Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred

Abstract

The most frequent localization of amyloid in transthyretin (TTR) mutations is in the peripheral nerve, causing familial amyloidpolyneuropathy (FAP). It is generally accompanied by involvement of other organs such as the myocardium and kidney. To date, over 70 TTR point mutations have been reported in literature, with different phenotypes depending on the location of the mutation in the TTR gene. This paper deals with a point mutation in exon 2 position 47 of the TTR gene, encoding the substitution of glycine with glutamate. The mutation was found in an Italian family with 5 patients over 3 generations. The phenotype was characterised by peripheral neuropathy and autonomic dysfunction, associated in some patients with cardiomyopathy and renal involvement. The symptoms were very severe and the patients did not survive long, thus suggesting the aggressive nature of the pathological process. Moreover, in the succeeding generations of this family, there was genetic anticipation in the age of onset of the disease.

An aggressive form of familial amyloid polyneuropathy caused by a Glu54Gly mutation in the transthyretin gene

“…And the phenotype may be influenced by the host's modifying genes, normal genetic heterogeneity and environmental factors (Mascalchi et al, 1999). Aggressive phenotypes of FAP have presented with a Leu55Pro variant, a Glu54Lys variant or a Gly47Glu variant of the TTR gene (Jacobson et al, 1992;Togashi et al, 1999;Pelo et al, 2002). The Leu55Pro and Glu54Lys variants affect the D strand of the TTR gene.…”

Familial amyloidotic polyneuropathy with severe renal involvement in association with transthyretin Gly47Glu in Dutch, British and American-Finnish families

“…Although the correlation between genotype and phenotype in FAP is very inconsistent, knowledge of the pattern and natural history of disease associated with particular mutations nevertheless offers the best guidance for management of individual patients, including the role and timing of treatment by orthotopic liver transplantation. FAP in association with TTR Gly47Glu has been identified previously 5 , and its clinical features have been described in an Italian kindred 6 . We report here its broader phenotype, notably including frequent severe renal disease, in members of Dutch, British and American families.…”

“…The only previous description of ATTR Gly47Glu has been in a single Italian family with FAP, two members of which were described in detail 6 . This report suggests that peripheral neuropathy may have been an earlier and more predominant feature, but autonomic dysfunction, amyloid cardiomyopathy and renal involvement were similarly present.…”

Clinical Profile and Prognosis of Hereditary Transthyretin Amyloid Cardiomyopathy: A Single-Center Study in South China

“…Ten different TTR gene mutations, including 9 missense variants and 1 small deletion mutation, were identified. All of the missense variants have been listed as pathogenic or likely pathogenic in the TTR mutation and ClinVar databases (Table 4) (15)(16)(17)(18)(19)(20)(21)(22)(23). The missense mutations were related to the mixed phenotype.…”