X-linked recessive disease

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... 

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

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

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. 

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]). 

A human female has two X chromosomes, and a male has an X and a Y chromosome. In the human, the Y chromosome is almost without genes, but the X chromosome has an average number. Because the X and Y chromosomes determine sex, traits caused by genes on the X chromosome will be associated with gender, although the traits themselves (e.g., colorblindness) have nothing to do with sex. In particular, because the male has only one X chromosome, even an unpaired recessive gene is expressed in the absence of a dominant allele to mask it. A consequence is that X-linked recessive diseases cure much more common in males than in females. 

Characteristics of X-linked recessive diseases include an oblique pedigree pattern, affliction of males only, frequent female carriers, and a 25% recurrence risk for carrier females (see pedigree C on chart). Corollary Haldane s law predicts a 2/3 chance that the mother of an affected male with X-linked recessive disease is a carrier (and a 1/3 chance the affected male represents a new mutation). 

Females occasionally have symptoms of X-linked recessive diseases such as Duchenne s muscular dystrophy, hemophilia, or color blindness. The most common explanation is... 

The answer is a. (Murray, pp 812-828. Scriver, pp 3-45. Sack, pp 97-158. Wilson, pp 23—39.) Females have two alleles for each locus on the X chromosome because of their 46,XX karyotype. One normal allele is by definition sufficient for normal function in X-linked recessive disorders, so that females with one abnormal allele are carriers instead of affected individuals. Only when the companion normal allele is disrupted or missing does the abnormal allele cause disease. The Lyon hypothesis predicts that X inactivation is early, irreversible, and random, but some females inactivate only the X chromosome carrying the normal allele. X autosome translocations may disrupt an X chromosome locus and cause disease because the translocated autosome must remain active to avert embryonic death nonrandom inactivation of the normal X chromosome thus ablates expression of its normal allele. Females with Turner s syndrome, like males with 46,XY karyotypes, have only one X chromosome and can be affected with X-linked recessive diseases. Conversely, females with triple X or trisomy X syndrome have three alleles at each X chromosome locus and are not affected with X-linked recessive disorders. Since choices c, d, and e each require two genetic changes, they are less common than choice a. 

Menkes disease is a rare X-linked recessive disease of copper metabolism, the frequency of which has been estimated at between 0.8 and 2 per 100000 live male births (Tonnesen et al. 1991). Clinical manifestations begin in the first few months of life, or even in the neonatal period. Symptoms include hypothermia, hypotonia, poor weight gain, seizures, and neurodevelop-mental delay or regression. The outcome is poor, with death occurring usually by three years of age. Diagnostic characteristics include facial appearance with steely hair, and reduced levels of serum ceruloplasmin and copper (Menkes 1999, Jayawant etal. 

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. 

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],... 

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. 

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. 

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

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. 

DMD is a severe X-linked recessive, progressive muscle wasting disease that affects approximately 1 in 3500 newborn males (Emery, 1991). An allelic variant of DMD is also known, referred to as Becker muscular dystrophy (BMD). It has a later onset and lesser phenotype than DMD, resulting in longer life expectancy (reviewed in O Brien and Kunkel, 2001). DMD is caused by mutations in the DMD gene that encodes the cytoskeletal linker protein dystrophin. The vast majority of DMD mutations result in the... 

Mis-localisation of annexin 2 has recently been implicated in the pathogenesis of Dent s disease. This term is now used collectively to describe what was previously four conditions that affect kidney function X-linked recessive nephrolithiasis with renal failure, X-linked recessive hypophosphatemic rickets, idiopathic low molecular weight proteinuria with hypercalciuria and nephrocalcinosis and Dent s disease. Patients with this condition present with low molecular weight proteinuria and hypercalciuria. Renal stones, nephrocalcinosis and renal failure are common late-stage developments. The condition has been attributed to abnormal acidification within endosomes of the proximal tubular cells. It is very rare and is usually caused by mutations in the voltage-dependent Cl /H+ chloride antiporter CLCN5, but occasionally in the PI4,5P2 5-phosphatase, OCRL1 (oculocerebrorenal syndrome of Lowe protein 1). 

Table 7-5. The dominant, X-linked, recessive, and chromosomal classes cure assumed to have a mutation component of 1. (Actually, the value is somewhat less if environmentally caused or multifactorial diseases are mistakenly classified in these categories.) The mutation component for congenital malformation and other multifactorial traits is taken as 0.10. The basis for this was explained earlier by the data in Table 7-2.

The most common forms of ichthyosis — autosomal dominant ichthyosis vulgaris (IV) and X-linked recessive ichthyosis (XRI) — in many countries occur at frequencies a high as 1/300 and 1/2500, respectively. In fact, the genetic traits for IV and XRI are so frequent that the two diseases sometimes coexist in one and the same family, which may cause confusion as to the inheritance pattern. Although the incidence of IV and XRI is probably similar around the world, climate differences in particular will affect the severity of the disease, and hence its notification by the health care system. 

Lesch-Nyhan Syndrome produces a tremendous overproduction of uric acid. The defect in Lesch-Nyhan disease is the gene for the enzyme HGPRT. The lack of HGPRT activity is virtually complete and the disease is X-linked recessive and thus limited to males. It has a very early age of on-set and is characterized by extremely aggressive behaviour that generally leads to self-mutilation. Initially... 

X-linked recessive hemizygous males have a characteristic skin lesion usually lacking in heterozygous females pain in the extremities death usually in the fourth decade results from renal failure or cerebral or cardiovascular disease. 

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