Inherited connective tissue

Persikov, A. V., Pillitteri, R. J., Amin, P., Schwarze, U., Byers, P. H., and Brodsky, B. (2004). Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders. Hum. Mut. 24, 330-337. 

Several inherited connective tissue disorders predispose to arterial dissection and other vascular abnormalities, including aneurysms and vasoocclusive disease. 

Gout. An inherited metabolic disorder occurring especially in men, characterized by a raised but variable blood uric acid level, recurrent acute arthritis of sudden onset, deposition of crystalline sodium urate in connective tissues and articular cartilage, and progressive chronic arthritis. 

Some inherited disorders of connective tissue (Table 3.2) can present with, or be complicated by, arterial dissection or even rupture, intra- and extracranial aneurysm formation. 

Marfan syndrome is genetic disease that involves defects in the connective tissues of the body with the cardinal collection of abnormalities affecting the skeletal, ocular, and cardiovascular systems. It is inherited as an autosomal dominant disorder, meaning that inheriting only one defective gene from either the paternal or maternal side will lead to the disorder. Although the majority of mutations are inherited from one of the parents, approximately 25% of affected individuals develop Marfan syndrome as a result of a new mntation. The prevalence is 1/20,000 and the disorder is inherited with variable expression. This means that each individual may have a different combination of the possible clinical features that characterize the disorder. 

Drockop DJ, Kuivanieni H, Tromp G, Ala-Kokko L. Inherited disorders of connective tissue. In Braunwald E, Fauci AS, Kasper DL et al. Harrison s Principles of Internal Medicine, 15th edn. New York, McGraw-HiU, 2001 2290-300 (specifically 2295-7). 

Several inherited disorders of methionine metabolism (Chapter 17) give rise to exeessive production of homocysteine, HS-CH2-CH2CH(NH3 )COO , and its excretion in urine. The most common form of homocystinuria is due to a deficiency of cystathionine synthase (Chapter 17). A major clinical manifestation of homocystinuria is connective tissue abnormalities that are probably due to the accumulation of homocysteine, which either inactivates the reactive aldehyde groups or impedes the formation of polyfunctional cross-links. 

D31. Dorfman, A., Heritable diseases of connective tissue. The Hurler syndrome. In The Metabolic Basis of Inherited Disease (J. B. Stanbury, J. B. Wyngaar-den, and D. S. Fredrickson, eds.), 2nd ed., pp. 963-994. McGraw-Hifl, New York, 1966. 

Osteogenesis imperfecta (01) is an inherited disorder of connective tissue resulting from abnormal quantity and/or quality of type I collagen, the major protein of bone. The phenotypic presentation is enormously varied, ranging from perinatal death to normal lifespan complicated by only a few fractures. Because fractures are a feature of the condition it must be given serious consideration in any child with unexplained fractures. There are four major types in the Sillence classification (Sillence et al. 1979), but it should be noted that there are no strict boundaries. Type IV is an uncommon type of 01 (only 5% of the patients in the Sillence study) with mild to severe bone disease. Patients with this type... 

Alterations of the connective tissue composition of the extracellular matrix are an important feature of various inherited and acquired disorders of soft tissue (Miller 1976). This phenomenon is particularly important in the lung in which elasticity is a vital determinant of function. Interstitial collagen is composed of at least two distinct trimeric polypeptide molecules designated as type 1 and type 111 collagens. Type 1 contains two ai(I) chains and one 02 chain, whereas type 111 contains 3 identical a, (HI) chains. Pulmonary fibroblasts produce more type I... 

AVM can be associated with hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome. It is an autosomal dominant inherited disease of the vascular connective tissue characterized by epistaxis, telangiectasia, and visceral arteriovenous malformation. The organs mostly affected are the lungs (Fig. 23.8a-c), liver, brain, and the gastrointestinal tract. HHT is difficult to treat and requires a multidisciplinary approach for its management. 

A group of inherited diseases in which there is abnormal metabolism and excretion of the various mucopolysaccharides. The features of these diseases are a reflection of the inability of the body to link the mucopolysaccharides with proteins to form the basic substance of connective tissue. Skeletal abnormalities l-esult from this. Affected individuals may also have grotesque facial expressions. The mucopolysaccharidoses have been classified as follows ... 

The myopathic features of IBMPFD vary tremendously between patients, but usually encompass the typical characteristics of inclusion-body myopathy (IBM), including the presence of ubiquitin-positive inclusions, centralized nuclei, and an increased prevalence of endomysial connective tissue [3, 10, 13]. In addition, inclusions containing TAR DNA-binding protein-43 (TDP-43), which colocahze with ubiquitin, are often found in the sarcolemma and sarcoplasm of affected musdes [14, 15]. However, TDP-43-positive inclusions are also found in several other myopathies, as well as dominantly inherited and sporadic cases of ALS [16], Other myopathic characteristics of IBMPFD may indude regional variations in muscle-fiber size, as weU as the presence of rimmed vacuoles and/or inflammatory infiltrates [3, 10, 11]. 

Several inherited diseases of connective tissues are known (McKusick, 1966), some of which involve a derangement of glycosaminoglycan metabolism, and, in particular, Hurler s syndrome has been extensively studied in many laboratories (Dorfman, 1966a Dorfman and Matalon, 1969). The disorder expresses itself biochemically as an accumulation of glycosaminoglycans in various tissues (particularly dermatan sulfate and heparan sulfate), and recent work by Fratantoni si al. (1968) and Neufeld and Fratantoni (1970) suggests that there is a defect in degradation of the glycosaminoglycans rather than an overproduction. 

On the other hand, durit morphogenesis of hi er organisms, the concept of repressors does not provide a logical explanation of the purposive inherited automation of development, and if we assume that differences in the spectrum of active and passive genes in different tissues are associated with differences in the assortment of repressors, we are naturally faced with a question of the same order of complexity why is it that a different assortment of repressors is formed in different tissues, and what controls the purposiveness of this phenomenon in time and in connection with its localization ... 

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