Neurocase, 2015 Vol. 21, No. 4, 535–541, http://dx.doi.org/10.1080/13554794.2014.951058
Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia E. Devenneya,b,c*, D. Foxea, C. Dobson-Stonea,d, J.B. Kwoka,d, M.C. Kiernana,c and J.R. Hodgesa,d a
Neuroscience Research Australia, Sydney, NSW, Australia; bPrince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia; cBrain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia; dSchool of Medical Sciences, University of New South Wales, Sydney, NSW, Australia (Received 14 January 2014; accepted 29 July 2014) The C9orf72 genetic mutation represents the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Studies over the last 2 years have revealed a number of key features of this mutation in the fields of clinical neurology, imaging, pathology, and genetics. Despite these efforts, the clinical phenotype appears to extend beyond FTD and ALS into the realm of psychiatric disease, and while highly variable survival rates have been reported, the clinical course of carriers remains relatively unexplored. This report describes two contrasting C9orf72 cases, one with a protracted indolent course dominated by neuropsychiatric features and the other with a rapidly progressive dementia. In both cases, initial structural brain imaging was relatively normal. Keywords: C9orf72; frontotemporal dementia; amyotrophic lateral sclerosis neuroimaging; neuropsychiatry
The recently discovered C9orf72 genetic mutation is a common finding in familial cases of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and is also present in a small but important proportion of apparently sporadic cases (Boeve et al., 2012; Devenney et al., 2014; Mahoney et al., 2012; Snowden et al., 2012). A number of publications have described the clinical profile associated with this mutation. The majority of FTD carriers conform to the behavioral variant of FTD (bvFTD), although progressive non-fluent aphasia (PPA-nf) cases have also been noted. The presence of prominent psychotic features appears to be a hallmark of this syndrome (Boeve et al., 2012; Devenney et al., 2014; Dobson-Stone et al., 2012; Hsiung et al., 2012; Mahoney et al., 2012; Sha et al., 2012; Simon-Sanchez et al., 2012; Snowden et al., 2012). The family history also provides an important clue to the presence of this mutation as at least one half of bvFTD mutation-positive patients described a family history of ALS (Boeve et al., 2012; DeJesus-Hernandez et al., 2011; Devenney et al., 2014; Hsiung et al., 2012; Snowden et al., 2012), as well as a number of carriers describing significant psychiatric illness in family members (Byrne et al., 2013; Devenney et al., 2014). Survival rates have varied, with reports ranging from 1 to 17 years (Irwin et al., 2013). A recent report described two patients who initially satisfied international criteria for possible bvFTD, but both were slow to progress without typical imaging features of bvFTD and were subsequently termed bvFTD-slow progressor (bvFTD-SP) (Khan et al., 2012). In contrast to variable findings on imaging, the underlying pathology in C9orf72 appears uniformly TDP-43, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
with the addition of TDP-43-negative ubiquitin positive inclusions present in subcortical structures (Al-Sarraj et al., 2011; Snowden et al., 2012). With effective pathology targeted pharmacological treatments on the horizon for neurodegenerative disease, the presence of TDP-43 renders the C9orf72 mutation an ideal model for interventional studies in neurodegeneration (Turner et al., 2013). Despite significant developments in our understanding of this mutation, little has been written about the clinical course and variability in presentations. This report highlights the clinical heterogeneity by describing two contrasting cases with the C9orf72 mutation, one with a protracted indolent progression dominated by neuropsychiatric features and the other with a rapidly progressive dementia. Case 1 A 54-year-old male retired public servant was referred in 2008, with a history spanning over a decade of insidious change in personality and behavior. His wife, who met him in 1980, first noticed a change in his personality in the 1990s. When they first met, he was functioning well in a high-ranking job until an accident in the mid-1980s rendered him unable to continue working. During the early years of marriage, he was astute with finances, had no trouble with the law and showed no signs of disinhibition. They had a happy marriage, had an active social life, enjoyed sporting activities, and had many friends. In the late 1990s, he began to overspend and failed to pay the mortgage. Over the ensuing few years, he was imprisoned
536
E. Devenney et al.
on three occasions for fraudulent behavior. Although he remained outgoing, he was disinhibited in social situations, at times in a sexual manner. He told fantastical stories portraying himself as a hero, for example he often described saving people from drowning. On one occasion, he reported that he had been abducted in a helicopter and drugged, which is why he had not appeared in court. There was a hint of paranoia associated with this delusion; he was certain that his abductors meant him harm and that they had interfered with him. He was able to describe the physical attributes of the abductors in detail, but there was no clear evidence of ongoing hallucinations. In contrast to relatively preserved motivation, his ability to empathize and sympathize was profoundly reduced. He favored spending time with his stamp and coin collections over spending time with his family. He could be mentally rigid, secretive, and at times aggressive. He consumed only moderate amounts of alcohol throughout his life. In stark contrast to his wife’s reports, the patient had no insight into these problems. Instead, when pressed, he complained of recent problems with balance and mild long-standing memory complaints since a motorcycle accident. He was moderately impaired for activities of daily living (ADLs). His past medical history was significant for a neck injury following the motorcycle accident 30 years previously. His recovery was fraught with problems, and despite undergoing neurosurgery he required regular opiate medication to control neck pain and sensory disturbances in the right arm. His mother was diagnosed with parkinsonism in late life, which may have been accompanied by cognitive decline. His father may have had a psychotic episode, which was attributed to a “mini-stroke.” He was paranoid and convinced that he was being watched, while his family could see no one watching him. There was no other family history of neurodegenerative disorders. On physical examination, there was evidence of mild symmetrical parkinsonism with rigidity and bradykinesia, but without tremor. There were no ALS features or evidence of apraxia. Based on a formal test of reading and demographic information, his premorbid intellectual ability was estimated to be within the average range. General cognitive screening revealed overall mild impairment (ACE-R 79; Table 1). More formal cognitive tests showed severe impairments in learning and memory, confrontation naming, visuoconstruction, and on measures of executive function (including verbal fluency and switching between two trains of thought). Borderline impairment was also noted in working memory, verbal comprehension, and on an executive measure of inhibitory control. By contrast, his attentional, language reception, word repetition, and basic visuoperceptual skills remained within normal limits. On a self-report measure of
mood, he reported normal (i.e., low) levels of depression, anxiety, and stress symptoms. A structural MRI brain revealed mild central atrophy compared to an aged matched control but no evidence of significant frontal or temporal atrophy (Figure 1). A subsequent fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) was essentially normal with equivocal reduced uptake in the medial frontal lobes only. Over the next 4 years, he remained disinhibited with increasingly sexualized behaviors including indecent exposure. He continued to spend money without concern for the financial struggles of his family. His stories became increasingly delusional, claiming that he was a champion sportsman which was blatantly untrue. He believed that he was a war veteran and took part in Anzac day celebrations despite having never been involved in the military or conflict of any kind. Over the years, he became apathetic which was most notable at review this year when he barely participated in conversation. He developed obvious memory problems and was disorientated at last review. The degree of parkinsonism had not changed. At follow-up testing, he showed general decline in cognitive functioning, with a fall on the ACE-R from 79 to 62 together with declines in his attention, learning and memory, visuoconstruction ability, and measures of executive function, whereas overall language and visuoperceptual skills were relatively unchanged (see Table 1). Measures of mood were unchanged, whereas ADLs had deteriorated and were now considered to be severely impaired. There was little progression on MRI until 2012. At this time, atrophy was unequivocally present and involved the frontal and parietal regions (Figure 1). In summary, he presented with a 20-year history of insidious social decline and prominent neuropsychiatric features with only minimal structural brain changes; over the next 4 years he showed cognitive and functional decline. Case 2 A 55-year-old woman attended the FTD clinic in 2009. She was accompanied by her daughter who reported that her mother’s problems began at work 1 year beforehand. As a salesperson, the patient had been acknowledged as an accomplished worker. This changed 12 months prior to the initial assessment when she began to make mistakes, became repetitive and aggressive, and was subsequently dismissed. She declined rapidly becoming obsessional, perseverative, disinhibited, and tactless in social situations with little insight. Her house was shambolic and disorganized. Her aggression escalated with episodes of physical violence. Motivation and appetite declined. Her days were spent wandering around her home doing very little and she continually repeated herself and appeared disorientated. She had a number of car accidents and no longer drove. There were no delusions or hallucinations.
Neurocase Table 1.
537
Neuropsychological test scores. Case 1
Domain General
Cognitive test
Subtest (maximum score)
NART MMSE ACE-R Trails
December 2008
Predicted IQ (30) (100) Executive function A time (errors) B time (errors) Animal fluency 60 seconds Hayling Test 1 time Test 2 time Errors SS Overall SS Brixton Errors Learning and memory Digit span Longest forward Longest backward Doors and people Doors A RCFT Copy (36) 3-min recall (36) RAVLT Total A list (75) B list (15) A7 delayed (15) Language SYD-BAT Naming (30) Repetition (30) Comprehension (30) Semantic association (30) Visuospatial VOSP Dot counting (10) Position discrimination (10) Cube analysis (20) Mood DASS Depression Anxiety Stress Behavior CBI-R Total (180) DAD Total (40) FRS Total (100) Total NPIa
97 28 79 32 (1) 126 (1)** 9** 22 86 16* 3* 19 6 3* 11 27** 7** 22** 3 3** 21** 30 27* 27 10 19 10 1 (normal) 3 (normal) 1 (normal) 35 33/36 (92%) 70 (moderate) 19
April 2012
Case 2 March 2008
October 2013
– 82 – 26 25 – 63 75 – 65 (1)** 54 (1)** – Discontinued 298 (5)** – 6** 16 – 19 22 – 107* 57 – 22* 2 – 1** 5 – 36* – 4** 5 – 3* 4 – 7** 6** – 16.5** 11** – 5.5** 1** – 18** 40 – 1** 2* – 3** 4* – 23* 21** – 30 30 – 28 25** – 24** 24** – 9 10 – 20 17 (fail) – 6 9 – 2 (normal) 0 (normal) – 1 (normal) 0 (normal) – 3 (normal) 0 (normal) – 87 39 138 12 (32%) 15 1 19 (severe) 28 (severe) 10 (very severe) 14 6 79
Notes: NART: national adult reading task; MMSE: mini-mental state examination; ACE-R: Addenbrooke’s cognitive examination; Trails: trail making test; Hayling: Hayling sentence completion test; Brixton: Brixton spatial anticipation test; Digit span: digit span subtest of the Wechsler adult intelligence scaleIII (WAIS-III); RCFT: Rey complex figure test; RAVLT: Rey auditory verbal memory test; SYD-BAT: The Sydney language battery; VOSP: dot counting, position discrimination and cube analysis subtests from the visual object and space perception; DASS: depression anxiety stress scale; CBI-R: Cambridge behavioral inventory – revised; DAD: disability assessment for dementia; FRS: frontotemporal dementia rating scale; NPI: The neuropsychiatric inventory; SS: scaled score. a NPI total score excluding sexuality scores. * indicates borderline impairment: z < −1.4; percentile
Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia E. Devenneya,b,c*, D. Foxea, C. Dobson-Stonea,d, J.B. Kwoka,d, M.C. Kiernana,c and J.R. Hodgesa,d a
Neuroscience Research Australia, Sydney, NSW, Australia; bPrince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia; cBrain and Mind Research Institute, University of Sydney, Sydney, NSW, Australia; dSchool of Medical Sciences, University of New South Wales, Sydney, NSW, Australia (Received 14 January 2014; accepted 29 July 2014) The C9orf72 genetic mutation represents the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Studies over the last 2 years have revealed a number of key features of this mutation in the fields of clinical neurology, imaging, pathology, and genetics. Despite these efforts, the clinical phenotype appears to extend beyond FTD and ALS into the realm of psychiatric disease, and while highly variable survival rates have been reported, the clinical course of carriers remains relatively unexplored. This report describes two contrasting C9orf72 cases, one with a protracted indolent course dominated by neuropsychiatric features and the other with a rapidly progressive dementia. In both cases, initial structural brain imaging was relatively normal. Keywords: C9orf72; frontotemporal dementia; amyotrophic lateral sclerosis neuroimaging; neuropsychiatry
The recently discovered C9orf72 genetic mutation is a common finding in familial cases of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) and is also present in a small but important proportion of apparently sporadic cases (Boeve et al., 2012; Devenney et al., 2014; Mahoney et al., 2012; Snowden et al., 2012). A number of publications have described the clinical profile associated with this mutation. The majority of FTD carriers conform to the behavioral variant of FTD (bvFTD), although progressive non-fluent aphasia (PPA-nf) cases have also been noted. The presence of prominent psychotic features appears to be a hallmark of this syndrome (Boeve et al., 2012; Devenney et al., 2014; Dobson-Stone et al., 2012; Hsiung et al., 2012; Mahoney et al., 2012; Sha et al., 2012; Simon-Sanchez et al., 2012; Snowden et al., 2012). The family history also provides an important clue to the presence of this mutation as at least one half of bvFTD mutation-positive patients described a family history of ALS (Boeve et al., 2012; DeJesus-Hernandez et al., 2011; Devenney et al., 2014; Hsiung et al., 2012; Snowden et al., 2012), as well as a number of carriers describing significant psychiatric illness in family members (Byrne et al., 2013; Devenney et al., 2014). Survival rates have varied, with reports ranging from 1 to 17 years (Irwin et al., 2013). A recent report described two patients who initially satisfied international criteria for possible bvFTD, but both were slow to progress without typical imaging features of bvFTD and were subsequently termed bvFTD-slow progressor (bvFTD-SP) (Khan et al., 2012). In contrast to variable findings on imaging, the underlying pathology in C9orf72 appears uniformly TDP-43, *Corresponding author. Email: [email protected] © 2014 Taylor & Francis
with the addition of TDP-43-negative ubiquitin positive inclusions present in subcortical structures (Al-Sarraj et al., 2011; Snowden et al., 2012). With effective pathology targeted pharmacological treatments on the horizon for neurodegenerative disease, the presence of TDP-43 renders the C9orf72 mutation an ideal model for interventional studies in neurodegeneration (Turner et al., 2013). Despite significant developments in our understanding of this mutation, little has been written about the clinical course and variability in presentations. This report highlights the clinical heterogeneity by describing two contrasting cases with the C9orf72 mutation, one with a protracted indolent progression dominated by neuropsychiatric features and the other with a rapidly progressive dementia. Case 1 A 54-year-old male retired public servant was referred in 2008, with a history spanning over a decade of insidious change in personality and behavior. His wife, who met him in 1980, first noticed a change in his personality in the 1990s. When they first met, he was functioning well in a high-ranking job until an accident in the mid-1980s rendered him unable to continue working. During the early years of marriage, he was astute with finances, had no trouble with the law and showed no signs of disinhibition. They had a happy marriage, had an active social life, enjoyed sporting activities, and had many friends. In the late 1990s, he began to overspend and failed to pay the mortgage. Over the ensuing few years, he was imprisoned
536
E. Devenney et al.
on three occasions for fraudulent behavior. Although he remained outgoing, he was disinhibited in social situations, at times in a sexual manner. He told fantastical stories portraying himself as a hero, for example he often described saving people from drowning. On one occasion, he reported that he had been abducted in a helicopter and drugged, which is why he had not appeared in court. There was a hint of paranoia associated with this delusion; he was certain that his abductors meant him harm and that they had interfered with him. He was able to describe the physical attributes of the abductors in detail, but there was no clear evidence of ongoing hallucinations. In contrast to relatively preserved motivation, his ability to empathize and sympathize was profoundly reduced. He favored spending time with his stamp and coin collections over spending time with his family. He could be mentally rigid, secretive, and at times aggressive. He consumed only moderate amounts of alcohol throughout his life. In stark contrast to his wife’s reports, the patient had no insight into these problems. Instead, when pressed, he complained of recent problems with balance and mild long-standing memory complaints since a motorcycle accident. He was moderately impaired for activities of daily living (ADLs). His past medical history was significant for a neck injury following the motorcycle accident 30 years previously. His recovery was fraught with problems, and despite undergoing neurosurgery he required regular opiate medication to control neck pain and sensory disturbances in the right arm. His mother was diagnosed with parkinsonism in late life, which may have been accompanied by cognitive decline. His father may have had a psychotic episode, which was attributed to a “mini-stroke.” He was paranoid and convinced that he was being watched, while his family could see no one watching him. There was no other family history of neurodegenerative disorders. On physical examination, there was evidence of mild symmetrical parkinsonism with rigidity and bradykinesia, but without tremor. There were no ALS features or evidence of apraxia. Based on a formal test of reading and demographic information, his premorbid intellectual ability was estimated to be within the average range. General cognitive screening revealed overall mild impairment (ACE-R 79; Table 1). More formal cognitive tests showed severe impairments in learning and memory, confrontation naming, visuoconstruction, and on measures of executive function (including verbal fluency and switching between two trains of thought). Borderline impairment was also noted in working memory, verbal comprehension, and on an executive measure of inhibitory control. By contrast, his attentional, language reception, word repetition, and basic visuoperceptual skills remained within normal limits. On a self-report measure of
mood, he reported normal (i.e., low) levels of depression, anxiety, and stress symptoms. A structural MRI brain revealed mild central atrophy compared to an aged matched control but no evidence of significant frontal or temporal atrophy (Figure 1). A subsequent fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) was essentially normal with equivocal reduced uptake in the medial frontal lobes only. Over the next 4 years, he remained disinhibited with increasingly sexualized behaviors including indecent exposure. He continued to spend money without concern for the financial struggles of his family. His stories became increasingly delusional, claiming that he was a champion sportsman which was blatantly untrue. He believed that he was a war veteran and took part in Anzac day celebrations despite having never been involved in the military or conflict of any kind. Over the years, he became apathetic which was most notable at review this year when he barely participated in conversation. He developed obvious memory problems and was disorientated at last review. The degree of parkinsonism had not changed. At follow-up testing, he showed general decline in cognitive functioning, with a fall on the ACE-R from 79 to 62 together with declines in his attention, learning and memory, visuoconstruction ability, and measures of executive function, whereas overall language and visuoperceptual skills were relatively unchanged (see Table 1). Measures of mood were unchanged, whereas ADLs had deteriorated and were now considered to be severely impaired. There was little progression on MRI until 2012. At this time, atrophy was unequivocally present and involved the frontal and parietal regions (Figure 1). In summary, he presented with a 20-year history of insidious social decline and prominent neuropsychiatric features with only minimal structural brain changes; over the next 4 years he showed cognitive and functional decline. Case 2 A 55-year-old woman attended the FTD clinic in 2009. She was accompanied by her daughter who reported that her mother’s problems began at work 1 year beforehand. As a salesperson, the patient had been acknowledged as an accomplished worker. This changed 12 months prior to the initial assessment when she began to make mistakes, became repetitive and aggressive, and was subsequently dismissed. She declined rapidly becoming obsessional, perseverative, disinhibited, and tactless in social situations with little insight. Her house was shambolic and disorganized. Her aggression escalated with episodes of physical violence. Motivation and appetite declined. Her days were spent wandering around her home doing very little and she continually repeated herself and appeared disorientated. She had a number of car accidents and no longer drove. There were no delusions or hallucinations.
Neurocase Table 1.
537
Neuropsychological test scores. Case 1
Domain General
Cognitive test
Subtest (maximum score)
NART MMSE ACE-R Trails
December 2008
Predicted IQ (30) (100) Executive function A time (errors) B time (errors) Animal fluency 60 seconds Hayling Test 1 time Test 2 time Errors SS Overall SS Brixton Errors Learning and memory Digit span Longest forward Longest backward Doors and people Doors A RCFT Copy (36) 3-min recall (36) RAVLT Total A list (75) B list (15) A7 delayed (15) Language SYD-BAT Naming (30) Repetition (30) Comprehension (30) Semantic association (30) Visuospatial VOSP Dot counting (10) Position discrimination (10) Cube analysis (20) Mood DASS Depression Anxiety Stress Behavior CBI-R Total (180) DAD Total (40) FRS Total (100) Total NPIa
97 28 79 32 (1) 126 (1)** 9** 22 86 16* 3* 19 6 3* 11 27** 7** 22** 3 3** 21** 30 27* 27 10 19 10 1 (normal) 3 (normal) 1 (normal) 35 33/36 (92%) 70 (moderate) 19
April 2012
Case 2 March 2008
October 2013
– 82 – 26 25 – 63 75 – 65 (1)** 54 (1)** – Discontinued 298 (5)** – 6** 16 – 19 22 – 107* 57 – 22* 2 – 1** 5 – 36* – 4** 5 – 3* 4 – 7** 6** – 16.5** 11** – 5.5** 1** – 18** 40 – 1** 2* – 3** 4* – 23* 21** – 30 30 – 28 25** – 24** 24** – 9 10 – 20 17 (fail) – 6 9 – 2 (normal) 0 (normal) – 1 (normal) 0 (normal) – 3 (normal) 0 (normal) – 87 39 138 12 (32%) 15 1 19 (severe) 28 (severe) 10 (very severe) 14 6 79
Notes: NART: national adult reading task; MMSE: mini-mental state examination; ACE-R: Addenbrooke’s cognitive examination; Trails: trail making test; Hayling: Hayling sentence completion test; Brixton: Brixton spatial anticipation test; Digit span: digit span subtest of the Wechsler adult intelligence scaleIII (WAIS-III); RCFT: Rey complex figure test; RAVLT: Rey auditory verbal memory test; SYD-BAT: The Sydney language battery; VOSP: dot counting, position discrimination and cube analysis subtests from the visual object and space perception; DASS: depression anxiety stress scale; CBI-R: Cambridge behavioral inventory – revised; DAD: disability assessment for dementia; FRS: frontotemporal dementia rating scale; NPI: The neuropsychiatric inventory; SS: scaled score. a NPI total score excluding sexuality scores. * indicates borderline impairment: z < −1.4; percentile
