Two‐tiered DNA‐based diagnosis of transthyretin amyloidosis reveals two novel point mutations

Abstract

We analyzed 11 consecutive unrelated cases of polyneuropathy due to transthyretin amyloidosis. Direct sequencing of the promoter region, exons, and splice junctions revealed that each patient was heterozygous for a mutation: six patients had valine 30 substituted by methionine (V30----M; Portuguese-Japanese type), one had threonine 60 substituted by alanine (T60----A; Appalachian type), and two had serine 77 substituted by tyrosine (S77----Y; Illinois type). In addition, two patients had previously undescribed mutation: phenylalanine 33 substituted by leucine (F33----L) and phenylalanine 64 substituted by leucine (F64----L). From present information, the probands of these novel mutations do not exhibit any pathology that clearly distinguishes them from individuals with the other mutations. The mutations extend the range of mutations associated with amyloidotic polyneuropathy. In our 11 patients, the different mutations did not seem to correlate with distinct clinical phenotypes. We developed PASA assays (PCR amplification of specific alleles) for each of the five mutations. PASA can be used by any diagnostic laboratory that can perform PCR to rapidly detect any of the known mutations. The minority of samples with an undescribed mutation can be sent to a specialty laboratory for delineation of the mutation by direct genomic sequencing. The presently described combination of methods may have widespread utility in the diagnosis of genetic disease.

Familial amyloid with a transthyretin leucine 33 mutation presenting with ascites

“…One previous case of TTR-amyloidosis due to a TTR leucine 33 mutation has been reported by two groups [8,9]. Similar to our case, this patient was also of PolishAmerican ethnic origin, had no family history of amyloidosis, and had a late onset of symptoms at age 53.…”

“…More than 50 TTR mutations are known to cause amyloid [1,2,4,7]. The TTR substitution of leucine for phenylalanine at position 33 (TTR leucine 33 mutation) has been described in only one previous case, reported by two groups [8,9].…”

Extended Phenotype in the Transthyretin Tyr77 Familial Amyloid Polyneuropathy

“…Several Mendelian disorders occur with relatively high frequency in Yemenite Jews, including Machado-Joseph disease, which like FAP is common among individuals with Portuguese ancestry [28]. However, Portuguese descendants are not among the reported Tyr77 carriers from North America [4, 7,10,11,12] or Europe [5, 6, 8, 9,13,14,15], and since haplotype analysis indicates multiple Tyr77 founders in most studies [5, 13, 15, 29], it seems reasonable to assume an independent mutation event in the present family.…”

“…In contrast to Met30, the Tyr77 phenotype has been described in much fewer patients [6,7,8,9,10], often in a short or tabular form [4, 5,11,12,13,14,15], and the full spectrum of its clinical expression is still not clear. We report the first Jewish family of Yemenite origin with FAP due to the Tyr77 TTR mutation presenting atypical clinical features.…”

Misdiagnosed case of transthyretin amyloidosis in a fully investigated patient

“…Впервые она описана в США в 1991 г. двумя группами авторов у проживающего в США единственного больного в семье польско-ли-товского происхождения с преимущественно невро-логическим фенотипом и дебютом в 53 года [9,10]. В последующем описана пациентка 65 лет с аналогич-ной мутацией без семейного анамнеза.…”