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MAPT-Related Disorders

Synonym: MAPT-Related Tauopathies

, MD, PhD, , MD, PhD, and , PhD.

Author Information
, MD, PhD
Department of Neurology
Erasmus Medical Center
Rotterdam, Netherlands
, MD, PhD
Department of Neurology
Havenziekenhuis
Rotterdam, Netherlands
, PhD
Department of Clinical Genetics
Vrije Universiteit Medical Center
Amsterdam, Netherlands

Initial Posting: ; Last Update: October 26, 2010.

Summary

Disease characteristics. The clinical manifestations of MAPT-related disorders (MAPT-related tauopathies) are most typically those of frontotemporal dementia (FTDP-17), but also include progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), mild late-onset parkinsonism, and dementia with epilepsy. Clinical presentation of frontotemporal dementia (FTD) is variable: some present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs, whereas others present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders. Onset is usually between ages 40 and 60 years, but may be earlier or later. The disease progresses over a few years into profound dementia with mutism. PSP is characterized by progressive vertical gaze palsy in combination with a prominent loss of balance at early stages of the disease. With progression, axial rigidity, dysarthria, and dysphagia become prominent, often in combination with a frontal dysexecutive syndrome. CBD is a progressive neurodegenerative disorder which affects both the frontoparietal cortex and the basal ganglia, resulting in a mild to moderate dementia in combination with asymmetric parkinsonism, ideomotor apraxia, aphasia, and an alien-hand syndrome.

Diagnosis/testing. The diagnosis of a MAPT- related disorder relies on: typical clinical findings; often on characteristic findings on neuroimaging, single-photon emission computed tomography (SPECT), or positron emission tomography with 18F-fluorodeoxyglucose (FDG-PET); a positive family history; and most importantly, demonstration of a disease-causing mutation in MAPT, the gene encoding the protein tau.

Management. Treatment of manifestations: Sedative or antipsychotic drugs help to reduce extreme restlessness, roaming behavior, delusions, and hallucinations; seizures are treated in the customary manner. Psychological support for partners or other caregivers is essential. Extrapyramidal signs are usually unresponsive or only partially responsive to L-dopa treatment.

Agents/circumstances to avoid: The selective serotonin reuptake inhibitor (SSRI) paroxetine may increase cognitive impairment in persons with FTD.

Genetic counseling. MATP-related disorders are inherited in an autosomal dominant manner. Most individuals diagnosed with a MAPT-related disorder have had an affected parent; 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. De novo mutations are extremely rare. Each child of an individual with a MAPT-related disorder has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk is possible when the disease-causing allele in the family is known; however, requests for prenatal diagnosis of (typically) adult-onset diseases are not common.

GeneReview Scope

MAPT-Related Disorders: Included Disorders 1
  • Frontotemporal dementia with parkinsonism-17 (FTDP-17)
  • Progressive supranuclear palsy (PSP)
  • Corticobasal degeneration (CBD)
  • Mild late-onset parkinsonism
  • Dementia with epilepsy

For synonyms and outdated names see Nomenclature.

1. Forms of disorders associated with genes other than MAPT are not addressed in this GeneReview.

Diagnosis

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 MAPT, 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, encoding the tau protein, is the only gene in which mutation is known to cause 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

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
MAPTSequence analysis of select exonsMutations in exons 1 and 9-13 and flanking intron regions 4Unknown, depends on type of cohort tested. Frequency range: 1%-10%
Sequence analysis 5Sequence variantsUnknown
Deletion/duplication analysis 6Exonic or whole-gene deletionsUnknown, but presumed to be low

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

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

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

5. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

Interpretation of test results. If testing of a proband identifies a previously reported mutation for which additional studies have demonstrated its pathogenicty, 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 pathogenic. 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.

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.

Clinical Description

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].

Frontotemporal Dementia (FTD, FTDP-17)

FTD is a presenile dementia affecting the frontal and temporal cortex and some subcortical nuclei. Clinical presentation is variable. Affected individuals may present with slowly progressive behavioral changes, language disturbances, and/or extrapyramidal signs. Some present with rigidity, bradykinesia, supranuclear palsy, and saccadic eye movement disorders.

Symptoms usually start between ages 40 and 60 years, but may occur earlier or later. Disease duration is usually between five and ten years, but occasionally may be as long as 20 to 30 years. The disease progresses over a few years into profound dementia with mutism.

Behavioral changes. Disinhibition and loss of initiative are the most common presenting symptoms. Affected individuals lose interest in their environment and neglect their personal hygiene. Obsessive-compulsive behavior and delusions or hallucinations are early clinical features in some. Roaming, restlessness, verbal aggressiveness, hyperorality including alcohol abuse, and financial mismanagement are frequently seen [Foster et al 1997, Bird et al 1999].

Psychiatric symptoms. Persecutory delusions and visual or auditory hallucinations are rare, but can occur.

Cognitive decline. Word-finding difficulties and semantic paraphasias in conversational speech are common early findings. Orientation in time and place, visuo-constructive functions, and short-term memory remain intact initially. Executive functions, attention, concentration, and abstract reasoning ability become impaired in all affected individuals. Comprehension of language remains relatively preserved over the course of the disease. Perseveration, repetitive utterances, and echolalia lead to mutism after several years [Foster et al 1997].

Extrapyramidal signs. Parkinsonian signs may be the first manifestations of the disease, sometimes in conjunction with behavioral changes. Affected individuals show decreased facial expression, bradykinesia, postural instability, and rigidity without resting tremor. The extrapyramidal signs are unresponsive or only partially responsive to L-dopa treatment.

Epilepsy. Epileptic seizures usually do not occur in individuals with FTDP-17 except for those with the c.901C>T mutation [Bugiani et al 1999, Sperfeld et al 1999].

Motor neuron disease. Some members of the family with frontotemporal dementia reported by Lynch et al [1994] and a person with the novel p.Lys317Met MAPT mutation reported by Zarranz et al [2005] had motor neuron disease consistent with the diagnosis of amyotrophic lateral sclerosis (ALS).

Headache. Affected individuals may complain about headache for years preceding the onset of the disease [Sperfeld et al 1999, van Swieten et al 1999].

Neuropathology

  • Aside from focal atrophy, the frontal and temporal lobes are macroscopically normal.
  • Neuronal loss, gliosis, and spongiosis in the superficial cortical layers are seen on routine microscopic staining.
  • Immunohistochemical analysis shows pathologic accumulation of hyperphosphorylated tau protein in all individuals with MAPT mutations.

Progressive Supranuclear Palsy (PSP)

PSP is characterized by progressive vertical gaze palsy in combination with a prominent loss of balance at early stages of the disease. With progression, axial rigidity, dysarthria, and dysphagia become prominent, often in combination with a frontal dysexecutive syndrome.

Age at onset is usually between 50 and 80 years, with average disease duration of seven years.

Several individuals with a clinical and pathologic phenotype similar to PSP have been described with MAPT mutations [Morris et al 2003, Soliveri et al 2003, Rossi et al 2004, Kaat et al 2009]. MAPT is probably also of importance in simplex cases of PSP, as the H1 haplotype of the tau gene is overrepresented in these individuals [de Silva et al 2001, Pastor et al 2002].

At autopsy, there are numerous tau-positive aggregates present in affected brain regions (mainly basal ganglia, diencephalon, and brain stem), containing typically 4-repeat isoforms.

Corticobasal Degeneration (CBD)

CBD is a progressive neurodegenerative disorder which affects both the frontoparietal cortex and the basal ganglia, resulting in clinical symptoms of a mild to moderate dementia in combination with asymmetric parkinsonism, ideomotor apraxia, aphasia, and an alien-hand syndrome.

The age at onset is between 60 and 80 years, with average disease duration of eight years. Possibly females are more often affected.

The diagnosis may be supported by neuroimaging showing focal, asymmetric atrophy of the frontoparietal cortex.

The definitive diagnosis is made at autopsy: affected brain regions show a typical tauopathy with astrocytic plaques and ballooned neurons.

MAPT mutations have been found in a small number of individuals with CBD [Bugiani et al 1999, Spillantini et al 2000, Rossi et al 2008].

Mild Late-Onset Parkinsonism

Pastor et al [2001] described two brothers with atypical PSP with onset in the late thirties and homozygosity for the p.Asn296del MAPT mutation. Among heterozygous family members, both individuals with typical dopa-responsive Parkinson disease and individuals with no symptoms were identified. Similarly Rossi et al [2004] described a proband with a PSP-like syndrome with a MAPT mutation resulting in p.Asn296del; the proband had an aunt with the mutation who showed signs typical of Parkinson disease. The authors suggested that the p.Asn296del mutation is a risk factor for both atypical PSP as well as Parkinson disease, and that the mutation is characterized by reduced penetrance.

Dementia with Epilepsy

The combination of (frontotemporal) dementia and epileptic seizures has been described in individuals with the p.Pro301Ser mutation [Sperfeld et al 1999].

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].

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 MAPT was suspected for the first time when a family with so-called dementia-disinhibition-parkinsonism-amyotrophy complex (DDPAC) showed significant linkage to the MAPT-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 (hereditary) Pick's disease, familial progressive subcortical gliosis, hereditary dysphasic disinhibition dementia, pallidopontonigral degeneration, Wilhelmsen-Lynch disease, 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.

Differential Diagnosis

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].

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.

Management

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.

Evaluation 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults is possible 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 position statement on genetic testing of minors for adult-onset conditions 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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association for Frontotemporal Degeneration (AFTD)
    290 King of Prussia Road
    Radnor Station Building #2, Suite 320
    Radnor PA 19087
    Phone: 866-507-7222 (Toll-free Helpline); 267-514-7221
    Email: info@theaftd.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • Alzheimer's Disease Education and Referral Center (ADEAR)
    PO Box 8250
    Silver Spring MD 20907
    Phone: 800-438-4380 (toll-free)
    Fax: 301-495-3334
    Email: adear@alzheimers.org
  • Parkinson's Disease Foundation (PDF)
    1359 Broadway
    Suite 1509
    New York NY 10018
    Phone: 800-457-6676 (Toll-free Helpline); 212-923-4700
    Fax: 212-923-4778
    Email: info@pdf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. MAPT-Related Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for MAPT-Related Disorders (View All in OMIM)

157140MICROTUBULE-ASSOCIATED PROTEIN TAU; MAPT
172700PICK DISEASE OF BRAIN
600274FRONTOTEMPORAL DEMENTIA; FTD
601104SUPRANUCLEAR PALSY, PROGRESSIVE, 1; PSNP1

Gene structure. The gene consists of 15 exons.

Six different isoforms, composed of 352 to 441 amino acids, are produced from the single MAPT gene by alternative splicing of exons 2, 3, and 10. Three isoforms contain three amino acid repeats, encoded by exons 9, 11, and 12, whereas the inclusion of the amino acid repeat encoded by exon 10 gives rise to the other three isoforms, which all have four repeats. See Entrez Gene for information on different isoforms and transcripts.

Benign allelic variants. Several non-pathogenic allelic variants that cause amino acid changes have been found.

Pathogenic allelic variants. Pathogenic mutations consist of missense mutations and intronic and exonic mutations affecting alternative splicing of exon 10 [Hutton et al 1998, Heutink 2000].

MAPT mutations can be divided into two distinct types. In the first type, missense mutations in exon 9, 10, 11, 12, or 13 reduce the ability of the tau protein to bind to microtubuli and some also enhance the rate of heparin-induced assembly of tau into filaments. In the second type, the effect of the intronic and some coding mutations in exon 10 is at the messenger RNA level, resulting in a change in the ratio of tau isoforms of three amino-acid repeats to those of four amino-acid repeats.

Table 2. Selected MAPT Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.14G>Ap.Arg5HisNM_005910​.5
c.14G>Tp.Arg5Leu
c.837T>Gp.Asn279Lys
c.838_840delAAGp.280Lysdel
(delK280)
c.886_888delAATp.Asn296del
(delN296)
c.901C>Tp.Pro301Ser
c.914G>Ap.Ser305Asn
c.944T>Ap.Leu315Arg
c.950A>Tp.Lys317Met
c.1009G>Ap.Val337Met
c.1216C>Tp.Arg406Trp
c.1883+14C>T
(exon 10 plus 14)
NANM_001123066​.3

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

NA = not applicable

1. Variant designation that does not conform to current naming conventions

Normal gene product. MAPT promotes tubulin polymerization, reduces microtubule instability, and plays a role in maintaining neuronal integrity, axonal transport, and axonal polarity. MAPT protein is abundant in both the central and peripheral nervous system. In brain, it is predominantly found in nerve cells where it is concentrated in nerve cell axons.

The tau protein isoforms found in human brain are encoded by eleven exons. A total of six different major MAPT mRNA transcripts are generated as a result of alternative splicing that encodes proteins of 352-441 amino acids. In the carboxy-terminal part of MAPT, three or four tandem imperfect repeats are present containing domains important for the binding to microtubules. One alternatively spliced exon (exon 10) encodes the additional fourth repeat.

Alternative splicing of MAPT is developmentally regulated in that in immature brain only the transcript encoding the shortest isoform with three repeats is expressed, but in adult cerebral cortex all six isoforms are present. MAPT is post-translationally modified by phosphorylation in a dynamic process and it has been suggested that this is an additional mechanism to regulate MAPT function.

Abnormal gene product. Missense mutations lead to reduced binding capacity of the tau protein to microtubuli [Hasegawa et al 1998]. The localization of mutations in MAPT is associated with different morphology of tau filaments and composition of tau isoforms [Goedert et al 1999].

References

Published Guidelines/Consensus Statements

  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 online. 1995. Accessed 6-30-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2012. Accessed 6-30-14.

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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]

Chapter Notes

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
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