Frontotemporal Dementia And/or Amyotrophic Lateral Sclerosis 4

A number sign (#) is used with this entry because of evidence that frontotemporal dementia and/or amyotrophic lateral sclerosis-4 (FTDALS4) is caused by heterozygous mutation in the TBK1 gene (604834) on chromosome 12q14.

Description

Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by Freischmidt et al., 2015).

For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Clinical Features

Freischmidt et al. (2015) reported 13 Caucasian families of European origin with amyotrophic lateral sclerosis. The mean age at onset was 60 years, and about 50% of patients showed cognitive impairment, often progressing to fulminant FTD. Bulbar symptoms were reported in 87% of patients during the disease course, with bulbar-onset observed in 15%. Postmortem examination of 1 patient showed massive TDP43 (605078)-positive perinuclear inclusions in the temporal lobe and p62 (SQSTM1; 601530)-positive perinuclear inclusions in the parahippocampal gyrus, but not in other parts of the brain.

Pottier et al. (2015) reported 3 unrelated woman with FTDALS4 presenting as frontotemporal dementia or Alzheimer disease. The age at onset ranged from 70 to 80 years and death occurred between 72 and 90 years.

Inheritance

The transmission pattern of FTDALS4 in the families reported by Freischmidt et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance.

Pottier et al. (2015) reported a deceased patient (case B) showing digenic inheritance of a neurodegenerative disorder: whole-genome sequencing identified heterozygous mutations in the OPTN (602432; G538EfsX27) and TBK1 (R117X) genes. He presented with rapidly progressive cognitive and language difficulties at age 68 years, becoming almost mute by age 69. Other features included trouble swallowing, jerky movements of the hands, and slow movements, but there was no obvious clinical evidence of motor neuron disease. The patient showed symptoms of frontal dementia and was diagnosed with primary progressive aphasia. He died at age 72. Postmortem examination showed severe focal cortical atrophy of the frontal lobe, atrophy of the amygdala and hippocampus, loss of pigment in the substantia nigra, and midbrain atrophy. There were p62- (601530) and TDP43-positive neuronal and glial inclusions. There was no neuronal loss in the motor cortex or brainstem. He had no family history of a similar disorder.

Molecular Genetics

Cirulli et al. (2015) performed whole-exome sequencing of 2,869 ALS patients and 6,405 controls. The analysis implicated TBK1 as an ALS gene (discovery p = 1.12 x 10(-5), replication p = 5.78 x 10(-7), combined p = 3.60 x 10(-11)), to potentially explain 0.905% of ALS cases. TBK1 binds to and phosphorylates a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN; 602432) and p62 (SQSTM1; 601530), both of which have been implicated in ALS. Cirulli et al. (2015) concluded that these observations revealed a key role of the autophagic pathway in ALS.

In affected members from 13 European Caucasian families with FTDALS4, Freischmidt et al. (2015) identified 8 different heterozygous loss-of-function mutations in the TBK1 gene (see, e.g., 604834.0001-604834.0005). Mutations in the first 9 families were found by whole-exome sequencing of 252 patients with ALS, and accounted for about 4% of cases overall. In vitro studies of most of the mutations indicated that they resulted in haploinsufficiency. There was evidence of incomplete penetrance. One of the families also carried a mutation in the FUS gene (137070), consistent with oligogenic inheritance. In addition, 4 heterozygous missense mutations were found (see, e.g., E696K, 604834.0006) that were shown to cause impaired TBK1 function in in vitro studies.

In 3 unrelated patients with FTDALS4, Pottier et al. (2015) identified heterozygous missense mutations in the TBK1 gene (see, e.g., 604834.0006 and 604834.0007). The mutations were found by whole-genome sequencing of 107 deceased patients with FTD. Western blot analysis of patient cells showed decreased levels of the mutant protein in 2 of the patients.