Mucopolysaccharidoses

The mucopolysaccharidoses, as discussed in Chapter 5 , are a group of lysosomal storage diseases caused by deficiencies in the enzymes that degrade dermatan sulfate, heparan sulfate,

and keratan sulfate. The implicated enzymes are mainly acid hydrolases. Mesenchymal cells, especially chondrocytes, play an important role in the metabolism of extracellular matrix

mucopolysaccharides and therefore are most severely affected. Consequently, many of the skeletal manifestations of the mucopolysaccharidoses result from abnormalities in hyaline

cartilage, including the cartilage anlage, growth plates, costal cartilages, and articular surfaces. It is not surprising therefore that patients with mucopolysaccharidoses are frequently of

short stature and have chest wall abnormalities and malformed bones.

DISEASES ASSOCIATED WITH DEFECTS IN METABOLIC PATHWAYS (ENZYMES, ION CHANNELS, AND TRANSPORTERS)

Osteopetrosis

Osteopetrosis refers to a group of rare genetic diseases that are characterized by reduced osteoclast bone resorption, resulting in diffuse symmetric skeletal sclerosis ( Fig. 26-9 ). The

term osteopetrosis was coined because of the stonelike quality of the bones; however, the bones are abnormally brittle and fracture like a piece of chalk. Osteopetrosis, which is also

known as marble bone disease and Albers-Schönberg disease, is classified into variants based on both the mode of inheritance and the clinical findings. The autosomal recessive

malignant type and the autosomal dominant benign type are the most common variants.

Pathogenesis.

Four types of osteopetrosis have been identified: infantile malignant osteopetrosis, type II carbonic anhydrase deficiency, and autosomal-dominant types I and II. However, the precise

nature of the osteoclast dysfunction in many cases remains unknown. An example of a form of the disease in which the molecular mechanism is understood is the variant associated with

carbonic anhydrase II deficiency.[19] Carbonic anhydrase II is required by osteoclasts and renal tubular cells to excrete hydrogen ions and acidify their environment. The absence of this

enzyme prevents osteoclasts from acidifying the resorption pit and solubilizing the hydroxyapatite crystals and also blocks the acidification of urine by renal tubular cells. In another

form of the disease, a mutation in the ClC-7 chloride channel gene causes osteoclast dysfunction by interfering with the chloride channel that is important in the proton pump of the H+ -

ATPase located on the osteoclast ruffled border. Consequently, osteoclasts cannot acidify the resorption pit, thus preventing the digestion of bone.[20] In mice, osteopetrosis can also be

caused by targeted mutations in the genes coding for M-CSF, c-src, RANK, and OPG.[19] It is possible that some of these genes will be linked to the human disease.

Morphology.

The morphologic changes of osteopetrosis are explained by deficient osteoclast activity. Grossly the bones lack a medullary canal, and the

Figure 26-8Skeletal radiograph of a fetus with lethal type II osteogenesis imperfecta. Note the numerous fractures of virtually all bones, resulting in accordion-like shortening of the

limbs.

Figure 26-9Radiograph of the upper extremity in a patient with osteopetrosis. The bones are diffusely sclerotic, and the distal metaphyses of the ulna and radius are poorly formed

(Erlenmeyer flask deformity).

Figure 26-10Section of proximal tibial diaphysis from a fetus with osteopetrosis. The cortex (1) is being formed, and the medullary cavity (2) is abnormally filled with primary

spongiosa replacing the hematopoietic elements.

TABLE 26-4-- Categories of Generalized Osteoporosis

Primary

Postmenopausal ••Idiopathic

Senile

Secondary

Date: 2016-04-22; view: 825