Amyotrophic Lateral Sclerosis 14 With Or Without Frontotemporal Dementia
A number sign (#) is used with this entry because amyotrophic lateral sclerosis-14 with or without frontotemporal dementia (ALS14) is caused by heterozygous mutation in the VCP gene (601023) on chromosome 9p13.
DescriptionAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic TDP43 (TARDBP; 605078) aggregates. Patients with ALS14 may develop frontotemporal dementia (FTD) (summary by Johnson et al., 2010).
See inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD; 167320), which is also caused by mutation in the VCP gene and shows some overlapping features. In some families with a VCP mutation, some family members may have ALS14, and other members may have IBMPFD.
For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Clinical FeaturesJohnson et al. (2010) reported an Italian family in which 4 affected members had ALS. Affected individuals presented in adulthood (range, 37 to 53 years) with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classic ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. In another family, 2 patients had ALS with frontotemporal dementia, and a third had Paget disease followed by ALS, suggesting an overlap with IBMPFD.
Johnson et al. (2010) reported a patient with classic ALS confirmed by postmortem studies, who was a member of a large family with IBMPFD previously reported by Watts et al. (2004). However, the family member reported by Johnson et al. (2010) had rapidly progressive ALS without evidence of Paget disease, myopathy, or FTD. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43-positive immunostaining, and mild pallor of the lateral corticospinal tracts, all features consistent with a diagnosis of ALS. The patient carried the same heterozygous mutation as his family members with IBMPFD (R155H; 601023.0001), indicating an expanded phenotype associated with this mutation.
Molecular GeneticsUsing exome sequencing, Johnson et al. (2010) identified a heterozygous mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of an Italian family with ALS14 with or without FTD. Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (601023.0001; 601023.0008, and 601023.0009) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS.