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Progranulin Mutations in Primary Progressive Aphasia:  The PPA1 and PPA3 Families

Marsel Mesulam, MD; Nancy Johnson, PhD; Thomas A. Krefft, MD; Jennifer M. Gass, BS; Ashley D. Cannon, BS; Jennifer L. Adamson, MS; Eileen H. Bigio, MD; Sandra Weintraub, PhD; Dennis W. Dickson, MD; Michael L. Hutton, PhD; Neill R. Graff-Radford, MBBCh FRCP(London)
Arch Neurol. 2007;64(1):43-47. doi:10.1001/archneur.64.1.43.
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Background  Primary progressive aphasia (PPA) is a language-based dementia characterized by fluent or nonfluent language disorder as its principal feature.

Objective  To describe progranulin gene mutations in 2 families with PPA.

Design  Report of affected families.

Setting  Academic research.

Patients  Two families, PPA1 and PPA3, were studied. Genomic DNA was isolated from 3 of 4 siblings in PPA1, from all 3 siblings in PPA3, and from more than 200 control subjects.

Main Outcome Measures  All 12 coding exons of the progranulin gene and the 5" and 3" untranslated regions were amplified by polymerase chain reaction and were sequenced in both directions using relevant primers.

Results  Both affected members of PPA1 for whom DNA was available and both affected sisters of PPA3 had a progranulin gene mutation not found in the unaffected siblings or in the controls. The mutations likely cause a null allele and a reduction in the level of functional progranulin protein. Both affected members of PPA1 with autopsies had frontotemporal lobar degeneration with tau-negative ubiquinated inclusions.

Conclusions  To our knowledge, these are the only known families in which affected members display phenotypical homogeneity for PPA in the initial stages of the disease. In both families, the disease segregated with progranulin gene mutations. Whether progranulin dysfunction also extends to sporadic PPA and how it affects the initial anatomical specificity of neurodegeneration remain to be determined.

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Figure.

The PPA1 and PPA3 families. PPA1:B and PPA3:C were unaffected, with neither dementia nor progranulin gene mutations. Squares represent men; circles, women; solid symbols, affected members; open symbols, unaffected members; diagonal lines, deceased; and numbers, age at death in years.

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Figure.

Neuropathologic findings in affected patient PPA1:D. A, The left hemisphere shows diffuse cortical atrophy that is accentuated in the perisylvian region. Note the marked widening of the sylvian fissure (arrow). B, A coronal section at the level of the columns of the fornix reveals enlargement of the frontal horn of the lateral ventricle, widening of the transverse fissure, and thinning of the cortical ribbon of the opercular frontal and temporal cortices, as well as of the inferior insular cortex. C-E, Ubiquitin immunohistochemistry shows sparse cytoplasmic inclusions of the hippocampal dentate fascia (C), while the temporal cortex (D) has many short neuritic processes and neuronal intranuclear inclusions (arrows) in superficial cortical layers, and the striatal pathologic condition (E) is characterized by dystrophic neurites and by neuronal intranuclear inclusions (arrow).

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Figure.

Genomic sequence chromatograms showing the mutations found in the PPA1 and PPA3 families. A and B, Analysis of exon 9 (arrow) in an affected member of the PPA1 family shows the single nucleotide deletion, in contrast to the unaffected member PPA1:B. C and D, Analysis of exon 11 (arrow) in an affected member of the PPA3 family shows the C>T transition that creates a premature stop codon, which is not seen in the unaffected member PPA3:C.

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