Comparison of family histories in FTLD subtypes and related tauopathies

Frontotemporal lobar degeneration (FTLD) is a progressive dementia with typical age at onset before 65 years. Research criteria divide FTLD into three clinical subtypes: frontotemporal dementia (FTD), semantic dementia (SD), and progressive nonfluent aphasia (PNFA). FTD begins with changes in behavior and personality, while SD and PNFA begin as language disorders. With FTLD, there is a strong association with parkinsonism and ALS. FTLD disorders overlap clinically and neuropathologically with two related tauopathies: corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP).¹

Previous reports suggest that 30 to 50% of patients with FTLD have a family history of dementia^2,3 with approximately 10 to 40% of cases following an autosomal dominant inheritance pattern. As many as 18% of FTLD families with an autosomal dominant pattern of inheritance have a mutation in the tau gene on chromosome 17.¹ Other families have been linked to chromosomes 3, 9, and a non-tau region of chromosome 17^1,4 and to presenilin 1 (PSEN1).³ Other syndromes with FTD-like symptoms include inclusion body myopathy associated with Paget disease of the bone and FTD caused by mutations in the VCP gene, Naku-Hakola disease caused by mutations in DAP12 and TREM2, and parkinsonism-dementia complex of Guam in which no clear genetic etiology has been found. The H1H1 tau genotype has a strong association with PSP and CBD.¹ New linkages to these diseases, such as PSP and chromosome 1q, are reported frequently in the scientific literature. In addition to genetic heterogeneity, there is phenotypic and pathologic heterogeneity even within families.¹

We analyzed family history in FTD, SD, PNFA, PSP, and CBD to assess whether the hereditary patterns were similar or differed with differences suggesting the existence of genetically distinctive groups.

Methods.

Genetic counselors from the dementia programs at the University of California, San Francisco (UCSF) and the University of Pennsylvania independently reviewed pedigrees consisting of at least three generations from their research cohorts. Collectively these cohorts consisted of 99 patients with FTD, 27 with FTD/ALS, 53 with SD, 29 with PNFA, 18 with PSP, and 43 with CBD. FTLD subtypes were defined by the Neary criteria,⁵ ALS by El Escorial criteria,⁶ PSP by Litvan criteria,⁷ CBD by UCSF and the University of Pennsylvania criteria, and Alzheimer disease by National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer’s Disease and Related Disorders Association criteria.⁸ Whenever possible, medical history records and autopsy reports were obtained for affected family members. Each pedigree was classified into one of the following categories: 1) autosomal dominant if there were at least three people in two generations affected with FTLD, ALS, CBD, or PSP with one person being a first-degree relative of the other two (mitochondrial inheritance may also fit this pattern); 2) family aggregation if there were at least three relatives with dementia or ALS and criteria for autosomal dominant inheritance were not met; 3) a single affected first-degree family member with dementia or ALS (if the proband had PSP, a first-degree relative with Parkinson disease was included); 4) no contributory family history, unknown family history. Twenty-one patients were autopsy confirmed; six with FTD, eight with FTD/ALS, five with CBD, and two with PSP. MAPT mutations were reported in two unrelated cases. When there was more than one case in a family, only a single proband was included to avoid overestimation of hereditary cases.

Statistical analyses were performed to assess the association of a patient’s disease diagnostic group and family history of dementia using exact tests for contingency tables⁹ and computer routines in the StatXact package. In addition to calculating the significance probability of the test of independence, we also examined the contribution to χ² of each cell in the table to identify disease-family history combinations that departed most from independence.

Results.

When all the groups are analyzed together, 13.4% of cases are autosomal dominant and 37.6% have a significant family history (categories 1, 2, and 3). However, analysis of the cohorts separately demonstrates significant differences in the degree of heritability of the FTLD subtypes and related tauopathies (figure, table).

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Figure. Percentage of positive family history in subtypes of frontotemporal lobar degeneration and related tauopathies.

Diagnosis and family history were shown to be associated (p < 0.001). An examination of the contributions to χ² identified two cells with large discrepancies from independence (χ² contributions > 3.84): 1) There were more patients with FTD/ALS with an autosomal dominant history. 2) There were fewer patients with SD with an autosomal dominant history.

Of the six cohorts, FTD/ALS showed a significantly higher percentage of autosomal dominant inheritance (37.0%) and of overall significant family history of dementia or ALS (59.2%) than other subtypes. SD showed the least heritability, with only 1.9% of cases with an autosomal dominant pattern and 17% demonstrating a significant family history of dementia or ALS. In our cohort, the familiality of both PSP and CBD was greater than has been reported in earlier studies. This difference may reflect recruitment through a behavioral neurology clinic as opposed to a movement disorder clinic.

Discussion.

This study examined family histories in a large cohort of patients with FTLD and analyzed the heritability of the three major subtypes and two highly related disorders, PSP and CBD. Our overall FTLD cohort shows percentages of autosomal dominant cases and cases with strong family histories that are similar to prior work that used different approaches for diagnosis.¹

These prior studies analyzed the different subtypes of FTLD together, but our findings suggest that approaching FTLD as a single genetic entity can be misleading, both underestimating and overestimating the genetic tendency within different FTLD subtypes. For example, FTD/ALS showed a strong familiality (59.2%) while SD had a very low frequency (17%) of familial cases.

The finding that FTD/ALS is the most heritable form of FTLD and that SD is the least heritable form has significant clinical implications. First, families with a relative affected with SD can be counseled that the likelihood that the disease in their relative is sporadic and should be reassured regarding the risk of recurrence. In contrast, ALS, particularly in association with FTD, appears to be more heritable than previously suspected. Previous studies on the heritability of ALS have not included careful assessment of dementia, which may have artificially lowered estimates of heritability. Both ALS and dementia should be considered when counseling families on recurrence risk.

A limitation of this study was the inability to confirm the dementia diagnosis for many deceased family members, and the majority of our patients did not have an autopsy-proven diagnosis. Despite this potential confound, our group has demonstrated that in at least 90% of our patients clinically diagnosed with FTLD that FTLD-type pathology is confirmed at autopsy.¹⁰

Future research on the heritability of FTLD subtypes will need to examine family histories in a large autopsy-proven cohort. Learning that the FTLD subtypes and related tauopathies are genetically distinct diseases is important for counseling families on inheritance risk and for guiding genetic association studies. Instead of using an overall FTLD cohort, association studies can be directed at modifier genes influencing specific brain region sensitivity resulting in the various FTLD, PSP, and CBD phenotypes. Mutations in tau account for relatively few FTLD cases. Other genes, including autosomal dominant genes, await discovery.