Alternative titles; symbols
SNOMEDCT: 702393003; ORPHA: 275864, 282, 803; DO: 0111227;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3p11.2 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 | 600795 | Autosomal dominant | 3 | CHMP2B | 609512 |
A number sign (#) is used with this entry because of evidence that frontotemporal dementia and/or amyotrophic lateral sclerosis-7 (FTDALS7) is caused by heterozygous mutation in the CHMP2B gene (609512) on chromosome 3p11.
Frontotemporal dementia and/or amyotrophic lateral sclerosis-7 (FTDALS7) is an autosomal dominant neurodegenerative disorder characterized by onset of ALS or FTD in adulthood. Some patients have ALS, manifest as muscle weakness and wasting of the upper and lower limbs, bulbar signs, and respiratory insufficiency, whereas others have FTD, manifest as behavioral and personality changes, memory loss, cognitive decline, and disinhibition. A few patients may have both phenotypes. Pathology typically shows UBB (191339), p62/sequestosome (SQSTM1; 601530), and TDP43 (605078)-immunoreactive intraneuronal inclusions (summary by Brown et al., 1995 and Cox et al., 2010).
For a general phenotypic description and a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).
Brown et al. (1995) and Brown (1998) studied a large kindred from the Jutland region of Denmark, constituting the largest published pedigree with multiple members affected by dementia unassociated with distinctive histopathologic features. The family had previously been described by Gydesen et al. (1987). Gydesen et al. (2002) provided additional clinical information on 22 affected individuals spanning 3 generations of this Danish kindred. The disease presented at an average age of 57 years with an insidious change in personality and behavior, including memory loss, cognitive decline, apathy, aggressiveness, stereotyped behavior, and disinhibition. Later in the illness, most patients developed a motor syndrome with abnormal gait, rigidity, hyperreflexia, and pyramidal signs. PET scan of 2 affected individuals revealed a global reduction in cerebral blood flow, and pathologic examination of several individuals showed generalized cerebral atrophy most prominent in the frontal and parietal lobes. Microscopic examination revealed cortical neuronal loss, astrocytosis, and white matter changes due to loss of myelin, but no plaques, fibrillary tangles, or inclusions. The authors termed the disorder FTD3 (chromosome 3-linked frontotemporal dementia). Gydesen et al. (2002) noted that the phenotype in the family reported by Kim et al. (1981) was similar.
Parkinson et al. (2006) reported a 75-year-old man with rapidly progressive ALS. At age 74 years, the patient developed bulbar-onset weakness with flaccid dysarthria and tongue fasciculations. He later developed weakness and wasting of the intrinsic hand muscles and respiratory weakness. Although he had a previous right leg amputation from trauma, neurophysiologic testing showed neurogenic changes in all 4 limbs. Deep tendon reflexes were depressed and plantar responses were flexor. The patient died of respiratory failure 15 months after symptom onset. There was no evidence of dementia or extramotor neurologic involvement. A cousin reportedly died of ALS. Neuropathologic examination showed a predominantly lower motor neuron disease with intraneuronal inclusions immunopositive for ubiquitin (UBB; 191339) and p62/sequestosome (SQSTM1; 601530) within lower motor neurons in the ventral horn of the spinal cord. Although initial studies showed no upper motor neuron pathology in the motor cortex, special repeat studies showed SQSTM1-reactive inclusions within oligodendroglia in the cerebral motor cortex. A second unrelated patient developed progressive frontotemporal dementia in his late sixties. After 5 years, he developed motor disturbances, including atrophy of the tongue and facial muscles, spastic dysarthria, pseudobulbar paresis, and progressive paresis of the limbs, consistent with a diagnosis of ALS. He had brisk tendon reflexes and extensor plantar responses. His father reportedly had motor disturbances and frontal lobe dysfunction.
Van der Zee et al. (2008) reported a Belgian woman with onset of frontotemporal dementia at age 58 years. Initial symptoms included progressive dysgraphia, memory loss, and mild disinhibition. Two years later, she had a light disorientation in space and time, severe dysgraphia, confabulation, dyspraxia, and dyscalculia. Brain CT scan showed mild frontal cortical atrophy. At the age of 64, she was clearly disoriented in space and time, her handwriting had become unreadable, and she was dyslexic with logorrhoea and perseveration. Repeat CT scan showed generalized cortical atrophy. Her mother and maternal aunt were reportedly similarly affected.
Cox et al. (2010) reported 3 unrelated patients with ALS without dementia. All had symptoms of predominant lower motor neuron degeneration without upper motor neuron involvement. One man presented at age 54 years with bulbar and respiratory dysfunction and later developed wasting and fasciculation in the upper and lower limbs. Reflexes were normal. A 64-year-old woman presented with leg weakness, with later development of the upper limb, bulbar, and respiratory muscles. Reflexes were normal and plantar reflexes were flexor. The third patient was a 49-year-old man who presented with weakness of the legs and had rapid disease progression with wasting and fasciculations in the upper limbs and bulbar involvement. None of the patients had dementia. All patients died of the disorder. Neuropathologic examination of these 3 patients and 1 of the patients reported by Parkinson et al. (2006) showed no evidence of corticospinal involvement on conventional stains, consistent with the lack of upper motor neuron clinical signs. However, 1 patient had some subcortical microglial activation in the precentral gyrus and mild changes in the medulla. The lower motor neuron pathology was typical of the primary muscular atrophy variant of ALS. There was severe loss of motor neurons at all levels of the spinal cord, and surviving neurons had UBB-/p62-/TDP43 (605078)-positive inclusion bodies. There did not appear to be extramotor involvement of the CNS. Skein-like inclusion bodies and Bunina bodies, which are often found in ALS, were notably absent in these patients.
Gydesen et al. (2002) noted that the transmission pattern of dementia in a large affected Danish family was consistent with autosomal dominant inheritance.
In a large Danish kindred segregating dementia, Brown et al. (1995) mapped the disease locus to a 12-cM region of chromosome 3 spanning the centromere. Haplotype analysis demonstrated a region between markers D3S1284 and D3S1603 that was shared by all affected individuals. The disease appeared to present at an earlier age when paternally inherited. On gathering more information from affected individuals in this family, however, Gydesen et al. (2002) found that evidence for paternal anticipation had been weakened.
Urwin et al. (2010) described endosomal pathology in CHMP2B mutation-positive patient brains and also identified and characterized abnormal endosomes in patient fibroblasts. Functional studies demonstrated a specific disruption of endosome-lysosome fusion but not protein sorting by the multivesicular body (MVB). The authors proposed a mechanism for impaired endosome-lysosome fusion whereby mutant CHMP2B constitutively binds to MVBs and prevents recruitment of proteins, such as Rab7 (602298), that are necessary for fusion to occur.
In 11 affected members of a large Danish family with frontotemporal dementia reported by Brown et al. (1995) and Gydesen et al. (2002), Skibinski et al. (2005) identified a heterozygous mutation in the CHMPB2 gene (609512.0001). The authors identified a different CHMPB2 mutation (609512.0002) in a single unrelated patient with nonspecific dementia.
Momeni et al. (2006) did not identify pathogenic mutations in the CHMPB2 gene in 128 probands with frontotemporal dementia in whom MAPT mutations had been excluded. A truncating mutation in the CHMPB2 gene was identified in 2 middle-aged unaffected Afrikaner individuals from a large affected family; however, their affected father and 5 affected paternal relatives did not have the mutation. The maternal side of the family had no reported dementia. Momeni et al. (2006) noted that the large Danish family reported by Skibinski et al. (2005) had a similar truncating mutation in the CHMPB2 gene, which resulted from a different nucleotide change. The findings raised questions about the pathogenicity of the CHMPB2 mutation identified by Skibinski et al. (2005) and suggested that CHMPB2 mutations are not a common cause of frontotemporal dementia.
Cannon et al. (2006) did not identify pathogenic CHMPB2 mutations in 141 familial frontotemporal probands from the U.S. and U.K. In addition, the splice site mutation reported by Skibinski et al. (2005) was not found in 450 control individuals.
In a 75-year-old man with rapidly progressive ALS, Parkinson et al. (2006) identified a heterozygous mutation in the CHMP2B gene (Q206H; 609512.0003). A second unrelated patient with frontotemporal dementia and ALS had a different heterozygous mutation (I29V; 609512.0005).
Van der Zee et al. (2008) identified a truncating mutation in the CHMPB2 gene (609512.0004) in a Belgian patient with autosomal dominant frontotemporal lobar degeneration.
Cox et al. (2010) identified mutations in the CHMP2B gene (see, e.g., 609512.0003, 609512.0005, and 609512.0006) in 4 (1%) of 433 patients with ALS. However, CHMP2B mutations were found in 10% of those with the lower motor neuron variant of ALS, suggesting an enrichment of mutations in patients with that specific disease subtype. Microarray analysis of motor neurons with CHMP2B mutations showed downregulation of genes involved in axonal transport, autophagy induction, protein translation, and certain signaling pathways, such as MAPK-related pathways (see, e.g., 600289). Transfection of mutant CHMP2B into HEK293 and COS-7 cells resulted in the formation of large cytoplasmic vacuoles, aberrant lysosomal localization, and impaired autophagy. Cox et al. (2010) hypothesized that CHMP2B mutations may contribute to motor neuron injury through dysfunction of the autophagic clearance of cellular proteins.
MacKenzie et al. (2010) suggested that the neuropathologic term 'FTLD-UPS' be used for CHMPB2-related FTLD, because the inclusions are only detectable with immunohistochemistry against proteins of the ubiquitin proteasome system (UPS).
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