A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis.
BACKGROUND
More than 80 transthyretin (TTR) mutations have been described, most associated with amyloidosis. Peripheral neuropathy is the most common clinical presentation in TTR amyloidosis although the carpal tunnel syndrome (CTS) may be the first symptom and skin can be involved, as transthyretin amyloidosis is a systemic disease.


METHODS
The 78 year-old proband, belonging to a French family of Italian origin, presented with a 5 year history of peripheral neuropathy in the lower extremities. However, 15 years earlier he had had surgery for bilateral CTS. Amyloidosis was diagnosed on salivary gland and skin biopsies. Immunohistochemistry on skin biopsy was positive using anti-TTR. The proband has 10 siblings, 5 have CTS.


METHODS
SSCP and direct sequencing of exons 2, 3, and 4 of the TTR gene were done on DNA from the proband and his brother who had had CTS. To confirm the mutation a PCR-IMRA was done.


RESULTS
SSCP analysis of TTR exons 2, 3, and 4 did not suggest a mutation. Sequence analysis of TTR exon 3 revealed heterozygosity in both subjects for a single basepair transversion from A to T in codon 78 (TAC-->TTC) indicating a tyrosine to phenylalanine change. The mutation was confirmed by PCR-IMRA.


CONCLUSIONS
This TTR mutation (Tyr78Phe) is associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. It is also associated with late onset of the disease.
Magy
Nadine
N
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Medical Research and Library Building, IB-5th Floor, 975 West Walnut Street, Indianapolis, IN 46202, USA.
Liepnieks
Juris J
JJ
Gil
Helder
H
Kantelip
Bernadette
B
Dupond
Jean-Louis
JL
Kluve-Beckerman
Barbara
B
Benson
Merrill D
MD
D000368:Aged; D000686:Amyloidosis / Q000175:diagnosis* / Q000503:physiopathology; D001483:Base Sequence; D002349:Carpal Tunnel Syndrome / Q000503:physiopathology*; D006801:Humans; D008297:Male; D010375:Pedigree; D010523:Peripheral Nervous System Diseases / Q000503:physiopathology*; D010649:Phenylalanine / Q000378:metabolism; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D011228:Prealbumin / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000473:pathology*; D014443:Tyrosine / Q000378:metabolism
D011228:Prealbumin; D014443:Tyrosine; D010649:Phenylalanine