Frontotemporal dementia in a Brazilian kindred with the c9orf72 mutation

Abstract

Objectives: To describe the clinical features of a Brazilian kindred with C9orf72 frontotemporal dementia-amyotrophic lateral sclerosis and compare them with other described families with C9orf72 and frontotemporal dementia-amyotrophic lateral sclerosis-causing mutations.

Design: Report of a kindred.

Setting: Dementia center at a university hospital.

Patients: One kindred encompassing 3 generations.

Results: The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed polymerase chain reaction and Southern blot. The observed phenotypes were behavioral variant frontotemporal dementia and amyotrophic lateral sclerosis with dementia, with significant variability in age at onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations, and more posterior atrophy on neuroimaging than is typical for frontotemporal dementia were seen.

Conclusions: Behavioral variant frontotemporal dementia due to C9orf72 expansion displays some phenotypic heterogeneity and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede the diagnosis of dementia by many years and may be a distinguishing feature of this mutation.

Figure 1. UCSFBR1 kindred pedigree

Legend: Open symbols represent unaffected individuals. Arrowhead denotes the proband. The symbol “+” indicates individuals who were tested for the mutation. Roman numerals denote the generation; Arabic numbers identify each individual in his/her generation. bvFTD= behavioral variant of frontotemporal dementia. ALS= amyotrophic lateral sclerosis.

Figure 2. Brain MRI – Patients III-1 and II-4

Legend: Parasagittal and axial T1-weighted 3T brain MRI. 2-A: Patient III-1 - mild atrophy in the dorsal and posterior aspects of the brain; 2-B: Patient II-4 - mild atrophy of the anterior temporal lobes, insula and orbitofrontal region, as well as dorsal atrophy.

Figure 3. Molecular genetic analyses of C9orf72 repeat expansions in UCSFBR1 family

Legend: (A) Fluorescent fragment length analysis of a PCR fragment containing the GGGGCC repeat in C9orf72 in 4 patients (II-1, III-1, II-2 and II-4) and one unaffected spouse (II-0). A lack of transmission from the affected parent (II-1) to the affected offspring (III-1) is seen. Numbers under the peaks indicate number of GGGGCC hexanucleotide repeats. (B) PCR products of repeat-primed PCR reactions separated on an ABI3730 DNA Analyzer and visualized by GENEMAPPER software. Electropherograms are zoomed to 2,000 relative fluorescence units to show stutter amplification. One expanded repeat carrier (II-1) and one healthy control are shown. (C) Southern blotting of 3 expanded repeat carriers and one unaffected spouse using genomic DNA extracted from blood. Patients with expanded repeats (II-1, III-1 and II-2) show additional alleles ranging from 5–23 kb, while the normal spouse (II-0) only shows the expected ~2.3 kb wild-type allele.