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CLINICAL PRACTICE

APP-Related Corticobasal Syndrome: Expanding the List of Corticobasal Degeneration Look Alikes Filomena Abate, MD,1 Giovanna Dati, MSc,1 Monia Ginevrino, PhD,2,3 Enza M. Valente, MD, PhD,4,5 Marina Picillo, MD, PhD1,*

Corticobasal syndrome (CBS) is a clinical entity characterized by asymmetric rigidity, bradykinesia, myoclonus, and dystonia combined with lateralized higher cortical features (ie, oro-buccal and limb apraxia, cortical sensory loss, and alien limb phenomena). This clinical presentation reflects the neuroanatomic distribution of disease in the frontal and parietal cortices and the basal ganglia1,2 and may be underpinned by different pathologies. Beyond the widespread deposition of hyperphosphorylated 4-repeat tau configuring corticobasal degeneration, CBS has been linked to Alzheimer’s disease (AD), progressive supranuclear gaze palsy, Pick’s disease, and Creutzfeldt-Jakob’s disease.3 Furthermore, several CBS phenotypes associated with pathogenic variants in distinct genes have been described,4 and the list of these conditions is steadily growing with the widespread adoption of nextgeneration sequencing (NGS) techniques. The identification of pathogenic genetic variants in CBS is pivotal for stratification of these subjects in clinical trials aimed at testing disease-modifying therapies. In addition, genetic counseling is advisable for affected families. Herein we report on a CBS patient carrier of the amyloid precursor protein (APP) heterozygous variant c.2149G > A (p.V717I) and provide a review of the literature of genetic CBS

Case Report A 52-year-old left-handed woman with a 10-year history of depressive symptoms presented with imbalance and an overt dementia. According to her relatives, memory deficits started 5 years before, and motor difficulties appeared in the past 3 years. The family history was positive for dementia, parkinsonism, and behavioral disorders (Fig. 1). Mental examination revealed a

Paolo Barone, MD, PhD,1 and

Mini-Mental Examination score of 16 with impairment in shortterm and long-term memory, executive functions, visuospatial abilities, and language. She also presented apathy and depressive symptoms. On neurological examination, she showed an apathetic face, asymmetric rigidity, and stimulus-sensitive and action myoclonus plus oro-buccal and limb apraxia and cortical sensory loss (all with left-side prevalence), thus fulfilling the criteria for probable CBS. The patient also presented akinesia prevalent on the left side and gait apraxia (Video S1). A computed tomography scan showed generalized cortical atrophy and 2-deoxy2-[fluorine-18]fluoro-D-glucose positron emission tomography bilateral temporo-parietal hypometabolism. Despite the different medications attempted (including levodopa, rivastigmine, memantine), her clinical condition worsened over the years. The patient underwent an NGS-based targeted analysis of a panel of 32 genes related to neurodegenerative diseases (Table S1). Genomic DNA was used to prepare an amplicon-based targeted library with the HaloPlex polymerase chain reaction Target Enrichment System (Agilent Technologies, Santa Clara, CA), which was run on a MiSeq instrument (Illumina, San Diego, CA). Data were subjected to bioinformatic analysis and filtering to exclude common variants (frequency > 1% in the gnomAD database) as well as synonymous and noncoding variants not predicted to impact splicing. After variant filtering and prioritization, the patient was found to carry the heterozygous c.2149G > A (p.V717I) variant in the APP gene (rs63750264), confirmed by Sanger sequencing. A revision of the literature disclosed 10 genes associated with CBS with GRN, C9orf72, and MAPT being the most frequent (Table S2). Apart from a few cases with negative familial history, a positive familial history of dementia and/or parkinsonism is noted in the majority of patients. Language impairment and

1

Center for Neurodegenerative Diseases, Department of Medicine, Surgery and Dentistry, Neuroscience Section, University of Salerno, Salerno, Italy; 2Institute of Genomic Medicine, Catholic University, Agostino Gemelli IRCCS University Hospital Foundation, Rome, Italy; 3Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, Rome, Italy; 4Department of Molecular Medicine, University of Pavia, Pavia, Italy; 5IRCCS Mondino Foundation, Pavia,, Italy

*Correspondence to: Dr. Marina Picillo, Center for Neurodegenerative Diseases, University of Salerno, Via Allende, Baronissi (Salerno), 84131, Italy; E-mail: [email protected], [email protected] Keywords: genetics, dementia, parkinsonism. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 27 April 2020; revised 18 July 2020; accepted 21 July 2020. Published online 00 Month 2020 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mdc3.13037

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CASE REPORT

APP-RELATED CBS

FIG 1. Pedigree. I-3 died with cognitive impairment; II-1 was affected by dementia; II-2 was deceased at 55 years old with kidney failure; II-3 was affected by dementia; II-4 was affected by parkinsonism and dementia; II-5 was diagnosed with major depression and committed suicide; III-2 was the proband. Neurological history for all relatives was reported by the proband and caregiver. None of the living relatives consented on examination and/or blood sampling.

behavioral changes are the most frequent complaints in GRN, C9orf72, and MAPT. On the other hand, both clinical and familial histories for amyotrophic lateral sclerosis represent a red flag for C9orf72 and TARDBP.

Discussion Given the presence of asymmetric limb rigidity, akinesia, and myoclonus associated with oro-buccal and asymmetric limb apraxia and cortical sensory loss, our patient was initially diagnosed with probable CBS.1 Both patient history and imaging findings prompted us to consider a diagnosis of primary dementia. However, the relatively young age at onset and the autosomal dominant pattern of inheritance for dementia and parkinsonism strongly suggested a monogenic cause underlying her phenotype. To date, genetic CBS are known to be caused by a growing number of genes, as listed in the Table S2. The most frequent genes associated with CBS are GRN, C9orf72, and MAPT, all determining tau-related frontotemporal lobar degeneration. However, NGS excluded pathogenic variants in such genes and disclosed the APP variant c.2149G > A (p.V717I), also called the London mutation.5 To the best of our knowledge, this is the first case of CBS associated with mutations in this gene. Dominant mutations of the APP gene, located on chromosome 21q21, are associated with early-onset dementia related with AD pathology. In line with previous APP cases, our proband disclosed memory involvement at onset and myoclonus. Differently from other reports of APP carriers, seizures were lacking.5 However, our patient also presented aspecific involvement of executive and visuo-spatial functions as well as behavioral changes, including apathy and depressive symptoms, as previously reported in other Italian families with APP mutations.6 Although in vivo markers of AD pathology (ie, through lumbar puncture and nuclear medicine assessments) were not obtained, it is 2

reasonable to assume that, in our patient, CBS is underlined by AD pathology. The key point of this case is the family history for dementia and the prominent cognitive impairment suggestive of a gene variant for a dementia syndrome. The present report supports the power of NGS-based strategies in reaching genetic diagnoses able to expand the phenotypic spectrum of known genes or even specific mutations. Indeed, this case further supports the knowledge that genetic conditions, such as those associated with APP variants, present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria in defining boundaries between distinct conditions. In conclusion, our case expands the list of mutations causing CBS, suggesting that the APP gene should be included among the genes screened in CBS with atypical features, such as young age at onset and positive familial history for dementia and/or parkinsonism.

Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. F.A.: 1C, 2A G.D.: 1C, 2B M.G.: 1C, 2B E.M.V.: 1A, 2B P.B.: 1A, 2B M.P.: 1A, 1B, 1C, 2C

Disclosures Ethical Compliance Statement: The study has been approved by the appropriate ethics committee (Campania Sud) and have

MOVEMENT DISORDERS CLINICAL PRACTICE 2020. doi: 10.1002/mdc3.13037

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ABATE F. ET AL.

therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The patient signed written informed consent. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: This study was in part funded by Actelion Pharmaceuticals. On behalf of all authors, the corresponding author states that there is no conflict of interest. Financial Disclosures for Previous 12 Months: Marina Picillo is supported by the Michael J Fox Foundation for Parkinson’s research; Paolo Barone received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie and Acorda; the other authors report no financial diclosures for the previous 12 months. ■

References 1. Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013;80:496–503. 2. Murray R, Neumann M, Forman MS, et al. Cognitive and motor assessment in autopsy-proven corticobasal degeneration. Neurology 2007;68: 1274–1283.

3. Boeve BF, Marangore DM, Parisi JE, et al. Pathologic heterogeneity in clinically diagnosed corticobasal degeneration. Neurology 1999;53:795–800. 4. Stamelou M, Quinn NP, Bhatia KP. "Atypical" atypical parkinsonism: new genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy-a diagnostic guide. Mov Disord 2013;28:1184–1199. 5. Ryan NS, Nicholas JM, Weston PS, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol 2016;15:1326–1335. 6. Talarico G, Piscopo P, Gasparini M, et al. The London APP mutation (Val717Ile) associated with early shifting abilities and behavioral changes in two Italian families with early-onset Alzheimer’s disease. Dement Geriatr Cogn Disord 2010;29:484–490.

Supporting Information Supporting information may be found in the online version of this article. Video S1. Upper limb apraxia (left > right). Left side of the body is neglected. Orobuccal apraxia. Rigidity is prevalent on the left side. Stimulus-sensitive myoclonic jerks. Gait apraxia, mildly broad based. Table S1. List of genes included in the next generation sequencing panel. Table S2. List of known genes associated with corticobasal syndrome.

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