Progranulin mutations in primary progressive aphasia: the PPA1 and PPA3 families.

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.

Normal pressure hydrocephalus and large head size.

OBJECTIVE: To determine if patients with normal pressure hydrocephalus (NPH) have larger head size than normal controls. BACKGROUND: In 1989, Graff-Radford and Godersky noted that 3 of 30 patients diagnosed with NPH had large heads. They hypothesized that the cause of NPH in their patients was arrested congenital hydrocephalus becoming symptomatic later in life. METHODS: Participants included 31 newly diagnosed NPH patients (21 male, 10 female) seen by the same neurologist (N.R.G.-R.) at Mayo Clinic Jacksonville from January 1, 1995 through December 31, 2000, and 459 normal controls (226 male, 233 female) from the Charlotte County Healthy Aging Study. RESULTS: Head size was statistically larger for NPH males (median, 59.0 cm, range, 57.0-63.0 cm) compared with normal males (median, 57.8 cm, range, 53.3-62.8) (p < 0.01). Head size was also larger for NPH females (median, 6.3 cm, range, 53.5-58.0 cm) compared with normal females (median, 54.6 cm, range, 51.4-59.7 cm) (p < 0.02). CONCLUSION: Patients with NPH have larger head circumferences as a group than normal controls. This was found in both males and females. Results suggest that a significant proportion of patients with NPH may have congenital hydrocephalus that becomes symptomatic later in life.

Familial primary progressive aphasia.

Primary progressive aphasia (PPA) is a neurodegenerative disease presenting with isolated, progressive, language dysfunction. After at least 2 years, dementia may develop, but the aphasia predominates. Few families with hereditary PPA have been reported; some have autosomal dominance. A chromosome 17 mutation in tau exon 13 has been found in one family, and a few have linkage to chromosome 17. However, early appearance of prominent memory, behavior, and motor impairments differentiates these patients from typical PPA. The objective was to report clinical features, pathology, and genetic analysis of a family with typical PPA. We report three siblings with the typical clinical syndrome of PPA. Each presented with word-finding difficulties and early anomia. Ages at onset were 60, 61, and 65 years. Aphasia was the only symptom for at least 2 years. A nonaffected brother is 75 years of age. Family history review found no other affected relatives. Neuropathology in one patient demonstrated "dementia lacking distinctive histopathology" with ubiquitin-positive cortical neurons. DNA analysis of the proband did not detect any known mutation in tau exons 1-5, 7, or 9-13. To our knowledge, this is the first family presenting with hereditary aphasia in which typical PPA occurs in all affected members.