Two causative genes are certified in this packet: MAPT (chromosome 17) and PSEN1 (chromosome 14). No ClinGen clinical validity classifications are provided for either gene-disease association. MAPT encodes microtubule-associated protein tau; the GeneReviews chapter for MAPT-related frontotemporal dementia documents multiple genotype-phenotype correlations, with different MAPT variants associated with distinct predominant clinical presentations — behavioral variant FTD, parkinsonian features, or (in a minority) amnesic or language-predominant presentations.

Certified inheritance patterns are sporadic and autosomal dominant. GeneReviews penetrance guidance notes that MAPT-related disease is commonly considered fully penetrant, though occasional reduced penetrance may exist in some families with specific variants.

No certified diagnostic method list is present in this packet. According to GeneReviews for MAPT-related frontotemporal dementia, no consensus clinical diagnostic criteria have been published. GeneReviews specifies that MAPT-FTD should be suspected in individuals presenting with behavioral changes consistent with behavioral variant FTD, parkinsonian features suggesting corticobasal syndrome or progressive supranuclear palsy, or, less commonly, an amnesic presentation. Mean age of onset is 49.5 years per GeneReviews observational data.

GeneReviews diagnostic guidance notes that neuroimaging can evaluate for other conditions that may mimic frontotemporal dementia, including white matter disease, focal cortical lesions, frontotemporal tumors, and cerebrovascular disease. The clinical characteristics of MAPT-related disease overlap substantially with those of other conditions including FTD of unknown cause, other genetic FTD subtypes, and non-FTD spectrum disorders, making clinical prediction of specific molecular etiology difficult without molecular testing.

No FDA-approved therapies for Pick disease are certified in this packet's approved-treatment records. According to GeneReviews for MAPT-related frontotemporal dementia, there is no cure. Supportive management aimed at improving quality of life and maximizing function is described in GeneReviews as the available approach. GeneReviews treatment guidance describes a multidisciplinary care framework encompassing neurologic, nursing, speech-language, physical therapy, occupational therapy, nutrition, psychiatric, and social work involvement.

For parkinsonian manifestations, GeneReviews documents a levodopa trial as a management approach, with the note that the majority of affected individuals do not show significant levodopa response. For psychiatric and behavioral manifestations, GeneReviews documents selective serotonin reuptake inhibitors as a pharmacologic approach for affective disorders and behavioral disturbances; for severe refractory agitation and psychosis, atypical antipsychotics are noted as a temporizing measure in GeneReviews. For dysarthria, GeneReviews specifies involvement of speech-language pathology and use of augmentative communication devices. Dysphagia is addressed with evaluation and dietary modification per GeneReviews guidance.

One withdrawn orphan drug record is present in this packet, pertaining to a cellular therapy for cytomegalovirus infection — an unrelated indication. This record does not represent a therapy for Pick disease.

According to GeneReviews for MAPT-related frontotemporal dementia, a worldwide observational study reported a mean age of death of 58.5 years (range 24 to 93 years) and an average disease duration of approximately nine years from onset to death. Penetrance is described in GeneReviews as commonly thought to be full, with occasional reduced penetrance observed in some families with specific variant profiles. No additional certified natural history or prognosis data is present in this packet.

Several active trial records are certified for Pick disease, with 27 active records documented. Certified records include a pivotal Phase 3 study of N-Acetyl-L-Leucine in Niemann-Pick disease type C (NCT05163288, IntraBio); the Swedish BioFINDER 2 Study examining neurodegenerative disease biomarkers (NCT03174938); a study of peripheral biomarkers and integrative modeling for prognostic confidence in neurodegenerative dementias (NCT06529744); a study of retinal hyperspectral imaging in neurodegenerative diseases (NCT07545473); and cord blood transplant and oligodendrocyte-like cell administration for inherited metabolic diseases (NCT02254863). The research landscape digest for Pick disease documents 265 total classified publications with a predominant focus on basic science and preclinical research, 46 review articles, and 33 case reports. Biomarker research activity and gene therapy investigations are also represented in the research landscape.