Partners in FTD Care, Winter 2022
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Most cases of FTD are sporadic, meaning that there is no clear-cut, singular genetic cause. Many cases, however, are said to be familial: Neurodegenerative diseases such as ALS, Parkinson’s, and FTD recur throughout the family tree. A variety of factors can contribute to a family’s propensity for developing FTD, but the most direct cause is a genetic variant that can be inherited from a parent and passed onto one’s children.

In the following case study, Brian S. begins showing FTD symptoms in his 50s. After reviewing his family’s health history – which includes relatives with vaguely defined and undiagnosed neurological conditions – a genetic counselor expresses concern that Brian’s FTD may be familial, and perhaps even have a specific genetic cause. With the genetic counselor’s help, Brian’s daughter Sarah must prepare to learn the results of her father’s genetic testing – and then, if a gene variant is present, decide whether to get tested herself.

The Case of Brian S.

Brian S. was a loving father and lawyer from a close-knit family. When he was 52, his only daughter, Sarah, noticed he seemed less interested in her, and that he no longer called her back when she left voicemails. His wife, Rose, sensed that he was feeling overwhelmed at work, which was unusual for him. At his wife’s urging, Brian saw his family doctor, who suspected he might be experiencing job-related stress and anxiety and encouraged him to meditate and take more frequent vacations. Nine months later, after Brian started dressing in unwashed clothes, his wife convinced him to return to the doctor for additional investigations. A brain CT scan yielded normal results, as did routine bloodwork. But with his symptoms worsening, Brian was referred to a specialty neurology clinic for further evaluation.

During Brian’s initial assessment at the specialty clinic, a behavioral neurologist provided a complete neuromedical assessment and reviewed his CT images. Although the CT scan was reported as “normal,” the neurologist noticed subtle signs of atrophy in Brian’s frontal lobes. The neurologist said he suspected that Brian’s symptoms represented the early stages of frontotemporal degeneration (FTD) and arranged for an MRI and detailed neuropsychological testing. He scheduled a follow-up appointment in a few months to review the results.

By the time of the follow-up appointment, Brian was on leave from his job. Throughout the appointment, Brian said he did not understand why he was there, and repeatedly asked if he could go home. The neurologist explained that his MRI revealed atrophy of the frontal and temporal regions of the brain, and that the results of his neuropsychological testing were also in keeping with frontotemporal degeneration. He said that he was quite certain that Brian had behavioral variant FTD.

Sarah and Rose had spent the past year reading about FTD symptoms, so this news did not surprise them. In some ways, it was a relief for them to have a concrete explanation for Brian’s symptoms and a better understanding of what to expect. The neurologist said he would arrange for the family to speak with the clinic social worker for information about additional resources and supports.

Is It Genetic?
Increasingly anxious that her father’s FTD may have a genetic cause, Sarah scheduled a session with a genetic counselor. The genetic counselor recorded Brian’s family history: his parents were alive and well in their late 70s, his two older siblings were likewise healthy and in their 50s, and there was no known family history of dementia or other neurological disorders.

The genetic counselor provided some reassuring information about FTD’s genetic nature. In the majority of FTD cases, she noted, the condition is sporadic, meaning it does not run in the family. Meanwhile, some people with FTD have a family history of dementia, psychiatric illness, or movement disorders such as ALS or Parkinson’s disease; these cases are considered familial and reflect an elevated, but unclear, risk of inheritance. In a portion of these cases, the disease is genetic, or inherited, caused by variants in single genes. These cases of genetic FTD are suspected when someone reports several close relatives over several generations with FTD or other neurodegenerative conditions.

After the session, Sarah spent time contacting her father’s relatives to learn more about his family’s health history. She reached out to the genetic counselor to share her findings. While no one else in the family was known to have FTD, Sarah learned that one of her father’s paternal uncles had died in his 80s with “some type of neurological condition” that started just a couple of years before he died and required him to use a wheelchair. Sarah also learned that her father’s paternal grandmother showed “odd behavior” and lived in isolation before dying in her 70s.

Sarah was newly concerned about the possible genetic implications of her father’s diagnosis. The genetic counselor said that Brian’s FTD could still very well be sporadic; she noted his father’s good health, his uncle’s and grandmother’s longevity, and the lack of detail about their conditions. However, the updates to the family history were significant: the genetics of FTD are highly complex, and several FTD-causing genes have been discovered over the past two decades. Variants in these FTD-causing genes can give rise to a wide variety of symptoms and trigger different ages of onset, even in the same family. This “variable expression” of FTD-causing genetic variants means that FTD, parkinsonism, ALS, and/or psychiatric conditions can all appear within a single family in which genetic FTD is present. Furthermore, some people who carry an FTD genetic variant live into their 80s or 90s without ever developing a neurological condition. This “reduced penetrance” of some FTD gene variants means that in some families, FTD may appear to come out of nowhere or skip a generation.

With this added information, Sarah expressed a strong interest in genetic testing. The counselor explained that several clinical genetics laboratories offer testing for known FTD gene variants. The testing process would begin by analyzing a DNA sample from Brian. A positive genetic test result would confirm he has genetic FTD – and would also confirm that Sarah and each of Brian’s siblings have a 50% of chance developing FTD in the future. Predictive genetic testing could determine whether those relatives carried the same gene variant as the one identified in Brian.

Sarah, who was ready to start a family, wanted to know if she was going to develop FTD or another neurological disease so that she could plan accordingly. She worried, however, about putting her father through the stress of any more testing and said that she would rather take the genetic test herself.

The counselor explained that Sarah’s testing would be more informative if they were first able to confirm that Brian’s FTD was caused by a detectable FTD gene variant. If Sarah were tested first and received a negative result (no variant found), this could mean that her father had an FTD-causing gene variant and did not pass it on to Sarah. But it could also mean that her father’s FTD is sporadic, or caused by a variant in a gene that has yet to be discovered. Sarah’s own likelihood of developing FTD would remain difficult to assess.

The family understood and decided to proceed with Brian’s genetic testing. Brian was no longer able to make decisions about his medical care; as his medical representative, Rose authorized her husband’s genetic testing and signed the requisite consent forms on his behalf. Using a saliva collection kit, she helped administer the test. The family agreed to pay privately for testing, given that its costs were much lower than they had anticipated.

About eight weeks later, the genetic counselor invited Rose and Sarah to review Brian’s results. (Brian had just moved into a care facility and was no longer able to travel.) Brian’s genetic testing confirmed that he carried a disease-causing, or “pathogenic,” variant in the C9orf72 gene. Variants in this gene are known to cause symptoms of FTD, ALS, and psychiatric illness, and are also known to have reduced penetrance. The counselor gently told Rose and Sarah that this finding confirmed the inherited nature of Brian’s condition, and that each of Brian’s first-degree relatives had a 50% chance of carrying the same variant. All of these relatives would now have the option of predictive C9orf72 genetic testing for themselves.

Next Steps
Rose and Sarah were understandably saddened to learn that Brian’s condition was genetic, and that Sarah and other relatives could develop FTD and/or ALS in the future. The genetic counselor explained that Brian’s FTD was most likely inherited from his father, and that the neurological symptoms displayed by his older paternal relatives most likely resulted from a C9orf72 gene mutation.

Rose acknowledged that it was difficult to process this information. She had just learned that Brian’s older brother was about to undergo testing for symptoms which could be caused by ALS. She hadn’t realized that there was a connection between FTD and ALS until Brian started the genetic testing process. She also hadn’t understood that FTD can develop so late in life; most of what she had read about FTD suggested onset before age 60. This meant that Brian’s father, though nearing 80, could still develop FTD before he died.

Sarah said that she wanted to proceed with predictive genetic testing to find out her own C9orf72 status. The genetic counselor explained that such testing would only be done after an additional session to review the implications of a positive and negative test result, motivations for testing, psychological readiness, and support systems.

Sarah returned to the clinic with her husband for pre-test genetic counseling. The counselor
explained that a positive test result would indicate that Sarah will most likely develop FTD and/or ALS in her lifetime, but that her specific age of onset, disease progression, and symptoms would remain unknown. The genetic counselor also noted that there is still no way to prevent the onset of FTD or ALS in a C9orf72 gene variant carrier, but that human clinical trials of C9orf72-specific therapies are now underway.

To Test or Not to Test?
Although a part of Sarah wanted to know if she carried a C9orf72 gene variant, she was simultaneously nervous about the possibility of a positive test result. Knowing her genetic status before she started a family was important – she would not want to pass the disease to her future children. But at the same time, the experience of caring for her father weighed heavily upon her; she wasn’t entirely sure she could cope with a positive test result given her life’s current stressors. A positive test result would likely be detrimental to her current mental health and well-being.

Given her wish to avoid potential transmission of a C9orf72 gene variant to her children, Sarah asked the genetic counselor about assisted reproductive technologies, such as in vitro fertilization (IVF) with donor eggs or IVF with pre-implantation genetic diagnosis. These could be done without Sarah learning her own C9orf72 status, the counselor noted.

Ultimately, Sarah decided not to proceed with predictive genetic testing for the time being. She and her husband would seek out additional information about assisted reproductive technologies from the local fertility clinic. The genetic counselor invited them to reach out should Sarah wish to proceed with predictive testing in the future, for periodic updates regarding C9orf72-specific therapies, or if they had any additional questions or concerns.

See also:

• The Role of Genetics in FTD: An Overview
• Providing Support to Those Considering Genetic Testing: Guidance for Healthcare Professionals
• From a Caregiver’s Perspective: Deciding to Learn One’s Genetic Status
• What to Know Before Ordering Genetic Testing
• What to Do About…The Decision to Learn One’s Genetic FTD Status
• Download the full issue (pdf)