Psychosomatics 39:291-294, June 1998
© 1998 The Academy of Psychosomatic Medine
An Unusual Presentation of Huntington's Disease
Paul R. Rivkin, M.D., and
Godfrey D. Pearlson, M.D.
Received January 16, 1998; accepted January 26, 1998. From the Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland. Address reprint requests to Dr. Rivkin, Division of Psychiatric Neuroimaging, Department of Psychiatry and Behavioral Sciences, Meyer 3–166, 600 North Wolfe Street, Baltimore, MD 21287–7362.
Key Words: Case Report • Huntington's Disease • Case Report
The evaluation of atypical dementias presents a diagnostic challenge. This case describes a 59-year-old woman who presented with an 8-year history of difficulties with her mood and memory in addition to a more recent history of pupillary abnormalities and a movement disorder. Although her evaluation ultimately yielded a diagnosis of Huntington's disease (HD), this diagnosis was delayed because of the slow aggregation of her symptoms and an apparently unsupportive family history. Recent developments in the genetics of HD show this patient's illness can be reconciled with a family history that superficially weighs against its diagnosis. The order of clinical presentation and gradual accumulation of symptoms in this case interfered with early identification, diagnosis, and treatment. The very high prevalence of Alzheimer's disease (AD) (accounting for about 50% of progressive dementias1) can itself lead to diagnostic bias. In the present case, an initial diagnosis of AD was sustained even as the hallmark features of HD began to emerge. Another biasing feature of this patient's presentation is a family history that would apparently exclude the diagnosis of an autosomal-dominant inherited disorder.
Case Report
This 59-year-old Caucasian woman came to our neuropsychiatry clinic on referral from her daughter. She was without notable psychiatric symptoms until she began to experience mood and memory problems at age 51. The patient and family described pervasive low mood and apathy interspersed with periods of irritability. These mood symptoms paralleled a waxing-and-waning decline in concentration and memory, which prompted her to seek psychiatric treatment at age 54. She was diagnosed at this time with major depression and probable AD. She had a several month trial of nortriptyline (dosages and levels unavailable); however, despite some improvement in mood, this was discontinued because of the side effect of weight gain. She was subsequently switched to fluoxetine (20 mg/day), and although this was associated with some improvement in mood, her medication compliance was intermittent, probably due to her cognitive problems. In 1993, at age 56, worsening cognitive decline forced the patient's retirement from her secretarial position. Around this time, the patient became prone to episodes of social inappropriateness, such as effusively greeting strangers and losing her temper in public. In 1994, the patient's family began to notice 2 neurological problems: restless foot and finger movements and a persistently dilated right pupil. Around this time, the patient was given tacrine for her presumed diagnosis of AD, with dosage titrated to 40 mg qid, with equivocal improvement. Worsening of the earlier described symptoms prompted the patient and her family to seek further evaluation at our neuropsychiatric clinic.
The patient had no neuropsychiatric problems until the onset of the foregoing symptoms. The neuropsychiatric history of three prior generations of the patient's family was only notable for a mild vascular dementia in her father and an unknown psychiatric diagnosis of early onset in her maternal great-grandmother (see Figure 1). The patient has 4 children in their 30s, 2 of whom may have some motor abnormalities, but they have not been formally evaluated. Thus, there is little support for a diagnosis attributable to inherited, autosomal-dominant neuropsychiatric disorders until the patient's generation.
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FIGURE 1. The patient is depicted by the shaded polygon. Note:We would expect to find an average of 50% of family members at risk for inheriting the Huntington's disease (HD) gene to manifest the disorder. In view of the negative histories for HD in three prior generations, the genogram suggests that the patient's generation is the first to be at risk for developing HD. This is explained by the phenomenon of cytosine–adenosine–guanine expansion discussed in the article text.
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Mental Status and Physical Examination: The patient presented as a casually dressed, alert, cooperative white woman. Her eye contact was good. Her speech was of normal tone and rate. No formal thought disorder was noted. The patient reported that her mood was good at the time of the interview; however, she noted predominantly low mood in the preceding several weeks. Her self-attitude was undiminished. Her energy level and initiative were subjectively decreased. The patient's facial expression was notable for occasional inappropriate smiling. No delusions, hallucinations, obsessions, compulsions, phobias, anxieties, and suicidal or homicidal ideation were noted. She received a Mini-Mental State Exam score of 25 out of 30 (minus 2 for memory, minus 3 for serial 7s). Brief formal cognitive testing showed 1) decreased verbal fluency with normal naming; 2) poor word-list learning; 3) impaired mental tracking (Trail-Making Test, Part B, <2nd percentile); and a mild constructional apraxia.
The nonneurological portion of the patient's physical examination was unremarkable. Pertinent positive findings on neurological examination included a tonically dilated and sluggishly reactive right pupil, jerky saccadic eye movements, writhing tongue movements, a frequent expiratory tic, frequent choreiform movements of the upper and lower extremities, and a mildly weaving gait.
Diagnostic Laboratory and Imaging Studies: The patient was formulated as having a depressive disorder, a subcortical dementing disorder, a choreiform movement disorder, and a pupillary abnormality. Laboratory and neuroimaging studies were directed toward 1) ruling out atypical delirium; 2) assessment of reversible dementing/affective syndromes (neurosyphilis, thyroid disease, collagen-vascular diseases, human immunodeficiency virus [HIV], Wilson's disease, nutritional dementias, and normal pressure hydrocephalus); and 3) evaluating static and progressive dementing disorders (AD, HD, vascular dementias, and tumors). The patient had a normal initial laboratory profile, which included complete blood count, electrolytes, serum chemistries, thyroid-function tests, erythrocyte sedimentation rate, B-12, folate, serum rapid plasmin reagin test, HIV test, and ceruloplasmin. Brain single photon emission computed tomography and magnetic resonance imaging, respectively, showed decreased basal-ganglia perfusion bilaterally and mild cortical atrophy with decreased putaminal size. Both the neuroimaging and physical examination were consistent with HD, despite the apparently unsupportive family history. Consequently, blood was obtained for genetic analysis, which showed 41 triplet cytosine–adenosine–guanine (CAG) repeats on chromosome 4 at the HD locus (greater than 35 triplet CAG repeats is abnormal), and this was diagnostic for HD.
Discussion
Recent advances in the genetics of HD illuminate how the disease may affect patients in whom their family history apparently excludes it. As we have noted, HD is an autosomal-dominant inherited disorder. It presents as the aggregation of affective, choreiform movement disorder, and subcortical dementia syndromes either simultaneously or over time, although affective symptoms often occur early in its course.2 In 1993, the abnormal gene bearing the mutation for HD was located on the short arm of chromosome 4,3 which has allowed for its precise genetic diagnosis. This gene codes for the protein huntingtin, the function of which is currently unknown, as is the mechanism by which its abnormalities in HD cause cell death.4 HD is one of several neurodegenerative disorders associated with an expansion of repeated sequences of nucleotides in genomic deoxyribonucleic acid (DNA).5 The genetic test for HD measures the CAG repeat length in leukocyte DNA, which is abnormally long in affected persons.6 The median CAG repeat length is 44 in HD patients and 19 in control subjects,5 whereas persons with CAG repeat length in the 36 to 39 range may or may not manifest the disease.7,8 The CAG repeat is a region of meiotic instability, which may expand in length in successive generations.9 The repeat length has been inversely correlated with the age of onset and positively correlated with the rate of progression of neurological and psychiatric symptoms.10 The phenomenon of expansion of CAG repeat length in successive generations and the progressively earlier onset of symptoms is referred to as "anticipation."9 Expansion of CAG repeat length is associated with paternal transmission of the abnormal gene, whereas maternally transmitted CAG repeat lengths tend to remain more stable in transmission.5
The mutation for HD in this patient may have derived from 1 of 3 sources: 1) her mother; 2) her biological father; and 3) spontaneous mutation. If the patient's mother supplied the mutation, then her lack of symptoms could have been due to a CAG-repeat length that was unstable but not sufficiently long itself to yield symptoms during her life. Upon meiosis, the CAG repeat may have expanded into the symptomatic range. An expansion of only two CAG repeats could suffice to explain the presence of symptoms in the patient and their absence in her mother. However, this mechanism is more likely in paternal transmission due to the anticipation phenomenon. In addition to this mechanism, paternal transmission could be due to misattribution of the patient's paternity (e.g., if her mother had an extramarital relationship resulting in the patient's conception). If her biological father had HD, then the patient would have a 50% chance of inheriting the disease. The possibility of spontaneous mutation from normal DNA is very small; most "de novo" cases are probably due to the foregoing mechanism.9,11
In the course of this patient's workup, her father's DNA was submitted for analysis and found to have CAG repeat lengths of 19 and 20 (within normal limits). The discrepancy between the patient's and father's repeat lengths is too small to make inferences about paternity, but the result is consistent with his being the biological parent. The patient and family chose not to pursue formal paternity testing, and genetic material could not be obtained from the patient's deceased mother. HD does not account for this patient's pupillary abnormality, and it is currently an unexplained finding (the patient deferred neuroophthalmological evaluation).
This case brings up several important aspects in the evaluation of atypical dementias. The family history is important when evaluating dementias with a known genetic component. However, the absence of supporting family history should not rule out a diagnosis even when Mendelian laws apparently exclude it. The mechanisms we have discussed show how a molecular genetic explanation of this patient's illness can be reconciled with an apparently unsupportive family history. Finally, the convergence of the examination and neuroimaging focused the evaluation toward appropriate genetic testing. The diagnostic power derived from the synergy between neuroimaging and genetic studies is likely to increase with advances in these two fields and aid in the evaluation of a broader array of neuropsychiatric disorders.
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