- Email: [email protected]
Familial benign frontotemporal deterioration with C9ORF72 hexanucleotide expansion
Alzheimer’s & Dementia - (2013) 1–6
Short Report
Familial benign frontotemporal deterioration with C9ORF72 hexanucleotide expansion Estrella G omez-Tortosaa,*, Soledad Serranob, Marıa de Toledob, Julian Perez-Perezc, M. Jose Sainza a
Department of Neurology, Fundacion Jimenez Dıaz, Madrid, Spain Department of Neurology, Hospital Severo Ochoa, Madrid, Spain c Secugen S.L., Madrid, Spain
b
Abstract
Background: In recent years, a benign variant of frontotemporal lobar degeneration (FTLD) has been recognized, with a particularly slow progression of cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies. Patients with FTLD have been considered “phenocopies,” with an underlying nondegenerative neurologic process. Results: We report the first family with three affected members having benign FTLD associated with C9ORF72 gene hexanucleotide expansion. Onset of symptoms occurred during the fifth decade, with naming and memory problems as the main features. Two siblings have stabilized at mild cognitive impairment or incipient dementia for more than a decade, and remain quite independent for their activities of daily living at the current ages of 69 and 65 years, respectively. Their mother’s cognitive deterioration evolved slowly during .30 years. Conclusion: This family demonstrates that a benign evolution can be part of the growing spectrum of clinical phenotypes associated with neurodegenerative diseases caused by the C9ORF72 hexanucleotide expansion. Screening of this genetic marker should be considered in cases with this slow deterioration, especially if there is a family history. Ó 2013 The Alzheimer’s Association. All rights reserved.
Keywords:
Frontotemporal dementia; C9ORF72 gene; Hexanucleotide expansion; Neurogenetics
1. Introduction Frontotemporal lobar degeneration (FTLD) is a common cause of dementia and encompasses very heterogeneous clinical phenotypes, most of which evolve to substantial neurologic deterioration in a few years [1–3]. However, in recent years, some investigators have pointed to a benign variant of FTLD, represented by cases with a particularly slow progression of the cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies [4–6]. These patients have been considered as
This work was supported by the Ministry of Science and Technology (Spain) (Grant SAF2010-18277). *Corresponding author. Tel.: 134-91-5504913; Fax: 134-91-5504882. E-mail address: [email protected]
“phenocopies” and a nondegenerative neurologic underlying process has been suggested, as the few individuals who have been examined by brain autopsy did not reveal FTLD pathology [7]. However, two nonrelated cases with this profile of scarce deterioration during 2 and 7 years, respectively, have been recently reported as being associated with C9ORF72 gene hexanucleotide expansions [8], a major genetic cause of FTLD/amyotrophic lateral sclerosis (ALS) familial phenotypes [9,10]. We report the first family with three affected members of benign FTLD variant associated with the C9ORF72 gene hexanucleotide expansion, one of whom had an evolution of .30 years. We emphasize that these cases have maintained a status of mild cognitive impairment or very early-stage dementia over more than a decade, despite the fact that their genetic marker undoubtedly classifies them as within the neurodegenerative FTLD spectrum.
1552-5260/$ - see front matter Ó 2013 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2013.09.013
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E. Gomez-Tortosa et al. / Alzheimer’s & Dementia - (2013) 1–6
2. Case Reports The family tree is presented in the Figure 1 and includes the mother and two siblings (brother and sister). A third sibling is cognitively asymptomatic and has not undergone medical studies. One of the three siblings of the mother had also had a dementia process, but no further information is available. The study of this family is included in a prospective clinical–genetic project of familial dementias that has been approved by the research ethics committee at Fundaci on Jimenez Dıaz (Madrid, Spain). 2.1. Proband 1 This 69-year-old man had been followed-up for 11 years because of cognitive problems. His first consultation was at 59 years of age because his family referred ongoing memory problems, attention deficits, mental rigidity, and mild apathy during the previous 2 years. Cognitive evaluation was normal but free recall and naming were within the lower normal range. Computed tomography (CT) scan showed slight frontal atrophy. In spite of these symptoms, the patient continued working as a truck mechanic, performing activities of daily living (ADL) normally. It was not until he was 63 years of age when memory and naming performance degraded to abnormal scores on neuropsychological tests. Together with a brain single-photon emission CT (SPECT) showing decreased bitemporal perfusion, he was diagnosed with early-stage dementia of the Alzheimer’s type, with the possibility of frontotemporal dementia not being ruled out. He did not tolerate procholinergic treatments and was left without specific medication. Diagnosis was reconsidered when his cognitive and functional status remained stable after 5 years. Table 1 shows his most current neuropsychological evaluation at 69 years of age. His only behavioral
symptoms have been apathy, lack of initiative, and impulsive reactions. He has never exhibited psychotic or motor symptoms. His frontal reflexes are negative. Regarding functional status, he is independent for self-care, is able to hold a conversation, and is aware of some current events. He is able to use pocket currency and public transportation, and he continues to drive. However, he constantly needs stimuli to begin any activity, he is not able to conduct demanding duties (handling bank accounts), and he is unreliable for any task involving memory. Occasionally, during these years, he has had a few transient episodes of spatial disorientation or confusion. Neuroimaging studies have shown slow progression of frontotemporal atrophy (in CT and magnetic resonance imaging studies) and hypoperfusion (in brain SPECT) (Figure 1). A genetic study, performed with informed consent, revealed a C9ORF72 hexanucleotide expansion of .30 repeats (repeated primer polymerase chain reaction analysis, as described elsewhere [9]). His apolipoprotein E (apoE) genotype is ε3/ε3. 2.2. Proband 2 The 65-year-old sister of proband 1 began to complain of subjective memory loss at 54 years of age. These complaints had been considered as part of a moderate depression for which she was under treatment from 57 to 61 years of age. At age 60, she had consulted her general doctor because of word-finding problems, difficulties explaining herself in common conversations, and attention problems (such as leaving faucets on, lights on, or food outside the refrigerator). Her capability for ADL remained intact, her Mini-Mental State Examination (Folstein) score was 30/30, her speech was fluent and coherent, and no further studies were performed. In the following years, her symptoms persisted, referring more to language than to memory problems. She
Fig. 1. Family tree and recent brain MRI studies of probands 1 and 2 showing mild–moderate atrophy at ages 68 and 65 years, respectively, both after a decade of clinical symptoms.
E. Gomez-Tortosa et al. / Alzheimer’s & Dementia - (2013) 1–6
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Table 1 Description of main clinical features of probands 1 and 2
First symptoms
Evolution Symptoms Cognition
Functional status Current evaluation MMSE Verbal fluency (1 min) Boston Naming HVLT (12 items)
Digit Symbol Clock Test CDR (0–3) FBI Neuroimaging
Proband 1: man 69 years
Proband 2: woman 65 years
57 years Apathy, impulsivity, mental rigidity, memory deficits MMSE 29/30; CDR 0 (still working) 63 years Same as previous, word-finding problems
54 years, subjective memory complaints 57–61 years: depression, attentional problems CDR 0 59–64 years Word-finding problems, decreased verbal fluency, attentional problems MMSE 30/30
MMSE 29/30 Logical memory*: short 10/50, long 7/50 TAVEC short recall 2/16 Verbal fluency animals: 11; letter S: 8 Naming and executive functions: normal Rey Figure Test of short-term memory 13/36 CDR 0.5 69 years 29/30 Animals: 10; letter S: 8 26/60 1 16 with phonetic clues, paraphasias Learning trials: 3-4-4 Free recall: 1 1 1 with clues Recognition: 10/12 1 5 false positives (DI 5) 19 1 1 error Order 10/10, copy 10/10 1 18 (negative symptoms) Frontal and temporal atrophy
—
CDR 0 65 years 30/30 Animals: 10; letter S: 10 39/60 1 6 with phonetic clues, paraphasias Learning trials: 5-4-7 Free recall: 2 Recognition: 11/12 1 4 false positives (DI 7) 25 1 6 errors Order 4/10, copy 10/10 0.5 8 (negative symptoms) Mild frontal atrophy
Abbreviations: MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating scale (0–3); HVLT, Hopkins Verbal Learning Test; DI, discrimination index (maximum 12); FBI, Frontal Behavioral Inventory. *Weschler Memory Scale–Revised.
has not had behavioral, psychiatric, or motor symptoms. She has remained fully able to undertake her responsibilities as a home-maker (e.g., shopping and cooking), but has refused to use public transportation or handle bank accounts by herself. She underwent a complete examination after her brother’s diagnosis. Cognitive examination revealed significant deficits in verbal memory and naming tests (Table 1). Brain magnetic resonance imaging (MRI) showed mild frontotemporal atrophy (Figure 1). A genetic study confirmed a C9ORF72 hexanucleotide expansion of .30 repeats with apoE genotype ε3/ε3. 2.3. Proband 3 The mother of both of the aforementioned probands died with the diagnosis of Alzheimer’s dementia at 89 years of age. According to several family members, her first symptoms appeared at around 54 years of age and consisted of mild attention and memory problems, slight anomia, and depressed mood. She occasionally became disoriented on her way home, but despite these symptoms, which progressed very slowly, she was able to carry out household chores and routine ADL until she was in her mid-70s. During the last decade she had temporal and spatial disorientation, shortterm memory problems, and increasing verbal fluency problems, and had become mute near the end of her life. She did not have disruptive behavioral/psychiatric disturbances or motor deterioration at any time. She came to neurologic
attention just once—at 79 years of age, when the diagnosis of senile dementia of Alzheimer’s type was made—but no formal medical reports are available. 3. Discussion This initial report of a family with benign frontotemporal deterioration associated with a C9ORF72 hexanucleotide expansion raises several issues, and further reflects how current advances in genetic markers are changing our clinical comprehension and diagnostic criteria of cognitive disorders. First, the family reported links this benign evolution with mild symptoms over a decade with an underlying neurodegenerative disease, most likely transactive response DNA-binding protein (TDP) and p62 pathology related, as have been the proteinopathies demonstrated in a majority of cases with the C9ORF72 expansion [11–13]. Together with the two cases reported by Khan et al. [8], this family’s findings suggest that C9ORF72 gene alterations are a likely cause of this benign phenotype and should be screened for. Second, the scarce functional impact over many years places this phenotype closer to the diagnosis of mild cognitive impairment (MCI) than to a dementia syndrome, which raises the issue of exploring whether some cases within the MCI diagnosis may have C9ORF72 hexanucleotide expansions. Based on clinical and neuroimaging evolution, at this time, probands 1 and 2 meet current criteria for the benign FTLD
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variant [5,8], although we emphasize how the sister had been without a diagnosis of neurologic disease for many years. It is possible that some of these cases could progress without appropriate diagnosis, especially if the family history is obscure. It is also remarkable that the main cognitive features in the family were anomia with decreased verbal fluency and memory deficits, which in proband 1 had supported a primary diagnosis of dementia of the Alzheimer’s type. None of the cases displayed disruptive behavioral or psychiatric symptoms typical of FTLD, only less specific mild negative symptoms (apathy and depressed mood). The mother’s clinical profile could not be established in great detail, although from what is known of her condition she survived for more than 3 decades from onset of the symptoms, which is likely the time of development her children will experience with their current evolution. Within the first series reported with the C9ORF72 expansion there have also been occasional patients with survival as long as 17 and 22 years [12–14], which was considered exceptional for pathologically confirmed FTLD. It seems that the C9ORF72 hexanucleotide expansion is responsible for a wider spectrum of phenotypes beyond our clinical understanding of FTLD as a presenile and aggressive dementia with language and behavioral deficits. Besides the definitive link with ALS, the hexanucleotide expansion has been found to be associated with a variety of psychiatric features including: bipolar disorders [15]; middle-age and late-onset psychosis [16,17]; and longterm depression and somatizations [18,19], with some of these cases evolving to dementia only years later. Furthermore, C9ORF72 expansions have been reported in typical Alzheimer’s dementia [20–22], cases clinically diagnosed as sporadic Creutzfeldt–Jakob disease, Huntington disease–like syndrome, and other nonspecific neurodegenerative disease syndromes [23], illustrating the wide variability of clinical phenotypes associated with this genetic marker. The family assessed in our study expands this list with the clinical picture of mild cognitive impairment and slowly progressive dementia over a time frame of .30 years. Of interest is that, according to preliminary studies, the C9ORF72 expansion does not seem to be a major cause of typical schizophrenia [24] and it is rare in idiopathic Parkinson’s disease [25,26]. In any case, the frequency of C9ORF72 repeat expansions exceeds that of any other neurodegenerative disease– causing mutation, and is particularly high in Caucasian populations of northern European countries and in North America, where it has already been associated with around 30% of the familial and 7% of sporadic FTLD/ALS cases [27]. All these data support the notion that, in clinical settings, screening for the C9ORF72 expansion should be extended to cases with psychiatric disturbances and/or cognitive problems and a strong family history of similar problems, independently of the dementia profile or severity of the cognitive impairment. As expected, cases with an autosomal
dominant pattern of disease have shown a higher prevalence of the C9ORF72 mutation [13]. Genetic study in sporadic cases must be decided upon on an individual basis, but, even if a small percentage of cases turn out to be positive, they may receive the most appropriate treatment. Given the current data, providing genetic counseling to families with the C9ORF72 expansion is a great challenge. We do not yet have clear information on penetrance, genetic anticipation, and the likelihood of developing one or another clinical phenotype and over which age span. Also, this prognosis is of greatest importance when such disparate possibilities as ALS or mild cognitive impairment are under consideration. In previous series, the frequency of C9ORF72 expansion carriers in the healthy control population ranged from 0% to 0.6%, with no details about age and no formal evaluations in these “false positive” cases [9,11,21,27]. Moreover, there are also few carriers (10%) within families with FTLD who remain asymptomatic after 70 years of age [28], which suggests incomplete penetrance of the mutation or very benign phenotypes. Better understanding of the genetics of the hexanucleotide expansion and of the disease mechanisms and progression will be crucial in the effort to give these families appropriate advice in the near future. With regard to physiopathologic research, expansion in the C9ORF72 gene has opened a whole new chapter in the neurodegeneration field. Initial studies with animal models showed that expression of the expanded hexanucleotide repeat RNA is sufficient to cause neurodegeneration [29]. It remains to be elucidated why the expansion manifests with TDP and p62 pathology in different neuronal networks, resulting in a variety of clinical phenotypes. Variables such as the number of hexanucleotide repeats expressed in different brain regions, other genes, or environmental factors could be involved in modulating the susceptibility and distribution of the pathology in different patterns. The three members of this family showed a homogeneous benign phenotype, suggesting that they share the same genetic conditioning factors. Finally, the hexanucleotide expansion has also been reported in a few cases with pathologically confirmed AD [21], and TDP pathology sometimes co-occurs with other neurodegenerative pathologic features. Brain-bank studies should determine the frequency of the C9ORF72 expansion in other pathologically confirmed neurodegenerative diseases to establish whether it can trigger a spectrum of pathologically different diseases. Our challenge for the future will be clarify how far upstream in the neurodegenerative cascade is the altered C9ORF72 protein and the mechanisms by which it turns into TDP and p62 inclusions pathology. Acknowledgments The authors thank the family members who contributed to this study; V. Sanchez, RN, C. Almaraz, and G. Sanchez for the collection and processing of blood samples; and A.
E. Gomez-Tortosa et al. / Alzheimer’s & Dementia - (2013) 1–6
Dıaz for the genetic studies. We also thank Oliver Shaw for editing the manuscript.
RESEARCH IN CONTEXT
1. Systematic review: In recent years, a benign variant of frontotemporal lobar degeneration (FTLD) has been recognized, with a particularly slow progression of cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies. Those with FTLD have been considered “phenocopies,” with an underlying nondegenerative neurologic process. 2. Interpretation: We describe the first family with three affected members having benign FTLD associated with C9ORF72 gene hexanucleotide expansion. Onset of symptoms occurred during the fifth decade, with naming and memory problems as the main features. Two siblings have stabilized at mild cognitive impairment or incipient dementia for more than a decade, and remain quite independent in their activities of daily living at the ages of 69 and 65 years, respectively. Their mother’s cognitive deterioration evolved slowly during 33 years. 3. Future directions: This family demonstrates that a benign frontotemporal deterioration can be part of the spectrum of neurodegenerative diseases caused by the C9ORF72 hexanucleotide expansion. Screening of this genetic marker should be considered in cases with this clinical phenotype, especially if there is a family history.
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[24] Huey ED, Nagy PL, Rodriguez-Murillo L, Manoochehri M, Goldman J, Lieberman J, et al. C9ORF72 repeat expansions not detected in a group of patients with schizophrenia. Neurobiol Aging 2013;34:1309. [25] Lesage S, Le Ber I, Condroyer C, Broussolle E, Gabelle A, Thobois S, et al. C9orf72 repeat expansions are a rare genetic cause of parkinsonism. Brain 2013;136:385–91. [26] Daoud H, Noreau A, Rochefort D, Paquin-Lanthier G, Gauthier MT, Provencher P, et al. Investigation of C9orf72 repeat expansions in Parkinson’s disease. Neurobiol Aging 2013;34:1710. [27] Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, et al. Frequency of the C9ORF72 hexanucleotide
repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012;11:323–30. [28] van Langenhove T, van der Zee J, Gijselinck I, Engelborghs S, Vandenberghe R, Vandenbulcke M, et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol 2013;70:365–73. [29] Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson DL, et al. Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci USA 2013;110:7778–83.
Short Report
Familial benign frontotemporal deterioration with C9ORF72 hexanucleotide expansion Estrella G omez-Tortosaa,*, Soledad Serranob, Marıa de Toledob, Julian Perez-Perezc, M. Jose Sainza a
Department of Neurology, Fundacion Jimenez Dıaz, Madrid, Spain Department of Neurology, Hospital Severo Ochoa, Madrid, Spain c Secugen S.L., Madrid, Spain
b
Abstract
Background: In recent years, a benign variant of frontotemporal lobar degeneration (FTLD) has been recognized, with a particularly slow progression of cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies. Patients with FTLD have been considered “phenocopies,” with an underlying nondegenerative neurologic process. Results: We report the first family with three affected members having benign FTLD associated with C9ORF72 gene hexanucleotide expansion. Onset of symptoms occurred during the fifth decade, with naming and memory problems as the main features. Two siblings have stabilized at mild cognitive impairment or incipient dementia for more than a decade, and remain quite independent for their activities of daily living at the current ages of 69 and 65 years, respectively. Their mother’s cognitive deterioration evolved slowly during .30 years. Conclusion: This family demonstrates that a benign evolution can be part of the growing spectrum of clinical phenotypes associated with neurodegenerative diseases caused by the C9ORF72 hexanucleotide expansion. Screening of this genetic marker should be considered in cases with this slow deterioration, especially if there is a family history. Ó 2013 The Alzheimer’s Association. All rights reserved.
Keywords:
Frontotemporal dementia; C9ORF72 gene; Hexanucleotide expansion; Neurogenetics
1. Introduction Frontotemporal lobar degeneration (FTLD) is a common cause of dementia and encompasses very heterogeneous clinical phenotypes, most of which evolve to substantial neurologic deterioration in a few years [1–3]. However, in recent years, some investigators have pointed to a benign variant of FTLD, represented by cases with a particularly slow progression of the cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies [4–6]. These patients have been considered as
This work was supported by the Ministry of Science and Technology (Spain) (Grant SAF2010-18277). *Corresponding author. Tel.: 134-91-5504913; Fax: 134-91-5504882. E-mail address: [email protected]
“phenocopies” and a nondegenerative neurologic underlying process has been suggested, as the few individuals who have been examined by brain autopsy did not reveal FTLD pathology [7]. However, two nonrelated cases with this profile of scarce deterioration during 2 and 7 years, respectively, have been recently reported as being associated with C9ORF72 gene hexanucleotide expansions [8], a major genetic cause of FTLD/amyotrophic lateral sclerosis (ALS) familial phenotypes [9,10]. We report the first family with three affected members of benign FTLD variant associated with the C9ORF72 gene hexanucleotide expansion, one of whom had an evolution of .30 years. We emphasize that these cases have maintained a status of mild cognitive impairment or very early-stage dementia over more than a decade, despite the fact that their genetic marker undoubtedly classifies them as within the neurodegenerative FTLD spectrum.
1552-5260/$ - see front matter Ó 2013 The Alzheimer’s Association. All rights reserved. http://dx.doi.org/10.1016/j.jalz.2013.09.013
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E. Gomez-Tortosa et al. / Alzheimer’s & Dementia - (2013) 1–6
2. Case Reports The family tree is presented in the Figure 1 and includes the mother and two siblings (brother and sister). A third sibling is cognitively asymptomatic and has not undergone medical studies. One of the three siblings of the mother had also had a dementia process, but no further information is available. The study of this family is included in a prospective clinical–genetic project of familial dementias that has been approved by the research ethics committee at Fundaci on Jimenez Dıaz (Madrid, Spain). 2.1. Proband 1 This 69-year-old man had been followed-up for 11 years because of cognitive problems. His first consultation was at 59 years of age because his family referred ongoing memory problems, attention deficits, mental rigidity, and mild apathy during the previous 2 years. Cognitive evaluation was normal but free recall and naming were within the lower normal range. Computed tomography (CT) scan showed slight frontal atrophy. In spite of these symptoms, the patient continued working as a truck mechanic, performing activities of daily living (ADL) normally. It was not until he was 63 years of age when memory and naming performance degraded to abnormal scores on neuropsychological tests. Together with a brain single-photon emission CT (SPECT) showing decreased bitemporal perfusion, he was diagnosed with early-stage dementia of the Alzheimer’s type, with the possibility of frontotemporal dementia not being ruled out. He did not tolerate procholinergic treatments and was left without specific medication. Diagnosis was reconsidered when his cognitive and functional status remained stable after 5 years. Table 1 shows his most current neuropsychological evaluation at 69 years of age. His only behavioral
symptoms have been apathy, lack of initiative, and impulsive reactions. He has never exhibited psychotic or motor symptoms. His frontal reflexes are negative. Regarding functional status, he is independent for self-care, is able to hold a conversation, and is aware of some current events. He is able to use pocket currency and public transportation, and he continues to drive. However, he constantly needs stimuli to begin any activity, he is not able to conduct demanding duties (handling bank accounts), and he is unreliable for any task involving memory. Occasionally, during these years, he has had a few transient episodes of spatial disorientation or confusion. Neuroimaging studies have shown slow progression of frontotemporal atrophy (in CT and magnetic resonance imaging studies) and hypoperfusion (in brain SPECT) (Figure 1). A genetic study, performed with informed consent, revealed a C9ORF72 hexanucleotide expansion of .30 repeats (repeated primer polymerase chain reaction analysis, as described elsewhere [9]). His apolipoprotein E (apoE) genotype is ε3/ε3. 2.2. Proband 2 The 65-year-old sister of proband 1 began to complain of subjective memory loss at 54 years of age. These complaints had been considered as part of a moderate depression for which she was under treatment from 57 to 61 years of age. At age 60, she had consulted her general doctor because of word-finding problems, difficulties explaining herself in common conversations, and attention problems (such as leaving faucets on, lights on, or food outside the refrigerator). Her capability for ADL remained intact, her Mini-Mental State Examination (Folstein) score was 30/30, her speech was fluent and coherent, and no further studies were performed. In the following years, her symptoms persisted, referring more to language than to memory problems. She
Fig. 1. Family tree and recent brain MRI studies of probands 1 and 2 showing mild–moderate atrophy at ages 68 and 65 years, respectively, both after a decade of clinical symptoms.
E. Gomez-Tortosa et al. / Alzheimer’s & Dementia - (2013) 1–6
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Table 1 Description of main clinical features of probands 1 and 2
First symptoms
Evolution Symptoms Cognition
Functional status Current evaluation MMSE Verbal fluency (1 min) Boston Naming HVLT (12 items)
Digit Symbol Clock Test CDR (0–3) FBI Neuroimaging
Proband 1: man 69 years
Proband 2: woman 65 years
57 years Apathy, impulsivity, mental rigidity, memory deficits MMSE 29/30; CDR 0 (still working) 63 years Same as previous, word-finding problems
54 years, subjective memory complaints 57–61 years: depression, attentional problems CDR 0 59–64 years Word-finding problems, decreased verbal fluency, attentional problems MMSE 30/30
MMSE 29/30 Logical memory*: short 10/50, long 7/50 TAVEC short recall 2/16 Verbal fluency animals: 11; letter S: 8 Naming and executive functions: normal Rey Figure Test of short-term memory 13/36 CDR 0.5 69 years 29/30 Animals: 10; letter S: 8 26/60 1 16 with phonetic clues, paraphasias Learning trials: 3-4-4 Free recall: 1 1 1 with clues Recognition: 10/12 1 5 false positives (DI 5) 19 1 1 error Order 10/10, copy 10/10 1 18 (negative symptoms) Frontal and temporal atrophy
—
CDR 0 65 years 30/30 Animals: 10; letter S: 10 39/60 1 6 with phonetic clues, paraphasias Learning trials: 5-4-7 Free recall: 2 Recognition: 11/12 1 4 false positives (DI 7) 25 1 6 errors Order 4/10, copy 10/10 0.5 8 (negative symptoms) Mild frontal atrophy
Abbreviations: MMSE, Mini-Mental State Examination; CDR, Clinical Dementia Rating scale (0–3); HVLT, Hopkins Verbal Learning Test; DI, discrimination index (maximum 12); FBI, Frontal Behavioral Inventory. *Weschler Memory Scale–Revised.
has not had behavioral, psychiatric, or motor symptoms. She has remained fully able to undertake her responsibilities as a home-maker (e.g., shopping and cooking), but has refused to use public transportation or handle bank accounts by herself. She underwent a complete examination after her brother’s diagnosis. Cognitive examination revealed significant deficits in verbal memory and naming tests (Table 1). Brain magnetic resonance imaging (MRI) showed mild frontotemporal atrophy (Figure 1). A genetic study confirmed a C9ORF72 hexanucleotide expansion of .30 repeats with apoE genotype ε3/ε3. 2.3. Proband 3 The mother of both of the aforementioned probands died with the diagnosis of Alzheimer’s dementia at 89 years of age. According to several family members, her first symptoms appeared at around 54 years of age and consisted of mild attention and memory problems, slight anomia, and depressed mood. She occasionally became disoriented on her way home, but despite these symptoms, which progressed very slowly, she was able to carry out household chores and routine ADL until she was in her mid-70s. During the last decade she had temporal and spatial disorientation, shortterm memory problems, and increasing verbal fluency problems, and had become mute near the end of her life. She did not have disruptive behavioral/psychiatric disturbances or motor deterioration at any time. She came to neurologic
attention just once—at 79 years of age, when the diagnosis of senile dementia of Alzheimer’s type was made—but no formal medical reports are available. 3. Discussion This initial report of a family with benign frontotemporal deterioration associated with a C9ORF72 hexanucleotide expansion raises several issues, and further reflects how current advances in genetic markers are changing our clinical comprehension and diagnostic criteria of cognitive disorders. First, the family reported links this benign evolution with mild symptoms over a decade with an underlying neurodegenerative disease, most likely transactive response DNA-binding protein (TDP) and p62 pathology related, as have been the proteinopathies demonstrated in a majority of cases with the C9ORF72 expansion [11–13]. Together with the two cases reported by Khan et al. [8], this family’s findings suggest that C9ORF72 gene alterations are a likely cause of this benign phenotype and should be screened for. Second, the scarce functional impact over many years places this phenotype closer to the diagnosis of mild cognitive impairment (MCI) than to a dementia syndrome, which raises the issue of exploring whether some cases within the MCI diagnosis may have C9ORF72 hexanucleotide expansions. Based on clinical and neuroimaging evolution, at this time, probands 1 and 2 meet current criteria for the benign FTLD
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variant [5,8], although we emphasize how the sister had been without a diagnosis of neurologic disease for many years. It is possible that some of these cases could progress without appropriate diagnosis, especially if the family history is obscure. It is also remarkable that the main cognitive features in the family were anomia with decreased verbal fluency and memory deficits, which in proband 1 had supported a primary diagnosis of dementia of the Alzheimer’s type. None of the cases displayed disruptive behavioral or psychiatric symptoms typical of FTLD, only less specific mild negative symptoms (apathy and depressed mood). The mother’s clinical profile could not be established in great detail, although from what is known of her condition she survived for more than 3 decades from onset of the symptoms, which is likely the time of development her children will experience with their current evolution. Within the first series reported with the C9ORF72 expansion there have also been occasional patients with survival as long as 17 and 22 years [12–14], which was considered exceptional for pathologically confirmed FTLD. It seems that the C9ORF72 hexanucleotide expansion is responsible for a wider spectrum of phenotypes beyond our clinical understanding of FTLD as a presenile and aggressive dementia with language and behavioral deficits. Besides the definitive link with ALS, the hexanucleotide expansion has been found to be associated with a variety of psychiatric features including: bipolar disorders [15]; middle-age and late-onset psychosis [16,17]; and longterm depression and somatizations [18,19], with some of these cases evolving to dementia only years later. Furthermore, C9ORF72 expansions have been reported in typical Alzheimer’s dementia [20–22], cases clinically diagnosed as sporadic Creutzfeldt–Jakob disease, Huntington disease–like syndrome, and other nonspecific neurodegenerative disease syndromes [23], illustrating the wide variability of clinical phenotypes associated with this genetic marker. The family assessed in our study expands this list with the clinical picture of mild cognitive impairment and slowly progressive dementia over a time frame of .30 years. Of interest is that, according to preliminary studies, the C9ORF72 expansion does not seem to be a major cause of typical schizophrenia [24] and it is rare in idiopathic Parkinson’s disease [25,26]. In any case, the frequency of C9ORF72 repeat expansions exceeds that of any other neurodegenerative disease– causing mutation, and is particularly high in Caucasian populations of northern European countries and in North America, where it has already been associated with around 30% of the familial and 7% of sporadic FTLD/ALS cases [27]. All these data support the notion that, in clinical settings, screening for the C9ORF72 expansion should be extended to cases with psychiatric disturbances and/or cognitive problems and a strong family history of similar problems, independently of the dementia profile or severity of the cognitive impairment. As expected, cases with an autosomal
dominant pattern of disease have shown a higher prevalence of the C9ORF72 mutation [13]. Genetic study in sporadic cases must be decided upon on an individual basis, but, even if a small percentage of cases turn out to be positive, they may receive the most appropriate treatment. Given the current data, providing genetic counseling to families with the C9ORF72 expansion is a great challenge. We do not yet have clear information on penetrance, genetic anticipation, and the likelihood of developing one or another clinical phenotype and over which age span. Also, this prognosis is of greatest importance when such disparate possibilities as ALS or mild cognitive impairment are under consideration. In previous series, the frequency of C9ORF72 expansion carriers in the healthy control population ranged from 0% to 0.6%, with no details about age and no formal evaluations in these “false positive” cases [9,11,21,27]. Moreover, there are also few carriers (10%) within families with FTLD who remain asymptomatic after 70 years of age [28], which suggests incomplete penetrance of the mutation or very benign phenotypes. Better understanding of the genetics of the hexanucleotide expansion and of the disease mechanisms and progression will be crucial in the effort to give these families appropriate advice in the near future. With regard to physiopathologic research, expansion in the C9ORF72 gene has opened a whole new chapter in the neurodegeneration field. Initial studies with animal models showed that expression of the expanded hexanucleotide repeat RNA is sufficient to cause neurodegeneration [29]. It remains to be elucidated why the expansion manifests with TDP and p62 pathology in different neuronal networks, resulting in a variety of clinical phenotypes. Variables such as the number of hexanucleotide repeats expressed in different brain regions, other genes, or environmental factors could be involved in modulating the susceptibility and distribution of the pathology in different patterns. The three members of this family showed a homogeneous benign phenotype, suggesting that they share the same genetic conditioning factors. Finally, the hexanucleotide expansion has also been reported in a few cases with pathologically confirmed AD [21], and TDP pathology sometimes co-occurs with other neurodegenerative pathologic features. Brain-bank studies should determine the frequency of the C9ORF72 expansion in other pathologically confirmed neurodegenerative diseases to establish whether it can trigger a spectrum of pathologically different diseases. Our challenge for the future will be clarify how far upstream in the neurodegenerative cascade is the altered C9ORF72 protein and the mechanisms by which it turns into TDP and p62 inclusions pathology. Acknowledgments The authors thank the family members who contributed to this study; V. Sanchez, RN, C. Almaraz, and G. Sanchez for the collection and processing of blood samples; and A.
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Dıaz for the genetic studies. We also thank Oliver Shaw for editing the manuscript.
RESEARCH IN CONTEXT
1. Systematic review: In recent years, a benign variant of frontotemporal lobar degeneration (FTLD) has been recognized, with a particularly slow progression of cognitive deficits and scarce frontotemporal atrophy or hypoperfusion in neuroimaging studies. Those with FTLD have been considered “phenocopies,” with an underlying nondegenerative neurologic process. 2. Interpretation: We describe the first family with three affected members having benign FTLD associated with C9ORF72 gene hexanucleotide expansion. Onset of symptoms occurred during the fifth decade, with naming and memory problems as the main features. Two siblings have stabilized at mild cognitive impairment or incipient dementia for more than a decade, and remain quite independent in their activities of daily living at the ages of 69 and 65 years, respectively. Their mother’s cognitive deterioration evolved slowly during 33 years. 3. Future directions: This family demonstrates that a benign frontotemporal deterioration can be part of the spectrum of neurodegenerative diseases caused by the C9ORF72 hexanucleotide expansion. Screening of this genetic marker should be considered in cases with this clinical phenotype, especially if there is a family history.
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