A number sign (#) is used with this entry because of evidence that frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8) is caused by heterozygous mutation in the CYLD gene (605018) on chromosome 16q12. One such family has been reported.

Frontotemporal dementia and/or amyotrophic lateral sclerosis-8 (FTDALS8) is an autosomal dominant neurodegenerative disorder characterized by adult-onset dementia manifest as memory impairment, executive dysfunction, and behavioral or personality changes. Some patients may develop ALS or parkinsonism. Neuropathologic studies show frontotemporal lobar degeneration (FTLD) with tau (MAPT; 157140)- and TDP43 (605078)-immunoreactive inclusions (summary by Dobson-Stone et al., 2020).

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

Dobson-Stone et al. (2013) reported a large multigenerational kindred of European Australian descent (Aus-12) in which at least 10 individuals spanning 4 generations had a similar neurodegenerative disorder. The family was subsequently reported by Dobson-Stone et al. (2020). Most patients had FTD; 1 had FTD and ALS, and 3 had ALS without dementia. All patients were deceased at the time of the report. Clinical details were provided for some of the patients. The proband presented at 56 years of age with memory deficits and personality changes. Her features were initially consistent with Alzheimer disease (AD; 104300), but progression of the disorder and frontotemporal hypoperfusion on imaging led to a diagnosis of FTD. She died at age 68. Another family member showed progressively abnormal behavior in his fifties and died at age 64. Two more family members had features of adult-onset ALS with fasciculations and active limb denervation. One of these patients with ALS also had FTD, Paget disease, and parkinsonism, whereas the other had severe ALS with paralysis, dysarthria, dysphagia, and muscle wasting, but no apparent dementia. Neuropathologic examination of 2 patients showed frontotemporal atrophy with neuronal and glial accumulation of phospho-tau, as well as TDP43-positive neuronal cytoplasmic inclusions. The pathologic diagnosis was FTLD-TDP type B.

The transmission pattern of FTDALS8 in the family reported by Dobson-Stone et al. (2020) was consistent with autosomal dominant inheritance.

In 5 affected individuals from a large multigenerational family of European Australian descent (Aus-12) with FTDALS8, Dobson-Stone et al. (2013) and Dobson-Stone et al. (2020) identified a heterozygous missense mutation in the CYLD gene (M719V; 605018.0012). Mutations in the FUS gene (137070) were excluded. The CYLD mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. It was not present in several public databases, including gnomAD. Transfection of primary mouse cortical neurons with mutant M719V CYLD resulted in an increased proportion of neurons with cytoplasmic TDP43 (605078) staining (55%) compared to cells transfected with wildtype CYLD (34%). The mutation also altered axonal morphology, leading to a decrease in axonal length. Additional in vitro cellular studies showed that the M719V mutation resulted in increased K63 deubiquitinase activity, enhanced inhibition of NFKB, and impaired autophagosome fusion with lysosomes compared to wildtype, indicating a gain-of-function effect. The authors noted that other disorders associated the CYLD mutations result in a loss of function. CYLD was found to directly interact with TBK1 (604834), OPTN (602432), and SQSTM1 (601530), all of which are implicated in autophagy and, when mutated, are causative of FTD or ALS. Neuropathologic analysis of postmortem brain tissue of 2 affected individuals showed widespread glial CYLD immunoreactivity that was not present in other patients with sporadic FTD. There were also patchy areas of diffuse neuronal cytoplasmic CYLD staining in the hippocampus and frontal cortex, as well as CYLD immunoreactivity in the nuclei of pyknotic neurons. CYLD did not colocalize with either tau or TDP43 inclusions. The report thus identified another molecular mechanism by which impaired autophagy can result in a neurodegenerative disorder. CYLD mutations were not found in several cohorts of ALS and FTD patients comprising several thousand individuals, suggesting that it is a rare cause of the disorder.

In 2 of 65 Portuguese patients with FTD who underwent whole-exome sequencing, Tabuas-Pereira et al. (2020) identified heterozygous missense variants in the CYLD gene (S615F and P229S). Both variants had low frequencies in the gnomAD database (less than 9 x 10(-6)); functional studies of the variants were not performed and family members were not available for segregation studies. The patients had onset of progressive dementia with executive dysfunction and memory impairment at 53 and 74 years of age, respectively. The phenotype was reminiscent of Alzheimer disease.