ALS17 is an adult-onset progressive neurodegenerative disorder with predominantly lower motor neuron involvement, manifest as muscle weakness and wasting of the upper and lower limbs, bulbar signs, and respiratory insufficiency (summary by Cox et al., 2010).
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 ... 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. Cox et al. (2010) reported 3 unrelated patients with ALS17. 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.
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). ... 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). 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.