- Email: [email protected]
Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation
Journal of the Neurological Sciences 287 (2009) 253–256
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation A.J. Larner ⁎ Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ, United Kingdom
a r t i c l e
i n f o
Article history: Received 5 May 2009 Received in revised form 31 August 2009 Accepted 31 August 2009 Available online 18 September 2009
a b s t r a c t Two families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) resulting from the microtubule associated protein tau (MAPT) gene IVS10+16C>T splice site mutation are reported, members of which showed variable clinical phenotypes at presentation. Possible explanations for the intraand interfamilial clinical heterogeneity associated with this MAPT mutation are discussed. © 2009 Elsevier B.V. All rights reserved.
Keywords: Diagnosis FTDP-17 Heterogeneity IVS10+16C>T mutation MAPT gene Tauopathy
1. Introduction It is now more than 10 years since the first descriptions of pathogenic mutations within the gene encoding the microtubule associated protein tau (MAPT) as the cause of some cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [1–3]. Over 40 different pathogenic sequence variants have now been described, including splice site and missense mutations and deletions, in both coding regions and introns (OMIM#157140) [4]. With the description of more MAPT gene mutations, clinical and neuropathological heterogeneity of FTDP-17 cases has become increasingly apparent, including cases manifesting with the phenotype of a cognitive disorder (Alzheimer's disease) or a movement disorder (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD]). Both inter- and intrafamilial phenotypic heterogeneities with the same MAPT mutation have been reported on occasion [4,5]. Two further examples of intrafamilial heterogeneity are presented, associated with the MAPT gene splice site IVS10+16C>T mutation [1]. 2. Case reports 2.1. Family 1 In a previously reported pedigree harbouring the IVS10+16C>T mutation, the four observed patients all presented with a clinical phenotype suggestive of early-onset Alzheimer's disease (AD), not frontotem⁎ Tel.: +44 151 529 5727; fax: +44 151 529 8552. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.08.063
poral dementia (FTD; Table 1), diagnosis only being established following neuropathological examination which showed typical tau pathology, and subsequent genetic testing which showed the MAPT mutation in the proband (III.1) [6]. A further member of this family (Fig. 1) has subsequently been seen (patient III.12). He presented at age 54 years with a 3-year history of altered behaviour, including motor restlessness, wandering the streets for many hours each day but always returning, and a change in dietary habits with a predilection for chocolate biscuits. He was increasingly unable to manage his own finances, and recently had been incontinent of both urine and faeces. In the immediate family history, the patient's father (II.4) was said to have suffered from AD, dying at age 53 years (patient not seen at this centre). His brother (III.9) had been assessed some 10 years earlier [6], presenting at age 48 years with a two-year history of difficulty remembering new information, repetitive questioning, inability to perform monetary transactions, and getting lost a short distance from home. His Mini-Mental State Examination (MMSE) score was 26/30 with disorientation in time, impairments of recent memory, naming and visuospatial tasks. Primitive reflexes (grasp, pout, and palmomental) were evident on examination. CT brain scan showed marked atrophy, especially of the temporal lobes. A clinical diagnosis of early-onset familial AD was made; therapeutic trials of cholinesterase inhibitors and memantine were not helpful. He later developed urinary incontinence, became unsettled and made repeated attempts to leave the house and care facilities, and had mild parkinsonian features. He died at the age of 50 years but without neuropathological examination or neurogenetic testing for MAPT mutations. Patient III.12 was assessed with the MMSE and the Addenbrooke's Cognitive Examination—Revised (ACE-R), scoring 20/30 and 49/100,
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A.J. Larner / Journal of the Neurological Sciences 287 (2009) 253–256
Table 1 Prior and current reports of FTDP-17 with IVS10+16C>T mutation. Reference
N; M:F
Age at onset (years)
Pickering-Brown et al. [12]
13 (8 families); M:F 9:4 38 (9 families); M:F 24:14
46–62
Janssen et al. [13]
Morris et al. [15] Stanford et al. [14] Doran et al. [6] + current paper
1 (M) – 5 (all M)
Larner [16]
1 (M)
Larner [17]
1 (M)
Current paper
1 (M)
Clinical phenotype at disease onset and follow up
All showed disinhibition, restless overactivity, fatuous affect, puerile behaviour, verbal and motor stereotypies. Parkinsonism developed in 4. 37–59 (n = 30, M:F 18:12) Disinhibition (23), frontal executive symptoms (2), apathy (2), impaired episodic memory (2), depression (1). Personality and behavioural change developed in all, e.g. ritualistic obsessions (21), hyperorality (14). Parkinsonism developed in 12/23. 40 Sporadic young onset PSP. 54–57 FTDP. 39–46 (“AD”); 50 (behavioural “AD” in 4, all later developed behavioural features; behavioural variant variant frontotemporal dementia) frontotemporal dementia in 1. 56 “AD”; developed behavioural features 3 years later (verbal and motor stereotypies). Family history of “early-onset AD” in two siblings. 48 “AD”; developed PSP features 4 years later. Family history of “early-onset AD” in mother. 45 Parkinsonism. Family history of “frontal lobe dementia” in mother, and “Parkinson's with dementia” in maternal grandmother.
respectively. Examining ACE-R subscores, there were impairments in all areas, the weakest being verbal fluency (1/14, especially phonemic fluency), memory (10/26), and language (15/26). He demonstrated marked anomia with largely phonemic errors on picture naming. Using the Patient Health Questionnaire-9, a measure of depression severity [7], there was no evidence of depression (= 0). On the Informant Questionnaire on Cognitive Decline in the Elderly (range 1–5, lower scores better), completed by his ex-wife who still saw him regularly, his score was 4.07, above the cutoff (3.60) for optimal accuracy for diagnosis of dementia in this clinic [8]. Brain magnetic resonance (MR) imaging showed cerebral atrophy which appeared global, with no focal predominance, with some periventricular white matter change. 1H-MR spectroscopy of normal appearing frontal white matter showed reduced N-acetyl aspartate and raised myoinositol, consistent with gliotic change. Electroencephalography was within normal limits. Genetic testing confirmed the presence of the MAPT IVS10+16C>T mutation, as found in another family member (III.1) with early-onset dementia. However, all previously seen individuals, including the patient's brother, had manifested an AD-like phenotype [6] in contrast to the prototypical FTD phenotype in this individual. 2.2. Family 2 The proband in this family was a 45-year-old man who presented with complaints of poor balance and difficulty concentrating at work, where he was noted to be slow and possibly sometimes slurred in his speech. On examination he had facial hypomimia and bradykinesia but no tremor or rigidity. MR brain imaging was within normal limits. A provisional diagnosis of a parkinsonian syndrome, possibly early Parkinson's disease, was made. Trials of dopamine agonist and of levodopa were without clinical benefit.
In the family history, his mother had a dementia disorder, and his maternal grandmother was said to have had “Parkinson's with dementia” (no further details available). His mother presented at age 64 years to another centre with a 2–3-year history of memory problems. Her neurological examination was normal. On Mental Status Examination she was noted to be mildly disinhibited. Testing cognition, MMSE was 25/30, and on the CAMCOG-R she scored 76/ 105 (below 5th percentile). Individual subtests showed normal attention, orientation, calculation and praxis, but impaired memory (below 25th percentile), especially for remote memory with relative sparing of new learning and recent memory, and of language (below 25th percentile), especially naming and expressive fluency. CT brain imaging showed marked atrophy, especially in the frontal and temporal lobes. A diagnosis of “frontal lobe dementia” was made. In light of the family history, the proband was referred for cognitive assessment. On MMSE and ACE-R he scored 28/30 and 93/100, respectively, indicating no dementia [9]. Formal neuropsychological assessment was unremarkable: there was no evidence for decline in intellectual function (WTAR predicted FSIQ 105; WASI FSIQ 106). Looking specifically at frontal lobe function using the Delis–Kaplan Executive Functioning System, he performed in the average range on Trail Making Test, Colour Word Interference Test, and letter fluency, but was borderline on category fluency. Hayling Sentence Completion Test and Brixton Spatial Anticipation Test were both within normal limits. The Test of Everyday Attention was normal on tasks examining divided attention but impaired on sustained attention. No significant changes were observed on repeat testing with the same instruments 1 year later. By this time his neurological examination revealed slow voluntary saccades and reduced arm swing when walking but still no rigidity was apparent. On the Frontal Assessment Battery he scored 18/18 (cutoff score < 12/18 discriminates FTD [10]).
Fig. 1. Pedigree of Family 1, extended from that previously reported [6].
A.J. Larner / Journal of the Neurological Sciences 287 (2009) 253–256
In view of the family history, genetic testing had already been undertaken for Huntington's disease and spinocerebellar atrophy type 3, both negative. Sequencing of the MAPT gene identified the IVS10+ 16C>T splice site mutation. 3. Discussion The current cases show that intrafamilial heterogeneity may be encountered with the MAPT IVS10+16C>T mutation. The presenting phenotypes were AD and FTD in Family 1, and FTD and isolated parkinsonism in Family 2, although subtle cognitive dysfunction was found in the non-demented patient (reduced category fluency, impaired sustained attention). Cognitive deficits preceding dementia by decades have been reported in individuals from FTDP-17 pedigrees harbouring MAPT mutations [11]. Previous reports of pedigrees with the MAPT IVS10+16C>T mutation (Table 1) have emphasised the clinical features typical of FTD [12–14]. One other report presented a patient with sporadic young onset PSP [15]. From this centre, there have been prior reports of cases presenting with an AD-like phenotype [6,16], one evolving over 4 years to a PSP-like phenotype [17]. Hence, there is clearly interfamilial phenotypic variability associated with the IVS10+16C>T mutation. Intrafamilial clinical phenotypic heterogeneity has also been reported with other MAPT mutations [5]: PSP or idiopathic Parkinson's disease (ΔN296) [18], FTD or CBD (P301S) [19,20], and parkinsonism or behavioural change (P301L) [21]. Currently there is no clear explanation for the clinical heterogeneity associated with MAPT mutations. Genotypic alterations correlate poorly with the variable phenotype. It has been said that the overproduction of 4R tau isoforms with mutations that affect exon 10 splicing may be associated with more prominent parkinsonian symptoms, whilst mutations not affecting exon 10 are more frequently associated with dementia-prominent forms. Age at onset might be significant. In Family 1, mean age at onset was 42 years in the patients presenting with AD-like phenotype [6], but about 50 years in the patient reported here with FTD phenotype, and in Family 2 the proband presented with a parkinsonian syndrome in the 5th decade whereas his mother had presented with dementia in the 7th decade. Apolipoprotein E genotype does not appear to affect age of dementia onset in families with tau mutations [22], unlike the situation in AD, but possession of an apolipoprotein E ε4 allele has been associated with deposition of Aβ deposits in frontal cortex in patients with frontotemporal lobar degeneration [23], an observation which might be relevant to the AD-like phenotype seen with some MAPT mutations. Aβ burden has been suggested to modify clinical features in FTD [24]. The two common tau haplotypes, H1 and H2, do not affect age at symptomatic onset or disease duration, but may be associated with either the parkinsonian (H1/H1 genotype) or FTD (H1/H2 genotype) phenotype, suggesting that tau genotype may predispose to specific clinical signs at disease onset [25]. In two P301L patients with different phenotypes, differences in tau haplotype were observed, which might possibly have been the factor modifying the phenotype [21]. However, given that all our patients originate from the same geographical region, the odds of the mutation arising de novo in the different families is highly unlikely, and the finding of a highly conserved 17q21 haplotype on analysis of eight other families with the IVS10+16C>T mutation from this region [12] suggested a founder effect [26]. A more recent analysis of more families with this mutation from the UK, Australia and USA has suggested a common ancestor of Welsh origin [27]. Expression of clinical phenotype may require the combination of the specific mutation and other risk alleles. The clinical heterogeneity associated with the IVS10+16C>T mutation might be further elucidated by study of H1/H2 haplotypes which might have haplotype-specific effects upon tau transcript splicing. In addition, other risk alleles, potential modifier genes and polymorphisms in patients and family
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control populations might be investigated to search for epistatic mechanisms (synergy, masking). Genome-wide studies might be helpful in identifying additional genetic risk factors. Pragmatically, a family history of dementia suggestive of autosomal dominant transmission (meaning at least 3 affected individuals in at least 2 generations) is the most important factor in determining whether genetic testing should be undertaken. MAPT gene analysis should be considered in individuals with a phenotype suggestive of early-onset familial AD but who prove negative for mutations in other genes (Amyloid Precursor Protein, Presenilin-1, and Presenilin-2) known to be deterministic for AD, as shown in Family 1 and elsewhere [16]. Likewise, MAPT gene analysis should be considered if multiple family members have neurodegenerative disease but different phenotypes, including FTD, as in Family 2. Progranulin gene testing may also be considered in this latter situation, since mutations seem to occur at a similar frequency to MAPT mutations in large cohorts of patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration [28]. However, family history of dementia is not always present in progranulin cases, unlike MAPT. Moreover, disease onset is later, and certain phenotypic features (progressive nonfluent aphasia, limb apraxia) are more common [28]. References [1] Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5′ splice site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–5. [2] Poorkaj P, Bird T, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43:815–25. [3] Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:7737–41. [4] Alzheimer disease and frontotemporal dementia mutation database. http://www. molgen.ua.ac.be/Admutations (accessed 01/07/09). [5] Larner AJ, Doran M. Clinical heterogeneity associated with tau gene mutations. European Neurological Review 2009;3(2):31–2. [6] Doran M, Du Plessis DG, Ghadiali EJ, Mann DMA, Pickering-Brown S, Larner AJ. Alzheimer's disease-like presentation of familial early-onset dementia with tau intron 10+ 16 mutation. Arch Neurol 2007;64:1535–9. [7] Hancock P, Larner AJ. Clinical utility of Patient Health Questionnaire-9 (PHQ-9) in memory clinics. Int J Psychiatry Clin Practice 2009;13:188–91. [8] Hancock P, Larner AJ. Diagnostic utility of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and its combination with the Addenbrooke's Cognitive Examination—Revised (ACE-R) in a memory clinicbased population. Int Psychogeriatr 2009;21:526–30. [9] Larner AJ. Addenbrooke's Cognitive Examination—Revised (ACE-R) in day-to-day clinical practice. Age Ageing 2007;36:685–6. [10] Slachevsky A, Villalpando JM, Sarazin M, Hahn-Barma V, Pillon B, Dubois B. Frontal Assessment Battery and differential diagnosis of frontotemporal dementia and Alzheimer disease. Arch Neurol 2004;61:1104–7. [11] Geschwind DH, Robidoux J, Alarcón M, et al. Dementia and neurodevelopmental predisposition: cognitive dysfunction in presymptomatic subjects precedes dementia by decades in frontotemporal dementia. Ann Neurol 2001;50:741–6. [12] Pickering-Brown SM, Richardson AMT, Snowden JS, et al. Inherited frontotemporal dementia in nine British families associated with intronic mutations in the tau gene. Brain 2002;125:732–51. [13] Janssen JC, Warrington EK, Morris HR, et al. Clinical features of frontotemporal dementia due to the intronic tau 10+ 16 mutation. Neurology 2002;58:1161–8. [14] Stanford PM, Brooks WS, Teber ET, et al. Frequency of tau mutations in familial and sporadic frontotemporal dementia and other tauopathies. J Neurol 2004;251: 1098–104. [15] Morris HR, Osaki Y, Holton J, et al. Tau exon 10+ 16 mutation FTDP-17 presenting clinically as sporadic young onset PSP. Neurology 2003;61:102–4. [16] Larner AJ. Mutation negative “early-onset familial Alzheimer's disease”: consider screening for tau gene mutations. Alzheimer Dis Assoc Disord 2008;22:194–5. [17] Larner AJ. A 50-year old man with deteriorating cognitive function and impaired movement. PLoS Medicine 2009;6(1):e19. [18] Pastor P, Pastor E, Carnero C, et al. Familial atypical progressive supranuclear palsy associated with homozygosity for the delN296 mutation in the tau gene. Ann Neurol 2001;49:263–7. [19] Bugiani O, Murrell JR, Giaccone G, et al. Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in Tau. J Neuropathol Exp Neurol 1999;58:667–77. [20] Casseron W, Azulay JP, Guedj E, Gastaut JL, Pouget J. Familial autosomal dominant cortico-basal degeneration with the P301S mutation in the tau gene: an example of phenotypic variability. J Neurol 2005;252:1546–8. [21] Kobayashi T, Mori H, Okuma Y, et al. Contrasting genotypes of the tau gene in two phenotypically distinct patients with P301L mutation of frontotemporal dementia and parkinsonism linked to chromosome 17. J Neurol 2002;249:669–75.
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[22] Houlden H, Rizzu P, Stevens M, et al. Apolipoprotein E genotype does not affect the age of onset of dementia in families with defined tau mutations. Neurosci Lett 1999;260:193–5. [23] Mann DM, McDonagh AM, Pickering-Brown SM, Kowa H, Iwatsubo T. Amyloid beta protein deposition in patients with frontotemporal lobar degeneration: relationship to age and apolipoprotein E genotype. Neurosci Lett 2001;304:161–4. [24] Ishii K, Ishiwata K, Oda K, et al. Does amyloid-β accumulation modify clinical features of frontotemporal dementia? Alzheimer's & Dementia 2008;4(Suppl2): T288–9 abstract P1-250. [25] Baba Y, Tsuboi Y, Baker MC, et al. The effect of tau genotype on clinical features in FTDP-17. Parkinsonism Relat Disord 2005;11:205–8.
[26] Pickering-Brown SM, Baker M, Bird T, et al. Evidence of a founder effect in families with frontotemporal dementia that harbour the tau + 16 splice mutation. Am J Med Genet 2004;125B:79–82. [27] 27. Colombo R, Tavian D, Baker MC et al. Recent origin and spread of a common Welsh MAPT splice mutation causing frontotemporal lobar degeneration. Neurogenetics 2009 [Epub ahead of print]. [28] Pickering-Brown SM, Rollinson S, Du Plessis D, 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.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short communication
Intrafamilial clinical phenotypic heterogeneity with MAPT gene splice site IVS10+16C>T mutation A.J. Larner ⁎ Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, L9 7LJ, United Kingdom
a r t i c l e
i n f o
Article history: Received 5 May 2009 Received in revised form 31 August 2009 Accepted 31 August 2009 Available online 18 September 2009
a b s t r a c t Two families with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) resulting from the microtubule associated protein tau (MAPT) gene IVS10+16C>T splice site mutation are reported, members of which showed variable clinical phenotypes at presentation. Possible explanations for the intraand interfamilial clinical heterogeneity associated with this MAPT mutation are discussed. © 2009 Elsevier B.V. All rights reserved.
Keywords: Diagnosis FTDP-17 Heterogeneity IVS10+16C>T mutation MAPT gene Tauopathy
1. Introduction It is now more than 10 years since the first descriptions of pathogenic mutations within the gene encoding the microtubule associated protein tau (MAPT) as the cause of some cases of frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) [1–3]. Over 40 different pathogenic sequence variants have now been described, including splice site and missense mutations and deletions, in both coding regions and introns (OMIM#157140) [4]. With the description of more MAPT gene mutations, clinical and neuropathological heterogeneity of FTDP-17 cases has become increasingly apparent, including cases manifesting with the phenotype of a cognitive disorder (Alzheimer's disease) or a movement disorder (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD]). Both inter- and intrafamilial phenotypic heterogeneities with the same MAPT mutation have been reported on occasion [4,5]. Two further examples of intrafamilial heterogeneity are presented, associated with the MAPT gene splice site IVS10+16C>T mutation [1]. 2. Case reports 2.1. Family 1 In a previously reported pedigree harbouring the IVS10+16C>T mutation, the four observed patients all presented with a clinical phenotype suggestive of early-onset Alzheimer's disease (AD), not frontotem⁎ Tel.: +44 151 529 5727; fax: +44 151 529 8552. E-mail address: [email protected]. 0022-510X/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2009.08.063
poral dementia (FTD; Table 1), diagnosis only being established following neuropathological examination which showed typical tau pathology, and subsequent genetic testing which showed the MAPT mutation in the proband (III.1) [6]. A further member of this family (Fig. 1) has subsequently been seen (patient III.12). He presented at age 54 years with a 3-year history of altered behaviour, including motor restlessness, wandering the streets for many hours each day but always returning, and a change in dietary habits with a predilection for chocolate biscuits. He was increasingly unable to manage his own finances, and recently had been incontinent of both urine and faeces. In the immediate family history, the patient's father (II.4) was said to have suffered from AD, dying at age 53 years (patient not seen at this centre). His brother (III.9) had been assessed some 10 years earlier [6], presenting at age 48 years with a two-year history of difficulty remembering new information, repetitive questioning, inability to perform monetary transactions, and getting lost a short distance from home. His Mini-Mental State Examination (MMSE) score was 26/30 with disorientation in time, impairments of recent memory, naming and visuospatial tasks. Primitive reflexes (grasp, pout, and palmomental) were evident on examination. CT brain scan showed marked atrophy, especially of the temporal lobes. A clinical diagnosis of early-onset familial AD was made; therapeutic trials of cholinesterase inhibitors and memantine were not helpful. He later developed urinary incontinence, became unsettled and made repeated attempts to leave the house and care facilities, and had mild parkinsonian features. He died at the age of 50 years but without neuropathological examination or neurogenetic testing for MAPT mutations. Patient III.12 was assessed with the MMSE and the Addenbrooke's Cognitive Examination—Revised (ACE-R), scoring 20/30 and 49/100,
254
A.J. Larner / Journal of the Neurological Sciences 287 (2009) 253–256
Table 1 Prior and current reports of FTDP-17 with IVS10+16C>T mutation. Reference
N; M:F
Age at onset (years)
Pickering-Brown et al. [12]
13 (8 families); M:F 9:4 38 (9 families); M:F 24:14
46–62
Janssen et al. [13]
Morris et al. [15] Stanford et al. [14] Doran et al. [6] + current paper
1 (M) – 5 (all M)
Larner [16]
1 (M)
Larner [17]
1 (M)
Current paper
1 (M)
Clinical phenotype at disease onset and follow up
All showed disinhibition, restless overactivity, fatuous affect, puerile behaviour, verbal and motor stereotypies. Parkinsonism developed in 4. 37–59 (n = 30, M:F 18:12) Disinhibition (23), frontal executive symptoms (2), apathy (2), impaired episodic memory (2), depression (1). Personality and behavioural change developed in all, e.g. ritualistic obsessions (21), hyperorality (14). Parkinsonism developed in 12/23. 40 Sporadic young onset PSP. 54–57 FTDP. 39–46 (“AD”); 50 (behavioural “AD” in 4, all later developed behavioural features; behavioural variant variant frontotemporal dementia) frontotemporal dementia in 1. 56 “AD”; developed behavioural features 3 years later (verbal and motor stereotypies). Family history of “early-onset AD” in two siblings. 48 “AD”; developed PSP features 4 years later. Family history of “early-onset AD” in mother. 45 Parkinsonism. Family history of “frontal lobe dementia” in mother, and “Parkinson's with dementia” in maternal grandmother.
respectively. Examining ACE-R subscores, there were impairments in all areas, the weakest being verbal fluency (1/14, especially phonemic fluency), memory (10/26), and language (15/26). He demonstrated marked anomia with largely phonemic errors on picture naming. Using the Patient Health Questionnaire-9, a measure of depression severity [7], there was no evidence of depression (= 0). On the Informant Questionnaire on Cognitive Decline in the Elderly (range 1–5, lower scores better), completed by his ex-wife who still saw him regularly, his score was 4.07, above the cutoff (3.60) for optimal accuracy for diagnosis of dementia in this clinic [8]. Brain magnetic resonance (MR) imaging showed cerebral atrophy which appeared global, with no focal predominance, with some periventricular white matter change. 1H-MR spectroscopy of normal appearing frontal white matter showed reduced N-acetyl aspartate and raised myoinositol, consistent with gliotic change. Electroencephalography was within normal limits. Genetic testing confirmed the presence of the MAPT IVS10+16C>T mutation, as found in another family member (III.1) with early-onset dementia. However, all previously seen individuals, including the patient's brother, had manifested an AD-like phenotype [6] in contrast to the prototypical FTD phenotype in this individual. 2.2. Family 2 The proband in this family was a 45-year-old man who presented with complaints of poor balance and difficulty concentrating at work, where he was noted to be slow and possibly sometimes slurred in his speech. On examination he had facial hypomimia and bradykinesia but no tremor or rigidity. MR brain imaging was within normal limits. A provisional diagnosis of a parkinsonian syndrome, possibly early Parkinson's disease, was made. Trials of dopamine agonist and of levodopa were without clinical benefit.
In the family history, his mother had a dementia disorder, and his maternal grandmother was said to have had “Parkinson's with dementia” (no further details available). His mother presented at age 64 years to another centre with a 2–3-year history of memory problems. Her neurological examination was normal. On Mental Status Examination she was noted to be mildly disinhibited. Testing cognition, MMSE was 25/30, and on the CAMCOG-R she scored 76/ 105 (below 5th percentile). Individual subtests showed normal attention, orientation, calculation and praxis, but impaired memory (below 25th percentile), especially for remote memory with relative sparing of new learning and recent memory, and of language (below 25th percentile), especially naming and expressive fluency. CT brain imaging showed marked atrophy, especially in the frontal and temporal lobes. A diagnosis of “frontal lobe dementia” was made. In light of the family history, the proband was referred for cognitive assessment. On MMSE and ACE-R he scored 28/30 and 93/100, respectively, indicating no dementia [9]. Formal neuropsychological assessment was unremarkable: there was no evidence for decline in intellectual function (WTAR predicted FSIQ 105; WASI FSIQ 106). Looking specifically at frontal lobe function using the Delis–Kaplan Executive Functioning System, he performed in the average range on Trail Making Test, Colour Word Interference Test, and letter fluency, but was borderline on category fluency. Hayling Sentence Completion Test and Brixton Spatial Anticipation Test were both within normal limits. The Test of Everyday Attention was normal on tasks examining divided attention but impaired on sustained attention. No significant changes were observed on repeat testing with the same instruments 1 year later. By this time his neurological examination revealed slow voluntary saccades and reduced arm swing when walking but still no rigidity was apparent. On the Frontal Assessment Battery he scored 18/18 (cutoff score < 12/18 discriminates FTD [10]).
Fig. 1. Pedigree of Family 1, extended from that previously reported [6].
A.J. Larner / Journal of the Neurological Sciences 287 (2009) 253–256
In view of the family history, genetic testing had already been undertaken for Huntington's disease and spinocerebellar atrophy type 3, both negative. Sequencing of the MAPT gene identified the IVS10+ 16C>T splice site mutation. 3. Discussion The current cases show that intrafamilial heterogeneity may be encountered with the MAPT IVS10+16C>T mutation. The presenting phenotypes were AD and FTD in Family 1, and FTD and isolated parkinsonism in Family 2, although subtle cognitive dysfunction was found in the non-demented patient (reduced category fluency, impaired sustained attention). Cognitive deficits preceding dementia by decades have been reported in individuals from FTDP-17 pedigrees harbouring MAPT mutations [11]. Previous reports of pedigrees with the MAPT IVS10+16C>T mutation (Table 1) have emphasised the clinical features typical of FTD [12–14]. One other report presented a patient with sporadic young onset PSP [15]. From this centre, there have been prior reports of cases presenting with an AD-like phenotype [6,16], one evolving over 4 years to a PSP-like phenotype [17]. Hence, there is clearly interfamilial phenotypic variability associated with the IVS10+16C>T mutation. Intrafamilial clinical phenotypic heterogeneity has also been reported with other MAPT mutations [5]: PSP or idiopathic Parkinson's disease (ΔN296) [18], FTD or CBD (P301S) [19,20], and parkinsonism or behavioural change (P301L) [21]. Currently there is no clear explanation for the clinical heterogeneity associated with MAPT mutations. Genotypic alterations correlate poorly with the variable phenotype. It has been said that the overproduction of 4R tau isoforms with mutations that affect exon 10 splicing may be associated with more prominent parkinsonian symptoms, whilst mutations not affecting exon 10 are more frequently associated with dementia-prominent forms. Age at onset might be significant. In Family 1, mean age at onset was 42 years in the patients presenting with AD-like phenotype [6], but about 50 years in the patient reported here with FTD phenotype, and in Family 2 the proband presented with a parkinsonian syndrome in the 5th decade whereas his mother had presented with dementia in the 7th decade. Apolipoprotein E genotype does not appear to affect age of dementia onset in families with tau mutations [22], unlike the situation in AD, but possession of an apolipoprotein E ε4 allele has been associated with deposition of Aβ deposits in frontal cortex in patients with frontotemporal lobar degeneration [23], an observation which might be relevant to the AD-like phenotype seen with some MAPT mutations. Aβ burden has been suggested to modify clinical features in FTD [24]. The two common tau haplotypes, H1 and H2, do not affect age at symptomatic onset or disease duration, but may be associated with either the parkinsonian (H1/H1 genotype) or FTD (H1/H2 genotype) phenotype, suggesting that tau genotype may predispose to specific clinical signs at disease onset [25]. In two P301L patients with different phenotypes, differences in tau haplotype were observed, which might possibly have been the factor modifying the phenotype [21]. However, given that all our patients originate from the same geographical region, the odds of the mutation arising de novo in the different families is highly unlikely, and the finding of a highly conserved 17q21 haplotype on analysis of eight other families with the IVS10+16C>T mutation from this region [12] suggested a founder effect [26]. A more recent analysis of more families with this mutation from the UK, Australia and USA has suggested a common ancestor of Welsh origin [27]. Expression of clinical phenotype may require the combination of the specific mutation and other risk alleles. The clinical heterogeneity associated with the IVS10+16C>T mutation might be further elucidated by study of H1/H2 haplotypes which might have haplotype-specific effects upon tau transcript splicing. In addition, other risk alleles, potential modifier genes and polymorphisms in patients and family
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control populations might be investigated to search for epistatic mechanisms (synergy, masking). Genome-wide studies might be helpful in identifying additional genetic risk factors. Pragmatically, a family history of dementia suggestive of autosomal dominant transmission (meaning at least 3 affected individuals in at least 2 generations) is the most important factor in determining whether genetic testing should be undertaken. MAPT gene analysis should be considered in individuals with a phenotype suggestive of early-onset familial AD but who prove negative for mutations in other genes (Amyloid Precursor Protein, Presenilin-1, and Presenilin-2) known to be deterministic for AD, as shown in Family 1 and elsewhere [16]. Likewise, MAPT gene analysis should be considered if multiple family members have neurodegenerative disease but different phenotypes, including FTD, as in Family 2. Progranulin gene testing may also be considered in this latter situation, since mutations seem to occur at a similar frequency to MAPT mutations in large cohorts of patients fulfilling clinical diagnostic criteria for frontotemporal lobar degeneration [28]. However, family history of dementia is not always present in progranulin cases, unlike MAPT. Moreover, disease onset is later, and certain phenotypic features (progressive nonfluent aphasia, limb apraxia) are more common [28]. References [1] Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5′ splice site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–5. [2] Poorkaj P, Bird T, Wijsman E, et al. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43:815–25. [3] Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci USA 1998;95:7737–41. [4] Alzheimer disease and frontotemporal dementia mutation database. http://www. molgen.ua.ac.be/Admutations (accessed 01/07/09). [5] Larner AJ, Doran M. Clinical heterogeneity associated with tau gene mutations. European Neurological Review 2009;3(2):31–2. [6] Doran M, Du Plessis DG, Ghadiali EJ, Mann DMA, Pickering-Brown S, Larner AJ. Alzheimer's disease-like presentation of familial early-onset dementia with tau intron 10+ 16 mutation. Arch Neurol 2007;64:1535–9. [7] Hancock P, Larner AJ. Clinical utility of Patient Health Questionnaire-9 (PHQ-9) in memory clinics. Int J Psychiatry Clin Practice 2009;13:188–91. [8] Hancock P, Larner AJ. Diagnostic utility of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) and its combination with the Addenbrooke's Cognitive Examination—Revised (ACE-R) in a memory clinicbased population. Int Psychogeriatr 2009;21:526–30. [9] Larner AJ. Addenbrooke's Cognitive Examination—Revised (ACE-R) in day-to-day clinical practice. 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