Autosomal recessive diseases

In patients with ataxia-telangiectasia, an autosomal recessive disease in humans resulting in the development of cerebellar ataxia and lymphoreticular neoplasms, there appears to exist an increased sensitivity to damage by x-ray. Patients with Fanconi s anemia, an autosomal recessive anemia characterized also by an increased frequency of cancer and by chromosomal instability, probably have defective repair of cross-linking damage. 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Wilson s disease is another autosomal recessive disease leading to cirrhosis. Protein abnormalities result in excessive copper deposition in body tissues. The faulty protein is responsible for facilitating copper excretion in the bile, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson s disease usually present with symptoms of liver or neurologic disease while still in their teens. 

MF effects on FA relatives and healthy donors. (Fanconi anemia is an autosomal recessive disease associated with the overproduction of free radicals, Chapter 31.) It has been shown earlier [215] that FA leukocytes produce the enhanced amount of hydroxyl or hydroxyl-like free radicals, which are probably formed by the Fenton reaction. It was suggested that MF would be able to accelerate hydroxyl radical production by FA leukocytes. Indeed, we found that MF significantly enhanced luminol-amplified CL produced by non-stimulated and PMA-stimulated FA leukocytes but did not affect at all oxygen radical production by leukocytes from FA relatives and healthy donors (Table 21.3). It is interesting that MF did not also affect the calcium ionophore A23187-stimulated CL by FA leukocytes, indicating the absence of the calcium-mediated mechanism of MF activity, at least for FA leukocytes. 

Cystic fibrosis is the most common lethal autosomal-recessive disease, in which oxidative stress takes place at the airway surface [274]. This disease is characterized by chronic infection and inflammation. Enhanced free radical formation in cystic fibrosis has been shown as early as 1989 [275] and was confirmed in many following studies (see references in Ref. [274]). Contemporary studies also confirm the importance of oxidative stress in the development of cystic fibrosis. Ciabattoni et al. [276] demonstrated the enhanced in vivo lipid peroxidation and platelet activation in this disease. These authors found that urinary excretion of the products of nonenzymatic lipid peroxidation PGF2 and TXB2 was significantly higher in cystic fibrotic patients than in control subjects. It is of importance that vitamin E supplementation resulted in the reduction of the levels of these products of peroxidation. Exhaled ethane, a noninvasive marker of oxidative stress, has also been shown to increase in cystic fibrosis patients [277]. 

This is a rare, autosomal recessive disease that was first described when giant cytoplasmic granules were observed in neutrophils, monocytes and... 

Cystic fibrosis (CF) is the most common potentially lethal autosomal recessive disease among Caucasians. The incidence is estimated to be approximately 1 in 2000 births (Bl). Since it is inherited as an autosomal recessive condition, screening to identify couples at risk has been suggested. However, CF screening is complicated because many mutations of the CF gene exist. Thus, the feasibility of screening a population for carriers of cystic fibrosis gene mutations is primarily dependent upon the frequency of the common mutation in that population. 

Answer C. CP is an autosomal recessive disease. Choices A, B, and D best illustrate AD, XR and mitochondrial pedigrees, respectively. 

In contrast to autosomal dominant diseases, autosomal recessive diseases are typically seen in only one generation of a pedigree (Fig II-1-5). 

Environmental influences (e.g., the autosomal recessive disease xeroderma pigmento-siun will be expressed more severely in individuals who are exposed more frequently to ultraviolet radiation)... 

For autosomal recessive diseases, such as PKU, the prevalence of heterozygous carriers is much higher than the prevalence of affected homozygotes. In effect, the vast majority of recessive genes are hidden in the heterozygotes. 

C. The couple has an increased risk of producing a child with an autosomal recessive disease. 

A man is a known heterozygous carrier of a mutation that causes hemochromatosis (autosomal recessive disease). Suppose that 1% of the general population consists of homozygotes for this mutation. If the man mates with somebody from the general population, what is the probability that he and his mate will produce a child who is an affected homozygote ... 

Answer C. Because the couple shares conunon ancestors (i.e., one set of grandparents), they are more likely to be heterozygous carriers of the same autosomal recessive disease-causing mutations. Thus, their risk of producing a child with an autosomal recessive disease is elevated above that of the general population. 

Consanguinity (choice A) could elevate the incidence of this autosomal recessive disease in a specific family, but it does not account for the elevated incidence of this specific disease in the African American population in general. 

Cystinuria is an autosomal recessive disease with an incidence of 1 In 15,000 live births in the United States. 

Rare autosomal recessive diseases also occur with high frequency among genetically isolated populations due to inbreeding. 

This autosomal recessive disease occurs in Ashkenazi Jews, the Pennsylvania Amish, and several other populations with an incidence of 1 in 3600,100 times higher than the overall population the carrier frequency in these populations is about 3%. 

Ataxia telangiectasia is an autosomal recessive disease characterized by neurologic, endocrine, and hepatic abnormalities, as well as a predisposition to malignancy (119). The defect has been traced to a gene on chromosome 11, the ATM gene that codes for a phosphatidylinositol 3-kinase-like protein which is related to the catalytic subunit of DNA-dependent protein kinase. This protein has a role in signal transduction, DNA repair, and control of the cell cycle (120). Affected patients have a defect in cell-mediated immunity. A decrease in semm IgA is seen in a majority of affected patients. IgG2 or total IgG and IgE levels may be decreased, with an increase in IgM. Patients are susceptible to chronic respiratory... 

Genetic mutations are a major cause of DPD impairment (24,58). Polymorphism of the DPYD gene has been well characterized as an autosomal recessive disease, with 0.5% and 3%-5% of the Caucasian population being subsequently affected by total and partial deficiencies, respectively (7,59,60). Thymine uraciluria is a condition caused by inherited total DPD deficiency that can be either associated with neurological disorders or be asymptomatic (61,62,63). 

These distinctly different autosomal recessive diseases present as childhood rickets that do not respond to conventional doses of vitamin D. Type I vitamin D-dependent rickets, now known as pseudovitamin D deficiency rickets, is due to an isolated deficiency of l,25(OH)2D production caused by mutations in 25(OH)D-la-hydroxylase (CYP27B1). This condition... 

Bloom s syndrome is a rare autosomal recessive disease characterized by a high level of spontaneous chromosomal aberrations and sister chromatid exchange (SCE). Bloom s syndrome involves exhibiting numerous clinical features including predisposition to cancer. The importance of oxidative stress in Bloom s syndrome follows from the overproduction of superoxide, an increase in free radical-mediated damaging processes, and SOD induction... 

Fish odour syndrome is an autosomal recessive disease. Mutations have been found in the FM03 gene. Molecular genetic analysis can therefore be used as a diagnostic test. Many pathogenic mutations have been described. The defect should be documented in patients with trimethylaminuria at the metabolite level and the diagnosis confirmed at the molecular genetic level. This chapter describes the available tests at the metabolite level. 

Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, DeMichele G, Filla A, DeFrutos R, Palau F, Patel PI, DiDonato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich s ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 1423-1427... 

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