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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.

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.

Author Affiliations: Cognitive Neurology and Alzheimer's Disease Center (Drs Mesulam, Johnson, Bigio, and Weintraub) and Departments of Neurology (Dr Mesulam), Psychiatry (Drs Johnson and Weintraub), and Pathology (Dr Bigio), Northwestern University Feinberg School of Medicine, Chicago, Ill; and Department of Neuroscience, Mayo Clinic College of Medicine, Rochester, Minn (Drs Krefft, Dickson, Hutton, and Graff-Radford and Mss Gass, Cannon, and Adamson).

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