212A > G (p.Glu71Gly)	H	AM	1	1/0	42	PNP	DE
c.250T > C (p.Phe84Leu)	CTS H PNP	IT AM	1	1/0	66	PNP	DE
c.262A > T/C (p.Ile88Leu)	H	DE AM IT	1	1/0	82	CM/PNP	DE
c.341T > C (p.Val114Ala)	AN H PNP	DE GR CYP AT	1	0/1	71	CM/PNP	DE
c.337-3T > C	H	–	1	0/1	58	CM	DE
c.209G > A (p.Ser70Asn)	NA	–	3	1/2	63, 65, 67	PNP-2 CM/PNP-1	DE
c.280G > C (p.Asp94His)	NA	DE	2	2/0	58, 78	PNP-2	DE
c.338T > C (p.Val113Ala)	NA	–	1	0/1	34	PNP	DE
c.355G > A (p.Asp119Asn)	NA	–	1	1/0	68	PNP	DE
c.79G > A (p.Glu27Lys)	NA	–	1	1/0	63	PNP	DE
c.69 + 5G > C	NA	–	1	1/0	43	PNP	DE

AN: autonomic neuropathy; CTS: carpal tunnel syndrome; E: eye; H: heart; LM: leptomeningeal; NA: non-amyloidogenic; CM: cardiomyopathy; PNP: polyneuropathy; AFR: African; AM: American; AP: Appalachian; AT: Austrian; BR: British; CN: Chinese; CYP: Cypriot; DE: German; DON: Donegan; EUR: European; ES: Spanish; FR: French; GR: Greek; IT: Italian; IE: Irish; PT: Portuguese; SE: Swedish; HU: Hungarian.

Figure 2. Comparison of TTR-positive and TTR-negative study participants (TTR-status on the x-axis in all charts). (A) Gender. (B) Ages at disease onset and enrolment. (C) Family history. (D) Manifestation as cardiomyopathy (CM), polyneuropathy (PNP), or both. (E) Body Mass Index (BMI). (F) Number of symptoms.

Figure 3. Frequency of individual symptoms with TTR-negative (TTR−) depicted in grey and TTR-positive (TTR+) in red colour. Symptoms that show discrepancies between TTR-negative and TTR-positive study participants are depicted on the left. Symptoms in alphabetical order: All: Allodynia; ana: Anaemia; arr: Arrhythmia; bur: “burning feet”; car: History of carpal tunnel syndrome; che: Chest pain; cad: Bouts of constipation that alternate with diarrhoea; con: Constipation; dia: Diarrhoea; dif: Difficulty urinating or holding urine; diz: Dizziness or fainting upon standing; dys: Dyshidrosis; ehc: Enlargement of heart cavities; ehm: Enlargement of heart muscle; hea: Abnormal (fluttering) heartbeat; mlw: Muscle weakness in the legs; mua: Muscle atrophy in the legs; num: Numbness; obm: Inability to obtain or maintain an erection; pai: Pain; pal: Palpitation; sen: Reduced ability to sense temperature; sho: Shortness of breath; tin: Tingling; unw: Unintentional weight loss; wat: Water accumulation in the ankles and lower limbs.

Data availability statement

The data that support the findings of this study are available upon reasonable request from the corresponding author, J.H. (email: [email protected]). The data are not publicly available due to containing information that could compromise the privacy of research participants.