TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia

Clinical characteristics: In this GeneReview, TARDBP amyotrophic lateral sclerosis-frontotemporal dementia (TARDBP-ALS-FTD) refers to the spectrum of phenotypes caused by pathogenic variants in TARDBP, the gene encoding TDP-43. The phenotypic spectrum encompasses pure (i.e., without other neurologic findings) amyotrophic lateral sclerosis (ALS; most common), pure (i.e., without other neurologic findings) frontotemporal dementia (FTD; rare), a combination of ALS and FTD, and atypical neurologic phenotypes (very rare). Individuals with the same TARDBP pathogenic variant (even within the same family) may have clinical features that vary in both type and severity. Common manifestations are dysarthria and dysphagia; less common manifestations can include parkinsonism, cognitive deterioration, and behavioral and psychological manifestations of dementia. Life expectancy for TARDBP-ALS is highly variable and mainly associated with an individual's clinical features; overall disease duration averages three to five years. For TARDBP-FTD, disease duration averages one to 16 years.

Diagnosis/testing: The diagnosis of TARDBP-ALS-FTD is established in a proband with suggestive findings and most commonly a heterozygous pathogenic (or likely pathogenic) variant in TARDBP identified by molecular genetic testing. Rarely, homozygous pathogenic (or likely pathogenic) variants in TARDBP have been reported.

Management: Treatment of manifestations: There is no cure for TARDBP-ALS-FTD. Individuals benefit from multidisciplinary supportive care to improve quality of life, maximize function, and reduce complications. This can include care by specialists in neurology, physiotherapy, occupational therapy, speech-language therapy, nutrition, respiratory therapy, pulmonology, psychology, social work, genetic counselling, palliative care, and special nursing.

Surveillance: Frequent monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations by the treating clinicians is recommended.

Genetic counseling: TARDBP-ALS-FTD is inherited in an autosomal dominant manner. About half of individuals diagnosed with TARDBP-ALS-FTD have an affected parent. Each child of an individual with TARDBP-ALS-FTD has a 50% chance of inheriting the TARDBP pathogenic variant. Once a TARDBP pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for the presence of the TARDBP pathogenic variant are possible. (Note: Because the clinical presentation of TARDBP-ALS-FTD may differ among heterozygous family members, accurate prediction of future possible clinical manifestations in an individual found to have a familial TARDBP pathogenic variant is not possible.)