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Age-related Neurodegenerative Disease Alzheimer’s Disease
Clinical Heterogeneity Associated with Tau Gene Mutations
a report by
AJ Larner and M Doran
Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool
It is now 10 years since the first descriptions of pathogenic mutations 10+16.
9–15
The PSP phenotype may be typical (i.e. conforming to widely
within the gene encoding the microtubule-associated protein tau accepted clinical research criteria for PSP) or atypical (e.g. absence of falls
(MAPT).
1–3
Over 60 different sequence variants have now been described, in the first year after symptom onset),
14
and cases may be familial or
including splice-site and missense mutations and deletions, in both sporadic. In some cases, dementia has been late or questionable.
15
In one
coding regions and introns, over 40 of which are thought to be family, atypical PSP was associated with a homozygous mutation
pathogenic.
4
Prior to the identification of MAPT mutations, the umbrella (∆N296), and typical levodopa-responsive Parkinson’s disease was
term ‘frontotemporal dementia with parkinsonism linked to chromosome observed in other family members with the heterozygous mutation.
11
17’ (FTDP-17) had been coined to describe autosomal-dominant kindreds
linked to chromosome 17q21-22 with a highly penetrant disorder Corticobasal Degeneration
characterised clinically by a phenotype of frontotemporal dementia and The phenotype of corticobasal degeneration (CBD) has been described in
parkinsonism.
5
The FTDP-17 nomenclature superseded the various clinical association with the P301S and G389R MAPT mutations.
16–18
In the initial
and clinicopathological labels previously applied to some of these report, two family members carried the mutant P301S gene: a father with
kindreds, which included disinhibition–dementia–parkinsonism– FTD and his son with CBD, both with age at onset in the late 20s.
16
In a
amyotrophy complex, hereditary dysphasic disinhibition dementia, Jewish-Algerian family with the same P301S mutation, cases with the
pallido-ponto-nigral degeneration, progressive subcortical gliosis and typical FTDP-17 and CBD phenotypes were described; one patient with
multiple system tauopathy with pre-senile dementia. CBD was levodopa-responsive.
17
The G389R mutation, previously
described in FTD cases, was found in a patient with sporadic corticobasal
With the description of more MAPT mutations, the clinical and syndrome (no pathology available); his asymptomatic 87-year-old father
neuropathological heterogeneity of FTDP-17 cases has become also carried the same mutation, suggesting incomplete penetrance.
18
increasingly apparent. An awareness of this clinical heterogeneity may be
of importance to neurologists managing patients with neurodegenerative Idiopathic Parkinson’s Disease
disease, informing differential diagnostic considerations and the need for Cases diagnosed clinically as idiopathic Parkinson’s disease (PD)
tau gene mutation testing. A brief review of clinical variants associated but harbouring MAPT mutations have been reported on occasion
with MAPT mutations may therefore be of pragmatic use; (∆N296, Q424K).
4,11
neuropathological features are not considered in this article, since these
are generally available only post mortem and are hence of limited use in Alzheimer’s Disease
clinical practice. Alzheimer’s disease (AD) is the most common cause of a dementia
syndrome. Although it is generally straightforward to distinguish AD
Clinical Phenotypes of MAPT Mutations from the canonical forms of FTD, differential diagnosis is not always
The ‘classic’ or ‘prototypical’ phenotype associated with MAPT easy since widely accepted clinical diagnostic criteria for AD and FTD
mutations is a frontotemporal dementia syndrome with altered show some overlap. Patients clinically diagnosed with AD who were
behaviour and personality, with additional parkinsonian features, hence subsequently found to have FTDP-17 with MAPT mutations have been
‘FTDP’. Either the cognitive syndrome or the movement disorder may be reported, with the P301L, IVS10+16 and R406W mutations.
19–24
A
more clinically evident. Prominent early epileptic seizures have been patient with an AD phenotype who subsequently developed a PSP
reported on occasion.
6
phenotype, leading to identification of the MAPT IVS10+16 mutation,
has also been seen (Larner, unpublished observations). The
The frequency with which tau mutations are identified in FTD patients ∆K280/∆K281 sequence change has also been reported in a patient
varies depending on the source of the cohort examined, ranging from
none in a community-based dementia series, to around 10% in cases of
AJ Larner works in the Cognitive Function Clinic at the
familial FTD, to 33% in familial FTD with confirmed tau pathology.
7,8
Walton Centre for Neurology and Neurosurgery in
Phenotypes other than FTDP have also been described in association with
Liverpool. A consultant neurologist with an interest in
cognitive disorders, his main interests are in the clinical
MAPT mutations.
phenomenology of dementia syndromes, particularly in
relation to genetic mutations in the tau and presenilin-1
Progressive Supranuclear Palsy
genes, and also in the pragmatic assessment of cognitive and
behavioural rating scales used in the diagnosis of dementia.
There have been a number of reports of patients with a phenotype of
progressive supranuclear palsy (PSP) who are shown to harbour MAPT
E:
a.larner@thewaltoncentre.nhs.uk
mutations, including R5L, N279K, ∆N296, G303V, S305S and IVS
© TOUCH BRIEFINGS 2008 31
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