Abstract-Mutation in the CHMP2B gene has been implicated in frontotemporal dementia. The authors screened CHMP2B in patients with ALS and several cohorts of control samples. They identified mutations (Q206H; I29V) in two patients with non-SOD1 ALS. Neuropathology of the Q206H case showed lower motor neuron predominant disease with ubiquitylated inclusions in motor neurons. Antibodies to p62 (sequestosome 1) showed novel oligodendroglial inclusions in the motor cortex. NEUROLOGY 2006;67:1074-1077 1 Here we show that CHMP2B (charged multivesicular body protein 2B), a gene that was recently shown to be linked to FTD, 2 was altered in two unrelated patients with ALSspectrum disorders. One mutation is predicted to alter a conserved functional domain. Pathology from this case strengthens the hypothesis of a common molecular pathology between ALS and FTD. 3 The second case showed a point substitution that has been previously described as a low-frequency variation in the CHMP2B gene. A 75-year-old man reported bulbaronset weakness for 11 months, which progressed to involve his hands after 5 months. Examination findings at that stage were a wasted, weak, fasciculating tongue, flaccid dysarthria, and bilateral weakness and wasting of the intrinsic hand muscles. Tendon reflexes were depressed, and the plantar responses were flexor. There was no evidence of significant cognitive dysfunction on bedside testing. He had a right below-knee amputation for trauma 15 years previously. Neurophysiology showed widespread neurogenic changes in bulbar, upper limb, and lower limb territories, and a diagnosis of progressive muscular atrophy (PMA) (El Escorial category of suspected ALS) was made. His weakness rapidly progressed until his death from respiratory failure 15 months after symptom onset. There was no evidence of extramotor neurologic signs or symptoms or dementia throughout the illness. A cousin was also said to have died of ALS, but it was not possible to obtain DNA from other family members.Patient 2. This 65-year-old man had behavioral and personality changes, including depression, excessive alcohol consumption, and inappropriate sexual behavior. In the next 4 years, this progressed to fulminant FTD. After 5 years, he developed motor disturbances including atrophy of the tongue and facial muscles. There was spastic dysarthria, pseudobulbar paresis causing dysphagia, and weight loss. Motor symptoms progressed to paresis of the right arm and hand and both legs. He retained normal sensation and autonomic function. There were brisk tendon reflexes and upgoing plantar responses. A diagnosis of ALS (El Escorial ALS ϩ dementia) was established on clinical and neurophysiologic grounds. Six years after the onset of behavioral symptoms, he died suddenly, but no autopsy was performed. His father was reported to have frontal lobe dysfunction and motor disturbances. This familial history was not verified by case note review, and DNA could not be obtained from other family members because of lack of permission.

A locus on chromosome 9p21.3-p13.3 is linked to ALS-FTD.

This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.

The authors report a 73-year-old patient with a natural history of early-onset ALS for 49 years presenting with limb and bulbar amyotrophy and a pyramidal syndrome. Analysis of the locus SPG4 identified a heterozygous duplication mutation (c.304_309dupGCCTCG) within exon 1 of the spastin gene. We propose that sequence alterations of spastin may comprise a genetic risk factor in a greater spectrum of motor neuron disorders including clinical variants of ALS.

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