Case Report: Concurrent Wilson Disease and Huntington Disease: Lightning Can Strike Twice

Differential diagnosis in clinical genetics often involves an exercise in logical deductive reasoning with a sequential approach in pursuit of an etiology. In the medical genetics field, the differential diagnosis is guided by a combination of pedigree analysis, medical and developmental histories, and physical examination, imaging studies, cytogenetics, molecular genetics/next generation sequencing and a myriad of metabolic and hematologic studies. However, even with all these testing options, there is still value in the art of gestalt – that observation of the whole – when considering a diagnosis. We know that the thunder of hooves is likely to be the horse rather than the zebra. But what if the two are grazing side by side? We present a patient with physical, cognitive and psychiatric symptoms, all of which are evident in both Wilson and Huntington diseases. In addition to the complexities of having co-morbid diagnoses, this case illustrates the psychosocial consequences of having two conditions with discordant natures; one being autosomal recessive and treatable, the other being autosomal dominant and not treatable. Lastly, this case illustrates the importance of timely genetic counseling in the face of a difficult diagnostic picture and complex family dynamics. Mr. G was 41 years old when he became aware of and frustrated by his impaired handwriting and significantly declining tennis game. By his mid 40's, Mr. G felt jittery, walked with a shuffling gait and had restless leg movements. Simultaneously, Mr. G experienced emotional withdrawal from his family and uncharacteristic bouts of anger. Chronic and excessive alcohol use was initially believed to be responsible for the changes in his behavior. Mr. G was an architect, with graduate degrees and a successful practice. He was an accomplished athlete and socially prominent in the community. Mr. and Mrs. G were married for 13 years and parents of 2 children; a son, age 10 and a daughter, age 7. Mr. G's parents were described as alcoholics and when the family was questioned later by the genetic counselor, it was revealed that Mr. G's mother had progressive, involuntary movements and erratic behaviors which the family had attributed to her chronic alcohol use. Additionally, the genetic counselor learned that a maternal aunt and the maternal grandfather were described as fidgety with mood swings and anxiety. Mr. G's three siblings (ages 49, 45, and 37 years) were professionally employed with no known physical or psychological symptoms. Prior to the genetic counselor's involvement with this family, the family history had not been adequately explored or interpreted. When Mr. G's emotional lability and physical compromise did not improve with sobriety, the family physician referred him for a neurological consultation. This evaluation included an MRI of the brain, which was interpreted as normal, and screening for Wilson disease (WD) which detected elevated urinary copper and low serum ceruloplasmin concentration. The presence of Kayser-Fleischer rings of the cornea confirmed the diagnosis of WD. The family was devastated by the diagnosis, but relieved that it explained Mr. G's features and behaviors and they were hopeful that treatment would ameliorate his symptoms. Mr. G was treated for 18 months with Cuprimine (penicillamine, a copper binding agent). Then, following a liver biopsy that indicated he was free of excess copper and had no evidence of cirrhosis, he began zinc therapy to decrease copper absorption from the GI tract. However, medical intervention did not reduce Mr. G's progressive mood swings, mild dysarthria, and flat affect. The family informed the neurologist of their concern and they were advised to be patient and allow time for Mr. G's system to adjust to the medication. It is also reported that some individuals actually have neurological worsening when they begin treatment. (Brewer et al. 1994). However, because of their frustration, the family sought a second opinion. A neurological evaluation performed approximately 2 years after the initial diagnosis of WD noted an alert, fully oriented male with mild dysarthria. Mr. G's score on the Mini-Mental Status Exam, a commonly used quantifiable cognitive function screening test, was 28/30, reported to be mildly abnormal for his level of education. (Folstein and Folstein 2001). There were saccadic-pursuit eye movements, choreoathetosis of the upper extremities with some dystonic posturing of the lower extremities, an athetoid gait, increased tone and mild rigidity without cog wheeling. The neurologist consulted a colleague specializing in WD, who agreed with the initial diagnosis, citing the high urine copper excretion of 265 mcg/day;(normal is under 100 mcg/day) and low ceruloplasmin. However, both physicians concurred that his response to treatment was atypical, and that it was important to consider expanding the workup. The neurologist suggested exploring another possible explanation: Huntington disease (HD). The family was advised that HD was unlikely since Mr. G's family history was perceived to be positive only for alcoholism, not for a neurological disease. Mr. G was offered DNA testing for HD and he consented. The genetic counselor later learned that Mr. G agreed to be tested because he believed that the study would surely rule out HD. No genetic counseling was provided or offered to the family prior to testing. Mr. and Mrs. G were completely unprepared for the positive HD result, which revealed an expanded huntingtin gene (HTT) allele of 44 CAG trinucleotide repeats (normal is 5–35 CAG repeats, [The Huntington's Disease Collaborative Research Group 1993]). The confirmation of the HD diagnosis brought about a severe, acute depression for which Mr. G required hospitalization for monitoring and management. He and his family had only begun to adjust to a recessively inherited, treatable disorder; now they were told Mr. G had a dominantly inherited, untreatable, progressive, lethal disorder. It was at the point of the HD diagnosis that the family was referred for genetic counseling. Wilson disease (WD) is an autosomal recessive disorder of copper metabolism with extremely variable expression. Individuals may present with neurologic or psychiatric changes and/or hepatic disease. The diagnosis is based on low serum copper and ceruloplasmin, increased urinary copper excretion, and/or increased hepatic copper concentration (Werline et al. 1978). Kayser-Fleisher rings are present in the cornea in approximately 90 % of individuals with neurologic or psychiatric findings. The diagnosis is now confirmed by biallelic ATP7B mutations, (chromosome locus 13q14.3- q21.1), with over 200 mutations identified (www.uofa-medicalgenetics.org/wilson; Roberts and Schilsky 2008). The prevalence of Wilson disease is estimated at one in 30,000 in most populations, with a carrier frequency in the general population of one in 90 [Olivarez et al. 2001]. WD is a treatable disorder, with life-long therapy based on early institution of chelating agents which block copper absorption and assist in the rapid recycling of copper. (Brewer et al. 1994; Roberts and Schilsky 2008). See Appendix A for further discussion of WD. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder notable for extremely variable expression and relentless progression (Folstein et al. 1984; Kessler 1993; Harper 1996; Paulson et al. 2001; Ross 2010). The diagnosis is based on clinical presentation, positive family history and a positive DNA mutation (expansion of ≥36 CAG trinucleotide repeats in the HTT gene, with alleles of 36–39 incurring potentially non or reduced/late penetrance (Rubenstein et al. 1996)). The prevalence of Huntington disease (HD) is estimated to be 13.7 per 100,000 in the population with European ancestry (Fisher and Hayden 2014), with some data supporting a prevalence estimate exceeding 15 per 100,000 [Bates et al. 2002]. There is not yet an effective, long-term treatment or cure for HD. Some of the symptoms (e.g. depression, anxiety and chorea) may respond to pharmacologic therapy for periods of time (Nance et al. 2011; Mestre et al. 2009). Care is primarily supportive, encouraging a balanced nutritious diet, safe exercise, social engagement and continued appropriate creative endeavors and emotional support. See Appendix B for further discussion of HD. The day following the HD result disclosure to the couple, the neurologist telephoned this genetic counselor, A. Zanko (from here on, referred to as “I”) for guidance. The call was a cry for help and for damage control as the HD diagnosis had catapulted the family into crisis. The next day, Mrs. G called the genetics office and we spoke for the first time. She reported ‘being in shock’ from the sweeping consequences of her husband's second diagnosis and she disclosed very early in the call that their marriage had been faltering prior to the WD diagnosis. Living with someone who seemed like a stranger, particularly an often inebriated stranger, had taxed the marriage nearly to separation. This is a common conflict in spouses of individuals affected with neurodegenerative conditions, such as HD, particularly when negative behaviors are among the presenting symptoms. The behavior is often attributed to external factors, such as alcohol, loss of employment or relationship difficulties. But, when the diagnosis of HD is explained, there may be feelings of guilt for considering leaving or despair when feeling trapped. Mrs. G was desperately hoping to learn that the second diagnosis was a mistake. She requested a private consultation while her husband was being stabilized in the crisis center. For Huntington disease, as with many conditions, each member of a couple may constitute a separate patient; genetic counseling for the partner is as critical as for the proband. The Huntington Disease Society of America (HDSA) guidelines for DNA mutation analysis emphasize the critical need for pre-test counseling and psychological evaluation (www.HDSA.org) In the introductory moments of Mrs. G's session she required much calming, as she described feeling agitated and panicked over the past 48 hours. I reviewed the preceding events and accompanying emotional turmoil with Mrs. G, validating her devastation and disbelief; it would be unusual for her not to feel this way. In an attempt to learn what Mrs. G understood, I then encouraged her to describe what she had already been told. Her explanation revealed a reasonably accurate understanding of WD, but only the most fundamental, superficial knowledge about HD. I outlined the spectrum within the motor, cognitive and psychological triad of HD symptoms. Mrs. G was particularly surprised to learn the emotional sequelae of HD, and she poignantly mused about how long his disease may have been present but unrecognized. She understood the lack of effective treatment and she was devastated by the 50 % risk to her young children. Tears repeatedly punctuated the discussion, requiring time for silence and reassurance. In addition to her dismay, Mrs. G was frightened and angry. I encouraged her to express her fears and her frustration with the lengthy diagnostic process and the family's misfortune of involvement with not one, but two, serious and debilitating disorders. I validated these feelings and asked more about her relationship with Mr. G. Mrs. G revealed the evolution of an upwardly mobile couple with significant financial and social status. Her husband had gradually changed from a bright, athletic and witty man, who had been well liked and highly respected, to a withdrawn, irritable and indifferent man. Mrs. G reiterated that she had considered leaving her husband prior to the first (WD) diagnosis. With the diagnosis of WD, she had felt obligated to stay until his condition improved or stabilized with treatment. With the discovery of his second diagnosis, she felt trapped. Her genuine sadness regarding Mr. G's diagnosis of HD was clearly confounded by her personal desire to leave the marriage. Mrs. G was already in therapy because of her marital discord, but she had not had the opportunity to see her therapist following the HD diagnosis. The acute concerns regarding the HD diagnosis, along with the long term adjustment to Mr. G's illness, were adding to the chronic issues of their strained marriage. I offered to speak with the therapist since the HD issues were now so entwined with the marital discord. Mrs. G appreciated the offer and provided consent to contact her therapist. I had two extensive conversations with the therapist to provide her with information about HD complexities and nuances. While my first meeting with Mrs. G allowed her to express her sadness and fears, the purpose of the second visit was to meet with both Mr. and Mrs. G once Mr. G was psychologically stable following his stay in the acute care facility. Seventeen days after the initial meeting with Mrs. G, I met with the couple and reviewed the events of the past few weeks, primarily relying on Mrs. G's report, despite encouragement for Mr. G to engage. I then discussed the natural history, inheritance and variability of HD. The couple nodded their understanding of the symptoms shared by HD and WD. Mr. G, however, had a flat affect and little spontaneous speech. He was a well-groomed, soft-spoken, tall, lean man with an occasional engaging smile. He expressed no sadness or anger. He reported that he was doing fine and, although he was initially overwhelmed by the HD diagnosis, he said he now understood it, and actually felt relief that he “wasn't going crazy.” When he was asked focused questions about his immediate concerns, he complained that his children would often not complete their homework, they would not obey him, and they often talked back to him. He said that he wanted to keep working, but it was becoming increasingly difficult to manage his clients’ projects. Mrs. G sat quietly with downcast eyes. She briefly touched her husband's hand once during the meeting, but there was no other obvious affection or closeness. The counseling session focused on reducing Mr. G's stress and anger by identifying the triggers and by setting appropriate, achievable, short-range goals. Because much of Mr. G's anger was directed at his children, strategies were discussed which might increase their pleasurable time together and limit his role as disciplinarian. In an effort to reduce the stress related to his work, the possibility of a reduction in his hours and more shared responsibility with co-workers was explored. Mr. G agreed to try these new strategies. There was no mention of the marital discord at this visit. The focus was on Mr. G, his HD diagnosis, his emotional stability, feelings of competence and his relationship with his children. A third genetic counseling session was scheduled for the following month. Plans were made to discuss how to advise others about Mr. G's diagnosis of HD, which was particularly complex because friends and family had already been told about WD. I provided the couple with HD national and local newsletters, research articles and HD support group information. Mr. G was well integrated with his neurologist. In addition, he now saw a psychiatrist biweekly. I met with the couple once more to check in, provide anticipatory guidance and to give them tools with which to explain Mr. G's second diagnosis to significant family members and friends. Over the next 6 months, there were several phone calls with Mrs. G. With Mr. G's request and permission, I also spoke with one of his brothers and an aunt. Another brother had tested positive for HD on the East Coast and a third sibling was considering testing. I maintained occasional telephone contact, primarily with Mrs. G, discussing present and future concerns relating to Mr. G, Mrs. G and their children. Thirteen months after Mr. G's diagnosis, Mrs. G reported that he was no longer able to work. Mr. G sat on the couch most of the day watching sports on TV. He attended an adult day center twice a week. He continued to see his psychiatrist but at home he either withdrew or “yelled at the kids.” During that time, I received a frantic phone call from Mrs. G after the police arrested Mr. G for breaking a window to enter his own car. The neighbors were concerned that a man appeared to be burglarizing the neighborhood. The police had to use force when Mr. G resisted arrest. Mrs. G and I spoke about the unpredictable but relentless progression of HD. Mrs. G was considering future scenarios as she knew that when Mr. G needed full supervision, he would likely require placement in a care facility. Mrs. G worked full time and could not be his care-provider. However, as long as Mr. G was safe, manageable and comfortable, he would live at home. Mr. and Mrs. G's young children were also in counseling with a therapist. The children had questions about their dad's limited activities and they were sometimes sad, often frustrated and confused. However, they were well cared for and closely involved with some of the family's adult relatives and friends. Mrs. G and I discussed ways to respond to their questions honestly without heightening concerns. The virtues of patience and tolerance were discussed, realizing how difficult it was for the children to accept their dad's personality changes. The children felt protective of Mrs. G and together they did many of the household chores once managed by their dad. Mrs. G worried extensively about the risk to her children. Her hope for future intervention allowed her to sleep at night. This case history demonstrates a double diagnosis and the resultant complexities of understanding and adjusting to two genetic diseases with similar motor, cognitive and psychiatric symptoms, but different modes of inheritance, recurrence risk and treatment outcomes. It emphasizes the importance of therapeutic and nonjudgmental genetic counseling, to not only inform and educate, but to see a family through a crisis situation in order to establish some degree of stability. The first diagnosis of Wilson disease embodied fear and sadness, but also hope that treatment would allow resolution. This diagnosis was a reasonable one to make, as Mr. G was thought to be a simplex case and his work up was positive. The response to his WD diagnosis was confounded and stunned by the second, more tragic result. The diagnosis of WD had, for a time, ended the diagnostic work up, which was justified by clinical and laboratory findings and the unawareness of a positive family history. The diagnostic work up resumed only when symptoms persisted and progressed despite adjustment of the medications. No genetic counseling was suggested to the family at the time of the diagnosis of WD, although it is clearly an inherited disease for which support, information, resources and counseling would have been appropriate. Omission of genetic counseling was a grievous mistake once the additional study for HD was considered. This family could and should have been appropriately prepared, particularly in light of a family history that did in fact suggest physical, emotional and behavioral disturbances in two previous paternal generations. Not only should the family have been educated about the nature of HD, but they should also have been given time to consider their options and understand the implications of a second, devastating diagnosis. Perhaps Mr. G's acute emotional crisis would not have been averted, and perhaps his wife and children would still have fallen into chronic despair. But perhaps with more understanding and support at critical times through an established relationship with a genetic counselor, the edges might not have been as sharp. (Skirton et al. 2013). This case report provides numerous examples of the use of therapeutic and interventional skills available to the genetic counselor. These include primary and advanced empathy (validation of Mrs. G's feelings of horror and disbelief), allowing the patient to tell their narrative (encouraging Mrs. G to tell her story and to describe her understanding of the situation), reflection, validation, anticipatory guidance (discussing how to address the children's sadness and frustration and how to disclose the second diagnosis to family members), and goal setting (limiting the patient's role as disciplinarian, reducing work hours and increasing “pleasurable” family time). In addition, the counselor maintained an ongoing relationship with the family, monitoring their adjustment and their needs. The counselor collaborated with the existing mental health providers, offering information about the nuances of HD which could provide insight for treatment. By remaining available to the family over time, the counselor was able to provide guidance that could be integrated when certain events or changes had taken place, (such as when Mr. G needed more supervision, adult day care services, etc.). Disclosure of results and follow up counseling for devastating genetic conditions such as HD are very challenging tasks. As genetic counselors become more experienced in these roles, the use of therapeutic counseling will become available in their skill set. Because there is not yet effective treatment, this intervention, guidance and presence is a large part of what we have to offer. In order to provide empathetic genetic counseling, it is important for the counselor to be aware of his/her personal reaction to their patients’ situations and needs. (Abrams and Kessler 2002). Initially the counselor felt she was called to “clean up” the emotional mess created by doing DNA testing without genetic counseling; that she was appreciated and valued only when she was needed to fix this family in crisis. The counselor experienced identification with Mrs. G; she felt that Mrs. G was “trapped” and she felt Mrs. G's loss, fear and anger. This was partly because she did not know Mr. G when he was well, and thus simply had less communication with him. Typically, the counselor established a relationship with the patient prior to predictive testing. The counselor also felt a sense of survivor guilt; she was able to return to her home and a relatively sane existence while Mrs. G went home to a nightmare which the counselor could not fix. A critical lesson provided by this case is that the confirmation of a diagnosis should not blunt medical observation, sensitivity and response. Patients evolve and change. Health professionals need to remain alert to symptoms and nuances, and should investigate signs of contributing or alternative etiologies. Secondly, although it is often implied, it is important to remember that the patient is frequently a family—one with complex, divergent issues and extenuating circumstances. And, lastly, needless to say, the co-existing diagnoses in this family contributed to grave turmoil, for which timely, therapeutic genetic counseling was certainly warranted. Authors Abrams and Zanko declare they have no conflicts of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). No animal studies were carried out by the authors for this article. The authors have altered a number of insignificant details about the family to protect their privacy and identity. The copper toxicity primarily affects the liver and brain; however the hematological, renal, skeletal, ophthalmologic and cardiac systems may also be involved. (Packman 2001). Neurological manifestations may involve motor abnormalities (tremors, ataxia, chorea, spasticity, dysarthria, rigidity, gait disturbance, clumsiness and dystonia. Cognitive deficits (memory loss, confusion, disorganization) and psychiatric symptoms (depression, aggression, neurosis, lethargy, and mood disturbance) occur with significant frequency. Some individuals present with liver disease; others come to medical attention as a result of their neurological or psychiatric involvement. Hepatic symptoms often precede neurological symptoms in patients presenting in childhood or as young adults.(Wilson et al. 2000). Patients present as early as the first decade through the sixth (3 years to over 50 years). The ATP7B gene is the only one implicated in WD. Identification of two disease-causing mutations confirms the diagnosis. The physical-cognitive-psychiatric triad of symptoms involves motor impairment (restlessness, involuntary movements, clumsiness, awkward gait, dysarthria, dysphagia, rigidity, bradykinesia, chorea), global subcortical dementia (memory loss, altered judgment, diminished executive function), and emotional/behavioral disturbance (depression, apathy, disinhibition, hallucinations, anxiety, irritability, psychosis, anger, withdrawal, denial, paranoia, stubbornness, impulsivity) (Paulsen and Johnson 2014; Harper 2005; Rosenblatt 2007). In the majority of patients, the onset of HD is recognized in the third to fifth decades (35–44 years), but it may present from the first through the ninth decade. (Bates et al. 2002; Wexler et al. 2004). Juvenile onset Huntington disease (onset of symptoms prior to age 20 years) with disturbances in motor, cognition and psychiatric realms as well as often more severe cognitive loss, speech and language delay and more rapid decline, occurs approximately 10 % of the time (Nance and Myers 2001; Yoon et al. 2006; Nance 2007). Juvenile onset HD is most often transmitted paternally (Trottier et al. 1994; Nahhas et al. 2005). The disease causing mutation in the HTT gene (locus 4p16.3), is identified by the expanded trinucleotide CAG repeat (HD CRG 1993), with an inverse correlation between CAG repeat size and age of onset (Langbehn et al. 2004). Alleles with less than 26 CAG repeats are normal. Intermediate alleles with 27–35 CAG repeats do not cause HD disease however future generations may be at risk due to instability in the CAG tract (Semaka et al. 2006). Though all individuals with 36 or greater CAG repeats are at risk for HD, the 36–39 CAG repeat range is considered to be incompletely penetrant, with some individuals remaining undiagnosed into their senior years (Langbehn et al. 2004). Individuals with ≥40 CAG repeats will develop HD with certainty; this range is considered fully penetrant. Direct DNA analysis provides the option for confirmatory, predictive and prenatal diagnostic testing.