The molecular basis for neuronal injury is not fully understood. Because in many cases the mutant protein is misfolded, it induces the so-called “unfolded protein” response (Chapter 2). If such misfolded enzymes are not stabilized by chaperones, they undergo proteasomal degradation, leading to accumulation of toxic substrates and intermediates within neurons. These findings have spurred clinical trials of molecular chaperone therapy for some variants of later-onset Tay-Sachs and other selected lysosomal storage diseases. Such therapy involves the use of synthetic chaperones that can cross the blood–brain barrier, bind to the mutated protein, and enable its proper folding. Sufficient functional enzyme can then be rescued to ameliorate the effects of the inborn error.
In the most common acute infantile variant of Tay-Sachs disease, infants appear normal at birth, but motor weakness begins at 3 to 6 months of age, followed by neurologic impairment, onset of blindness, and progressively more severe neurologic dysfunctions. Death occurs within 2 to 3 years.
Type A and type B Niemann-Pick diseases are related entities characterized by a primary deficiency of acid http://ebooksmedicine.net
Fig. 7.9 GanglioncellsinTay-Sachsdisease.(A)Underthelightmicroscope,alargeneuronhasobviouslipidvacuolation.(B)Aportionofaneuronundertheelectronmicroscopeshowsprominentlysosomeswithwhorledconfigurationsjustbelowpartofthenucleus.(A, Courtesy of Dr. Arthur Weinberg, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas. B, Courtesy of Dr. Joe Rutledge, Children’s Regional Medical Center, Seattle, Washington.) sphingomyelinase and the resultant accumulation of sphingomyelin. As with Tay-Sachs disease, Niemann-Pick disease types A and B are common in Ashkenazi Jews. The gene for acid sphingomyelinase maps to chromosome 11p15.4 and is one of the imprinted genes that is preferentially expressed from the maternal chromosome as a result of epigenetic silencing of the paternal gene (discussed later).
In type A, characterized by a severe deficiency of sphingomyelinase, the breakdown of sphingomyelin into ceramide and phosphorylcholine is impaired, and excess sphingomyelin accumulates in phagocytic cells and in neurons. Macrophages become stuffed with droplets or particles of the complex lipid, imparting a fine vacuolation or foaminess to the cytoplasm (
Fig. 7.10 ). Electron microscopy shows engorged secondary lysosomes that often contain membranous cytoplasmic bodies resembling concentric lamellated myelin figures, sometimes called “zebra” bodies. Because of their high content of phagocytic cells, the organs most severely affected are the spleen, liver, bone marrow, lymph nodes, and lungs. The splenic enlargement may be striking. In addition, the entire CNS, including the spinal cord and ganglia, is involved in this inexorable process. The affected neurons are enlarged and vacuolated as a result of the accumulation of lipids. This variant manifests in infancy with massive organomegaly and severe neurologic deterioration. Death usually occurs within the first 3 years of life. By comparison, patients with the type B variant, which is associated with mutant sphigomyelinase with some residual activity, have organomegaly but no neurologic manifestations. Estimation of sphingomyelinase activity in the leukocytes can be used for diagnosis of suspected cases, as well as for detection of carriers. Molecular genetic tests are also available for diagnosis at specialized centers.