Clinical Diagnosis

MAPT mutations are mainly found in individuals with typical frontotemporal dementia (FTDP-17); however, the identification of MAPT mutations in individuals with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), mild late-onset parkinsonism, and dementia with epilepsy suggests that FTDP-17 is part of a larger spectrum of tauopathies [Kertesz 2003]. The definitive diagnosis of a MAPT- related disorder (MAPT-related tauopathy) relies on demonstration of a disease-causing mutation in the MAPT gene, encoding the protein tau.

The diagnosis of FTDP-17 is supported by the presence of the following [Neary et al 1998]:

• Clinical features of frontotemporal dementia and/or parkinsonism

• Frontal and/or temporal pathology on neuroimaging:

  • Computed tomography (CT) or magnetic resonance imaging (MRI) typically shows frontal and/or temporal atrophy, but may be initially normal. Cortical atrophy and ventricular enlargement may be asymmetric; severity increases over time [Foster et al 1997, van Swieten et al 1999].

  • Single-photon emission computed tomography (SPECT) shows decreased cerebral perfusion anteriorly that is present early in the disease, preceding CT or MRI findings.

  • Positron emission tomography with ¹⁸F-fluorodeoxyglucose (FDG-PET) shows frontotemporal hypometabolism, distinguishing it from other neurodegenerative disorders such as Alzheimer disease [Foster 2007].

  • Striatal uptake of ¹⁸F-fluoro-L-dopa is reduced in individuals with early parkinsonism [Wszolek et al 1992].

• Family history of dementia and/or parkinsonism in two or more first-degree relatives consistent with autosomal dominant inheritance

• Presence of tau-positive neuronal inclusions in affected brain regions on immunohistochemistry

In most cases, persons with a MAPT mutation have multiple affected first-degree relatives.

Molecular Genetic Testing

Gene. MAPT gene encoding the tau protein is the only gene known to be associated with hereditary tauopathies.

Clinical testing

• Sequence analysis of select gene regions. Sequence analysis of exons 1 and 9 through 13 and their associated intronic sequences are typically offered; although some laboratories may perform analysis of additional exons.

• Sequence analysis. Most mutations are localized in and around the microtubule binding domains in exons 9 through 13. Additional mutations are present in the 5' part of the intron following exon 10, which affect the alternative splicing of exon 10. The only mutations that have been found in exon 1 are p.Arg5His [Hayashi et al 2002] and p.Arg5Leu [Poorkaj et al 2002].

• Deletion/duplication analysis: So far, only one individual with FTD has been described with a partial deletion of MAPT, encompassing exons 6 to 9, resulting in both loss of function as well as gain of toxicity of the truncated tau protein product [Rovelet-Lecrux et al 2009]. As this is the first case, the frequency of exonic and whole-gene deletions appears low.

Table 1. Summary of Molecular Genetic Testing Used in MAPT-Related Disorders

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
MAPT	Sequence analysis of select exons	Mutations in exons 1 and 9-13 and flanking intron regions 2	Unknown, depends on type of cohort tested. Frequency range: 1%-10%	Clinical
	Sequence analysis	Sequence variants 3	Unknown
	Deletion/duplication analysis 4	Exonic or whole-gene deletions	Unknown, but presumed to be low

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Most mutations are located in exons 9 through 13. Selected exons sequenced may vary between laboratories.

3. Examples of sequence variants detected by sequence analysis include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

If testing of a proband identifies a previously reported mutation for which additional studies have demonstrated its pathogenicty, then the diagnosis of a MAPT-related disorder is established.

In cases in which previously unidentified sequence variants are reported, further evidence is needed to determine if the variant is pathologic. For instance segregation analysis, healthy control panels, and/or functional assays (e.g., microtubule assembly rates).

Testing Strategy

To confirm/establish the diagnosis in a proband it is necessary to identify a mutation in MAPT using molecular genetic testing. Molecular genetic testing should be considered in persons with the phenotypes associated with a MAPT-related disorders and a positive family history of dementia and/or parkinsonism.

The order of sequence analysis should depend on the prevalence of mutations in the geographic region from which the proband originates.

• In general, most MAPT mutations cluster around exon 10 and the flanking intron region (and thus can be detected by sequence analysis of select exons).

• If this approach does not identify a mutation, MAPT sequence analysis should be extended to exons 9 through 13 and finally exon 1.

• It is unlikely that any mutations are to be found in the remainder of the gene. However, if there is a clear family history and evident tauopathy, sequence analysis of the entire MAPT gene and/or deletion/duplication analysis may be considered.

Note: (1) Mutations in MAPT are rare in simplex cases of frontotemporal dementia (i.e., a single occurrence in a family) [Houlden et al 1999, Rizzu et al 1999, Stanford et al 2000, Poorkaj et al 2001], with frequencies ranging from 0% to 4% of individuals in population-based samples. (2) The occurrence of de novo mutations has been confirmed [Boeve et al 2005].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with mutations in MAPT.

A common microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability [Koolen et al 2006, Shaw-Smith et al 2006].

Natural History

Although MAPT mutations are mainly found in individuals with typical frontotemporal dementia (FTDP-17), the identification of MAPT mutations in individuals with progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), mild late-onset parkinsonism, and dementia with epilepsy suggests that FTDP-17 is part of a larger spectrum of tauopathies [Kertesz 2003].

Genotype-Phenotype Correlations

Clinical presentation and neuropathologic changes vary widely according to the localization of the mutations within MAPT. Even intrafamilial variation exists, suggesting that other genetic or environmental factors influence the disease process. For instance, in a kindred with the p.Pro301Ser mutation a father presented with FTD and son with CBD [Bugiani et al 1999].

• The p.Pro301Ser mutation is significantly associated with an early onset between ages 20 and 40 years [Lossos et al 2003] and the occurrence of epileptic seizures or myoclonus [Bugiani et al 1999, Sperfeld et al 1999].

• A longer duration (up to 20 to 30 years) is associated with the p.Arg406Trp mutation [Reed et al 1997, van Swieten et al 1999, Ostojic et al 2004] and a clinical phenotype similar to Alzheimer disease [Rademakers et al 2003].

• Early parkinsonism and progressive supranuclear palsy are mainly encountered in individuals with the splice donor site mutations p.Asn279Lys, delK280, and p.Ser305Asn; they have also been described with homozygosity for the p.Asn296del mutation [Delisle et al 1999, Stanford et al 2000, Pastor et al 2001, Soliveri et al 2003].

• Neurofibrillary tangles (NFT) or tau-positive pretangles in neurons and tau deposits in glial cells are found in individuals with coding mutations in exons 9 and 10 and splice donor site mutations [Spillantini et al 1997, Spillantini et al 1998]. Individuals with the p.Val337Met and p.Arg406Trp mutations (in exons 12 and 13) show NFT in the absence of glial inclusions [Reed et al 1998, van Swieten et al 1999].

• Motor neuron disease occurred in a family with the c.1883+14C>T mutation and in the p.Lys317Met tau mutation [Zarranz et al 2005].

• Psychosis has been noted in several families, especially the single kindred with the p.Val337Met mutation [Poorkaj et al 1998].

Penetrance

The p.Leu315Arg mutation has been identified in individuals with FTDP-17 as well as in their unaffected parents, suggesting non-penetrance for this mutation in some individuals [van Herpen et al 2003].

Homozygosity for the p.Asn296del mutation was found in a person with atypical progressive supranuclear palsy. Among the heterozygous individuals in this family, two with probable Parkinson disease were identified, but none of heterozygotes developed atypical parkinsonism [Pastor et al 2001].

Asymptomatic individuals heterozygous for the p.Asn296del were also described by Rosso et al [2001].

Anticipation

No evidence for anticipation exists in the MAPT-related disorders.

Nomenclature

The etiologic role of the MAPT gene was suspected for the first time when a family with so-called dementia-disinhibition-parkinsonism-amyotrophy complex (DDPAC) showed significant linkage to the MAPT gene-containing region on chromosome 17q21-22 [Wilhelmsen et al 1994]. Subsequently, this linkage was confirmed for several familial disorders known in the older literature under different terms, including familial Pick's disease, familial progressive subcortical gliosis, hereditary dysphasic disinhibition dementia, and autosomal dominant dementia with widespread neurofibrillary tangles [Lanska et al 1994, Wijker et al 1996, Froelich et al 1997, Clark et al 1998, Lendon et al 1998].

The term frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) was proposed at the consensus meeting in Ann Arbor in 1996 in order to include the clinical and pathologic spectrum of 13 large families with FTD, often in combination with signs of parkinsonism, with significant linkage to chromosome 17q21-q22 [Foster et al 1997].

Prevalence

The prevalence of MAPT-related disorders in general is not known.

The frequency of MAPT mutations in persons with FTD with a positive family history for dementia ranges between 13% and 30% [Houlden et al 1999, Rosso et al 2002]. MAPT mutations are rare in individuals with FTD who are simplex cases (i.e., a single occurrence in a family), as well as in persons with other tauopathies such as PSP [Rosso et al 2002, Kaat et al 2009].

The prevalence of PSP is estimated to be 6:100,000, with males and females equally affected. Most PSP cases are simplex cases, with only about 7% of patients showing a clear positive family history. Even with a clear family history, MAPT mutations are relatively rare (<10%) [Kaat et al 2009].

CBD is probably even rarer than PSP, although the disease is often misdiagnosed and accurate prevalence figures are not available. A few cases of CBD with MAPT mutations have been published, but it is not known what proportion of individuals with CBD have these mutations.

Frontotemporal Dementia (FTD)

About 25% of persons with frontotemporal dementia (FTD) have a positive family history and demonstrate an autosomal dominant pattern of inheritance.

Mutations in MAPT are not identified in 60% of individuals with frontotemporal dementia with a positive family history [Rizzu et al 1999].

• In some families with frontotemporal dementia that show evidence of linkage to chromosome 17q21.1, neither mutations in the MAPT gene nor tau pathology at neuropathologic examination has been found. If affected individuals lack tau inclusions but develop ubiquitin-immunoreactive pathology typical of FTLD-U, the disease in these families may be caused by a mutation in the GRN gene (also known as PGRN) that is located ~1.5 Mb centromeric from the MAPT gene on chromosome 17q21. (See GRN-Related Frontotemporal Dementia.)

• Other genes associated with frontotemporal dementia have been identified on chromosome 3 (endosomal ESCRTIII-complex subunit CHMP2B gene (CHMP2B-related frontotemporal dementia) [Skibinski et al 2005] and chromosome 9p21.1-p12 (valosin-containing protein gene (inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia [IBMPFD]) [Watts et al 2004].

• Another hereditary form of frontotemporal dementia associated with amyotrophic lateral sclerosis has shown linkage to chromosome 9q21-q22 [Hosler et al 2000]; the gene has not yet been identified.

• Also, a mutation in the gene encoding the TAR DNA-binding protein 43 (TARDBP) has been found in an individual with FTD without signs of motor neuron disease [Borroni et al 2009], although it appears to be a rare cause of familial FTD in larger series. See TARDBP-Related Amyotrophic Lateral Sclerosis.

Other considerations. Structural imaging may show focal atrophy and may exclude other causes of dementia (e.g., frontal meningioma, chronic subdural hematoma).

• The diagnosis of Alzheimer disease should be considered in individuals with mild behavioral changes, prominent memory disturbance and loss of initiative, or word-finding problems in the absence of evident frontotemporal atrophy on neuroimaging.

• Although FTDP-17 may present with parkinsonism, several other gene defects or loci have been identified for familial Parkinson disease (see Parkinson Disease Overview).

• Other familial neurologic diseases associated with dementia or parkinsonian features including Huntington disease, dementia with Lewy bodies, and prion diseases also need to be considered.

• Non-genetic acquired causes of dementia should always be considered.

Progressive Supranuclear Palsy (PSP)

Most cases of PSP are simplex (i.e., a single occurrence in a family), although familial aggregation appears to be greater than in control groups, with rare families with an autosomal dominant mode of inheritance [Kaat et al 2009].

Corticobasal Degeneration (CBD)

Most cases are simplex, although a few families with a hereditary form have been described.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with a MAPT-related disorder, the following evaluations are recommended:

• A structured general medical history and family history

• Physical examination and neurologic examination

• Evaluation of the extent and profile of cognitive disturbance by neuropsychological examination

Treatment of Manifestations

Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations.

Individuals with seizures are treated with antiepileptic drugs.

The extrapyramidal signs are usually unresponsive or only partially responsive to L-dopa treatment.

Behavioral changes and the loss of insight and judgment in individuals with FTDP-17 often present a considerable burden for partners or other caregivers. Information about the disease and psychological support for partners or other caregivers is essential.

Agents/Circumstances to Avoid

A clinical trial with the selective serotonin reuptake inhibitor (SSRI) paroxetine showed an increase in cognitive impairment in FTD patients treated with this drug [Deakin et al 2004]. Conversely, a previous study with another SSRI, trazodone, showed a favorable effect on behavioral disturbances and agitation without cognitive decline [Lebert et al 2004]. Further studies are needed to clarify this issue.

Testing of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A phase II trial with davunetide, a neuroactive peptide believed to stabilize microtubules, is investigating safety and tolerability of this drug in patients with tauopathies such as PSP, CBD, and FTDP-17.

Several trials with memantine are underway in patients with FTD in general, as well as a trial with oxytocin and its effect on social cognition.

Search ClinicalTrials.gov for more information on FTD studies and for access to information on clinical studies for a wide range of other disorders and conditions.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

MATP-related disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with a MAPT-related disorder have had an affected parent with the clinical features of frontotemporal dementia and/or parkinsonism; however, because of the late onset and relatively rapid course of the disease, the affected parent has often died before onset of the disease in the offspring.

• A proband with a MAPT-related disorder may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is extremely low; one instance has been reported [Boeve et al 2005].

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of MAPT, as a few mutations have been described with reduced penetrance (p.Leu315Arg and p.Asn296del).

Note: Although most individuals diagnosed with a MAPT-related disorder have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, incomplete penetrance, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband was affected or had a disease-causing allele, the risk to the sibs of inheriting the allele is 50%. Because some mutations (e.g., p.Leu315Arg) show reduced penetrance, some individuals who inherit a disease-causing allele may not manifest symptoms.

• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. If neither parent of the proband has a MAPT mutation detectable in DNA extracted from leukocytes, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. One instance of possible germline mosaicism was reported by Boeve et al [2005], who determined that neither parent of two affected sibs was heterozygous for their MAPT mutation.

Offspring of a proband. Each child of an individual with a MAPT-related disorder is at a 50% risk of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent was affected or had a MAPT mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults is available according to the principles described in Molecular Genetic Testing. This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis in the family.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of MAPT-related tauopathy, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.

Testing of at-risk asymptomatic individuals during childhood. Consensus holds that at-risk asymptomatic individuals younger than age 18 years should not have testing. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal diagnosis of (typically) adult-onset diseases are not common. Differences in perspective may exist among medical professionals and within families regarding use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Published Statements and Policies Regarding Genetic Testing

1. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available at www.ashg.org. 1995. Accessed 10-22-10.
2. National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available at www.nsgc.org. 1995. Accessed 10-22-10.

Suggested Reading

1. Burrell JR, Hodges JR. From FUS to Fibs: what's new in frontotemporal dementia? J Alzheimers Dis. 2010;21:349–60. [PubMed: 20413882]
2. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM. Consortium for Frontotemporal Lobar Degeneration; Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114:5–22. [PMC free article: PMC2827877] [PubMed: 17579875]
3. Neumann M, Tolnay M, Mackenzie IR. The molecular basis of frontotemporal dementia. Expert Rev Mol Med. 2009;11:e23. [PubMed: 19638255]
4. Rademakers R, Cruts M, Dermaut B, Sleegers K, Rosso SM, Van den Broeck M, Backhovens H, van Swieten J, van Duijn CM, Van Broeckhoven C. Tau negative frontal lobe dementia at 17q21: significant finemapping of the candidate region to a 4.8 cM interval. Mol Psychiatry. 2002;7:1064–74. [PubMed: 12476321]
5. Snowden J, Neary D, Mann D. Frontotemporal lobar degeneration: clinical and pathological relationships. Acta Neuropathol. 2007;114:31–8. [PubMed: 17569065]
6. Spillantini MG, Yoshida H, Rizzini C, Lantos PL, Khan N, Rossor MN, Goedert M, Brown J. A novel tau mutation (N296N) in familial dementia with swollen achromatic neurons and corticobasal inclusion bodies. Ann Neurol. 2000;48:939–43. [PubMed: 11117553]

Revision History

• 26 October 2010 (me) Comprehensive update posted live

• 18 November 2005 (me) Comprehensive update posted to live Web site

• 5 August 2003 (me) Comprehensive update posted to live Web site

• 7 November 2000 (me) Review posted to live Web site

• 30 June 2000 (jvs) Original submission