X-linked recessive

Fabry s disease a-Gaiactosidase Cer—Gic—Gai-i-Gai Giobotriaosyiceramide Skin rash, kidney failure (full symptoms only in males X-linked recessive). 

Data in part from Ackerman NJ, Clapham DE Ion channels— basic science and clinical disease. N Engl J Med 1997,-336 1575. Other channelopathies include the long QT syndrome (MIM 192500) pseudoaldosteronism (Liddle syndrome, MIM 177200) persistent hyperinsulinemic hypoglycemia of infancy (MIM 601820) hereditary X-linked recessive type II nephrolithiasis of infancy (Dent syndrome, MIM 300009) and generalized myotonia, recessive (Becker disease, MIM 255700). The term "myotonia" signifies any condition in which muscles do not relax after contraction. 

Fabry s disease An x-linked recessive lipid storage disease with an accumulation of the glycosphingolipid. 

Haemophilia A (classical haemophilia, often simply termed haemophilia) is an X-linked recessive disorder caused by a deficiency of factor VIII. Von Willebrand disease is a related disorder, also caused by a defect in the factor VIII complex, as discussed below. 

Primary lysosomal hydrolase defects. Two-thirds of the lysosomal storage diseases involve defects in genes that code for acid hydrolases. Table 41-2 lists 29 defects that have been defined so far. They have an autosomal recessive mode of inheritance, except for Hunter s syndrome and Fabry s disease, where the mode is X-linked recessive. The defective genes have been identified and mutations have been defined for nearly all. The nervous system is involved in most. Many of the disorders show a wide range of clinical severity, which may range from death in early childhood to a moderate disability in adulthood. 

Phosphoglycerate kinase deficiency is an X-linked recessive disease (type IX, Fig. 42-1). The most common clinical presentation includes hemolytic anemia with or without CNS involvement (see below). Thus far, ten patients have been described with a purely myopathic... 

In liver phosphorylase deficiency (glycogenosis type VI, Hers disease Fig. 42-1) and in two genetic forms of phosphorylase kinase deficiency, one of which is X-linked recessive, the other of which is autosomal recessive, hypoglycemia is either absent or mild. Symptoms of brain dysfunction do not usually occur (type VIII, Fig. 42-1) [1],... 

Glucose-6-phosphate dehydrogenase (G6PD) deficiency in red blood cells X-linked recessive inheritance many specific mutations Common variants mild deficiency variant in African Americans, moderately severe deficiency variant in Caucasians of Mediterranean descent Frequency 1/10 males 1/100 males, African American and Mediterranean, respectively... 

X-linked recessive disorders are also caused by mutations in genes on the X chromosome. Males are more frequently affected than females, and the chance of passing on the disorder differs between men and women. Families with an X-linked recessive disorder often have affected males, but rarely affected females, in each generation. A striking characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons (no male-to-male transmission). 

Most cases of CGD, including Peter, are X-linked recessive traits in which the gp91 component of NADPH oxidase is affected. Autosomal recessive defects in p22, p47 and p67 also occur and these may present with symptoms in female children. 

Menkes disease, an X-linked recessive condition, is caused by mutations in the gene encoding a Cu efflux protein. Cells from an affected individual accumulate high concentrations of Cu " that cannot be released from the cell. The symptoms result from functional Cu deficiency inasmuch as Cu absorbed from the intestine becomes trapped in the intestinal epithelial cells and delivery to other tissues is inadequate. 

Carrier of an X-linked Recessive (Optional) [ h Dizygous Twins... 

Lesch-Nyhan syndrome is an X-linked recessive condition involving ... 

Normal females have two copies of the X chromosome, so they usually require two copies of the mutation to express the disease. However, because X inactivation is a random process, a heterozygous female will occasionally express an X-linked recessive mutation because, by random chance, most of the X chromosomes carrying the normal allele have been inactivated. Such females are termed manifesting heterozygotes. Because they usually have at least a small population of active X chromosomes carrying the normal allele, their disease expression is typically milder than that of a hemizygous male. 

Figure II-1-7 shows the recurrence risks for X-linked recessive disease.

Figure 11-1-7. Recurrence Risks for X-Linked Recessive Diseases...

Hemophilia B, another X-linked recessive bleeding disorder, is caused by a deficiency of dotting factor IX. 

As in X-linked recessive inheritance, male-male transmission of the disease-causing mutation is not seen Fig 11-1-8). 

A man who is affected with hemophilia A (X-linked recessive) mates with a woman who is a heterozygous carrier of this disorder. What proportion of this couple s daughters will... 

Both types of muscular dystrophy are X-linked recessive mutations, making a gain-of-function highly unlikely for either type (choice A). 

The other modes of inheritance can influence the relative proportions of affected individuals who belong to one gender or the other (e.g., more affected males under X-linked recessive inheritance, more affected females under X-linked dominant inheritance), but they do not involve any differences in expression depending on the transmitting parent. 

Because males have only one X chromosome, gene frequency estimation for X-Hnked traits differs from that of autosomal traits. Consider hemophilia A (Chapter 1), which is an X-linked recessive disease. If a male s X chromosome has a factor VIII mutation, he will have hemophilia A. If his X chromosome does not have the mutation, he will not develop the disease. Thus, the gene frequency for hemophilia A is obtained simply by counting the proportion of affected males in the population (i.e., the proportion of X chromosomes containing the mutation). Approximately one in 10,000 males has hemophilia A. Thus, the gene frequency for this disease, q, is 1/10,000. 

As with autosomal recessive traits, the majority of X-linked recessive genes are hidden in female heterozygous carriers (although a considerable number are seen in affected males). 

X-linked recessive traits will be seen much more commonly in males than in females, an observation also made in Chapter 1. 

The incidence of Duchenne muscular dystrophy in North America is about 1/3,000 males. On the basis for this figure, what is the gene frequency of this X-linked recessive mutation ... 

Answer A. Because males have only a single X chromosome, each affected male has one copy of the disease-causing recessive mutation. Thus, the incidence of an X-linked recessive disease in the male portion of a population is a direct estimate of the gene frequency in the population. 

Individuals with a family history of an autosomal or X-linked recessive disease may wish to know whether they are a heterozygous carrier of the disease. This can be established by genetic diagnosis (e.g., for cystic fibrosis, hemochromatosis, PKU, or albinism). In some specific cases, a population at high risk for a specific disease may be screened for carrier status using genetic diagnosis (e.g., Tay-Sachs disease in the Jewish population [see Clinical Correlate]). 

Nephrogenic diabetes insipidus (NDI) is characterized by renal tubular resistance to the antidiuretic effect of arginine vasopressin (AVP). NDI may be inherited as an autosomal dominant or X-linked recessive disorder. The autosomal dominant form of NDI results from mutations of the aquaporin 2 gene (AQP2). AQP2 encodes a water channel of the renal collecting duct. Its disruption causes autosomal dominant NDI (113,114) and occasionally recessive forms of the disease. 

Figure 13-3. Pedigrees illustrating X-linked recessive (A) and dominant (B) inheritance patterns. Note the absence of male-to-male transmission in both pedigrees and the predominance of affected males over females in the X-linked recessive pedigree.

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