Hereditary cancer testing in a diverse sample across three breast imaging centers.

PURPOSE: Up to 10% of all breast cancers (BC) are attributed to inherited pathogenic variants (PV) in BC susceptibility genes; however, most carriers of PVs remain unidentified. Here, we sought to determine the yield of hereditary cancer gene PVs among diverse women attending breast imaging centers, who could benefit from enhanced surveillance and/or risk reduction interventions. METHODS: This cross-sectional retrospective cohort study included consecutive women, unselected for personal or family cancer history, who were offered genetic testing for hereditary cancer genes at the time of breast imaging at three centers (November 2020-March 2022). RESULTS: Among 1943 patients (median age: 66 years), self-reported race/ethnicity was White (34.5%), Hispanic (27.7%), African American (17.9%), Asian (4.5%), Ashkenazi Jewish (0.6%), Other (3.5%), and missing (13.0%). Thirty-nine patients (2%) were identified as carriers of a PV in an autosomal dominant clinically actionable hereditary breast and ovarian cancer (HBOC)-related or Lynch syndrome gene, most frequently, BRCA2 (6/39; 15.4%), PALB2 (8/39; 20.5%), CHEK2 (10/39; 25.6%), and PMS2 (5/39; 12.8%). Of the 34 PVs with known race/ethnicity, 47% were detected among non-White patients. Overall, 354/1,943 (18.2%) of patients met NCCN guidelines for HBOC gene testing and only 15/39 (38.5%) patients with an autosomal dominant clinically actionable PV met guidelines. CONCLUSION: This population health approach extended the reach of genetic cancer risk assessment in a diverse population and highlighted the limits of a guideline-based approach. This may help address inequity in access to risk-appropriate screening and cancer prevention.

When cognitive evaluation does not disclose a neurologic disorder: experience of a university behavioral neurology clinic.

OBJECTIVE: We examined clinical features, referral patterns, and diagnostic outcome of patients receiving cognitive evaluation in a behavioral neurology clinic who had no neurologic disorder. BACKGROUND: Cognitive complaints may indicate Alzheimer Disease (AD) or many other conditions. Accurate early evaluation of these complaints is critical, and appropriate subspecialty clinic referral has public health policy implications. METHOD: This retrospective medical records review included 342 consecutive patients seen at the Neurobehavior Clinic of the University of Colorado Hospital from July 2006 through June 2008. All patients received an initial diagnosis by a clinic attending and subsequent consensus diagnosis by 3 subspecialists board certified in Behavioral Neurology & Neuropsychiatry. RESULTS: Among the 342 patients, 68% had a neurologic disorder, the most common of which was probable AD (17%). The remainder had nonneurologic diagnoses: 20% had a psychiatric diagnosis, 7% had no neuropsychiatric disorder, and 5% had a medical diagnosis. Of those with nonneurologic diagnoses, 65% were referred by primary care providers, and the most common symptom was memory loss (72%). In the psychiatric subgroup, depression was the most frequent diagnosis (56%). All normal individuals had concern about cognitive decline. In the medical subgroup, medication effect was the most frequent diagnosis (50%). CONCLUSIONS: Probable AD was the most common neurologic diagnosis, but 32% of the referred patients had no neurologic disorder, and most of these individuals had a psychiatric cause for cognitive complaints. These results highlight the need for policies promoting more effective use of subspecialty clinics dedicated to neurologic disorders of cognition.

Advances in genetic testing for Alzheimer's disease.

As the prevalence of Alzheimer's disease (AD), the most common dementia in the elderly, continues to increase, neurologists will encounter a growing number of questions about genetic testing for dementia patients, their relatives, and people concerned about memory or cognitive function who have no apparent risk except advancing age. Until recently, clinical gene testing only included apolipoprotein E genotyping and testing for presenilin 1 mutations. In 2008, testing expanded to include the presenilin 2 and amyloid precursor protein genes. Despite these advances, genetic testing is currently not appropriate for most individuals diagnosed with AD and has limited utility for predictive purposes. Further research, however, is likely to expand the usefulness of this testing for both dementia patients and their relatives. If genetic testing is undertaken, thorough counseling, whether by the physician or a qualified genetic counselor, is an integral component of the testing process for both affected individuals and their families.

Adult-onset Alexander disease with progressive ataxia and palatal tremor.

A novel glial fibrillary acidic protein (GFAP) mutation, Y257C, is reported in a patient with adult-onset Alexander disease. This is the oldest reported case with confirmation of a GFAP mutation. Onset was late in the sixth decade. Genetic analysis of the GFAP gene is recommended in cases of progressive ataxia and palatal tremor.

The genetics of very early onset Alzheimer disease.

OBJECTIVE: This study was undertaken to clarify the genetics of very early onset Alzheimer disease (VEOAD), defined as AD beginning before age 35. BACKGROUND: Early onset AD (EOAD) is defined by onset of symptoms before age 65, and affected individuals may harbor a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein. VEOAD is exceedingly rare, and PSEN1 mutations have been implicated. We encountered a man with phenotypic frontotemporal dementia beginning at age 32 and a strong family history of an autosomal dominant dementia who was found at autopsy to have AD. METHODS: Histologic and genetic analyses of the patient's brain were undertaken, and a review of all published VEOAD cases was performed. RESULTS: Histologic findings were diagnostic of advanced stage AD. Genetic evaluation of brain tissue identified an intronic PSEN1 polymorphism; no known pathogenic mutation was found. Literature review (1934 to 2007) disclosed 101 cases of VEOAD; the youngest age of dementia onset was 24 years. In all cases in which definitive genetic analysis was available, either a PSEN1 mutation or linkage to chromosome 14 was found. CONCLUSIONS: VEOAD can present with atypical clinical features, including findings suggestive of frontotemporal dementia. All reported cases of VEOAD with conclusive genetic analysis seem to be associated with PSEN1 mutations. Genetic testing in adults younger than 35 with dementia can identify the genetic defect and assist in diagnosis and family counseling.