Linked Diseases

SCA affects both males and females equally because it is not a sex-linked disease. Nine percent of African Americans possess the SCT and 1 in 600 has HbSS.5 Two thousand infants are identified with SCD annually in the United States.6 For every infant diagnosed with SCD, 50 are identified as carriers.6 HbSS (approximately 45%) is the most common genotypic expression, followed by HbSC (approximately 25%), HbS/5+-thalassemia (approximately 8%), and HbS/3° thalassemia (approximately 2%). Other variants account for less than 1% of patients.3,6... 

Inheritance is maternal, as in X-linked diseases, but children of both sexes are affected. 

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Heterozygous females are affected. Because females have two X chromosomes (and thus two chances to inherit an X-linked disease-causing mutation), whereas males have only one, X-linked dominant diseases are seen about twice as often in females as in males. 

C. Most X-linked diseases show a recessive inheritance pattern (Figure 13-3). 

Hemophilia, an X chromosome-linked disease that afflicts about 1 in every 5000 people, is characterized by the absence of at least one of a family of key enzymes involved in blood clotting.Two of the most prominent enzymes are factor VIII, the culprit in hemophilia A, and factor IX, which, when defective, causes hemophilia B, the less common of the two disease forms. 

An X-linked disease of boys, it may not be recognized until two to three years of age, but victims are usually in a wheelchair by age 12 and die around age 20. Individual muscle fibers disintegrate, die, and are replaced by fibrous or fatty tissue.a d The disease strikes about 1 out of 3500 boys born. The less serious Becker muscular dystrophy arises from defects in the same gene but affects only 1 in 30,000 males, some of whom have a normal life span. Because of its frequency and the knowledge that the gene must lie in the X-chromosome, an intensive search for the gene was made. It was found in 1986 after a five-year search.a e This was the first attempt to find a faulty gene whose protein product was totally unknown. 

There are over 40 lysosomal storage disorders (LSDs) characterized by the specific enzyme deficiency and accumulated substrate. Pathologies associated with LSDs are multisystemic and variable including CNS, skeletal, cardiovascular, renal, and ocular system involvement. The aggregate incidence is estimated to approach 1 in 7000 live births (Ellinwood et al., 2004). Inheritance for LSDs is primarily autosomal recessive with the exception of two X-linked diseases (Fabry and mucopolysaccharidosis (MPS) II). Treatment for LSDs relies on providing functional enzyme to the lysosomes of affected cells and has traditionally been confined to bone marrow transplantation, and enzyme replacement therapy (ERT). 

Thiamin-Responsive Pyruvate Dehydrogenase Deficiency Genetic deficiency of pyruvate dehydrogenase Ela (which is on the X chromosome) leads to potentially fatal lactic acidosis, with psychomotor retardation, central nervous system damage, atrophy of muscle fibers and ataxia, and developmental delay. At least some cases respond to the administration of high doses (20 to 3,000 mg per day) of thiamin. In those cases where the enzyme has been studied, there is a considerable increase in the of the enzyme for thiamin diphosphate. Female carriers of this X-linked disease are affected to a variable extent, depending on the X-chromosome inactivation pattern in different tissues (Robinson et al., 1996). 

R3. Rubin, C. S., and Balis, M. E., Stability of AMP Pyrophosphate phosphoribo-syltransferase, an autosomally determined enzyme in an x-linked disease. Biochim. Biophys. Acta 279, 163-174 (1972). 

Variable numbers of a gene can produce a greater or smaller amount of protein important to the body, but a duplicated section of DNA can also disrupt the function of an important gene. Structural differences in the genome (given as duplications, insertions, deletions, or inversions of genetic material) seem to be as important, or more important, to the causes of genetically linked diseases than are differences in the nucleotides A, T, G, and C (Olson, 2007). 

There are several rare disorders of the urea cycle. However, the most common is OTC deficiency, which is an X-linked disease. In severe neonatal forms of the disease, patients rapidly die from ammonium toxicity. However, the disease is variable and some boys have mild forms of the disease. In heterozygous females, the condition varies from being undetectable to a severity that matches that of the boys. 

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