The First Historically Reported Italian Family with FTD/ALS Teaches a Lesson on C9orf72 RE: Clinical Heterogeneity and Oligogenic Inheritance

Journal of Alzheimer's Disease : JAD
Maria Pia GiannoccaroSabina Capellari

Abstract

In 1969, Dazzi and Finizio reported the second observation of frontotemporal dementia (FTD) - amyotrophic lateral sclerosis (ALS) association in a large Italian kindred affected by an autosomal dominant form of ALS with high penetrance, frequent bulbar onset, and frequent cognitive decline. To expand the original characterization of this family and report the link with the C9orf72 repeat expansion (RE). We followed or reviewed the medical records of thirteen patients belonging to the original family and performed genetic analyses in four individuals. Eight patients presented with ALS, four with FTD, and one with schizophrenia. The C9orf72 RE was found in three patients but not in the healthy survivor. Additionally, we found a novel possible pathogenic variant in the ITM2B gene in one patient with a complex phenotype, associating movement disorders, psychiatric and cognitive features, deafness, and optic atrophy. The neuropathological examination of this patient did not show the classical features of ITM2B mutation related dementias suggesting that the putative pathogenic mechanism does not involve cellular mislocalization of the protein or the formation of amyloid plaques. We showed that the original Italian pedigree described ...Continue Reading

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Citations

Mar 27, 2021·Journal of Neurology·Anna Bartoletti-StellaUNKNOWN BoReALS
Sep 5, 2021·Cellular and Molecular Life Sciences : CMLS·Filipa MartinsSandra Rebelo

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Methods Mentioned

BETA
PCR

Software Mentioned

GeneMapper
Splicing Finder
MutationTaster
Gene Mapper
Polyphen2
FATHMM
Mutation assessor
SIFT

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