Clinical characteristics.

The spectrum of clinical manifestations of MAPT-related frontotemporal dementia (MAPT-FTD) has expanded from its original description of frontotemporal dementia and parkinsonian manifestations to include changes in behavior, motor function, memory, and/or language. A recent retrospective study suggested that the majority of affected individuals have either behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) or, less commonly, a parkinsonian syndrome (i.e., progressive supranuclear palsy, corticobasal syndrome, or Parkinson disease). Fewer than 5% of people with MAPT-FTD have primary progressive aphasia or Alzheimer disease. Clinical presentation may differ between and within families with the same MAPT variant. MAPT-FTD is a progressive disorder that commonly ends with a relatively global dementia in which some affected individuals become mute. Progression of motor impairment in affected individuals results in some becoming chairbound and others bedbound. Mean disease duration is 9.3 (SD: 6.4) years but is individually variable and can be more than 30 years in some instances.

Diagnosis/testing.

The diagnosis of MAPT-FTD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MAPT identified by molecular genetic testing.

Management.

Treatment of manifestations: There is no cure for MAPT-FTD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can involve multidisciplinary care that often includes a neurologist, specially trained nurses, speech-language pathologist or therapist, physical therapist, occupational therapist, nutritionist, psychiatrist/psychologist, social worker, and genetic counselor.

Surveillance: To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, routine evaluations by multidisciplinary specialists are recommended.

Genetic counseling.

MAPT-FTD is inherited in an autosomal dominant manner. Most individuals diagnosed with MAPT-FTD have an affected parent with the clinical features of FTD and/or parkinsonism; however, because of the late onset and relatively rapid course of the disease, the affected parent often dies before onset of the disease in the offspring. A proband with MAPT-FTD may have the disorder as the result of a de novo pathogenic variant; such variants have been reported but are thought to be rare. Once the MAPT pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

MAPT-FTD should be suspected in individuals with the following clinical features, neuroimaging findings, and family history.

Clinical features

• Age at onset ranges from 17 to 82 years; mean age of onset is 49.5 (SD: 10.0) years [Moore et al 2020].
• The most common initial manifestations are:
  • Behavioral changes consistent with a diagnosis of behavioral variant FTD (bvFTD) [Rascovsky et al 2011];
  • Parkinsonian features suggestive of either corticobasal syndrome [Armstrong et al 2013] or progressive supranuclear palsy [Höglinger et al 2017].
• Less common initial presentations include:
  • An amnesic presentation (which may be diagnosed as Alzheimer disease);
  • A language presentation (consistent with one of the primary progressive aphasia syndromes) [Gorno-Tempini et al 2011].

Neuroimaging findings

• CT and MRI. While both brain CT and MRI can show the atrophy patterns seen in MAPT-FTD, MRI shows greater detail. The hallmark feature is atrophy of the frontal and temporal lobes, which is often symmetric, but can be asymmetric.
  A recent study showed at least two patterns of atrophy:
  • A "temporal" type in which atrophy initially predominantly involved the hippocampus, amygdala, anteromedial temporal cortex, and insula;
  • A "frontotemporal" type in which atrophy involved both the frontal lobe and temporal lobe more laterally than observed in the "temporal" type [Young et al 2021].
• Additional neuroimaging studies approved in the US
  • Beta amyloid positron emission tomography (PET) scan to help differentiate Alzheimer disease (with beta amyloid accumulation) from MAPT-FTD
  • Fluorodeoxyglucose (FDG) PET scan to help differentiate non-genetic causes of dementia involving the frontal lobes

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Of note, diagnoses may vary in affected family members; for example, one family member may be diagnosed with bvFTD while another family member is diagnosed with a parkinsonian syndrome. Other family members (particularly in prior generations) may have received a diagnosis of an unspecified dementia, Alzheimer disease, or Parkinson disease.

Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of MAPT-FTD is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in MAPT identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous MAPT variant of uncertain significance does not itself establish or rule out the diagnosis of this disorder.

Because the phenotype of MAPT-FTD is indistinguishable from many other inherited disorders with frontotemporal dementia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of MAPT, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A neurodegenerative disease, dementia, or frontotemporal dementia multigene panel that includes MAPT and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

The spectrum of clinical manifestations of MAPT-related frontotemporal dementia (MAPT-FTD) has expanded from its original description of frontotemporal dementia and parkinsonian manifestations to include changes in behavior, motor function, memory, and/or language (see Table 2).

A recent retrospective study suggested that the majority of affected individuals have either behavioral variant FTD (bvFTD) or, less commonly, a parkinsonian syndrome (i.e., progressive supranuclear palsy, corticobasal syndrome, or Parkinson disease). Fewer than 5% of people with MAPT-FTD have primary progressive aphasia or Alzheimer disease [Moore et al 2020]. Of note, however, in this retrospective study many affected individuals had received only a diagnosis of an unspecified dementia. Furthermore, clinical presentation may differ between and within families with the same MAPT variant.

Age of onset. A recent worldwide observational study suggested that age of onset may be before that of the other two major genetic causes of FTD (C9orf72-FTD and GRN-FTD), with the mean age of onset being 49.5 (range: 17-82) years and the average age of death being 58.5 (range: 24-93) years. Mean disease duration is 9.3 (SD: 6.4) years, but duration is individually variable and can be more than 30 years in some instances [Moore et al 2020].

Behavioral manifestations. The most common presentation in MAPT-FTD is bvFTD. Affected individuals present with progressive changes in personality and behavior, including core changes in three of the following six areas [Rascovsky et al 2011]:

• Early behavioral disinhibition
• Early apathy or inertia
• Early loss of sympathy or empathy
• Early perseverative stereotype or compulsive/ritualistic behavior
• Hyperorality or dietary change
• Neuropsychological profile of executive function difficulties with relative sparing of memory and visuospatial symptoms

Motor manifestations. Parkinsonian features, a common finding in individuals with MAPT-FTD, can occur before or after behavioral changes; however, as the disease progresses most individuals have both findings. Individuals can present with an unspecified parkinsonism that does not meet diagnostic criteria for any particular disorder. However, individuals can also fit diagnostic criteria for atypical parkinsonian disorders corticobasal syndrome [Armstrong et al 2013] and progressive supranuclear palsy (Richardson syndrome) [Höglinger et al 2017].

Some individuals with MAPT-FTD can also receive a diagnosis of Parkinson disease [Im et al 2015, Valentino et al 2020].

Progression of motor impairment in affected individuals results in some becoming chairbound and others bedbound.

Memory impairment. Episodic memory impairment, unusual for FTD, occurs quite commonly in individuals with MAPT-FTD. This can present either along with behavioral change or as the primary and predominant manifestation. Memory impairment can lead to an initial diagnosis of Alzheimer disease.

Language impairment. In MAPT-FTD, a primary language presentation is less common; however, affected individuals often develop semantic impairment, most commonly co-occurring with behavioral change. On the rare occasion that it is the first manifestation, the presumed diagnosis may be semantic-variant primary progressive aphasia [Gorno-Tempini et al 2011, Moore et al 2020]. Rarely, affected individuals have presented with a nonfluent variant primary progressive aphasia [Munoz et al 2007, Villa et al 2011, Moore et al 2020].

MAPT-FTD is a progressive disorder that commonly ends with a relatively global dementia in which some affected individuals become mute.

Neuropathology. The neuropathologic hallmark of MAPT-FTD is presence of tau protein deposits in neurons and glia. Tau deposits typically involve the cerebral cortex, white matter, subcortical regions, and brain stem nuclei. A variety of different pathologic findings can be seen with some MAPT variants associated with predominantly four-repeat tau inclusions, some with predominantly three-repeat tau inclusions, and some with a mix of three- and four-repeat inclusions. This last group often has paired-helical filament tau inclusions similar to those seen in Alzheimer disease [Ghetti et al 2015, Forrest et al 2018].

Genotype-Phenotype Correlations

The following genotype-phenotype correlations have been observed [Moore et al 2020]:

• The common variants p.Pro301Leu and c.915+16C>T usually present with bvFTD.
• The variant p.Asn279Lys usually presents with a parkinsonian syndrome.
• A sizeable minority of individuals with the variant c.915+16C>T present with a parkinsonism syndrome.
• The less common variants p.Leu284Arg, c.853A>C, c.887_889delATA, p.Gly303Val, c.915T>C, and p.Lys317Met can present with a parkinsonian syndrome.
• The variants p.Val337Met, p.Gln351Arg, and p.Arg406Trp in particular may present with episodic memory problems, and in some individuals this can be the initial presentation, with a phenotype similar to Alzheimer disease.

Penetrance

MAPT-FTD is commonly thought to be a fully penetrant disorder. However, occasional reduced penetrance may exist in some families with specific MAPT variants (e.g., p.Leu315Arg, p.Val363Ile and p.Gly389Arg), and may be age related.

Nomenclature

MAPT-FTD may also be referred to as MAPT-related tauopathy.

MAPT-FTD was previously referred to as frontotemporal degeneration with parkinsonism linked to chromosome 17 (FTDP-17).

Prevalence

The prevalence of MAPT-FTD is unclear. A recent epidemiologic study in the UK suggests that prevalence of all FTD is 11:100,000 [Coyle-Gilchrist et al 2016]. In the authors' experience, genetic FTD accounts for ~30% of all FTD; thus the prevalence of genetic FTD is estimated to be 3.3:100,000. Based on the recent large retrospective study of genetic FTD [Moore et al 2020], MAPT-FTD accounts for about 25% of genetic FTD, resulting in an estimated prevalence of MAPT-FTD of 0.8:100,000.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with MAPT-FTD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for MAPT-FTD. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can involve multidisciplinary care that often includes a neurologist, specially trained nurses, speech-language pathologist or therapist, physical therapist, occupational therapist, nutritionist, psychiatrist/psychologist, social worker, and genetic counselor (see Table 5).

Surveillance

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MAPT-related frontotemporal dementia (MAPT-FTD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with MAPT-FTD have an affected parent with the clinical features of frontotemporal dementia (FTD) and/or parkinsonism; however, because of the late onset and relatively rapid course of the disease, the affected parent often dies before onset of the disease in the offspring.
• A proband with a MAPT-FTD may have the disorder as the result of a de novo pathogenic variant. De novo MAPT pathogenic variants have been reported but are thought to be rare [Ando et al 2020].
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with MAPT-FTD may appear to be negative because of failure to recognize the disorder in family members (e.g., a psychiatric disorder not diagnosed at the time as FTD), early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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 is affected or is known to have a MAPT pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
• MAPT-FTD is almost completely penetrant; thus, heterozygous sibs are extremely likely to develop manifestations during their lifetime. Although a strong correlation exists between individual age at onset and both parental and mean family age of onset [Moore et al 2020], the phenotype in affected family members may vary (e.g., bvFTD in one family member and parkinsonism in another family member).
• If the MAPT pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. Presumed parental germline mosaicism was reported by Boeve et al [2005], who determined that neither parent of two affected sibs was heterozygous for the MAPT pathogenic variant found in the affected offspring.

Offspring of a proband. Each child of an individual with MAPT-FTD is at a 50% risk of inheriting the MAPT pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the MAPT pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the MAPT pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals age <18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of MAPT-FTD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Once the MAPT pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

Tau protein, encoded by MAPT, is a microtubule-binding protein believed to be involved in assembly and stabilization of microtubules. Alternative mRNA splicing of MAPT in the human adult brain produces six isoforms of the tau protein that differ by either (1) the presence or absence of exons 2 or 3 in the amino-terminal half or (2) the presence or absence of exon 10 in the carboxy-terminal half. Exclusion of exon 10 leads to the production of three-repeat isoforms, whereas inclusion of exon 10 leads to four-repeat isoforms. While the expression levels of three-repeat and four-repeat isoforms are similar in normal adult human cerebral cortex, expression levels may change in neurodegenerative tauopathies.

Mechanism of disease causation. MAPT pathogenic variants alter the relative production of tau isoforms, resulting either in changes in how microtubules assemble or in the propensity of tau to aggregate.

Author Notes

Jonathan Rohrer is a Professor of Neurology at the Dementia Research Centre in the Queen Square UCL Institute of Neurology as well as a Consultant Neurologist at the National Hospital for Neurology and Neurosurgery. He is also a Clinical Co-Investigator at the UK Dementia Research Institute. After a Natural Sciences degree at the University of Cambridge he went on to study medicine at the University of Oxford and UCL. He started as a Wellcome Trust Clinical Research Fellow in 2005 at UCL, where he first began to study frontotemporal dementia (FTD) including the neuroimaging of genetic FTD, and completed his PhD in 2010. Dr Rohrer then became an NIHR Clinical Lecturer, during which time he started the Genetic Frontotemporal Dementia Initiative, GENFI, an international multicenter cohort study of presymptomatic genetic FTD. The research of his team focuses on the development of novel biomarkers in FTD and clinical trials for genetic forms of FTD through the FTD Prevention Initiative. Details about Dr Rohrer's work and about FTD more generally can be found at FTD Talk.

Acknowledgments

The authors would like to thank the patients and family members who take part in the Genetic Frontotemporal Dementia Initiative and the Rare Dementia Support FTD Support Group, who have contributed hugely to our understanding of this disorder.

Author History

Rebekah Ahmed, FRACP, PhD (2022-present)
Peter Heutink, PhD, Vrije Universiteit Medical Center, Amsterdam (2000-2022)
Jonathan Rohrer, FRCP, PhD (2022-present)
Sonia M Rosso, MD, PhD, Havenziekenhuis, Rotterdam (2000-2022)
Brigid Ryan, PhD (2022-present)
John C van Swieten, MD, PhD, Erasmus Medical Center, Rotterdam (2000-2022)

Revision History

• 18 August 2022 (bp) Comprehensive update posted live
• 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 live
• 30 June 2000 (jvs) Original submission

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