Chapter 9 GM(2) gangliosidoses.

LOGM(2)G results from the defective activity of the lyosomal enzyme beta-hexosaminidase A. Continued accumulation of undegraded substrate results in pathology in the central nervous system. The disease is progressive and disease dynamics may vary throughout life. Clinically, the disease variants present a remarkable spectrum of phenotypes ranging from the lethal form to a slowly progressive disease type. Genotype/phenotype correlations are imperfect. Homozygosity for the L444P genotype is almost always associated with the infantile form. The pathological mechanism of the central nervous system damage is still not fully understood. Neuronal loss and neurodegeneration have been reported, as well as gray matter and white matter involvement, leading to multisystem expression. Recently, the possibilities of using stem cells to replace damaged neurons or enzyme replacement therapy have been suggested for several neurodegenerative diseases. The anterior horn cells can theoretically be a target for this procedure. In fact, using stem cells engineered to carry a normal HEXA gene is potentially more likely to benefit LOGM(2)G cases than patients with other forms of motor neuron disease, since in ALS the degenerative process will continue and is likely to affect the transplanted cells whereas in LOGM(2)G a real correction of the metabolic abnormality could replace damaged motor neurons by normal ones.