Autosomal Recessive Disorders Genetic disease

By Live Dr - Sun Jan 11, 12:48 pm

Autosomal recessive conditions appear when there is some abnormality in the copy of the gene contributed by each parent. The unaffected parents, who carry only a single copy of the abnormal gene, are said to be “carriers,” or “heterozygotes.” An individual who inherits the abnormal copy of the gene from each parent is said to be a “homozygote.”

The important genetic consideration is that the homozygote cannot synthesize the normal product from the relevant genetic locus because he or she has received an abnormal copy of the gene from each parent. Because each parent has only one abnormal gene copy, there is a one-in-four chance that any given mating will result in a conceptus with two abnormal copies of the gene. This 25% likelihood is an important number for counseling considerations. It also can be useful in terms of providing information about recurrence risks.

A recessive gene or trait;expressed only in homozygotes for the abnormal gene.

4.2.  AR pedigree characteristics

⑴Affected individuals have phenotypically normal parents who are the obligate carriers.

⑵0nly matings beteen heterozygotes will produce affected individuals, with an expectation of 1 in 4(a quarter/one fourth/25%).Two-thirds of the unaffected siblings of an individual with an autosomal recessive disorder are likely to be heterozygotes.

⑶There is high morbidity when consanguineous marriage due to sharing of genes in families(more 1ikely if the gene is rare).

⑷Both sexes are equally affected.

⑸ Passed in atavistic fashion with  skipping.

Common diseases are Gaucher disease, cystic fibrosis,Tay-Sachs disease, phenylketonuria(PKU).

Several important aspects of recessive inheritance should be considered:

■Heterozygotes are generally unaffected clinically. (This is an important contrast to dominant disorders.)

■An individual manifesting a recessive disorder usually has heterozygous parents. Thus, the appearance of an affected person is often unprecedented in the family. (In comparison, the appearance of a newly affected individual with a dominant disorder usually means that a new mutation has occurred.)

■Once a homozygote is identified, the recurrence risk for other matings of the same parents is 25%. This can lead to a “horizontal” pedigree pattern, with multiple affected persons in the same generation and none in earlier generations.

■Two-thirds of the unaffected siblings of an individual with an autosomal recessive disorder are likely to be heterozygotes.

■ The likelihood that any two individuals selected randomly will be heterozygous for the same mutant allele is low, explaining the relative rarity of homozygotes for recessive phenotypes.

■ Consanguinity can lead to an increased likelihood of matings between heterozygotes. Because of inbreeding, consanguineous populations demonstrate a “founder effect,” meaning that they are enriched for whatever genetic traits were present in and propagated from the founders. Such groups may be relatively small and concentrated, such as the Parsis in India and the Old Order Amish. On the other hand, they may be less concentrated but still tend toward marriages within the community, either overtly or because of geographic limitations. Examples include religious communities and islanders. It is important at least to consider the possibility of consanguinity when counseling is offered or when a new homozygous individual is encountered.

■ A homozygote must contribute one abnormal gene copy to any offspring, because he or she has no normal copies of the gene at the responsible locus. This often is of no clinical consequence for the offspring, however, because the risk is relatively low that the mate will be a carrier. Thus, the pattern of seeing affected individuals in only a single generation is the most common.

■ Metabolic abnormalities are common in recessive disorders. Many of these can be considered “Inborn errors of metabolism”-a phrase introduced by Archibald Garrod. With no normal copies of the responsible gene, recessive metabolic diseases may be severe in fact, they may be lethal. Homozygotes for many recessive conditions often die early-sometimes in infancy-and others may not be able to reproduce.

■ Despite severe manifestations in homozygotes, heterozygous individuals can disseminate the abnormal allele, preserving the chance for homozygotes to appear again.

■ Many recessive disorders have been studied in detail from both biochemical and molecular genetic perspectives these often are detectable prenatally and/or presymptomatically.

■ The metabolic barriers created by recessive mutations have received considerable study, and some effective treatment strategies have been devised.

Discussion of several autosomal recessive disorders in detail will show these features:

4.3  Gaucher disease

Gaucher disease reflects malfunction in a specific enzymatic pathway. In this case, the enzyme affected is β-glucosidase. Heterozygous carriers of mutant alleles for this gene appear normal. However, homozygotes for mutations inβ-glucosidase develop a series of problems.

Gaucher disease stands in impressive contrast to sickle cell disease, and this contrast is important for a general perspective on recessive conditions. Sickle cell disease is due to a unique mutation, occurring consistently with the same molecular change in all affected individuals.

By contrast, many mutant alleles can lead to Gaucher phenotypes. The different mutations, occurring at different places within the responsible gene, can cause different problems. For example, some mutations produce no functional protein at all. Others, in contrast, produce a protein that has enzymatic function but altered activity. Obviously, there is the potential for considerable difference in phenotypes between individuals who make no protein and those who make a partly functional molecule. Not all of the mutations underlying Gaucher phenotypes have been identified, but a prominent group is shown in Figure 3.14. The large number of known mutations in Gaucher disease has led to another interesting contrast to sickle cell disease:

Many affected individuals are not true homozygotes but “compound heterozygotes” they have a different mutant allele of the β-glucosidase gene on each chromosome.

Because of the differences in β -glucosidase mutations, several different clinical presentations have been distinguished (see Table 3.1).

The common feature of all of these clinical pictures is that they are related to defective recycling of membrane glycolipids. The substrate is  glucocerebroside (glucosylceramide), derived from leukocyte membranes in the blood and from neuronal tissue in the nervous system.

. Gaucher disease phenotypes

Type Ⅰ Gaucher disease (OM1M # 230800) generally occurs in adults. In many it is a remarkably well-tolerated condition. Adult Gaucher disease is notable for gradual enlargement of the spleen due to the sequestration of membrane degradation products within macrophages. A characteristic finding in adult Gaucher disease is the Gaucher cell.

This cell is large and often seen in the bone marrow. It Figure 3.15 contains multiple intralysosomal layers of membranes that represent partially degraded molecules and whose final degradation and recycling has been either slowed or inhibited completely by the enzyme mutation(s). These cells accumulate in the spleen, and the resultant splenic enlargement gradually leads to platelet entrapment and thrombocytopenia. Despite the thrombocytopenia, many patients do not have severe bleeding difficulties and can go for many years without problems. Gaucher cells continue to accumulate, however, with complications involving the bone marrow. The accumulation of Gaucher cells in bones leads to spontaneous fractures because of progressive cortical weakness as well as degeneration of adjacent joints. Thus, the initial presentation of Gaucher disease in the formerly asymptomatic adult may be as a spontaneous fracture, often in the femur. Only after that event has occurred are splenomegaly and mild thrombocytopenia detected. The clinical course of Gaucher disease in adults varies, because there is such a broad spectrum of mutations underlying the phenotype.

Adult (“Type Ⅰ”) Gaucher disease is relatively common (see Table 3.1). It is more frequent in individuals with Eastern European Jewish heritage, but it is by no means confined to that population. Even within the Ashkenazic Jewish community, multiple mutations have been identified. “Type Ⅱ” Gaucher disease (OMIM # 230900) has been called the “infantile” form. This condition, fortunately quite rare, causes not only enlargement of the liver and spleen but also relatively rapid neurologic degeneration. This condition is generally lethal within the first several years of life, with progressive loss of neurologic function. There is little time for bone involvement to develop, and thus that is not an important part of the clinical picture in Type Ⅱ Gaucher disease. “Type Ⅲ” Gaucher disease (OMIM #231000) also is characterized by liver and spleen enlargement but has a more gradual onset and also is associated with loss of neurologic function. These individuals can reach the second decade of life but usually have severe neurodegeneration by that time. Types Ⅱ and Ⅲ are remarkably rare compared with the broad distribution of Type Ⅰ Gaucher disease. The treatment of individuals with Gaucher disease has undergone considerable study and represents an important joining of information about cell biology, enzymology, and protein chemistry. Because the β -glucosidase enzyme can be taken up by cells from their environment, early efforts at treatment employed intravenous administration of relatively purified enzyme. Although some results were promising, they did not reach the point of clinical applicability. More recently, the development of reliable enzyme replacement treatment has changed the management picture. For the newer treatment, large amounts of enzyme have been purified from placentas. As isolated, this enzyme has a complex set of carbohydrate additions. These carbohydrates change the chemical character of the enzyme and complicate readministration.

However, partial hydrolysis of the carbohydrate adducts yields a modified enzyme that can be administered intravenously and taken up reliably by macrophages in the spleen, liver, bone, and elsewhere.

Recently, recombinant enzyme has become available. Once taken up, the enzyme, known as “Ceredase,” functions appropriately to degrade accumulated glucocerebrosides, leading to both an improvement of bone disease and a reduction in spleen and liver size. The treatment is not simple, because recurrent infusions are needed. Currently, this treatment is very expensive, and Ceredase has “orphan drug” status.

A particular concern with regard to the success of this approach in treating accumulations in bones, liver, and spleen is the fact that the treatment fails to penetrate the central nervous system. Thus, the irony is that although the treatment can be remarkably effective for patients with Type Ⅰ disease, the adult form of the condition (for whom brain involvement is not a problem), it cannot prevent continued neurologic degeneration in individuals with Type Ⅱ or Ⅲ disease. Thus, the latter individuals can have somatic improvement despite progressive loss of neurologic function. Obviously, this cannot be considered an acceptable treatment for individuals with Type Ⅱ or Ⅲ Gaucher disease.

As described above for sickle cell disease, it is feasible to consider bone marrow transplantation for patients with adult Gaucher disease, but this is rarely performed, both because of the relatively recent availability of the enzyme replacement and because of the difficulties inherent in transplantation. Replacing resident bone marrow with unaffected stem cells can control many manifestations of TypeⅠdisease, but its long-term effect on neurologic function is not known, so it cannot be recommended for individuals with Types Ⅱ and Ⅲ disease. As noted, there is no known difficulty with being a carrier for any of the mutations in Gaucher disease. Apparently, the presence of one normal allele provides sufficient enzymatic activity so that reasonable metabolism can be achieved. Prenatal or presymptomatic diagnosis by DNA studies is possible for pregnancies and individuals at risk for Gaucher disease, but it is complicated by the existence of different mutations that can cause the same phenotype. Thus, prior to considering such diagnostic procedures, it is essential to determine the gene change(s) in an affected individual in the kindred. If the mutation(s) is(are) not known, it is possible that several mutations could be excluded by the testing, while the mutation(s) for which the pregnancy or the individual was at risk would not be recognized. This situation is a striking contrast to that in sickle cell disease, in which the mutation is always the same, but it is now becoming recognized in many other recessive conditions, as will be considered in detail below.

4.4  Cystic fibrosis

Cystic fibrosis (CF) (OMIM #219700), a disorder of membrane transport, is the most frequently encountered recessive condition in people of Caucasian and northern European descent. The understanding of the clinical spectrum of CF has been altered by the continuing discovery of older individuals with the disease. Conventional descriptions of CF involve complications from difficulty with managing secretions in infancy. This may present as intestinal blockade in the newborn due to meconium ileus, arising from firm intestinal secretions that resist peristalsis. This problem represents a combination of causes but especially reflects insufficient pancreatic secretions. The problem of pancreatic secretions is now manageable, however, with the use of oral enzyme replacements. Thus, many of the digestive and intestinal problems can be circumvented or minimized.

A more impressive and chronic difficulty is related to pulmonary secretions. Here the problem is largely that of clearing lung contaminants from the mucosal surfaces. The increased tenacity of the pulmonary secretions in CF reduces the rate of bronchial clearance, leading to the potential for establishment of chronic sites of bacterial contamination and, ultimately, infection. These poorly cleared areas ultimately allow damage to the underlying mucosal surfaces and the basic architecture of the lung, compromising gas exchange. The picture progresses from chronic bronchitis through changes of florid bronchiectasis to ultimate pulmonary insufficiency. This has been the pattern commonly recognized for untreated individuals.

More recent studies have revealed a much broader spectrum of clinical presentations for CF. Some individuals in the fourth and fifth decades of life with chronic lung disease have now been shown to carry mutations in the CF gene. These people may have had no difficulty with pancreatic exocrine secretions, and, in contrast to the more severely affected people manifesting problems earlier in life, they may have had relatively mild clinical courses. The gene whose mutations are responsible for CF has been isolated. It encodes a very large protein known as the “cystic fibrosis transmembrane regulator” (CFTR). Many mutations have been identified in the CFTR gene. These undoubtedly underlie the broad spectrum of clinical presentations. In addition, some CFTR mutations may not have very severe clinical effects others may represent relatively neutral changes, detectable only as molecular polymorphisms. The function of CFTR is still being clarified, but it clearly is related to ion transport across cell membranes. In particular, transport of the chloride ion, with its attendant sodium cation, is regulated by CFTR. Because ion transport obligates water movement as well, the defective movement of ions in areas such as the pancreas, intestine, and lung reduces the moisture in the secretions and consequently increases their viscosity. It is this thick layer of secretions that resists physiologic clearance mechanisms.

Although the spectrum of mutations in cystic fibrosis is broad, several are relatively common. The most common of these mutations represents an interesting three-base-pair deletion. This deletion neatly removes a single codon for phenylalanine. The mutation has thus achieved the designation “△F508” (OMIM #219700.0001). The absence of this single amino acid at position 508 in the protein is sufficient to cause the entire clinical picture.

The diagnosis of CF begins with suspicion based on the clinical presentation. Obviously, that suspicion must now be broadened to include young-and middle-aged adults with recurrent respiratory difficulties. The laboratory test most frequently used when CF is suspected clinically is known as the “sweat chloride test.” In this test, the relative concentration of chloride (and hence the conductivity) in skin secretions is measured. Affected individuals show increased sweat chloride levels. Although frequently possible, studying the CFTR gene for specific mutations is more time-consuming and expensive.

Furthermore, the large number of potentially responsible mutations can make this a difficult approach (although essential for prenatal and presymptomatic diagnosis in a given kindred).

Management of the care of individuals with CF has undergone considerable improvement, which has been responsible for increases in lifespan and in quality of life. The pediatric approaches to managing meconium ileus and intestinal motility are now generally successful, and replacing pancreatic enzymes with oral supplements can permit reasonable intestinal function, digestion, motility, and absorption. In contrast, the respiratory problems have been more of a challenge.

Appropriate antibiotic use has reduced the level of complications early in life. Nevertheless, the chronic bacterial colonization, particularly with Pseudomonas species, and difficulties with managing secretions generally lead to the loss of gas exchange surface and to chronic lung disease later in life. While oxygen supplementation may be helpful, it does not fundamentally affect the loss of gas exchange surface. Because pulmonary problems are so prominent in the long-term care of individuals with CF, the development of treatments based on biotechnology has received considerable emphasis. Because part of the difficulties with clearing secretions is their tenacity, and because much of this gel-like material represents cell debris and high-molecular-weight molecules, the introduction of agents that degrade these polymers has been considered as an option for improving pulmonary toilet. One approach that has had some success has been to introduce topical nucleases through pulmonary aerosols. These enzymes assist in degrading the DNA that is one of the highest-molecular-weight components of the secretions. Reducing the length of these DNA polymers assists in clearing the residual material by reducing its viscosity.

The fact that the respiratory epithelium is so frequently affected in CF has made it an obvious target for efforts at gene replacement. The notion of replacing the CFTR gene within the respiratory epithelium by aerosol delivery systems has been appealing. Delivery systems for pulmonary treatment often have been based on viruses, such as adenoviruses, that are known to have a host range limited to respiratory tissues. Attempts to develop successful gene replacement strategies using recombinant adenoviruses are currently under intense investigation. Unfortunately, the fact that the respiratory epithelium is constantly being shed at the surface and renewed from basal layers means that these treatments must be repeated at reasonable intervals so that the newly developed surfaces will continue to have a functional gene. These experimental efforts are promising and will be the basis of future, more successful gene-based treatment.

As noted above, CF is the most common recessive genetic condition in Caucasians. Nevertheless, the frequency of carriers for mutant alleles is not as high in this population as that for sickle cell anemia in African-descended populations. It needs to be reemphasized that sickle cell disease represents a unique and consistent mutation, in contrast to the many mutations that can cause a CF phenotype.

Thus, it is quite likely that many individuals presenting with, and receiving the diagnosis of, CF do not represent homozygotes but rather compound heterozygotes, similar to the situation with Gaucher disease. We already have considered clinical variations in the presentation and severity of sickle cell disease. We noted that the level of fetal hemoglobin, controlled by a gene unlinked to the globin locus, can substantially affect the clinical outcome. While such epistasis may appear complicated when just the single sickle cell mutation is involved (see above), the problem of how compound heterozygotes might respond to epistatic or environmental factors is very difficult to formulate. Thus, it is currently difficult to determine the underlying mutation on the basis of the clinical presentation in CF. As discussed above, this makes gene-based diagnosis more difficult because one cannot know a priori what mutations to test for. Cystic fibrosis resembles Gaucher disease with respect to the presence of a relatively common mutation (△F508) complicated by that of multiple other gene changes.

There is evidence that CFTR is essential for the entrance of Salmonella typhi into epithelial cells of the gastrointestinal tract. Thus, CFTR mutations may have provided some protection against this important pathogen and hence could have been valuable for survival in earlier populations.

4.5  Phenylketonuria

Phenylketonuria (PKU) (OMIM # 261600) is an important cause of mental retardation. PKU is caused by defective function of the phenylalanine hydroxylase (PAH) gene. This metabolic defect causes an increase in the level of the amino acid phenylalanine in the serum, the main chemical feature of the condition. PKU is relatively prominent in Caucasians, with a prevalence of about 1 in 10,000. It also is recognized in other populations throughout the world. The most prominent clinical characteristic of affected individuals is mental retardation. Few other characteristic clinical features have been defined, although some individuals do have seizures and abnormal postural changes.

The biochemical change in PKU is an example of a metabolic blockade. The normal metabolism of phenylalanine involves its hydroxylation by PAH, as shown in Figure 3.11. The absence or ineffective function of PAH causes a characteristic increase in the concentration of the substrate. Thus, high blood levels of phenylalanine develop. Human observations and animal studies indicate that prolonged high blood levels of this single amino acid cause neurologic damage, presumably explaining the mental retardation.

The diagnosis of PKU takes advantage of screening techniques to detect high blood levels of phenylalanine. In the United States since 1963, the Guthrie test has been performed by collecting a single blood specimen from the heel of a newborn. This screening test detects elevated blood levels of phenylalanine. Because of the screening program in the United States, individuals with high blood levels are regularly detected.

Although not all of them have classic PKU, this screening approach identifies infants who need further testing. The Guthrie test is one of the simplest and most broadly used genetic screening procedures. As Figure 3.18 will be discussed later, its design permits detection of infants affected with PKU, as well as those whose phenylalanine levels are elevated because of other causes. Some of these elevated levels may be transient others reflect even more rare genetic disorders.

The PAH gene has been studied in considerable detail. The mutations are varied and spread throughout the gene, resembling the patterns noted in Gaucher disease and CF. No single mutation can uniformly explain the presence of PKU. Furthermore, as might be expected, non-Caucasian populations have different PAH mutations. Because of the severe mental retardation characteristic of individuals with PKU, treatment is begun early. The basis of treatment is limitation of dietary phenylalanine. Reduced amounts of this essential amino acid decrease blood levels of phenylalanine. Long-term clinical studies have established the efficacy of this dietary treatment, and the mental function of treated adults is substantially improved. Nevertheless, the treatment is not without its difficulties. In the first place, it is difficult to maintain infants and children need to be kept away from other foods. In the second place, the diet is not particularly tasty, making compliance a difficult challenge. In the third place, the treatment has led to a new question regarding the appropriate management for phenylketonuric adults who were treated as infants and children. It is not currently possible to predict the long-term implications (neurologic or otherwise) of feeding a regular diet to an adult whose PKU was treated in childhood.

As anticipated, resuming a nonrestricted diet causes a predictable elevation in blood phenylalanine levels. What is not known is how these levels will affect the individual over an adult lifetime. One perspective is that the elevated levels might cause damage only in the developing nervous system. On the basis of this hypothesis, high adult levels should not create difficulties. On the other hand, if chronic high blood phenylalanine levels result in subtle neurotoxicity, there may be slow neurodegeneration in these individuals. Long-term observations and clinical measurements will be necessary to resolve this important question.

There is one situation, however, in which adults treated for their PKU in childhood need special attention: pregnancy. A woman with treated PKU who becomes pregnant and is no longer maintaining dietary control exposes her developing fetus to high levels of phenylalanine at a critical time in its neurologic development. Studies in animals have shown significant fetal damage due to high maternal phenylalanine levels. Thus, the care of pregnant individuals who themselves have PKU involves continued (or resumed) dietary control. The fetuses of such women necessarily are at least heterozygous for a mutation in the PAH gene and thus may be less able to tolerate high phenylalanine levels than those with no such mutation.

PKU has received considerable attention. Originally believed to represent an opportunity to “cure” mental retardation by biochemical manipulation, PKU is now recognized as a condition affecting different populations with different mutations, whose long-term neurologic effects after treatment are still unknown. The problems of normal diets in affected adults and especially the diet for mothers during pregnancy are still the subjects of long-term investigations that should clarify the picture. Nevertheless, the multiplicity of mutations and degrees of clinical severity make predictions difficult for individuals.


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