Late-onset familial amyloidosis polyneuropathy associated with c.186G>C in transthyretin

TL;DR

A 74-year-old man with late-onset nerve damage was found to have a new genetic variant in the TTR gene linked to a rare inherited disease.

Contribution

The study reports a novel TTR variant (c.186G>C) associated with late-onset familial amyloidosis polyneuropathy.

Findings

The patient showed progressive sensory and motor deficits consistent with polyneuropathy.

DNA sequencing identified the c.186G>C TTR variant, which results in the Glu62Asp amino acid change.

This variant has not been previously described in the literature.

Abstract

The most common form of hereditary amyloidosis is associated with variants of transthyretin (TTR). Familial amyloidosis polyneuropathy associated with variants of TTR (FAP-TTR) is an infrequent, multisystemic disease, with predominant involvement of the peripheral nervous system. More than 130 pathogenic variants have been identified so far and most of them are amyloidogenic, being Val30Met the most frequently described

A 74 year-old male was evaluated for progressive decreased sensitivity and associated loss of strength in four limbs in the previous two years, needing assistance for walking. Areflexia, bilateral tibialis anterior and gastrocnemius atrophy, bilateral anesthesia and apalesthesia were found in lower limbs. Bilateral hypoesthesia was reported in upper limbs. No painful dysesthesia, hyperalgesia or allodynia were found. DNA sequencing of the TTR gene led to the detection of the variant c.186G>C in heterozygous state. The resulting variant (Glu62Asp), located in the critical functional domain, has not been published before

The importance of considering late onset, sporadic FAP-TTR as a differential diagnosis of cryptogenic polyneuropathy is highlighted.

Tables

Tabla Nº 1. Complementary tests

Specific test	Result
Four limbs electromyography	Axonal sensory-motor polyneuropathy with signs of denervation
Echocardiogram	Left atrial dilatation, concentric ventricular hypertrophy and preserved ejection fraction
24-hours electrocardiography (Holter)	Sinus rhythm with a permanent first-degree atrioventricular block

Full text

Introduction

The most common form of hereditary amyloidosis is due to variants of transthyretin (TTR), ^ 1 ^ a protein associated with neurogenesis and nerve regeneration. ^ 2 ^ Familial amyloidosis polyneuropathy caused by variants of TTR(FAP-TTR) is a multisystemic disease with peripheral nervous system involvement and amyloid deposits in the endoneurium. ^ 3 ^ FAP-TTR variants were first described in endemic areas; currently, FAP-TTR is considered a worldwide disease, with a global prevalence of 5000 to 10 000 subjects. ^ 4 ^ Nevertheless, prevalence of TTRamyloidosis is likely higher than previously recognized. ^ 5 ^

Hereditary TTR amyloidosis is characterized by autosomal dominant inheritance, due to variants in the TTR gene.(4,6-7) More than 130 pathogenic variants have been identified, most of them amyloidogenic, ^ 6 ^ with phenotypes including neuropathy, cardiomyopathy, and, infrequently, ocular and cerebromeningeal involvement. ^ 4 ^ Val30Met is the most common pathogenic variant. ^ 8 ^ A registry has been started to record the significance of variants and phenotypes in hereditary TTR amyloidosis. ^ 9 ^ Several variants have been linked to clusters of families worldwide, including Thr60Ala, Phe64Leu, Ala97Ser, Glu89Gln, Ser50Arg, Ser77Tyr and Ser77Phe. Other variants have been reported only in a single family. ^ 8 ^

We describe the first patient with late-onset amyloidotic polyneuropathy with TTRGlu62Asp due to the variant c.186G>C.

Case report

A 74 year-old male was evaluated for decreased sensitivity in lower limbs during the previous 2 years. Upper limbs were also compromised in the last 12 months. He complained of associated loss of strength in four limbs, needing assistance for walking. Recent constipation and ill-defined class II dyspnea were also added. No orthostatic dizziness was present. He had no personal or family neurological medical history. He was the first of two siblings; his sister died of meningitis when she was 7 months old. His father died at the age of 77 (lung cancer) and his mother at the age of 63 (gallbladder cancer). His parents were non-consanguineous and of Argentinean native origin. He had a 41 year-old healthy son, whose 14 year-old son was diagnosed with autism spectrum disorder, and a 53 year-old healthy daughter, whose two daughters (29 and 15 years old) were healthy.

A neurological examination showed lower limbs areflexia, bilateral anesthesia and apalesthesia; hypotonia, weakness (Medical Research Council Scale grade 3), bilateral tibialis anterior and gastrocnemius atrophy were found in the muscular examination. In addition, bilateral hypoesthesia was reported in upper limbs. No painful dysesthesia, hyperalgesia, thermoalgesic dissociation or allodynia were found. Complete blood count, renal function tests, liver enzymes, glycemia, thyroid function tests, muscle enzymes and lipid profile were within normal range. Urine tests were negative for proteinuria. Test for detection of a serum and urine monoclonal component were negative. Blood tests for rheumatic biomarkers and hepatitis B, hepatitis C and human immunodeficiency virus were also negative.

Other complementary tests results are summarized in Table 1.

Tabla Nº 1: Complementary tests

DNA sequencing of the TTRgene was suggested as part of the screening for idiopathic polyneuropathy. DNA samples were collected and amplified using a primers pool designed using the Ion Ampliseq^TM^ software for TTRgene, according to the manufacturer recommendations. The analysis was performed by amplicon next generation sequencing using Post Light^TM^ Ion Semiconductor Sequencing in an Ion Personal Genome Machine System^TM^ platform. This methodology led to the detection of the variant c.186G>C in heterozygous state, which is associated with an alteration in the protein direction. The resulting variant (Glu62Asp) is located in the critical functional domain (Peptidase_M14NE-CP-C_like), ^ 10 ^ without known benign variants. Variant c.186G>C has not been published before and has been reported only in ClinVar, but not in projects 1000Genomes, Exome Aggregation Consortium, NHLBI and Genome Aggregation Database. A previous report of variant c.186G>T as a cause of TTR amyloidosis was found; ^ 1 ^ both variants are predicted to produce the same amino acid change. We concluded that this novel variant should be considered likely pathogenic according to the available information, the clinical phenotype suggesting FAP-TTR and the ACMG variant classification standards. ^ 11 ^ The proband's son and daughter were properly counseled, but they initially refused presymptomatic genetic testing.

Discussion

We report the first case of late-onset FAP-TTRassociated with the variant c.186G>C. Our affirmation is supported by the characteristic clinical manifestations, the results of complementary tests and the genetic analysis.

Dupuy et al has previously reported a patient with late-onset cardiac amyloidosis with a novel variant (Glu42Asp) in the same nucleotide; ^ 1 ^ nevertheless, they described a c.186G>T alteration, while DNA sequencing in our patient showed a previously unreported c.186G>C variant. In both the Dupuy et al's report and our case, the new codon results in transcription of aspartate. However, the case report from Dupuy et al presented with isolated late-onset amyloid cardiomyopathy and our patient had a predominant neuropathic phenotype. Phenotypic heterogeneity may be linked to differences among specific pathogenic TTR variants, geographic factors, the subtype of endemic versus non-endemic disease, and several probable environmental factors that are currently unknown. Any or all of these factors may be involved in the phenotypic difference of these patients with the same amino acid substitution.

Other TTR variants with an amino acid residue substitution at the same codon have been described. Ueno et al reported a Japanese 42 year-old male with isolated lower limbs neuropathy and chronic diarrhea. A nerve biopsy showed amyloid deposits and Glu42Gly variant was confirmed by genetic testing. ^ 12 ^ The same variant has also been reported by Skare et al in four siblings, with a clinical phenotype including peripheral neuropathy, diarrhea, vitreous opacity and cardiomyopathy. ^ 13 ^ By contrast, our patient showed polyneuropathy and constipation, without other clinical or echocardiographic alterations.

We underscore the importance of including FAP-TTR among early differential diagnosis in patients with presumably idiopathic polyneuropathy. However, a diagnosis delay of 8 years has been reported. ^ 14 ^ Misleading diagnoses are related with sporadic, late-onset and varied clinical presentation patterns. ^ 15 ^

Conclusion

Being a currently treatable condition, early diagnosis of FAP-TTR is essential for the rapid introduction of drugs that dramatically improve the quality of life and also for genetic counseling for the patient and at-risk family members. TTR gene sequencing may be considered the gold standard molecular diagnosis test, since this tool improves the probability of detecting new variants, as currently described.