Hyperkinesia and early-onset dementia in a female with co-occurring PSEN1 and HTT mutations: A case report

Introduction

The evaluation of dementia typically involves clinical pattern recognition before proceeding with confirmatory testing such as neuroimaging and genetic screening. Early-onset dementia accompanied by behavioral dysregulation, hyperkinesia, and strong family history may suggest Huntington’s disease (HD); however, other neurodegenerative mimics should be considered. In this report, we focus on early-onset familial Alzheimer’s disease (EOFAD), a condition not commonly known to be associated with motor abnormalities. We present a patient with progressive memory loss beginning in the fifth decade of life, later involving behavioral disturbances and myoclonus, who was found to have a pathogenic PSEN1 mutation in addition to an intermediate HTT allele. This case highlights the pitfalls of using hyperkinesia to differentiate EOFAD and HD; it also constitutes the first report of genetically-confirmed EOFAD occurring with abnormal HTT. Our patient’s evaluation hints at the possibility of an EOFAD-HD overlap syndrome, and further studies are needed to characterize the epidemiology and clinical features of this co-occurring neurodegenerative state.

Case presentation

A 44-year-old female started exhibiting difficulty forming new memories. At age 46, she underwent genetic testing for sporadic Alzheimer’s disease (AD) and was found to have APOE alleles that were E2 homozygous. Despite initiation of cholinesterase inhibitor therapy, her memory worsened, resulting in job loss by age 48. She also became increasingly disinhibited and aggressive to the extent of requiring inpatient psychiatric admission at age 49. During this hospitalization, the patient re-engaged with neurology consultants, and an interview with her daughter revealed several important details. First, at age 47 the patient started to ‘twitch and shake’ (her daughter’s words) and occasionally drop objects. Second, her father and sister were diagnosed with dementia at ages 52 and 48 respectively; they also developed similar abnormal movements in their mid-50s.

On neurologic exam, the patient demonstrated disorganized thinking, impulsivity, ideational and ideomotor apraxia, aphasia with paucity of speech, and restlessness with occasional non-rhythmic jerks in random limbs. Brain MRI showed minimal frontotemporal volume loss and very slight leukoaraiosis. Extensive workup including heavy metal, iron, copper, lipid profile, B-vitamin, TSH, HIV, and RPR screens was all unremarkable. Genetic testing revealed 30 trinucleotide CAG repeats in one HTT allele; this is classified as intermediate allele, with 36-39 repeats considered as reduced penetrance and 40+ as full penetrance. A pathogenic variant within PSEN1 (c.849T > G p.F283L heterozygous) was also discovered. The patient subsequently established care with a specialist in cognitive and behavioral neurology, while her daughter was referred to genetic counseling to discuss the implications of these test results.

Discussion

Our patient’s presenilin variant (p.F283L) is a known contributor to EOFAD. First described by Scahill et al. in 2013, ¹ this mutation is associated with a prominent amnestic syndrome beginning typically in the mid-40s. Cognitive decline rapidly follows, with behavioral disturbances and myoclonus observed as well. Our patient fit this clinical description aptly. F283L is also fairly common; a 2016 case series reported that out of 168 symptomatic patients with PSEN1 mutations, 15 harbored this particular variant. ²

Despite our patient’s genotypic-phenotypic concordance, we considered a broad differential for several reasons. First, EOFAD is relatively rare, comprising less than 10% of AD cases. Second, we wanted to avoid missing EOFAD mimics such as Wilson’s disease or HD, which can bear superficial resemblances in their early ages of onset and involvement of cognitive, behavioral, and affective domains. Accurate diagnosis is particularly important since these conditions differ in life expectancy, mortality risk factors, and inheritance pattern—crucial details for prognostication. ³ It should be emphasized that our patient’s specific motor and psychiatric profile did not fit the typical chorea and dysthymia, respectively, that is associated with HD. As such, the discovery of her intermediate CAG repeats was critical since without this result, her daughter would not have been referred to genetic counseling. Our case suggests that even if classic HD symptoms are absent, the constellation of early-onset cognitive decline and any hyperkinetic movement disorder amidst a strong family history of the same, should prompt screening for HD. The converse also holds; patients who present with this illness script and are found to have normal HTT, should be evaluated for EOFAD.

The importance of genetic testing in evaluating EOFAD and HD is underscored by the unreliability of motor symptoms in distinguishing these conditions. For instance, the presence of any hyperkinetic movement disorder may favor a diagnosis of HD. However, this is a pitfall due to significantly higher incidences of myoclonus and hyperreflexia reported in EOFAD compared to sporadic, late-onset AD. ⁴ Recognizing heritable variants of AD as more than purely neurocognitive syndromes may prevent delayed diagnosis. Moreover, neurologists may be tempted to differentiate EOFAD and HD by using specific hyperkinetic phenomenology, since these conditions would be expected to present with myoclonus and chorea, respectively. However, this dichotomy is overly simplistic; our case indicates that patients with motor features consistent with one condition, can harbor mutations related to both. Clinical phenotype may incompletely reflect the underlying genotype, making evaluation for both EOFAD and HD essential.

Finally, it is worth delving into the rarely-explored world of co-occurring AD and HD. Prior laboratory studies have noted these two neurodegenerative conditions to have overlapping pathophysiologic features including mitochondrial disturbances, ⁵ astrocytic reactivity, ⁶ and generation of reactive oxygen species. ⁷ Moreover, post-mortem analyses show that patients with genetically-confirmed HD exhibit pathologic changes reminiscent of AD,^8–9 and conversely, brains from AD patients demonstrate elevated levels of huntingtin protein. ¹⁰ This potential for AD-HD overlap has been extended to the genetic realm as well; a retrospective study noted about six percent of AD patients to have intermediate HTT alleles, ¹¹ and two patients diagnosed with AD have been reported to bear either a pathologic CAG expansion or a reduced penetrance phenotype.^11–12

However, the aforementioned analyses treated all AD patients as a single group and did not stratify for disease subtype. A knowledge gap exists in that no study to date has addressed whether patients specifically with early-onset, heritable variants of AD can also harbor abnormal HTT alleles. The answer to this question is important since HD bears a greater resemblance to EOFAD than it does to sporadic AD; EOFAD demonstrates an autosomal dominant inheritance, younger age of onset, more aggressive clinical course, and higher likelihood of hyperkinesia.^4,13 By reporting the first known patient with co-occurring HTT mutation and any EOFAD-associated monogenic abnormality (e.g., PSEN1, PSEN2, or APP), we suggest the possibility of an EOFAD-HD overlap syndrome whose epidemiology and clinical features merit further study. Indeed, if enough patients with early-onset dementia are found to have co-occurring neurodegenerative disorders, our current diagnostic framework may shift away from discrete disease categories and instead towards disease continua and spectra.

Besides large-scale population studies to characterize this potential EOFAD-HD overlap syndrome, we propose several research directions that mechanistically address how EOFAD and HD relate. One involves analyzing the impact of CAG expansion size on EOFAD symptomatology; our patient had an intermediate allele, and her disease course may have differed had her repeat size been in pathogenic range. Another involves determining the extent to which mutated presenilin and huntingtin augment each other’s pathogenicity; proteomic studies have already identified respective binding partners of these proteins, ¹⁴ but it is unclear whether these proteins themselves physically interact. The results of these studies may guide the development of future interventions that target multiple underlying disease pathways.

Conclusion

The utility of motor symptoms in differentiating EOFAD and HD is limited by 1) the greater prevalence of hyperkinesia in EOFAD compared to late-onset, sporadic AD and 2) the possibility of co-occurring mutations such that a particular phenomenology (i.e., myoclonus or chorea) incompletely reflects the underlying genotype. Patients presenting with early-onset dementia and any hyperkinetic movement disorder should be screened for both EOFAD and HD. We present the first case of pathogenic PSEN1 mutation occurring alongside abnormal HTT, suggesting the possibility of an EOFAD-HD overlap disorder that deserves further clinical characterization.