Wallace et al. (1986) found substitution of alanine for threonine at position 60 of transthyretin (T60A) in an Irish kindred with familial amyloid polyneuropathy (AMYLD1; 105210) from the Appalachian region of the United States. As in the Indiana form (176300.0006), major deposits of amyloid occurred in the heart, but otherwise the disorder appeared 'to have a unique disease progression.' Benson et al. (1987) gave the clinical description of the Appalachian kindred with hereditary amyloidosis and late-onset cardiomyopathy. The family was partially of Irish ancestry (Benson, 1988). The proband of the family was 65 years old when he died of cardiomyopathy. For several years he had symptoms of peripheral neuropathy, including chronic diarrhea, bladder dysfunction, and sexual impotence. Bladder and prostatic biopsies were positive for amyloid. During the last few months of his life, he developed severe congestive heart failure and heart block that required a pacemaker. There were at least 22 affected individuals in the family. Although in general the late onset of the ailment placed it in type II amyloid polyneuropathy, the authors believed that the lack of eye involvement set the entity apart from the Indiana form of the disease. They pointed out the hazard that patients with this disorder will be misdiagnosed as having the immunoglobulin type of systemic amyloidosis, an error that might lead to chemotherapy and unjustified risk to the patient.
Amyloidosis resulting from this variant has been referred to as the Appalachian type (Wallace et al., 1988; Benson, 2001).
Koeppen et al. (1990) restudied the family reported by Koeppen et al. (1985). They updated and revised the pedigree and determined that the underlying mutation was thr60-to-ala, the Appalachian mutation.
Staunton et al. (1987) described transthyretin-derived amyloid polyneuropathy of a hereditary nature in County Donegal, Ireland. The clinical picture was most consistent with that of the Portuguese type, although the age of onset was somewhat older. In fact, however, as reported by Staunton et al. (1991), the mutation proved to be the thr60-to-ala Appalachian mutation which had been found in a family of Irish ancestry living in the Appalachian region of the U.S.
In 5 patients with cardiac amyloidosis, 3 of whom also had renal and or splenic involvement, Lachmann et al. (2002) identified heterozygosity for the T60A mutation in the TTR gene. The predominant clinical feature in these patients was cardiomyopathy and/or neuropathy.
PubMed [ID: 3722385]