Other Lysosomal Storage Diseases

Wolman disease Acid lipase Cholesterol esters, triglycerides

Acid phosphate deficiency Lysosomal acid phosphatase Phosphate esters

of cytoplasmic inclusions can be visualized, the most prominent being whorled configurations within lysosomes composed of onion-skin layers of membranes ( Fig. 5-14B ). In time, there is

progressive destruction of neurons, proliferation of microglia, and accumulation of complex lipids in phagocytes within the brain substance. A similar process occurs in the cerebellum as well

as in neurons throughout the basal ganglia, brain stem, spinal cord, and dorsal root ganglia and in the neurons of the autonomic nervous system. The ganglion cells in the retina are similarly

swollen with GM2 ganglioside, particularly at the margins of the macula. A cherry-red spotthus appears in the macula, representing accentuation of the normal color of the macular choroid

contrasted with the pallor produced by the swollen ganglion cells in the remainder of the retina ( Chapter 29 ). This finding is characteristic of Tay-Sachs disease and other storage disorders

affecting the neurons.

Many alleles have been identified at the a-subunit locus, each associated with a variable degree of enzyme deficiency and hence with variable clinical manifestations. The affected infants

appear normal at birth but begin to manifest signs and symptoms at about age 6 months. There is relentless motor and mental deterioration, beginning with motor incoordination, mental

obtundation leading to muscular flaccidity, blindness, and increasing dementia. Sometime during the early course of the disease, the characteristic, but not pathognomonic, cherry-red spot

appears in the macula of the eye grounds in almost all patients. Over the span of 1 or 2 years, a complete, pathetic vegetative state is reached, followed by death at age 2 to 3 years.

Antenatal diagnosis and carrier detection are possible by enzyme assays and DNA-based analysis.[25] The clinical features of the two other forms of GM2 gangliosidosis (see Fig. 5-13 ),

Sandhoff disease, resulting from b-subunit defect, and GM2 activator deficiency, are similar to those of Tay-Sachs disease.

Figure 5-13The three-gene system required for hexosaminidase A activity and the diseases that result from defects in each of the genes. The function of the activator protein is to bind the

ganglioside substrate and present it to the enzyme. (Modified from Sandhoff K, et al: The GM2 gangliosidoses. In Scriver CR, et al [eds]: The Metabolic Basis of Inherited Disease, 6th ed.

New York, McGraw-Hill, 1989, p. 1824.)

Figure 5-14Ganglion cells in Tay-Sachs disease. A, Under the light microscope, a large neuron has obvious lipid vacuolation. (Courtesy of Dr. Arthur Weinberg, Department of Pathology,

University of Texas Southwestern Medical Center, Dallas.) B, A portion of a neuron under the electron microscope shows prominent lysosomes with whorled configurations. Part of the

nucleus is shown above. (Electron micrograph courtesy of Dr. Joe Rutledge, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-15Niemann-Pick disease in liver. The hepatocytes and Kupffer cells have a foamy, vacuolated appearance owing to deposition of lipids. (Courtesy of Dr. Arthur Weinberg,

Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-16Gaucher disease involving the bone marrow. A, Gaucher cells with abundant lipid-laden granular cytoplasm. B, Electron micrograph of Gaucher cells with elongated distended

lysosomes. (Courtesy of Dr. Matthew Fries, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

Figure 5-17Pathways of glycogen metabolism. Asterisks mark the enzyme deficiencies associated with glycogen storage diseases. Roman numerals indicate the type of glycogen storage

disease associated with the given enzyme deficiency. Types V and VI result from deficiencies of muscle and liver phosphorylases, respectively. (Modified from Hers H, et al: Glycogen

storage diseases. In Scriver CR, et al [eds]: The Metabolic Basis of Inherited Disease, 6th ed. New York, McGraw-Hill, 1989, p. 425.)

Figure 5-18Top, Simplified schema of normal glycogen metabolism in the liver and skeletal muscles. Middle, Effects of an inherited deficiency of hepatic enzymes involved in glycogen

metabolism. Bottom, Consequences of a genetic deficiency in the enzymes that metabolize glycogen in skeletal muscles.

Figure 5-19Pompe disease (glycogen storage disease type II). A, Normal myocardium with abundant eosinophilic cytoplasm. B, Patient with Pompe disease (same magnification) showing

the myocardial fibers full of glycogen seen as clear spaces. (Courtesy of Dr. Trace Worrell, Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.)

TABLE 5-7-- Principal Subgroups of Glycogenoses

Clinicopathologic

Date: 2016-04-22; view: 600