Diagnostic radioimmunoassay for familial amyloidotic polyneuropathy before clinical onset
Insights
This study introduces a radioimmunoassay (RIA) for early familial amyloidotic polyneuropathy (FAP) diagnosis. The method detects variant transthyretin (TTR) in serum, enabling pre-symptomatic identification and genetic counseling.
Area of Science:
- Neurology
- Genetics
- Biochemistry
Background:
- Familial amyloidotic polyneuropathy (FAP) is a hereditary disorder characterized by amyloid fibril deposition.
- Type I FAP (FAP1) involves a specific variant of transthyretin (TTR) with a methionine-for-valine substitution at position 30.
- Early diagnosis is crucial for managing FAP and providing genetic counseling, but current methods often rely on clinical manifestation.
Purpose of the Study:
- To develop a non-invasive, early diagnostic method for familial amyloidotic polyneuropathy (FAP) before the onset of clinical symptoms.
- To establish a reliable method for detecting the variant transthyretin (TTR) associated with FAP1 in patient serum.
Main Methods:
- Development of a radioimmunoassay (RIA) to measure serum levels of the variant transthyretin (TTR).
- The RIA utilizes a nonapeptide derived from the variant TTR (positions 22-30).
- Serum samples were analyzed from FAP1 patients, their children, healthy individuals, and patients with other forms of amyloidosis.
Main Results:
- The variant TTR was detected in serum of 45 Japanese FAP1 patients (mean level 9.18 mg/dl).
- Variant TTR was absent in 100 normal individuals, 4 primary amyloidosis cases, 6 secondary amyloidosis cases, and 26 non-inheriting family members.
- Variant TTR was identified in 9 asymptomatic children of FAP1 patients, indicating pre-clinical disease presence.
Conclusions:
- The developed RIA is a sensitive and specific non-invasive diagnostic tool for FAP1.
- This method allows for early diagnosis of FAP1 in childhood, even in asymptomatic individuals within affected families.
- The RIA facilitates timely genetic counseling and potential interventions for FAP1.
Abstract:
The purpose of this study is to develop an early diagnostic method for familial amyloidotic polyneuropathy (FAP) before clinical manifestations appear around the age of 30 yr. Amyloid fibrils isolated from type I FAP (FAP1) of Portuguese, Swedish, and Japanese origins consist of a variant transthyretin (TTR) that contains a methionine-for-valine substitution at position 30 or a mixture of normal TTR and this variant form. The variant TTR is present in the serum of FAP1 patients and can be measured by a radioimmunoassay (RIA) based on a nonapeptide (positions 22-30) derived from the variant TTR. Serum levels of the variant TTR in 45 Japanese FAP1 patients range from 4.71 to 17.61 mg/dl with a mean value of 9.18 mg/dl. The variant TTR is not present in the serum of 100 normal individuals, in four cases of primary and six cases of secondary amyloidosis, nor in 26 non-inheriting members of families with FAP1. The variant TTR level is measured in 24 children of 15 FAP1 patients as well. The variant TTR is already present in nine symptom-free children with the mean serum level of 11.90 mg/dl, but it is not present in 15 other children. FAP1 patients can be differentiated from non-FAP by this noninvasive diagnostic method even within families. The RIA can be applied worldwide to this intractable disorder for early diagnosis during childhood and for appropriate genetic counseling.
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