A number sign (#) is used with this entry because amyotrophic lateral sclerosis-15 with or without frontotemporal dementia (ALS15) is caused by mutation in the UBQLN2 gene (300264) on chromosome Xp11.

For a general phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis (ALS), see ALS1 (105400).

Deng et al. (2011) identified a 5-generation family with ALS15 including 19 affected individuals. The disease was transmitted in a dominant fashion with reduced penetrance in females. Deng et al. (2011) also identified 4 other unrelated families with ALS15 and obtained clinical data from a total of 40 individuals, including 35 patients and 5 obligate carriers. Penetrance was approximately 90% by age 70 years. The age of onset of disease ranged from 16 to 71 years. There was a significant difference in the age of onset between male and female patients, with male patients having an earlier age of onset (33.9 +/- 14.0 years vs 47.3 +/- 10.8 years, P = 0.003, 2-tailed Student's t-test). However, there were no statistically significant differences in the duration of the disease (43.1 +/- 42.1 months vs 48.5 +/- 19.9 months, P = 0.61). Eight patients manifested both ALS and dementia. Dementia in these patients was similar to frontotemporal lobar type (see 600274), including abnormalities in both behavior and executive function. The dementia was progressive and eventually global in most ALS/dementia patients. In some cases the dementia preceded motor symptoms, but all patients eventually developed motor disability. Pathologic analysis of spinal cord autopsy samples from 2 patients revealed axonal loss in the corticospinal tract, loss of anterior horn cells, and astrocytosis in the anterior horn of the spinal cord.

Fahed et al. (2014) reported a 5-generation family in which 6 individuals presented before 30 years of age with a severe neurodegenerative disorder. The family had previously been reported by DeMyer et al. (1964). Disease onset occurred before age 10 years in 3 males, whereas it began between 20 and 30 years of age in 3 females. Initial symptoms included dysarthria and decreased fine motor dexterity. Speech deficits progressively worsened, and drooling, dysphagia, and abnormal involuntary movements developed, followed by spastic paralysis in all limbs and behavioral dementia. Death occurred in both males and females within 17 years after symptom onset. Brain imaging showed progressive atrophy of the cerebral cortex, substantia nigra, caudate, and corticospinal tracts; imaging in 1 patient was suggestive of iron accumulation in deep brain regions. One additional family member was well until age 63 when she presented with typical signs and symptoms of ALS without dementia. Neuropathologic examination of 4 patients showed frontotemporal atrophy with neuronal loss, gliosis, and myelin pallor in the cortex, cerebrum, cerebellum, and corticospinal tracts. Two patients showed UBQLN2- and TDP43 (605078)-immunopositive neuronal inclusions in the brainstem and hippocampus.

The transmission pattern of a progressive neurodegenerative disorder in the family reported by Fahed et al. (2014) was consistent with X-linked dominant inheritance with incomplete penetrance.

In ALS, protein aggregates or inclusions are most common in spinal motor neurons and are typically skein-like in morphology. These ubiquitin-positive inclusions, among others, are considered to be a hallmark of ALS pathology. Deng et al. (2011) found that the skein-like inclusions from 2 ALS15 patients were immunoreactive with both ubiquilin-2 C-terminus and N-terminus antibodies, indicating that ubiquilin-2 is involved in inclusion formation in X-linked ALS. Furthermore, Deng et al. (2011) found that skein-like inclusions in the X-linked patients were also immunoreactive with antibodies to ALS-implicated proteins ubiquitin (see 191339), p62 (601530), TDP43 (605078), FUS (137070), and optineurin (602432), but not SOD1 (147450). In the brains of patients with UBQLN2 mutations with ALS and dementia, Deng et al. (2011) showed ubiquilin-2 inclusions in the hippocampus, small inclusions in the neuropil, and large inclusions (up to 20 microns in diameter) in some pyramidal neurons, especially those in the CA3 and CA1 regions. Deng et al. (2011) noted that this type of hippocampal pathology had not previously been observed in any other neurodegenerative disorder. Among hippocampal sections from 15 pathologically characterized ALS cases without UBQLN2 mutations, including 5 with dementia, Deng et al. (2011) observed prominent ubiquilin-2 pathology in sections from the cases with dementia but not in those from the 10 cases without dementia. The correlation of hippocampal ubiquilin-2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicated that ubiquilin-2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

Deng et al. (2011) performed linkage analysis with microsatellite markers on the X chromosome in a 5-generation family with ALS and obtained the highest 2-point lod score of 5.0 with marker DXS9736 at theta = 0. Detailed mapping defined a 21.3-Mb minimum candidate region containing 206 genes, of which 191 are protein-coding.

Based on expression profile, function, structure, and potential relevance of their encoded proteins, Deng et al. (2011) selected 41 genes for sequencing within the ALS15 candidate region. They identified 5 different proline substitutions in the PXX repeat domain of UBQLN2 as causative of ALS15 (300264.0001-300264.0005) in 5 unrelated families.

In affected members of a 5-generation family with a progressive neurodegenerative disorder, originally reported by DeMyer et al. (1964), Fahed et al. (2014) identified a heterozygous missense mutation in the UBQLN2 gene (P497L; 300264.0006). Functional studies of the variant were not performed.