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• W3109484009 abstract "•Pathogenic expansions in the HTT gene are a rare cause of FTD/ALS spectrum diseases•Autopsies showed both the expected TDP-43 pathology of FTD/ALS and polyQ inclusions•HTT repeat expansions were not seen in healthy subjects or Lewy body dementia cases•Clinicians should screen FTD/ALS patients for HTT repeat expansions We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40–64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington’s disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered. Frontotemporal dementia (FTD; OMIM: 600274) and amyotrophic lateral sclerosis (ALS; OMIM: 105400) are progressive neurological disorders that are characterized clinically by cognitive deficits, language abnormalities, and muscle weakness (Neary et al., 2005Neary D. Snowden J. Mann D. Frontotemporal dementia.Lancet Neurol. 2005; 4: 771-780Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar; Rowland and Shneider, 2001Rowland L.P. Shneider N.A. Amyotrophic lateral sclerosis.N. Engl. J. Med. 2001; 344: 1688-1700Crossref PubMed Scopus (1501) Google Scholar). These aggressive illnesses typically occur between the ages of 40 and 70 years, leading to death within 3–8 years of symptom onset (Chiò et al., 2013Chiò A. Logroscino G. Traynor B.J. Collins J. Simeone J.C. Goldstein L.A. White L.A. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature.Neuroepidemiology. 2013; 41: 118-130Crossref PubMed Scopus (441) Google Scholar; Neary et al., 2005Neary D. Snowden J. Mann D. Frontotemporal dementia.Lancet Neurol. 2005; 4: 771-780Abstract Full Text Full Text PDF PubMed Scopus (422) Google Scholar). Approximately 15,000 individuals die of FTD or ALS in the United States annually (Arthur et al., 2016Arthur K.C. Calvo A. Price T.R. Geiger J.T. Chiò A. Traynor B.J. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040.Nat. Commun. 2016; 7: 12408Crossref PubMed Scopus (165) Google Scholar), and there are no treatments that halt the degenerative process. Clinical, genetic, and neuropathologic data demonstrate that FTD and ALS are closely related conditions that exist along a spectrum of neurological disease (Lillo and Hodges, 2009Lillo P. Hodges J.R. Frontotemporal dementia and motor neurone disease: overlapping clinic-pathological disorders.J. Clin. Neurosci. 2009; 16: 1131-1135Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Though progress has been made, much remains unclear about the genetic etiology of the FTD/ALS spectrum. Approximately 40% of FTD cases are familial, and causative mutations have been identified, most notably in MAPT, GRN, C9orf72, and VCP (Ferrari et al., 2019Ferrari R. Manzoni C. Hardy J. Genetics and molecular mechanisms of frontotemporal lobar degeneration: an update and future avenues.Neurobiol. Aging. 2019; 78: 98-110Crossref PubMed Scopus (22) Google Scholar). In ALS, 10% of patients report a family history of the disease. The genetic etiology is known for two-thirds of these familial cases, whereas the underlying gene is recognized in 10% of sporadic cases (Chia et al., 2018Chia R. Chiò A. Traynor B.J. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.Lancet Neurol. 2018; 17: 94-102Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar; Renton et al., 2014Renton A.E. Chiò A. Traynor B.J. State of play in amyotrophic lateral sclerosis genetics.Nat. Neurosci. 2014; 17: 17-23Crossref PubMed Scopus (938) Google Scholar). The intronic repeat expansion of the C9orf72 gene is the most common cause of FTD and ALS (Majounie et al., 2012Majounie E. Renton A.E. Mok K. Dopper E.G. Waite A. Rollinson S. Chiò A. Restagno G. Nicolaou N. Simon-Sanchez J. et al.Chromosome 9-ALS/FTD ConsortiumFrench research network on FTLD/FTLD/ALSITALSGEN ConsortiumFrequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.Lancet Neurol. 2012; 11: 323-330Abstract Full Text Full Text PDF PubMed Scopus (767) Google Scholar). Other repeat expansions have been implicated in neurological diseases. These include polyglutamine repeats observed in Huntington’s disease (MacDonald et al., 1993MacDonald M.E. Ambrose C.M. Duyao M.P. Myers R.H. Lin C. Srinidhi L. Barnes G. Taylor S.A. James M. Groot N. et al.The Huntington’s Disease Collaborative Research GroupA novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes.Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (6740) Google Scholar) and spinobulbar muscular atrophy (La Spada et al., 1991La Spada A.R. Wilson E.M. Lubahn D.B. Harding A.E. Fischbeck K.H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy.Nature. 1991; 352: 77-79Crossref PubMed Scopus (2331) Google Scholar) and more complex expansions in the RFC1 gene that were recently associated with autosomal recessive cerebellar ataxia (Cortese et al., 2019Cortese A. Simone R. Sullivan R. Vandrovcova J. Tariq H. Yau W.Y. Humphrey J. Jaunmuktane Z. Sivakumar P. Polke J. et al.Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia.Nat. Genet. 2019; 51: 649-658Crossref PubMed Scopus (133) Google Scholar). Together, these data suggest that repeat expansions play a critical role in the pathogenesis of neurodegenerative diseases. This type of mutation may be amenable to antisense oligonucleotide therapy, adding further incentive to their identification (Tabrizi et al., 2019Tabrizi S.J. Leavitt B.R. Landwehrmeyer G.B. Wild E.J. Saft C. Barker R.A. Blair N.F. Craufurd D. Priller J. Rickards H. et al.Phase 1–2a IONIS-HTTRx Study Site TeamsTargeting Huntingtin Expression in Patients with Huntington’s Disease.N. Engl. J. Med. 2019; 380: 2307-2316Crossref PubMed Scopus (266) Google Scholar). The discovery of new genetic causes of FTD and ALS provides insights into the cellular mechanisms of neurodegeneration (Renton et al., 2014Renton A.E. Chiò A. Traynor B.J. State of play in amyotrophic lateral sclerosis genetics.Nat. Neurosci. 2014; 17: 17-23Crossref PubMed Scopus (938) Google Scholar). From a clinical perspective, the molecular characterization of the genetic causes of disease in a patient helps to establish an accurate diagnosis and genetic counseling of the patients and their families. It is also a necessary first step toward future precision medicine. To explore the genetic architecture of neurodegenerative disorders, we performed whole-genome sequencing in patients diagnosed with FTD/ALS, Lewy body dementia (LBD), and neurologically healthy individuals and systematically assessed the role of previously identified, disease-causing repeat expansions. After quality control, whole-genome sequence data from 2,442 patients diagnosed with FTD/ALS, 2,599 LBD patients, and 3,158 neurologically healthy individuals were available for analysis. We used the ExpansionHunter–Targeted tool to assess 10 repeat expansion motifs that have been previously associated with neurological disease and experimentally validated for this algorithm (Dolzhenko et al., 2017Dolzhenko E. van Vugt J.J.F.A. Shaw R.J. Bekritsky M.A. van Blitterswijk M. Narzisi G. Ajay S.S. Rajan V. Lajoie B.R. Johnson N.H. et al.US–Venezuela Collaborative Research GroupDetection of long repeat expansions from PCR-free whole-genome sequence data.Genome Res. 2017; 27: 1895-1903Crossref PubMed Scopus (122) Google Scholar, Dolzhenko et al., 2019Dolzhenko E. Deshpande V. Schlesinger F. Krusche P. Petrovski R. Chen S. Emig-Agius D. Gross A. Narzisi G. Bowman B. et al.ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions.Bioinformatics. 2019; 35: 4754-4756Crossref PubMed Scopus (39) Google Scholar). The examined genes included AR, ATN1, ATXN1, ATXN3, C9orf72, DMPK, FMR1, FXN, HTT, and PHOX2B (Table S1). Consistent with the previous publications (Dolzhenko et al., 2017Dolzhenko E. van Vugt J.J.F.A. Shaw R.J. Bekritsky M.A. van Blitterswijk M. Narzisi G. Ajay S.S. Rajan V. Lajoie B.R. Johnson N.H. et al.US–Venezuela Collaborative Research GroupDetection of long repeat expansions from PCR-free whole-genome sequence data.Genome Res. 2017; 27: 1895-1903Crossref PubMed Scopus (122) Google Scholar, Dolzhenko et al., 2019Dolzhenko E. Deshpande V. Schlesinger F. Krusche P. Petrovski R. Chen S. Emig-Agius D. Gross A. Narzisi G. Bowman B. et al.ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions.Bioinformatics. 2019; 35: 4754-4756Crossref PubMed Scopus (39) Google Scholar), we found excellent concordance between the identification of the known C9orf72 repeat expansion using the ExpansionHunter–Targeted algorithm and a repeat-primed PCR assay for C9orf72 (Majounie et al., 2012Majounie E. Renton A.E. Mok K. Dopper E.G. Waite A. Rollinson S. Chiò A. Restagno G. Nicolaou N. Simon-Sanchez J. et al.Chromosome 9-ALS/FTD ConsortiumFrench research network on FTLD/FTLD/ALSITALSGEN ConsortiumFrequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.Lancet Neurol. 2012; 11: 323-330Abstract Full Text Full Text PDF PubMed Scopus (767) Google Scholar) among our samples (n = 7 [0.3%] discordance out of 2,147 samples with information for both assays, kappa = 0.974). We identified three FTD/ALS patients who carried full-penetrance pathogenic repeat expansions (≥40) in the HTT gene, representing 0.12% of the patients diagnosed with FTD/ALS disorders. The sizes of the detected HTT expansions were 41, 40, and 40 repeats, which are deemed to be fully penetrant (Table 1). In contrast, none of the LBD cases or healthy control subjects carried pathogenic HTT expansions. The lengths of the repeat expansions in these three FTD/ALS patients were confirmed by repeat-primed PCR and cloning and Sanger sequencing (Figures 1A and S1). We did not observe a higher rate of intermediate (27–35) or low-penetrance (36–39) HTT repeat expansions among patients diagnosed with FTD/ALS or LBD compared to control subjects (Figure 1B). Aside from C9orf72 as a common cause of FTD and ALS, none of the other repeat expansions evaluated by the ExpansionHunter–Targeted algorithm displayed a similar pattern of being present in cases and absent in control subjects (see Table S1). For this reason, we focused our efforts on the HTT repeat expansion in FTD/ALS patients.Table 1Pathogenic HTT Repeat Expansions within the Discovery and Replication CohortsDiscovery CohortReplication CohortaThe replication control cohort included 210 neurologically healthy controls, 13,670 population controls from Gardiner et al. (2019), and 17,703 neurologically healthy individuals from the UK 100K Genomes Project. The replication case cohort included 1,236 samples analyzed by repeat-primed PCR for HTT repeats and 2,648 samples analyzed by next-generation sequencing. All samples that whole-genome sequencing predicted to possess ≥40 CAG repeats were verified by repeat-primed PCR and cloning and Sanger sequencing.Number of Carriers/Number ScreenedRate (%)Number of Carriers/Number ScreenedRate (%)FTD/ALSbWithin the FTD/ALS discovery cohort, 3 out of 1,377 FTD patients (0.2%) and 0 out of 1,065 ALS patients carried a pathogenic HTT repeat expansion. Within the FTD/ALS replication cohort, 2 out of 1,009 FTD patients (0.2%) and 3 out of 2,665 ALS patients (0.1%) carried a pathogenic HTT repeat expansion.3/24420.15/3,6740.1LBD0/2,5990––Controls0/3,158010/31,5830.03a The replication control cohort included 210 neurologically healthy controls, 13,670 population controls from Gardiner et al., 2019Gardiner S.L. Boogaard M.W. Trompet S. de Mutsert R. Rosendaal F.R. Gussekloo J. Jukema J.W. Roos R.A.C. Aziz N.A. Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts.JAMA Neurol. 2019; 76: 650-656Crossref PubMed Scopus (20) Google Scholar, and 17,703 neurologically healthy individuals from the UK 100K Genomes Project. The replication case cohort included 1,236 samples analyzed by repeat-primed PCR for HTT repeats and 2,648 samples analyzed by next-generation sequencing. All samples that whole-genome sequencing predicted to possess ≥40 CAG repeats were verified by repeat-primed PCR and cloning and Sanger sequencing.b Within the FTD/ALS discovery cohort, 3 out of 1,377 FTD patients (0.2%) and 0 out of 1,065 ALS patients carried a pathogenic HTT repeat expansion. Within the FTD/ALS replication cohort, 2 out of 1,009 FTD patients (0.2%) and 3 out of 2,665 ALS patients (0.1%) carried a pathogenic HTT repeat expansion. Open table in a new tab To replicate our findings, we assessed the HTT CAG repeat length in an independent cohort of 3,674 patients diagnosed with FTD/ALS spectrum disorders and 210 healthy control participants. We detected an additional five patients diagnosed with FTD/ALS who carried pathogenic HTT repeat expansions, representing 0.14% of this replication cohort (sizes 64, 40, 44, 40, and 41 for patients 4–8 in Table 1). We compared this to published data on the occurrence of HTT repeat expansions in the general population, which was only 0.03% (10 out of 31,373 individuals had ≥40 repeats) (Gardiner et al., 2019Gardiner S.L. Boogaard M.W. Trompet S. de Mutsert R. Rosendaal F.R. Gussekloo J. Jukema J.W. Roos R.A.C. Aziz N.A. Prevalence of carriers of intermediate and pathological polyglutamine disease-associated alleles among large population-based cohorts.JAMA Neurol. 2019; 76: 650-656Crossref PubMed Scopus (20) Google Scholar; Peplow, 2016Peplow M. The 100,000 Genomes Project.BMJ. 2016; 353: i1757Crossref PubMed Scopus (42) Google Scholar). Overall, the carrier rate among patients diagnosed with FTD/ALS spectrum disorders in the discovery and replication cohorts was 4.4 times higher than that observed among healthy individuals (Fisher’s exact test p value = 2.68 × 10−3; odds ratio, 4.55; 95% confidence interval, 1.56–12.80, Table 1). None of the patients found to carry the HTT full-penetrance expansions had additional disease-causing mutations in 50 other genes implicated in FTD/ALS and other neurodegenerative diseases (see STAR Methods for the gene list). We performed a genome-wide association study (GWAS) on the FTD/ALS discovery cohort, and single-variant analysis similarly failed to identify loci that would account for our findings (Figure S2). The FTD/ALS patients carrying HTT full-penetrance repeat expansions harbored several different haplotypes that have previously been associated with this locus (Figure S3). The presence of multiple haplotypes indicated diverse ancestral sources among our samples, making it unlikely that another genetic variant outside of the expansion was causing disease in these patients. Furthermore, we did not detect interruptions within the HTT repeat expansion in any of the patients. We only encountered the loss of the CAA-CAG trailing sequence in a single individual (patient 8; Figure 1D). Additionally, we examined somatic instability across multiple brain regions obtained from the postmortem tissues of two patients diagnosed with FTD/ALS (patients 5 and 8), and from a Huntington’s disease patient carrying 41 CAG repeats (Figure 2). We utilized repeat-primed PCR GeneMapper chromatograms to quantify CAG repeat length distributions, as recently published (Mouro Pinto et al., 2020Mouro Pinto R. Arning L. Giordano J.V. Razghandi P. Andrew M.A. Gillis T. Correia K. Mysore J.S. Grote Urtubey D.M. Parwez C.R. et al.Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1.Hum. Mol. Genet. 2020; 29: 2551-2567Crossref PubMed Scopus (22) Google Scholar) (Figure S4). The motor cortex and globus pallidus/putamen regions displayed the most instability in patients 5 and 8, whereas the spinal cord was among the most stable. A similar pattern was observed in the Huntington’s disease patient. The range of expansion indices (range, 0.042–0.985) observed in the FTD/ALS patients was also consistent with a study of Huntington’s disease patients carrying lower pathogenic-range HTT repeat expansions (Mouro Pinto et al., 2020Mouro Pinto R. Arning L. Giordano J.V. Razghandi P. Andrew M.A. Gillis T. Correia K. Mysore J.S. Grote Urtubey D.M. Parwez C.R. et al.Patterns of CAG repeat instability in the central nervous system and periphery in Huntington’s disease and in spinocerebellar ataxia type 1.Hum. Mol. Genet. 2020; 29: 2551-2567Crossref PubMed Scopus (22) Google Scholar). The clinical details of the eight patients carrying the HTT full-penetrance, pathogenic repeat expansions are summarized in Table 2 and described in Methods S1 in Supplemental Information. None of the patients reported choreoathetosis. Four patients reported a family history of neurological disease. Patient 4 (Table 2) was an outlier among the cases we identified as carrying HTT pathogenic repeat expansions. She presented at 17 years of age with cognitive decline, supranuclear vertical gaze palsy, parkinsonism, postural instability, gait disturbance, spasticity, and hyperreflexia in the lower limbs. Treatment with levodopa did not yield a clinical improvement. Genetic screening of HTT performed at the time of presentation was incorrectly reported as normal, and she was initially diagnosed with FTD-progressive supranuclear palsy (PSP) despite her young age. A repeat genetic panel conducted several years later to investigate possible causes of young-onset dementia correctly identified an expanded HTT repeat allele. Her diagnosis was updated to young-onset Huntington’s disease (Westphal variant). Her father had presented with a similar syndrome of cognitive decline, gait disorder, and dysarthria in his late 20s and was diagnosed with Huntington’s disease after his daughter’s genetic diagnosis.Table 2Clinical Details of the Eight Patients Carrying a Full-Penetrance Pathogenic HTT Repeat ExpansionPatientCohortCAG Repeats (A1/A2)Clinical DiagnosisAge at Onset (y)SexFamily HistoryPresenting Symptoms1discovery41/21PSP-FTD68Mno–2discovery40/16bvFTD56Fyesbehavioral changes3discovery40/17nfvPPA57Fnolanguage disturbance4replication64/17PSP-FTD17Fyesacademic decline, dysarthria, bradykinesia, and gait disturbance5replication40/15ALS56F––6replication44/28bvFTD44Myespersonality changes and apathy7replication40/19ALS76Myeslower limb weakness8replication41/17ALS61Mnoright foot weaknessClinical diagnoses include progressive supranuclear palsy, FTD type (PSP-FTD); behavioral variant FTD (bvFTD); nonfluent variant primary progressive aphasia subtype of FTD (nfvPPA); and amyotrophic lateral sclerosis (ALS). Family history refers to a family history of neurological disease. DNA for patients 5 and 8 was extracted from frozen cerebellar tissue, and DNA for the other six patients was extracted from blood. See also Methods S1. A1, allele 1; A2, allele 2. Open table in a new tab Clinical diagnoses include progressive supranuclear palsy, FTD type (PSP-FTD); behavioral variant FTD (bvFTD); nonfluent variant primary progressive aphasia subtype of FTD (nfvPPA); and amyotrophic lateral sclerosis (ALS). Family history refers to a family history of neurological disease. DNA for patients 5 and 8 was extracted from frozen cerebellar tissue, and DNA for the other six patients was extracted from blood. See also Methods S1. A1, allele 1; A2, allele 2. We examined postmortem brains obtained from two of our patients harboring HTT full-penetrance CAG repeats. The first patient was a woman carrying 40 HTT CAG repeats who developed ALS symptoms at the age of 56 years and died 11 years later of respiratory failure following a typical course of motor neuron disease (Table 2; patient 5). Postmortem examination showed mild atrophy of the precentral gyrus and thinning of the spinal cord anterior roots. Microscopic examination revealed classical neuropathological features of ALS; there was a loss of the motor neurons of the spinal cord and hypoglossal nuclei (Figures 3A and 3B ). Staining with anti-TDP-43 antibodies showed rare neurons with nuclear to cytoplasmic TDP-43 translocation and occasional neuropil skeins confined to the prefrontal cortex (Brodmann area 9 [BA9]; Figure 3C). Neither aberrant TDP-43 translocation nor ubiquitinated inclusions were detected in the dentate gyrus. Interestingly, dual staining of the prefrontal cortex and striatum using anti-huntingtin/p62 antibodies showed nuclear and cytoplasmic aggregates of huntingtin and p62 with the highest density observed in the infragranular layers of the prefrontal cortex (Figure 3D). Ubiquitinated nuclear inclusions were found in the tail of the caudate nucleus (Figure 3H) and the frontal cortex (not shown). However, there was no atrophy, neuronal loss, or active gliosis in the striatum (Figures 3E, 3F, 3H, and 3I). The second brain evaluated postmortem was that of a man carrying 41 CAG repeats in HTT who presented with right foot weakness at age 61 years. He was diagnosed with ALS based on disease progression and electromyography, and he died from respiratory failure 9 years after symptom onset following a typical course of motor neuron disease (patient 8; Table 2). Postmortem examination showed mild atrophy of the precentral gyrus and thinning of the anterior spinal roots. There was otherwise no cerebral cortical or striatal atrophy (Figure 4A) or evidence of neuronal loss or gliosis in the striatum on microscopic examination (Figure 4B). Staining for ubiquitin (Figure 4C) and polyglutamine showed scattered nuclear and cytoplasmic and neuropil aggregates within the striatum (Figure 4D) and motor cortex (Figure 4E). Polyglutamine aggregates were not detected in the spinal cord. There was a marked loss of spinal motor neurons (Figure 4F) and degeneration of the corticospinal tracts. Staining with anti-phospho-TDP-43 antibodies showed ALS-type TDP-43 cytoplasmic inclusions within some residual motor neurons (Figure 4F, inset). To confirm the specificity of our pathological findings, we examined the prefrontal cortex (BA9) obtained from postmortems of individuals without Huntington’s disease using the anti-huntingtin (2B4) immunostain previously used. These specimens consisted of four neurologically healthy individuals, three patients diagnosed with FTD/ALS, two patients with Alzheimer’s disease, and one patient with diffuse LBD. All 10 cases showed weak cytoplasmic immunostaining within neurons (Figures S5A and S5B) and did not show aggregation as seen in the two ALS cases with CAG expansions (Figures 3 and 4) or in Huntington’s disease patients (Figure S5C). Microscopic examination of the spinal cords of nine patients diagnosed with typical Huntington’s disease did not show spinal motor neuron loss. Our data indicate that pathogenic CAG repeat expansions in HTT can give rise to FTD/ALS syndromes that are clinically distinct from the classical Huntington’s disease syndrome. A careful review of the clinical features of the patients carrying pathogenic HTT expansions confirmed the diagnosis of FTD or ALS in seven out of the eight patients. None of the patients manifested choreoathetoid movements during their illness or reported a family history of Huntington’s disease. Furthermore, the postmortem findings of two of our patients with HTT full-penetrance repeat expansions displayed the classical neuropathologic features of ALS, including loss of motor neurons of the anterior horns and hypoglossal nuclei and the presence of TDP-43-positive inclusions, thereby ruling out mimic syndromes as an explanation of our findings. However, the pathogenic repeat expansions’ effects were corroborated by the occurrence of polyglutamine/huntingtin co-pathology within the frontal lobes. Finally, pathogenic HTT repeat expansions were specific to FTD/ALS cases, as they were not found in a similar-sized cohort of patients diagnosed with LBD. It is possible that the patients carrying a HTT repeat expansion were simply misdiagnosed cases of atypical Huntington’s disease or suffered from two different neurodegenerative diseases by chance, and they would have developed the classic Huntington’s disease symptoms had they lived long enough. We believe that these are unlikely scenarios for several reasons. First, we identified multiple FTD/ALS patients in our discovery cohort following the same clinical pattern and found a similar occurrence rate in our replication cohort. In contrast, full-penetrance pathogenic HTT expansions were not present in our LBD or control whole-genome sequence data. Second, the apparently healthy striatum in both patients who underwent postmortem evaluation diminishes the likelihood of subclinical Huntington’s disease as an explanation for their symptoms. The choreoathetoid movements observed in Huntington’s disease originate from the striatum, and the lack of detectable neuronal loss on general surveys or reactive gliosis in this region of our FTD/ALS patients implies that the motor neuron disease was not masking these symptoms. Third, two of our eight patients lived at least 9 years after symptom onset and did not manifest motor signs of Huntington’s disease during this extended survival period. Fourth, the prevalence rates of FTD (22 per 100,000 population) (Onyike and Diehl-Schmid, 2013Onyike C.U. Diehl-Schmid J. The epidemiology of frontotemporal dementia.Int. Rev. Psychiatry. 2013; 25: 130-137Crossref PubMed Scopus (240) Google Scholar), ALS (6 per 100,000) (Chiò et al., 2013Chiò A. Logroscino G. Traynor B.J. Collins J. Simeone J.C. Goldstein L.A. White L.A. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature.Neuroepidemiology. 2013; 41: 118-130Crossref PubMed Scopus (441) Google Scholar), and Huntington’s disease (3 per 100,000) (Pringsheim et al., 2012Pringsheim T. Wiltshire K. Day L. Dykeman J. Steeves T. Jette N. The incidence and prevalence of Huntington’s disease: a systematic review and meta-analysis.Mov. Disord. 2012; 27: 1083-1091Crossref PubMed Scopus (325) Google Scholar) indicate that, by chance, there should only be three cases of disease co-occurrence in the entire United States population of 327 million. Instead, we identified eight patients among a moderately sized cohort of FTD/ALS cases (n = 6,116 patients). Finally, the age at onset among our patients overlapped with the predicted age at onset of Huntington’s disease based on their CAG repeat length (Figure 1C). Regardless of the semantic debate as to whether it is correct to designate HTT repeat expansions as a genetic cause of FTD/ALS spectrum disorders, our findings have direct implications for the clinical care of patients presenting with these neurological conditions and the neuropathologic staging of disease. Although there have been previous reports of the coexistence of FTD/ALS and Huntington’s disease (Chhetri et al., 2014Chhetri S.K. Dayanandan R. Bindman D. Craufurd D. Majeed T. Amyotrophic lateral sclerosis and Huntington’s disease: neurodegenerative link or coincidence?.Amyotroph. Lateral Scler. Frontotemporal Degener. 2014; 15: 145-147Crossref PubMed Scopus (4) Google Scholar; Kanai et al., 2008Kanai K. Kuwabara S. Sawai S. Nakata M. Misawa S. Isose S. Hirano S. Kawaguchi N. Katayama K. Hattori T. Genetically confirmed Huntington’s disease masquerading as motor neuron disease.Mov. Disord. 2008; 23: 748-751Crossref PubMed Scopus (11) Google Scholar; Nielsen et al., 2010Nielsen T.R. Bruhn P. Nielsen J.E. Hjermind L.E. Behavioral variant of frontotemporal dementia mimicking Huntington’s disease.Int. Psychogeriatr. 2010; 22: 674-677Crossref PubMed Scopus (10) Google Scholar; Papageorgiou et al., 2006Papageorgiou S.G. Antelli A. Bonakis A. Vassos E. Z" @default.
• W3109484009 created "2020-12-07" @default.
• W3109484009 creator A5077095161 @default.
• W3109484009 date "2021-02-01" @default.
• W3109484009 modified "2023-10-15" @default.
• W3109484009 title "Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis" @default.
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• W3109484009 doi "https://doi.org/10.1016/j.neuron.2020.11.005" @default.
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