Neurobiology of Aging 35 (2014) 1214.e7e1214.e10
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Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia Daniela Galimberti a, *, Andreas Reif b, Bernardo Dell’Osso c, Sarah Kittel-Schneider b, Christine Leonhard b, Alexandra Herr b, Carlotta Palazzo c, Chiara Villa a, Chiara Fenoglio a, Maria Serpente a, Sara .M.G. Cioffi a, Cecilia Prunas c, Riccardo A. Paoli c, A. Carlo Altamura c, Elio Scarpini a a Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy b Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Wuerzburg, Germany c Psichiatry Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 August 2013 Received in revised form 28 November 2013 Accepted 5 December 2013 Available online 11 December 2013
A hexanucleotide repeat expansions in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. The same mutation has been described in a patient with bipolar disorder, but up to now, not in patients suffering from schizophrenia. We determined the frequency of the C9ORF72 hexanucleotide repeat expansions in a population of 298 patients with schizophrenia or schizoaffective disorder. The pathogenic repeat expansion was detected in 2 patients (0.67%). Both of them presented with auditory hallucinations and had comorbid alcohol abuse. In addition, a positive family history for psychiatric and/or neurodegenerative diseases was present. The repeat expansion in the C9ORF72 gene is a rare, but possible, cause of schizophrenic spectrum disorders. We cannot rule out however whether the number of repeats influence the phenotype. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Dementia Schizophrenia Psychosis C9ORF72 hexanucleotide repeat expansion Phenotype Clinical presentation
1. Introduction A hexanucleotide repeat expansion in the first intron of C9ORF72 was shown to be responsible for a high number of autosomal dominant inherited amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration (FTLD) cases, with or without concomitant motor neuron disease (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The function(s) of the protein encoded by this gene is so far unknown. Wild-type alleles contain not more than 30 repeats, whereas mutated alleles have hundreds to thousands of repeats (DeJesus-Hernandez et al., 2011). The relationship between the number of expansions and the phenotype is, however, not clear yet, as recent data described patients with frontotemporal lobar degeneration (FTLD) carrying an allele with 20e22 hexanucleotide repeats (Gómez-Tortosa et al., 2013). * Corresponding author at: via Francesco Sforza, 35, 20122, Milan, Italy. Tel.: þ39 02 55033847; fax þ39 02 55036580. E-mail address: [email protected] (D. Galimberti). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.004
It was suggested that psychosis and obsessive-compulsive disorder were common symptoms at disease onset in patients with FTLD carrying the repeat expansion (Calvo et al., 2012; Floris et al., 2012; Snowden et al., 2012). Moreover, a case showing mystic delusion with visual and auditory hallucinations, in the absence of neurologic symptoms and brain atrophy, has been recently described (Arighi et al., 2012). In a study carried out in a large population of patients with FTLD, it was shown that the presentation with late onset psychosis (particularly hallucinations and delusions) is significantly more frequent in C9ORF72 repeat expansion carriers than noncarriers (Galimberti et al., 2013a). In addition, presentation with memory impairment occurs quite often, possibly leading to a clinical diagnosis of Alzheimer’s disease (Galimberti et al., 2013a; Majounie et al., 2012b; Murray et al., 2011). Bipolar disorder (BD) patients carrying the C9ORF72 hexanucleotide repeat expansion have been recently described (Galimberti et al., 2013b; Meisler et al., 2013), whereas no carriers were found in a population of 192 patients with schizophrenia (Huey et al., 2013). In 2012, it was shown that a suicide attempt can
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D. Galimberti et al. / Neurobiology of Aging 35 (2014) 1214.e7e1214.e10
be the first manifestation of early dementia because of the recently identified C9ORF72 expansion (Synofzik et al., 2012). Herein, we genotyped a population of 298 patients with schizophrenia for the presence of the C9ORF72 expansion, and identified 2 mutation carriers (0.67%). 2. Methods 2.1. Patients and clinical workup Our cohort included 298 patients (274 Germans and 24 Italians; thereof 157 males, mean age at disease onset SD: 27 10 years, range: 9e72 years) recruited at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany, and at the Psychiatry Unit of the Fondazione Cà Granda, Ospedale Maggiore Policlinico (Milan), diagnosed with schizophrenia or schizoaffective disorder (i.e., psychotic disorders). Diagnoses were made according to Diagnostic and Statistical manual of Mental disorders, fourth edition, Text Revised (DSM-IVTR) criteria (First et al., 2002). German samples were described in greater detail previously (Scholz et al., 2010). 2.2. C9ORF72 genotyping High-molecular weight DNA was isolated from whole blood using a Flexigene Kit (Qiagen, Hildren, Gemany). C9ORF72 genotyping was carried out by repeat-primed polymerase chain reaction and sequencing, as previously described (Xi et al., 2012). A characteristic stutter amplification pattern (>40 repeats) on the electropherogram is considered evidence of a pathogenic repeat expansion. 3. Results We genotyped 298 patients with schizophrenia. A clinically documented family history for psychiatric diseases or dementia was reported for 122 patients. The pathogenic repeat expansion was detected in 2 patients (0.67% of cases; Table 1). Both of them were presented with acoustic hallucinations and showed comorbid alcohol abuse. In addition, they had a positive family history for dementia and psychiatric conditions. Detailed medical histories available are herein reported. The estimated number of repetitions in control subjects was 2e15; whereas in patients without the expansion was 2e30. 3.1. Patient #1 Patient #1, male, was first admitted to the Psychiatric Department of the University of Würzburg at the age of 33 years, for paranoid ideation with frequent acoustic hallucinations (imperative, commenting, but also benevolent voices). He developed ideas of grandiosity, but also showed depressed mood and reduced drive. Later, he developed formal thought disorder. In addition, a history of comorbid alcohol abuse was present. He was overweight (height 173 cm, body weight 115 kg, body mass index ¼ 38). His past
medical history included hypertension, diabetes, heart failure, and sleep apnea. His family history was positive for dementia, as his mother was diagnosed with dementia and Parkinson’s disease at about the age of 50 years. For unclear reasons, as no data on any psychiatric condition was present, she was treated with lithium since the age of 54 years. She died at the age of 65. Also, both her sisters suffered from dementia, although no information on age at onset and course of the disease were available. The patient himself is no longer able to work since 2005; since then, he had a fluctuating yet chronic course of the disease. In 2006, he underwent magnetic resonance imaging (MRI) that showed global brain atrophy and enlargement of the ventricles. A second MRI in 2012 showed no progression as compared with the previous scan. In 2012, neurologic examination revealed saccadic gaze, slowed tongue motility, dysarthria (not of the bulbar amyotrophic lateral sclerosis type), and dysdiadochokinesia, all of which were not present in 2006. 3.2. Patient #2 Patient #2 is a male, born in 1947, no longer working since the 90s. He was first admitted at the age of 44 years, and showed a fluctuating yet chronic course since then. His medical history disclosed congenital dysplasia syndrome (patella-nail-syndrome) mainly of the lower limbs, peripheral neuropathy, oral and manual dyskinesia, dysdiadochokinesia, as well as bronchial carcinoma, which was diagnosed in 2007. His mother suffered from chronic schizophrenia since her adolescence, whereas his father probably suffered from alcohol abuse. The patient showed paranoid ideation with acoustic hallucinations (imperative and derogatory voices), depressed mood, reduced drive, especially at later stages, and pronounced latency to answer. In 2004, his Mini-Mental State Examination score was 27/30, mainly because of dyscalculia. In 2007, he developed cognitive and amnestic deficits: at MMSE, he scored 16/30, because of dyscalculia, impaired delayed recall and executive functions. He suffered from comorbid alcohol abuse. A brain computed tomography scan showed mild but diffuse brain atrophy. 4. Discussion In this study, we show that the C9ORF72 hexanucleotide repeat expansion is a rare, although possible, cause of schizophrenia. Our data further support previous descriptions of C9ORF72 carriers presenting with psychosis (Calvo et al., 2012; Floris et al., 2012; Galimberti et al., 2013a), either developing FTLD over time, or as pure psychotic symptoms, that is, megalomaniac delusions in the absence of neurologic signs and with no atrophy at imaging (Arighi et al., 2012). Memory deficits represent another atypical feature of C9ORF72 carriers (Arighi et al., 2012; Galimberti et al., 2013a). In this regard, patient #1 did not show memory deficits in spite of the evidence of diffuse brain atrophy at MRI, whereas patient #2 developed cognitive impairment, as documented by MMSE. Moreover, both patients #1 and #2 had a positive family history for dementia and psychiatric disturbances. Interestingly, the C9ORF72
Table 1 Characteristics of C9ORF72 repeat expansion carriers Patient
Age at onset (y)
Symptoms at onset
Symptoms after onset
Family history
Diagnosis
#1
33
Paranoid ideation; acoustic hallucinations
Dementia (sister) and Parkinson’s disease; dementia (mother)
Schizophrenia
#2
44
Acoustic hallucinations
Ideas of grandiosity; depressed mood; formal thought disorder Paranoid ideation with acoustic hallucinations, depressed mood
Schizophrenia (mother)
Schizophrenia
D. Galimberti et al. / Neurobiology of Aging 35 (2014) 1214.e7e1214.e10
expansion has been observed in a patient with BD, with a positive family history for FTLD (Meisler et al., 2013). These data were confirmed in a replication study, describing a patient with BD with familial history for Alzheimer’s disease (Galimberti et al., 2013b). At the best of our knowledge, to date there are no causal mutations demonstrated for schizophrenia. Regarding other causes of autosomal dominant FTLD, namely GRN and MAPT, 2 patients with GRN mutations and a premorbid BD were described (Cerami et al., 2011), whereas no MAPT carriers with late onset psychiatric manifestations have been described so far. A subgroup of patients included in our cohort were previously included in a study including progranulin level evaluation (Galimberti et al., 2012b). None of the patients analyzed displayed low plasma levels, suggesting the absence of mutations in GRN. With the methodology we used, we were able to detect not more than 40 repeats. Therefore, we cannot rule out any correlation between the length of the expansion and the clinical phenotype and course of the disease. Intermediate repetitions (n ¼ 20e30) have been recently associated with a clinical diagnosis of Parkinson’s disease (Majounie et al., 2012a; Nuytemans et al., 2013), and FTLD (Galimberti et al., 2012a; Gómez-Tortosa et al., 2013). Nevertheless, a similar number of expansions has been reported also in healthy elderly subjects (Galimberti et al., 2012a). Although multiple studies demonstrated that the penetrance of the C9ORF72 mutation is definitely incomplete (Arighi et al., 2012; Galimberti et al., 2012a), the reasons for such observation are to date not known. Recent findings on the pathogenic mechanisms at the basis of this genetic defect demonstrate that the C9ORF72 GGGGCC-hexanucleotide repeat forms G-quadruplexes (Fratta et al., 2012). Whether the disease is caused by a toxic effect of the GGGGCC-repeat RNA, by a loss of function of the C9ORF72, or by both mechanisms, is yet to be determined. A common founder could be at the origin of cases descripted, although having 2 cases only, a haplotype sharing analysis has not been carried out. Previous data on the UK population provided however strong evidence against recent shared ancestry of a large proportion of C9orf72 expansion (Beck et al., 2013). In conclusion, the description of these cases broadens the spectrum of clinical presentations in carriers of the C9ORF72 hexanucleotide repeat expansion and suggests that genetic analysis of the expansion should be considered in patients presenting with schizophrenia, particularly in the presence of a positive family history for neurodegenerative or psychiatric disease. Disclosure statement The authors have no actual or potential conflicts of interest. Acknowledgements This research was supported by Fondazione Monzino and Italian Ministry of Health (Ricerca Corrente and Ricerca Finalizzata RF2010-2319722 to ES). References Arighi, A., Fumagalli, G.G., Jacini, F., Fenoglio, C., Ghezzi, L., Pietroboni, A.M., De Riz, M., Serpente, M., Ridolfi, E., Bonsi, R., Bresolin, N., Scarpini, E., Galimberti, D., 2012. Early onset behavioural variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations. J. Alzheimers Dis. 31, 447e452. Beck, J., Poulter, M., Hensman, D., Rohrer, J.D., Mahoney, C.J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R.W., Malaspina, A., Rowe, J., Brown, J., Hodges, J., Sidle, K., Polke, J.M., Houlden, H., Schott, J.M., Fox, N.C., Rossor, M.N., Tabrizi, S.J., Isaacs, A.M., Hardy, J., Warren, J.D., Collinge, J., Mead, S., 2013. Large C9orf72 hexanucleotide repeat expansions are seen in multiple
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neurodegenerative syndromes and are more frequent than expected in the UK population. Am. J. Hum. Genet. 92, 345e353. Calvo, A., Moglia, C., Canosa, A., Cistaro, A., Valentini, C., Carrara, G., Soldano, E., Ilardi, A., Bersano, E., Bertuzzo, D., Brunetti, M., Ossola, I., Restagno, G., Chiò, A., 2012. Amyotrophic lateral sclerosis/frontotemporal dementia with predominant manifestations of obsessive-compulsive disorder associated to GGGGCC expansion of the c9orf72 gene. J. Neurol. 259, 2723e2725. Cerami, C., Marcone, A., Galimberti, D., Villa, C., Scarpini, E., Cappa, S.F., 2011. From genotype to phenotype: two cases of genetic frontotemporal lobar degeneration with premorbid bipolar disorder. J. Alzheimers Dis. 27, 791e797. DeJesus-Hernandez, M., Mackenzie, I.R., Boeve, B.F., Boxer, A.L., Baker, M., Rutherford, N.J., Nicholson, A.M., Finch, N.A., Flynn, H., Adamson, J., Kouri, N., Wojtas, A., Sengdy, P., Hsiung, G.Y., Karydas, A., Seeley, W.W., Josephs, K.A., Coppola, G., Geschwind, D.H., Wszolek, Z.K., Feldman, H., Knopman, D.S., Petersen, R.C., Miller, B.L., Dickson, D.W., Boylan, K.B., Graff-Radford, N.R., Rademakers, R., 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245e256. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 2002. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version Patient Edition (SCID-I/P). Biometric research, New York State Psychiatric Institute, New York. Floris, G., Borghero, G., Cannas, A., Di Stefano, F., Costantino, E., Murru, M.R., Brunetti, M., Restagno, G., Traynor, B.J., Marrosu, M.G., Chiò, A., Marrosu, F., 2012. Frontotemporal dementia with psychosis, parkinsonism, visuo-spatial dysfunction, upper motor neuron involvement associated to expansion of C9ORF72: a peculiar phenotype? J. Neurol. 259, 1749e1751. Fratta, P., Mizielinska, S., Nicoll, A.J., Zloh, M., Fisher, E.M., Parkinson, G., Isaacs, A.M., 2012. C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes. Sci. Rep. 2, 1016. Galimberti, D., Arosio, B., Fenoglio, C., Serpente, M., Cioffi, S.M., Bonsi, R., Rossi, P., Abbate, C., Mari, D., Scarpini, E., 2012a. Incomplete penetrance of the C9ORF72 hexanucleotide repeat expansions: frequency in a cohort of geriatric nondemented subjects. J. Alzheimers Dis. 2013 Oct 10. [Epub ahead of print]. Galimberti, D., Dell’Osso, B., Fenoglio, C., Villa, C., Cortini, F., Serpente, M., KittelSchneider, S., Weigl, J., Neuner, M., Volkert, J., Leonhard, C., Olmes, D.G., Kopf, J., Cantoni, C., Ridolfi, E., Palazzo, C., Ghezzi, L., Bresolin, N., Altamura, A.C., Scarpini, E., Reif, A., 2012b. Progranulin gene variability and plasma levels in bipolar disorder and schizophrenia. PLoS One 7, e32164. Galimberti, D., Fenoglio, C., Serpente, M., Villa, C., Bonsi, R., Arighi, A., Fumagalli, G.G., Del Bo, R., Bruni, A.C., Anfossi, M., Clodomiro, A., Cupidi, C., Nacmias, B., Sorbi, S., Piaceri, I., Bagnoli, S., Bessi, V., Marcone, A., Cerami, C., Cappa, S.F., Filippi, M., Agosta, F., Magnani, G., Comi, G., Franceschi, M., Rainero, I., Giordana, M.T., Rubino, E., Ferrero, P., Rogaeva, E., Xi, Z., Confaloni, A., Piscopo, P., Bruno, G., Talarico, G., Cagnin, A., Clerici, F., Dell’Osso, B., Comi, G.P., Altamura, A.C., Mariani, C., Scarpini, E., 2013a. Autosomal dominant frontotemporal lobar degeneration due to the C9ORF72 hexanucleotide repeat expansion: late-onset psychotic clinical presentation. Biol. Psychiatry 74, 384e391. Galimberti, D., Reif, A., Dell’Osso, B., Palazzo, C., Villa, C., Fenoglio, C., KittelSchneider, S., Leonhard, C., Olmes, D.G., Serpente, M., Paoli, R.A., Altamura, A.C., Scarpini, E., 2013b. C9ORF72 hexanucleotide repeat expansion as a rare cause of bipolar disorder. Bipolar Disord. 2013 Dec 16. http://dx.doi.org/10.1111/bdi. 12169. [Epub ahead of print]. Gómez-Tortosa, E., Gallego, J., Guerrero-López, R., Marcos, A., Gil-Neciga, E., Sainz, M.J., Díaz, A., Franco-Macías, E., Trujillo-Tiebas, M.J., Ayuso, C., PérezPérez, J., 2013. C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology 80, 366e370. Huey, E.D., Nagy, P.L., Rodriguez-Murillo, L., Manoochehri, M., Goldman, J., Lieberman, J., Karayiorgou, M., Mayeux, R., 2013. C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol. Aging 34, 1309.e9e1309.e10. Majounie, E., Abramzon, Y., Renton, A.E., Keller, M.F., Traynor, B.J., Singleton, A.B., 2012a. Large C9orf72 repeat expansions are not a common cause of Parkinson’s disease. Neurobiol. Aging 33, 2527.e1e2527.e2. Majounie, E., Abramzon, Y., Renton, A.E., Perry, R., Bassett, S.S., Pletnikova, O., Troncoso, J.C., Hardy, J., Singleton, A.B., Traynor, B.J., 2012b. Repeat expansion in C9ORF72 in Alzheimer’s disease. N. Engl. J. Med. 366, 283e284. Meisler, M.H., Grant, A.E., Jones, J.M., Lenk, G.M., He, F., Todd, P.K., Kamali, M., Albin, R.L., Lieberman, A.P., Langenecker, S.A., McInnis, M.G., 2013. C9ORF72 expansion in a family with bipolar disorder. Bipolar Disord. 15, 326e332. Murray, M.E., DeJesus-Hernandez, M., Rutherford, N.J., Baker, M., Duara, R., GraffRadford, N.R., Wszolek, Z.K., Ferman, T.J., Josephs, K.A., Boylan, K.B., Rademakers, R., Dickson, D.W., 2011. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 122, 673e690. Nuytemans, K., Bademci, G., Kohli, M.M., Beecham, G.W., Wang, L., Young, J.I., Nahab, F., Martin, E.R., Gilbert, J.R., Benatar, M., Haines, J.L., Scott, W.K., Züchner, S., Pericak-Vance, M.A., Vance, J.M., 2013. C9ORF72 intermediate repeat copies are a significant risk factor for Parkinson disease. Ann. Hum. Genet. 2013 Jul 12. http://dx.doi.org/10.1111/ahg.12033. [Epub ahead of print]. Renton, A.E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J.R., Schymick, J.C., Laaksovirta, H., van Swieten, J.C., Myllykangas, L., Kalimo, H., Paetau, A., Abramzon, Y., Remes, A.M., Kaganovich, A., Scholz, S.W., Duckworth, J., Ding, J., Harmer, D.W., Hernandez, D.G., Johnson, J.O., Mok, K., Ryten, M., Trabzuni, D., Guerreiro, R.J., Orrell, R.W., Neal, J., Murray, A.,
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Neurobiology of Aging journal homepage: www.elsevier.com/locate/neuaging
The C9ORF72 hexanucleotide repeat expansion is a rare cause of schizophrenia Daniela Galimberti a, *, Andreas Reif b, Bernardo Dell’Osso c, Sarah Kittel-Schneider b, Christine Leonhard b, Alexandra Herr b, Carlotta Palazzo c, Chiara Villa a, Chiara Fenoglio a, Maria Serpente a, Sara .M.G. Cioffi a, Cecilia Prunas c, Riccardo A. Paoli c, A. Carlo Altamura c, Elio Scarpini a a Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy b Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Wuerzburg, Germany c Psichiatry Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy
a r t i c l e i n f o
a b s t r a c t
Article history: Received 21 August 2013 Received in revised form 28 November 2013 Accepted 5 December 2013 Available online 11 December 2013
A hexanucleotide repeat expansions in the first intron of C9ORF72 has been shown to be responsible for a high number of familial cases of amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration. The same mutation has been described in a patient with bipolar disorder, but up to now, not in patients suffering from schizophrenia. We determined the frequency of the C9ORF72 hexanucleotide repeat expansions in a population of 298 patients with schizophrenia or schizoaffective disorder. The pathogenic repeat expansion was detected in 2 patients (0.67%). Both of them presented with auditory hallucinations and had comorbid alcohol abuse. In addition, a positive family history for psychiatric and/or neurodegenerative diseases was present. The repeat expansion in the C9ORF72 gene is a rare, but possible, cause of schizophrenic spectrum disorders. We cannot rule out however whether the number of repeats influence the phenotype. Ó 2014 Elsevier Inc. All rights reserved.
Keywords: Dementia Schizophrenia Psychosis C9ORF72 hexanucleotide repeat expansion Phenotype Clinical presentation
1. Introduction A hexanucleotide repeat expansion in the first intron of C9ORF72 was shown to be responsible for a high number of autosomal dominant inherited amyotrophic lateral sclerosis and/or frontotemporal lobar degeneration (FTLD) cases, with or without concomitant motor neuron disease (DeJesus-Hernandez et al., 2011; Renton et al., 2011). The function(s) of the protein encoded by this gene is so far unknown. Wild-type alleles contain not more than 30 repeats, whereas mutated alleles have hundreds to thousands of repeats (DeJesus-Hernandez et al., 2011). The relationship between the number of expansions and the phenotype is, however, not clear yet, as recent data described patients with frontotemporal lobar degeneration (FTLD) carrying an allele with 20e22 hexanucleotide repeats (Gómez-Tortosa et al., 2013). * Corresponding author at: via Francesco Sforza, 35, 20122, Milan, Italy. Tel.: þ39 02 55033847; fax þ39 02 55036580. E-mail address: [email protected] (D. Galimberti). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.004
It was suggested that psychosis and obsessive-compulsive disorder were common symptoms at disease onset in patients with FTLD carrying the repeat expansion (Calvo et al., 2012; Floris et al., 2012; Snowden et al., 2012). Moreover, a case showing mystic delusion with visual and auditory hallucinations, in the absence of neurologic symptoms and brain atrophy, has been recently described (Arighi et al., 2012). In a study carried out in a large population of patients with FTLD, it was shown that the presentation with late onset psychosis (particularly hallucinations and delusions) is significantly more frequent in C9ORF72 repeat expansion carriers than noncarriers (Galimberti et al., 2013a). In addition, presentation with memory impairment occurs quite often, possibly leading to a clinical diagnosis of Alzheimer’s disease (Galimberti et al., 2013a; Majounie et al., 2012b; Murray et al., 2011). Bipolar disorder (BD) patients carrying the C9ORF72 hexanucleotide repeat expansion have been recently described (Galimberti et al., 2013b; Meisler et al., 2013), whereas no carriers were found in a population of 192 patients with schizophrenia (Huey et al., 2013). In 2012, it was shown that a suicide attempt can
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be the first manifestation of early dementia because of the recently identified C9ORF72 expansion (Synofzik et al., 2012). Herein, we genotyped a population of 298 patients with schizophrenia for the presence of the C9ORF72 expansion, and identified 2 mutation carriers (0.67%). 2. Methods 2.1. Patients and clinical workup Our cohort included 298 patients (274 Germans and 24 Italians; thereof 157 males, mean age at disease onset SD: 27 10 years, range: 9e72 years) recruited at the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Germany, and at the Psychiatry Unit of the Fondazione Cà Granda, Ospedale Maggiore Policlinico (Milan), diagnosed with schizophrenia or schizoaffective disorder (i.e., psychotic disorders). Diagnoses were made according to Diagnostic and Statistical manual of Mental disorders, fourth edition, Text Revised (DSM-IVTR) criteria (First et al., 2002). German samples were described in greater detail previously (Scholz et al., 2010). 2.2. C9ORF72 genotyping High-molecular weight DNA was isolated from whole blood using a Flexigene Kit (Qiagen, Hildren, Gemany). C9ORF72 genotyping was carried out by repeat-primed polymerase chain reaction and sequencing, as previously described (Xi et al., 2012). A characteristic stutter amplification pattern (>40 repeats) on the electropherogram is considered evidence of a pathogenic repeat expansion. 3. Results We genotyped 298 patients with schizophrenia. A clinically documented family history for psychiatric diseases or dementia was reported for 122 patients. The pathogenic repeat expansion was detected in 2 patients (0.67% of cases; Table 1). Both of them were presented with acoustic hallucinations and showed comorbid alcohol abuse. In addition, they had a positive family history for dementia and psychiatric conditions. Detailed medical histories available are herein reported. The estimated number of repetitions in control subjects was 2e15; whereas in patients without the expansion was 2e30. 3.1. Patient #1 Patient #1, male, was first admitted to the Psychiatric Department of the University of Würzburg at the age of 33 years, for paranoid ideation with frequent acoustic hallucinations (imperative, commenting, but also benevolent voices). He developed ideas of grandiosity, but also showed depressed mood and reduced drive. Later, he developed formal thought disorder. In addition, a history of comorbid alcohol abuse was present. He was overweight (height 173 cm, body weight 115 kg, body mass index ¼ 38). His past
medical history included hypertension, diabetes, heart failure, and sleep apnea. His family history was positive for dementia, as his mother was diagnosed with dementia and Parkinson’s disease at about the age of 50 years. For unclear reasons, as no data on any psychiatric condition was present, she was treated with lithium since the age of 54 years. She died at the age of 65. Also, both her sisters suffered from dementia, although no information on age at onset and course of the disease were available. The patient himself is no longer able to work since 2005; since then, he had a fluctuating yet chronic course of the disease. In 2006, he underwent magnetic resonance imaging (MRI) that showed global brain atrophy and enlargement of the ventricles. A second MRI in 2012 showed no progression as compared with the previous scan. In 2012, neurologic examination revealed saccadic gaze, slowed tongue motility, dysarthria (not of the bulbar amyotrophic lateral sclerosis type), and dysdiadochokinesia, all of which were not present in 2006. 3.2. Patient #2 Patient #2 is a male, born in 1947, no longer working since the 90s. He was first admitted at the age of 44 years, and showed a fluctuating yet chronic course since then. His medical history disclosed congenital dysplasia syndrome (patella-nail-syndrome) mainly of the lower limbs, peripheral neuropathy, oral and manual dyskinesia, dysdiadochokinesia, as well as bronchial carcinoma, which was diagnosed in 2007. His mother suffered from chronic schizophrenia since her adolescence, whereas his father probably suffered from alcohol abuse. The patient showed paranoid ideation with acoustic hallucinations (imperative and derogatory voices), depressed mood, reduced drive, especially at later stages, and pronounced latency to answer. In 2004, his Mini-Mental State Examination score was 27/30, mainly because of dyscalculia. In 2007, he developed cognitive and amnestic deficits: at MMSE, he scored 16/30, because of dyscalculia, impaired delayed recall and executive functions. He suffered from comorbid alcohol abuse. A brain computed tomography scan showed mild but diffuse brain atrophy. 4. Discussion In this study, we show that the C9ORF72 hexanucleotide repeat expansion is a rare, although possible, cause of schizophrenia. Our data further support previous descriptions of C9ORF72 carriers presenting with psychosis (Calvo et al., 2012; Floris et al., 2012; Galimberti et al., 2013a), either developing FTLD over time, or as pure psychotic symptoms, that is, megalomaniac delusions in the absence of neurologic signs and with no atrophy at imaging (Arighi et al., 2012). Memory deficits represent another atypical feature of C9ORF72 carriers (Arighi et al., 2012; Galimberti et al., 2013a). In this regard, patient #1 did not show memory deficits in spite of the evidence of diffuse brain atrophy at MRI, whereas patient #2 developed cognitive impairment, as documented by MMSE. Moreover, both patients #1 and #2 had a positive family history for dementia and psychiatric disturbances. Interestingly, the C9ORF72
Table 1 Characteristics of C9ORF72 repeat expansion carriers Patient
Age at onset (y)
Symptoms at onset
Symptoms after onset
Family history
Diagnosis
#1
33
Paranoid ideation; acoustic hallucinations
Dementia (sister) and Parkinson’s disease; dementia (mother)
Schizophrenia
#2
44
Acoustic hallucinations
Ideas of grandiosity; depressed mood; formal thought disorder Paranoid ideation with acoustic hallucinations, depressed mood
Schizophrenia (mother)
Schizophrenia
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expansion has been observed in a patient with BD, with a positive family history for FTLD (Meisler et al., 2013). These data were confirmed in a replication study, describing a patient with BD with familial history for Alzheimer’s disease (Galimberti et al., 2013b). At the best of our knowledge, to date there are no causal mutations demonstrated for schizophrenia. Regarding other causes of autosomal dominant FTLD, namely GRN and MAPT, 2 patients with GRN mutations and a premorbid BD were described (Cerami et al., 2011), whereas no MAPT carriers with late onset psychiatric manifestations have been described so far. A subgroup of patients included in our cohort were previously included in a study including progranulin level evaluation (Galimberti et al., 2012b). None of the patients analyzed displayed low plasma levels, suggesting the absence of mutations in GRN. With the methodology we used, we were able to detect not more than 40 repeats. Therefore, we cannot rule out any correlation between the length of the expansion and the clinical phenotype and course of the disease. Intermediate repetitions (n ¼ 20e30) have been recently associated with a clinical diagnosis of Parkinson’s disease (Majounie et al., 2012a; Nuytemans et al., 2013), and FTLD (Galimberti et al., 2012a; Gómez-Tortosa et al., 2013). Nevertheless, a similar number of expansions has been reported also in healthy elderly subjects (Galimberti et al., 2012a). Although multiple studies demonstrated that the penetrance of the C9ORF72 mutation is definitely incomplete (Arighi et al., 2012; Galimberti et al., 2012a), the reasons for such observation are to date not known. Recent findings on the pathogenic mechanisms at the basis of this genetic defect demonstrate that the C9ORF72 GGGGCC-hexanucleotide repeat forms G-quadruplexes (Fratta et al., 2012). Whether the disease is caused by a toxic effect of the GGGGCC-repeat RNA, by a loss of function of the C9ORF72, or by both mechanisms, is yet to be determined. A common founder could be at the origin of cases descripted, although having 2 cases only, a haplotype sharing analysis has not been carried out. Previous data on the UK population provided however strong evidence against recent shared ancestry of a large proportion of C9orf72 expansion (Beck et al., 2013). In conclusion, the description of these cases broadens the spectrum of clinical presentations in carriers of the C9ORF72 hexanucleotide repeat expansion and suggests that genetic analysis of the expansion should be considered in patients presenting with schizophrenia, particularly in the presence of a positive family history for neurodegenerative or psychiatric disease. Disclosure statement The authors have no actual or potential conflicts of interest. Acknowledgements This research was supported by Fondazione Monzino and Italian Ministry of Health (Ricerca Corrente and Ricerca Finalizzata RF2010-2319722 to ES). References Arighi, A., Fumagalli, G.G., Jacini, F., Fenoglio, C., Ghezzi, L., Pietroboni, A.M., De Riz, M., Serpente, M., Ridolfi, E., Bonsi, R., Bresolin, N., Scarpini, E., Galimberti, D., 2012. Early onset behavioural variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations. J. Alzheimers Dis. 31, 447e452. Beck, J., Poulter, M., Hensman, D., Rohrer, J.D., Mahoney, C.J., Adamson, G., Campbell, T., Uphill, J., Borg, A., Fratta, P., Orrell, R.W., Malaspina, A., Rowe, J., Brown, J., Hodges, J., Sidle, K., Polke, J.M., Houlden, H., Schott, J.M., Fox, N.C., Rossor, M.N., Tabrizi, S.J., Isaacs, A.M., Hardy, J., Warren, J.D., Collinge, J., Mead, S., 2013. Large C9orf72 hexanucleotide repeat expansions are seen in multiple
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