Juvenile-onset motor neuron disease caused by novel mutations in β-hexosaminidase

A 12 year-old female presented with a seven-year history of progressive muscle weakness, atrophy, tremor and fasciculations. Cognition was normal. Rectal biopsy revealed intracellular storage material and biochemical testing indicated low hexosaminidase activity consistent with juvenile-onset GM2-gangliosidosis. Genetic evaluation revealed compound heterozygosity with two novel mutations in the hexosaminidase β-subunit (c.512-3 C>A and c.1613+15_1613+18dup). Protein analysis was consistent with biochemical findings and indicated only a small portion of β-subunits were properly processed. These results provide additional insight into juvenile-onset GM2-gangliosidoses and further expand the number of β-hexosaminidase mutations associated with motor neuron disease.

► Child presented with Sandhoff disease chemically similar of “Hexosaminidase Paris”.
► Rectal biopsy revealed storage material in cells between the mucosa and submucosa.
► Evaluation revealed two mutations causing a cryptic splice site and exon skipping.
► Most of the mutant protein was misfolded and retained in the endoplasmic reticulum.
► Miglustat treatment was ineffective, initiation may have been too late for response.