Autosomal dominant congenital spinal muscular atrophy is characterized by 
predominantly lower limb weakness and wasting, and congenital or early-onset 
contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation 
channel, have recently been identified in one large dominant congenital spinal 
muscular atrophy kindred, but the genetic basis of dominant congenital spinal 
muscular atrophy in many families remains unknown. It has been hypothesized that 
differences in the timing and site of anterior horn cell loss in the central 
nervous system account for the variations in clinical phenotype between 
different forms of spinal muscular atrophy, but there has been a lack of 
neuropathological data to support this concept in dominant congenital spinal 
muscular atrophy. We report clinical, electrophysiology, muscle magnetic 
resonance imaging and histopathology findings in a four generation family with 
typical dominant congenital spinal muscular atrophy features, without mutations 
in TRPV4, and in whom linkage to other known dominant neuropathy and spinal 
muscular atrophy genes has been excluded. The autopsy findings in the proband, 
who died at 14 months of age from an unrelated illness, provided a rare 
opportunity to study the neuropathological basis of dominant congenital spinal 
muscular atrophy. There was a reduction in anterior horn cell number in the 
lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the 
ventral nerve roots at these levels, in the absence of additional peripheral 
nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young 
age of the child at the time of autopsy, there was no pathological evidence of 
ongoing loss or degeneration of anterior horn cells suggesting that anterior 
horn cell loss in dominant congenital spinal muscular atrophy occurs in early 
life, and is largely complete by the end of infancy. These findings confirm that 
dominant congenital spinal muscular atrophy is a true form of spinal muscular 
atrophy caused by a loss of anterior horn cells localized to lumbar and cervical 
regions early in development.