Early age of onset in fatal familial insomnia. Two novel cases and review of the literature.
Fatal familial insomnia (FFI) is a prion disease exhibiting the PRNP D178N/129M genotype. Features of this autosomal dominant illness are progressive insomnia, dysautonomia, myoclonus, cognitive decline and motor signs associated with thalamic nerve cell loss and gliosis. In contrast to the new variant of Creutzfeldt-Jakob disease (vCJD) the onset of FFI is in middle to late adulthood. We report two male patients who belong to a large German FFI kindred. They were examined clinically, and postmortem neuropathological examination was carried out in collaboration with the German reference centre for prion disease. Additionally, the prion protein gene (PRNP) was analysed. To identify further patients with disease onset under 30 years of age a comprehensive literature review was carried out. Two male patients presented with typical symptoms of FFI at the age of 23 and 24 years. In their kindred, the age of onset has never before been under 44 years of age. Our literature review identified five additional early onset cases who died at age 21 to 25 years. In all 22 reviewed FFI families the median manifestation age was 49.5 years. Although phenotypic variability of FFI is common, age of onset under 30 years has been considered to be a hallmark of vCJD with a mean manifestation at 27 years of age. Our findings underline that in addition to vCJD, FFI must be considered in cases of young-onset prion disease. This has considerable impact on clinical management and genetic counselling.
Harder
A
A
Institute of Neuropathology, Charité Humboldt University, Augustenburger Platz 1, 13353 Berlin, Germany. anja.harder@charite.de
Gregor
A
A
Wirth
T
T
Kreuz
F
F
Schulz-Schaeffer
W J
WJ
Windl
O
O
Plotkin
M
M
Amthauer
H
H
Neukirch
K
K
Kretzschmar
H A
HA
Kuhlmann
T
T
Braas
R
R
Hahne
H H
HH
Jendroska
K
K
D000328:Adult; D017668:Age of Onset; D001216:Asparagine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D005817:Genetic Counseling / Q000379:methods; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D034062:Insomnia, Fatal Familial / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008715:Methionine / Q000378:metabolism; D008875:Middle Aged; D009460:Neurologic Examination; D010375:Pedigree; D011180:Postmortem Changes; D011328:Prions / Q000235:genetics / Q000378:metabolism; D012196:Review Literature as Topic; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D014055:Tomography, Emission-Computed / Q000379:methods
D011328:Prions; D001224:Aspartic Acid; D001216:Asparagine; D008715:Methionine; D005947:Glucose