Frontotemporal Dementia And/or Amyotrophic Lateral Sclerosis 3
A number sign (#) is used with this entry because of evidence that frontotemporal dementia and/or amyotrophic lateral sclerosis-3 (FTDALS3) is caused by heterozygous mutation in the SQSTM1 gene (601530) on chromosome 5q35.
Heterozygous mutation in the SQSTM1 gene can also cause Paget disease of bone (PDB3; 167250).
DescriptionFrontotemporal dementia and/or amyotrophic lateral sclerosis-3 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. Some patients may also develop Paget disease of bone. The phenotype is highly variable, even within families (summary by Rea et al., 2014).
For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Clinical FeaturesHirano et al. (2013) reported 2 unrelated Japanese patients with onset of ALS at ages 59 and 76 years, respectively. Symptoms were variable but included progressive muscle weakness and atrophy, hyporeflexia, dysarthria, bulbar weakness, fasciculations, and hyperreflexia. Electromyography showed fibrillations, suggesting active denervation. Neither patient had apparent dementia, but both eventually became bedridden and needed assisted feeding and ventilation.
Le Ber et al. (2013) reported 4 French families with FTDALS3. Patients in 3 families presented with behavioral disorders consistent with FTD, including executive dysfunction, indifference, disinhibition, echolalia, apathy, and irritability. Only 1 patient developed distal motor deficits, amyotrophy, buccofacial apraxia, hyperreflexia, and fasciculations, consistent with ALS. Three patients from the fourth family presented with Paget disease of bone and later developed dementia; 1 patient from this family presented with dementia and also had PDB. None of these patients had ALS. The report demonstrated the inter- and intrafamilial variability of neurodegenerative features associated with SQSTM1 mutations.
Boutoleau-Bretonniere et al. (2015) reported 3 French sibs with a variant of FTD. The phenotype consisted of speech apraxia, visuoconstructional defects, executive dysfunction, and behavioral disorders with onset between 70 and 75 years of age. None of the patients had evidence of PDB or ALS.
Molecular GeneticsFecto et al. (2011) identified 9 different heterozygous missense mutations (see, e.g., P392L, 601530.0001 and A33V, 601530.0006) and 1 deletion in the SQSTM1 gene in 15 (2.8%) of 546 patients with amyotrophic lateral sclerosis. Six patients had a family history of the disorder, but DNA from relatives was not available for segregation analysis. All the mutations affected conserved residues, and none were present in the dbSNP or 1000 Genomes Project databases or in over 700 control individuals. Functional studies of the variants were not performed. The SQSTM1 gene was chosen as a candidate for direct sequencing because p62-positive aggregates have been found in neuronal and glial tissue from patients with various neurodegenerative disorders, including SOD1 (147450)-positive ALS1 (105400), Alzheimer disease (AD; 104300), Lewy body dementia (DLB; 127750), FUS (137070)-mutant ALS6 (608030), and FTDALS1 (105550). None of the patients had a personal or family history of PDB.
By direct sequencing of the SQSTM1 gene, Rubino et al. (2012) identified 3 missense variants in 3 of 170 Italian patients with FTD and 3 different missense variants in 3 of 124 Italian patients with ALS. None of the variants were found in 145 controls. Subsequent analysis identified 4 variants in the promoter region in 4 patients with FTD and 3 splice site variants in 1 patient with FTD and 3 with ALS. None of the variants were found in 145 control individuals or in 288 patients with Paget disease. Functional studies were not performed, and Rubino et al. (2012) suggested that further studies were warranted.
Hirano et al. (2013) identified 2 different heterozygous missense variants (A53T and P439L) in the SQSTM1 gene in 2 of 61 Japanese patients with ALS. Neither of the variants, which occurred at highly conserved residues, were detected in the dbSNP database or in 500 control Japanese chromosomes. Both patients had sporadic disease, yielding a frequency of 3.7% among 54 patients with sporadic ALS. Neither patient had evidence of Paget disease or dementia; functional studies of the variants were not performed.
Le Ber et al. (2013) identified 3 different heterozygous missense mutations in the SQSTM1 gene (see, e.g., 601530.0001 and 601530.0005) in 3 of 132 unrelated French families with FTD. The mutations were demonstrated to segregate with the disorder in 2 of the families. A heterozygous missense mutation (601530.0006) was found in 1 of 56 probands with FTDALS. The mutation in the first family was found by exome sequencing; subsequent mutations were found by directed sequencing of the SQSTM1 gene in 187 French patients with FTD. In the family carrying the P392L mutation (601530.0001), all patients with FTD also had PDB. Functional studies of the variants were not performed. Overall, mutations were found in 4 (2%) of 188 patients with either FTD or FTDALS, indicating a low frequency of SQSTM1 mutations in FTD.
In 3 French sibs with a variant of frontotemporal dementia, Boutoleau-Bretonniere et al. (2015) identified a heterozygous mutation in the SQSTM1 gene (601530.0007).
PathogenesisRea et al. (2014) reviewed potential pathogenic mechanisms resulting from mutations in the SQSTM1 gene, noting in particular the role of abnormal NFKB1 (164011) signaling and defective ubiquitin-mediated autophagy in neurodegeneration. However, Rea et al. (2014) noted that functional studies of variants found in patients with FTDALS3 had not been performed in cell lines used in ALS or FTD research or in neuronal cells. Some of the mechanisms were reminiscent of those caused by mutation in OPTN (602432), which causes ALS12 (613435); VCP (601023), which causes IBMPFD1 (167320); and UBQLN2 (300264), which causes ALS15 (300857).