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Intrafamilial clinical phenotypic heterogeneity with progranulin gene p.Glu498fs mutation
Journal of the Neurological Sciences 316 (2012) 189–190
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Intrafamilial clinical phenotypic heterogeneity with progranulin gene p.Glu498fs mutation A.J. Larner ⁎ Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
a r t i c l e
i n f o
Article history: Received 23 September 2011 Received in revised form 23 December 2011 Accepted 4 January 2012 Available online 26 January 2012 Keywords: Diagnosis GRN mutation Heterogeneity Phenotype Progranulin
a b s t r a c t A patient with a progressive aphasia syndrome underwent progranulin gene (GRN) testing in light of a family history of early-onset dementia in two of her brothers, one of whom had been previously examined and had the phenotype of frontal variant frontotemporal dementia. The proband was found to have the p.Glu498fs mutation. This is only the second English family, and the fifth family overall, to be described with this GRN mutation. There was marked intrafamilial phenotypic heterogeneity with respect to age at onset and clinical presentation. The mechanisms underpinning this heterogeneity, as seen with other GRN mutations, are currently unknown. Since all GRN mutations lead to progranulin haploinsufficiency, other modifying factors, possibly genetic, are implicated. © 2012 Elsevier B.V. All rights reserved.
1. Introduction
2. Case reports
Mutations in the progranulin gene (GRN) on chromosome 17 were first demonstrated to be a cause of frontotemporal lobar degeneration (FTLD) in 2006 [1,2]. Around 70 different pathogenic GRN sequence variants have now been described (as well as many non-pathogenic variants or sequences of uncertain pathogenic nature) including frameshift, premature termination, and splice site mutations [3], all of which appear to have a null effect [1,2]. Along with mutations in the microtubule associated protein tau (MAPT), progranulin mutations are the most commonly identified genetic mutations causing FTLD [4,5]. Carriers of GRN mutations tend to be older than MAPT mutation carriers at age of clinical onset, less likely to have a positive family history, more likely to manifest parietal lobe features and have asymmetric brain atrophy, and have a shorter disease duration [6–8]. GRN mutation carriers have been reported to present with a variable phenotype, including behavioural features typical of frontal variant frontotemporal dementia (fvFTD), language impairment typical of progressive nonfluent aphasia or dynamic aphasia, and the corticobasal syndrome (CBS) [1–9]. One possible difficulty in identifying GRN mutation carriers is intrafamilial phenotypic variability. A family pedigree is presented which emphasizes intrafamilial phenotypic heterogeneity with respect to age of onset and clinical presentation.
The proband was a 62 year-old woman who presented with a two year history of progressive decline in linguistic function. Her relatives, from whom virtually all the history came, reported impoverished spontaneous conversation with a tendency to repeat what was said to her as part of her own conversation. Despite this she was still managing all activities of daily living and there was no report of memory impairment. A more recent tendency to lapses in normal personal hygiene was the only behavioural feature elicited on direct questioning of relatives. The patient could repeat complex words and read simple sentences, but had marked difficulty with object naming, frequently identifying pictures as “a thing”. Her linguistic performance, characterised by decreased quantity of speech but without speech errors or articulatory impairment, was indicative of dynamic aphasia [6]. Brain imaging (CT) showed extensive, asymmetric, left hemisphere atrophy involving frontal and temporal lobes, consistent with a diagnosis of FTLD, with a phenotype of progressive aphasia. Family history revealed that the patient was the third of eleven siblings, of whom two brothers were reported to have died in their fifties with presenile dementia. Parental history was censored due to the early death of their mother in her late 40s with cancer. One of the proband's brothers, three years younger than his sister, had been seen some eight years earlier at this clinic, when aged 51 years. He was referred by a psychiatrist with a history of personality change over a few months, with marked neglect of personal hygiene, and a provisional diagnosis of “atypical depression”. On Mini-Mental State Examination he scored 20/30. On the Cambridge Cognitive Examination (CAMCOG) he was found to have deficits in
⁎ Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ, United Kingdom. Fax: + 44 151 529 8552. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.01.005
190
A.J. Larner / Journal of the Neurological Sciences 316 (2012) 189–190
abstract thought, executive functions, and attention and concentration, but memory, learning, perception, praxis and comprehension were relatively preserved. Only a partial neuropsychological assessment was possible because the patient required constant prompting. There was no significant discrepancy between verbal IQ (55) and performance IQ (60) on the Wechsler Abbreviated Scale of Intelligence but evidence of generalised intellectual loss in comparison with his predicted full scale IQ (98) on the Wechsler Test of Adult Reading. He was in the average range on language testing with the Graded Naming Test. Copy of the Complex Rey Figure was slow and disorganised (below 1st percentile). Examining executive functions, he was severely impaired on both the Benton Verbal Fluency Test (below 1st percentile) and the Stroop Colour Word Test (2nd percentile). On the Colour-Form Sorting test (Weigl) he was able to sort the pieces by colour but no other alternative; perseveration was evident. CT brain scan (performed elsewhere) was reported to be normal, as was an EEG. Based on these findings, a diagnosis of fvFTD was made. In light of the family history, giving a “Goldman score” of 2 (= three or more family members with dementia [10]), neurogenetic testing of the proband was undertaken. Sequencing of the GRN gene identified the 5 nucleotide deletion (c1494-1498delAGTGG) producing the p.Glu498fs mutation.
Other modifying factors may therefore influence age at onset and the topography of brain atrophy in GRN mutation carriers, but these have yet to be defined. Some series have reported apolipoprotein E4 genotype may delay age at onset in GRN mutation carriers [6] but others have not found this [8]. It is possible that GRN polymorphisms on the normal allele might influence phenotype but this has not been examined in extended families. Pragmatically, intrafamilial phenotypic heterogeneity associated with GRN mutations may influence clinical genetic testing policy, suggesting a need to lower the index of clinical suspicion for undertaking such testing. The algorithm for genetic testing in FTLD suggested by Goldman et al. [16] may assist in these circumstances. A patient with a PNFA presentation and a positive family history of dementia would indicate GRN mutation testing [16]. The algorithm also suggests that GRN testing might be undertaken in the absence of a family history of dementia (as was the case when the brother of our proband was seen, as he was not able to provide a family history) if the phenotype is bvFTD, because “sporadic” GRN mutations may occur (3%) [7]. Funding The author received no specific funding for this article.
3. Discussion Competing interests The current cases show that intrafamilial phenotypic heterogeneity may be encountered with the GRN p.Glu498fs mutation. The two examined members of this FTLD pedigree showed an approximately 10 year difference in age at clinical onset (60 years and 50 years) and different clinical features at onset (progressive aphasia and fvFTD). Structural neuroradiological changes may also have differed (asymmetric atrophy and reportedly normal). Phenotypic variability associated with GRN mutations has been previously noted [6–9]. In one series patients with aphasic presentations had mean onset three years later than bvFTD presentations [7]. There have been only two prior reports of FTLD families with the p.Glu498fs GRN mutation, in one English family (DRC430: mother and daughter) [6,11] and in three French families (F540, F741, F023) [8]. Indeed this was the most frequent GRN mutation detected in the French FTLD series, the families presenting with CBS (F540), fvFTD (P741) or primary progressive aphasia (F023) [3]. Although intrafamilial phenotype variability was noted overall in the French series of GRN mutation carriers, the intrafamilial phenotype seems to have been consistent in the three p.Glu498fs families [8]. Speech production impairment was the first symptom in the English family [6]. Detailed linguistic assessment was not undertaken in the proband of the current report, so it cannot be said whether she had the progranulin-associated phenotype of primary progressive aphasia (impoverished propositional speech, anomia, prolonged wordfinding pauses, impaired speech repetition for sentences, impaired verbal short-term memory) reported by Rohrer et al. [12]. In a cohort of patients with progressive language and speech disorders, agrammatic progressive aphasia was reported to be predictive for FTLDTDP pathology with two-thirds of these patients having GRN mutations [13]. Currently there is no clear explanation for the clinical heterogeneity associated with GRN mutations, nor for MAPT mutations which may also be associated with a variable clinical phenotype (including FTLD, especially fvFTD; CBS; progressive supranuclear palsy; and an amnestic syndrome more suggestive of Alzheimer's disease) [14]. Intrafamilial clinical heterogeneity has also been observed with MAPT mutations [15]. However, unlike the presumed gain of function/toxicity with MAPT mutations, all GRN mutations lead to progranulin haploinsufficiency and hence no genotype/phenotype correlations are anticipated.
The author declares that no competing interests exist. References [1] Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–9. [2] Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–4. [3] Alzheimer Disease and Frontotemporal Dementia Mutation Database. http:// www.molgen.ua.ac.be/Admutations (accessed 01/12/11). [4] Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi R, de Koning I, et al. Distinct genetic forms of frontotemporal dementia. Neurology 2008;71:1220–6. [5] Rohrer JD, Guerriero R, Vandrovcova J, Uphill J, Reiman D, Beck J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology 2009;73: 1451–6. [6] Beck J, Rohrer JD, Campbell T, Isaacs A, Morrison KE, Goodall EF, et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 2008;131:706–20. [7] Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AM, et al. Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 2008;131:721–31. [8] Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, et al. Phenotype variability in progranulin mutation carriers; a clinical, neuropsychological, imaging and genetic study. Brain 2008;131:732–46. [9] Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C>T (Arg493X) mutation: an international initiative. Lancet Neurol 2007;6:857–68. [10] Goldman JS, Farmer JM, Wood EM, Johnson JK, Boxer A, Neuhaus J, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 2005;65:1817–9. [11] Rohrer JD, Ridgway GR, Modat M, Ourselin S, Mead S, Fox NC, et al. Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage 2010;53:1070–6. [12] Rohrer JD, Crutch SJ, Warrington EK, Warren JD. Progranulin-associated primary progressive aphasia: a distinct phenotype? Neuropsychologia 2010;48:288–97. [13] Deramecourt V, Lebert F, Debachy B, Mackowiak-Cordoliani MA, Bombois S, Kerdraon O, et al. Prediction of pathology in primary progressive language and speech disorders. Neurology 2010;74:42–9. [14] Larner AJ, Doran M. Clinical heterogeneity associated with tau gene mutations. Eur Neurol Rev 2009;3(2):31–2. [15] Larner AJ. Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation. J Neurol Sci 2009;287:253–6. [16] Goldman JS, Rademakers R, Huey ED, Boxer AL, Mayeux R, Miller BL, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology 2011;76:475–83.
Contents lists available at SciVerse ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Short communication
Intrafamilial clinical phenotypic heterogeneity with progranulin gene p.Glu498fs mutation A.J. Larner ⁎ Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom
a r t i c l e
i n f o
Article history: Received 23 September 2011 Received in revised form 23 December 2011 Accepted 4 January 2012 Available online 26 January 2012 Keywords: Diagnosis GRN mutation Heterogeneity Phenotype Progranulin
a b s t r a c t A patient with a progressive aphasia syndrome underwent progranulin gene (GRN) testing in light of a family history of early-onset dementia in two of her brothers, one of whom had been previously examined and had the phenotype of frontal variant frontotemporal dementia. The proband was found to have the p.Glu498fs mutation. This is only the second English family, and the fifth family overall, to be described with this GRN mutation. There was marked intrafamilial phenotypic heterogeneity with respect to age at onset and clinical presentation. The mechanisms underpinning this heterogeneity, as seen with other GRN mutations, are currently unknown. Since all GRN mutations lead to progranulin haploinsufficiency, other modifying factors, possibly genetic, are implicated. © 2012 Elsevier B.V. All rights reserved.
1. Introduction
2. Case reports
Mutations in the progranulin gene (GRN) on chromosome 17 were first demonstrated to be a cause of frontotemporal lobar degeneration (FTLD) in 2006 [1,2]. Around 70 different pathogenic GRN sequence variants have now been described (as well as many non-pathogenic variants or sequences of uncertain pathogenic nature) including frameshift, premature termination, and splice site mutations [3], all of which appear to have a null effect [1,2]. Along with mutations in the microtubule associated protein tau (MAPT), progranulin mutations are the most commonly identified genetic mutations causing FTLD [4,5]. Carriers of GRN mutations tend to be older than MAPT mutation carriers at age of clinical onset, less likely to have a positive family history, more likely to manifest parietal lobe features and have asymmetric brain atrophy, and have a shorter disease duration [6–8]. GRN mutation carriers have been reported to present with a variable phenotype, including behavioural features typical of frontal variant frontotemporal dementia (fvFTD), language impairment typical of progressive nonfluent aphasia or dynamic aphasia, and the corticobasal syndrome (CBS) [1–9]. One possible difficulty in identifying GRN mutation carriers is intrafamilial phenotypic variability. A family pedigree is presented which emphasizes intrafamilial phenotypic heterogeneity with respect to age of onset and clinical presentation.
The proband was a 62 year-old woman who presented with a two year history of progressive decline in linguistic function. Her relatives, from whom virtually all the history came, reported impoverished spontaneous conversation with a tendency to repeat what was said to her as part of her own conversation. Despite this she was still managing all activities of daily living and there was no report of memory impairment. A more recent tendency to lapses in normal personal hygiene was the only behavioural feature elicited on direct questioning of relatives. The patient could repeat complex words and read simple sentences, but had marked difficulty with object naming, frequently identifying pictures as “a thing”. Her linguistic performance, characterised by decreased quantity of speech but without speech errors or articulatory impairment, was indicative of dynamic aphasia [6]. Brain imaging (CT) showed extensive, asymmetric, left hemisphere atrophy involving frontal and temporal lobes, consistent with a diagnosis of FTLD, with a phenotype of progressive aphasia. Family history revealed that the patient was the third of eleven siblings, of whom two brothers were reported to have died in their fifties with presenile dementia. Parental history was censored due to the early death of their mother in her late 40s with cancer. One of the proband's brothers, three years younger than his sister, had been seen some eight years earlier at this clinic, when aged 51 years. He was referred by a psychiatrist with a history of personality change over a few months, with marked neglect of personal hygiene, and a provisional diagnosis of “atypical depression”. On Mini-Mental State Examination he scored 20/30. On the Cambridge Cognitive Examination (CAMCOG) he was found to have deficits in
⁎ Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ, United Kingdom. Fax: + 44 151 529 8552. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2012.01.005
190
A.J. Larner / Journal of the Neurological Sciences 316 (2012) 189–190
abstract thought, executive functions, and attention and concentration, but memory, learning, perception, praxis and comprehension were relatively preserved. Only a partial neuropsychological assessment was possible because the patient required constant prompting. There was no significant discrepancy between verbal IQ (55) and performance IQ (60) on the Wechsler Abbreviated Scale of Intelligence but evidence of generalised intellectual loss in comparison with his predicted full scale IQ (98) on the Wechsler Test of Adult Reading. He was in the average range on language testing with the Graded Naming Test. Copy of the Complex Rey Figure was slow and disorganised (below 1st percentile). Examining executive functions, he was severely impaired on both the Benton Verbal Fluency Test (below 1st percentile) and the Stroop Colour Word Test (2nd percentile). On the Colour-Form Sorting test (Weigl) he was able to sort the pieces by colour but no other alternative; perseveration was evident. CT brain scan (performed elsewhere) was reported to be normal, as was an EEG. Based on these findings, a diagnosis of fvFTD was made. In light of the family history, giving a “Goldman score” of 2 (= three or more family members with dementia [10]), neurogenetic testing of the proband was undertaken. Sequencing of the GRN gene identified the 5 nucleotide deletion (c1494-1498delAGTGG) producing the p.Glu498fs mutation.
Other modifying factors may therefore influence age at onset and the topography of brain atrophy in GRN mutation carriers, but these have yet to be defined. Some series have reported apolipoprotein E4 genotype may delay age at onset in GRN mutation carriers [6] but others have not found this [8]. It is possible that GRN polymorphisms on the normal allele might influence phenotype but this has not been examined in extended families. Pragmatically, intrafamilial phenotypic heterogeneity associated with GRN mutations may influence clinical genetic testing policy, suggesting a need to lower the index of clinical suspicion for undertaking such testing. The algorithm for genetic testing in FTLD suggested by Goldman et al. [16] may assist in these circumstances. A patient with a PNFA presentation and a positive family history of dementia would indicate GRN mutation testing [16]. The algorithm also suggests that GRN testing might be undertaken in the absence of a family history of dementia (as was the case when the brother of our proband was seen, as he was not able to provide a family history) if the phenotype is bvFTD, because “sporadic” GRN mutations may occur (3%) [7]. Funding The author received no specific funding for this article.
3. Discussion Competing interests The current cases show that intrafamilial phenotypic heterogeneity may be encountered with the GRN p.Glu498fs mutation. The two examined members of this FTLD pedigree showed an approximately 10 year difference in age at clinical onset (60 years and 50 years) and different clinical features at onset (progressive aphasia and fvFTD). Structural neuroradiological changes may also have differed (asymmetric atrophy and reportedly normal). Phenotypic variability associated with GRN mutations has been previously noted [6–9]. In one series patients with aphasic presentations had mean onset three years later than bvFTD presentations [7]. There have been only two prior reports of FTLD families with the p.Glu498fs GRN mutation, in one English family (DRC430: mother and daughter) [6,11] and in three French families (F540, F741, F023) [8]. Indeed this was the most frequent GRN mutation detected in the French FTLD series, the families presenting with CBS (F540), fvFTD (P741) or primary progressive aphasia (F023) [3]. Although intrafamilial phenotype variability was noted overall in the French series of GRN mutation carriers, the intrafamilial phenotype seems to have been consistent in the three p.Glu498fs families [8]. Speech production impairment was the first symptom in the English family [6]. Detailed linguistic assessment was not undertaken in the proband of the current report, so it cannot be said whether she had the progranulin-associated phenotype of primary progressive aphasia (impoverished propositional speech, anomia, prolonged wordfinding pauses, impaired speech repetition for sentences, impaired verbal short-term memory) reported by Rohrer et al. [12]. In a cohort of patients with progressive language and speech disorders, agrammatic progressive aphasia was reported to be predictive for FTLDTDP pathology with two-thirds of these patients having GRN mutations [13]. Currently there is no clear explanation for the clinical heterogeneity associated with GRN mutations, nor for MAPT mutations which may also be associated with a variable clinical phenotype (including FTLD, especially fvFTD; CBS; progressive supranuclear palsy; and an amnestic syndrome more suggestive of Alzheimer's disease) [14]. Intrafamilial clinical heterogeneity has also been observed with MAPT mutations [15]. However, unlike the presumed gain of function/toxicity with MAPT mutations, all GRN mutations lead to progranulin haploinsufficiency and hence no genotype/phenotype correlations are anticipated.
The author declares that no competing interests exist. References [1] Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916–9. [2] Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920–4. [3] Alzheimer Disease and Frontotemporal Dementia Mutation Database. http:// www.molgen.ua.ac.be/Admutations (accessed 01/12/11). [4] Seelaar H, Kamphorst W, Rosso SM, Azmani A, Masdjedi R, de Koning I, et al. Distinct genetic forms of frontotemporal dementia. Neurology 2008;71:1220–6. [5] Rohrer JD, Guerriero R, Vandrovcova J, Uphill J, Reiman D, Beck J, et al. The heritability and genetics of frontotemporal lobar degeneration. Neurology 2009;73: 1451–6. [6] Beck J, Rohrer JD, Campbell T, Isaacs A, Morrison KE, Goodall EF, et al. A distinct clinical, neuropsychological and radiological phenotype is associated with progranulin gene mutations in a large UK series. Brain 2008;131:706–20. [7] Pickering-Brown SM, Rollinson S, Du Plessis D, Morrison KE, Varma A, Richardson AM, et al. Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 2008;131:721–31. [8] Le Ber I, Camuzat A, Hannequin D, Pasquier F, Guedj E, Rovelet-Lecrux A, et al. Phenotype variability in progranulin mutation carriers; a clinical, neuropsychological, imaging and genetic study. Brain 2008;131:732–46. [9] Rademakers R, Baker M, Gass J, Adamson J, Huey ED, Momeni P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C>T (Arg493X) mutation: an international initiative. Lancet Neurol 2007;6:857–68. [10] Goldman JS, Farmer JM, Wood EM, Johnson JK, Boxer A, Neuhaus J, et al. Comparison of family histories in FTLD subtypes and related tauopathies. Neurology 2005;65:1817–9. [11] Rohrer JD, Ridgway GR, Modat M, Ourselin S, Mead S, Fox NC, et al. Distinct profiles of brain atrophy in frontotemporal lobar degeneration caused by progranulin and tau mutations. Neuroimage 2010;53:1070–6. [12] Rohrer JD, Crutch SJ, Warrington EK, Warren JD. Progranulin-associated primary progressive aphasia: a distinct phenotype? Neuropsychologia 2010;48:288–97. [13] Deramecourt V, Lebert F, Debachy B, Mackowiak-Cordoliani MA, Bombois S, Kerdraon O, et al. Prediction of pathology in primary progressive language and speech disorders. Neurology 2010;74:42–9. [14] Larner AJ, Doran M. Clinical heterogeneity associated with tau gene mutations. Eur Neurol Rev 2009;3(2):31–2. [15] Larner AJ. Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation. J Neurol Sci 2009;287:253–6. [16] Goldman JS, Rademakers R, Huey ED, Boxer AL, Mayeux R, Miller BL, et al. An algorithm for genetic testing of frontotemporal lobar degeneration. Neurology 2011;76:475–83.