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doi: 10.1097/01.NT.0000359050.14985.92
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Netherlands investigators reported that 33 percent of the patients with progressive supranuclear palsy had at least one first-degree relative who had parkinsonism or dementia, compared with 25 percent of the control subjects.

A case-control study involving patients with progressive supranuclear palsy (PSP) found that they are more likely to have close relatives with parkinsonism — a finding that boosts the theory that PSP has a genetic cause.

In a paper published online on May 20 in advance of the July 14 print edition of Neurology, Netherlands investigators reported that 33 percent of the PSP patients had at least one first-degree relative who had parkinsonism or dementia, compared with 25 percent of the control subjects.

“Familial aggregation in PSP observed in this study supports the involvement of genetic factors and future studies that focus on identifying the genetic defect(s) underlying PSP and related disorders may help to elucidate the pathophysiological process of this disease,” the researchers concluded.

Study author Laura Donker Kaat, MD, a neurology resident at Erasmus University Medical Center in Rotterdam, told Neurology Today that “genetic factors definitely contribute to the onset of disease in some families.”

PSP, which is characterized by problems with balance and gait, had long been considered a sporadic disorder, but several studies have suggested that genetic factors are likely to be involved in at least some cases, according to the researchers.

For this study, the researchers focused on 172 PSP patients who were referred to them by neurologists and nursing home physicians. The patients, who were on average 66.5 years old at on onset of PSP, were examined and videotaped for review by a team that made a diagnosis using the NINDS criteria for PSP.



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Demographic data and family medical histories were gathered from the study participants or caregivers using questionnaires, and if possible, medical records and interviews were obtained from first-degree relatives to document what had been reported. The researchers defined parkinsonism as the presence of two or more of these symptoms: frequent falls, gait disturbance, speech problems, stiffness, slowness, tremor or medication use. Dementia was defined as memory problems with or without behavioral changes, a condition which may have required admission to a nursing home, according to the study. To add to the data on first-degree relatives, the researchers also sought out information on the grandparents of PSP patients.

Researchers looked at similar information for 519 control subjects, who were part of a population-based cohort study of people aged 55 or older living in the Rotterdam area. In all, the researchers obtained information on 3,023 first-degree relatives of controls and 986 first-degree relatives of PSP patients.

Family history was considered positive when at least one first-degree relative had dementia (any form) or parkinsonism (Parkinson disease or atypical parkinsonism), the researchers wrote. Autosomal dominance was defined as at least three relatives affected with dementia or parkinsonism over two or more generations.

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There was a stronger family history for parkinsonism and dementia among the PSP group, though there was not really a difference between the PSP group and the controls when it came to dementia cases alone.

“A total of 57 (33 percent) of PSP patients had at least one first-degree relative with dementia or parkinsonism,” the researchers wrote. “In 45 cases (26 percent), a single first-degree relative was affected, whereas, two or more affected first-degree relatives was found in 12 patients. If we take second-degree relatives into account, 12 families (7 percent) fulfilled the criteria for an autosomal dominant mode of inheritance.”

Within those families, “all families, except one, presented with a mixed phenotype of dementia or parkinsonism, with a PSP-like syndrome or parkinsonism in one or more affected relatives, and dementia in others.”

The researchers also noted that “tremor at disease onset occurred significantly more frequently in PSP patients with a positive family history compared to PSP patients with a negative family history” (9 percent versus 1 percent).

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The researchers also conducted genetic sequencing and brain autopsies on a subset of PSP patients. They reported that sequencing for the MAPT, LRRK2, and progranulin genes in families with autosomal dominance, as well as in some of the sporadic PSP patients, revealed a single MAPT mutation (P301L) in only one patient.

The researchers also reported that pathological examination of five cases with familial history “confirmed the clinical diagnosis of PSP, with predominant four repeat tau pathology in affected brain areas.”

Roger Kurlan, MD a professor of neurology at the University of Rochester School of Medicine, said the study “lends strong support to the notion that genetics are important to the development of PSP. There has already been a suggestion that genetics plays a role in PSP, but this provides additional support for that.”

He cautioned, however, that the study is limited by the fact that it was based largely on the gathering of family histories, an approach that is not always reliable.

“There can be problems with family history studies,” he said. “They are based on historical information provided by whoever is the informant and whatever medical records are obtained for review.” There is no way of knowing if a diagnosis is correct or if valuable information has been forgotten over time or overlooked, he added.

The research team acknowledged the study's potential pitfalls and said it was not the final word. But Dr. Donker Kaat told Neurology Today that clinicians should nonetheless be attentive to family history when seeing a patient for PSP.

“Practicing neurologists should ask PSP patients about parkinsonism and dementia in their first-degree relatives,” she said, and patients should ask questions, too. “Patients and their relatives are becoming increasingly aware of genetic causes, and will ask doctors about their risk for getting the same or related disorder.”

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• Donker Kaat L, Boon AJW, C. van Swieten JC, et al. Familial aggregation of parkinsonism in progressive supranuclear palsy. Neurology 2009; E-pub 2009 May 20.
    ©2009 American Academy of Neurology