Which condition is required for the inheritance of an autosomal recessive disorder?

Autosomal Recessive Disorders

AR disorders are those that are clinically apparent only when the patient is homozygous for the disease (i.e., both copies of the gene are mutant). The following pattern of inheritance is characteristic of AR disorders (see Fig. 1-7 B):

The parents of affected children may be clinically normal (i.e., carriers).

Assuming that the carrier frequency in the population is low, only siblings are affected, and vertical transmission does not occur; the pattern therefore tends to appear horizontal.

Males and females are affected in equal proportions.

When both parents are heterozygous carriers of the mutation, 25% of their children are affected, 50% are carriers, and 25% are normal.

Every person is a carrier of certain AR mutations. Fortunately, the carrier frequency for most of these mutations is so low that likelihood that carriers will have affected children is low.

Recessive mutations frequently involve enzymes, as opposed to regulatory and structural proteins. This is because 50% of the normal level of enzyme activity is usually sufficient for normal function. Complete enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such as the build-up of phenylalanine in phenylketonuria, and a deficiency of metabolites distal to the block. Either, or both, of these abnormalities may be responsible for the disease phenotype. Although many recessive disorders involve enzymes, two of the most common AR disorders are cystic fibrosis, resulting from a mutation in a chloride channel, and sickle cell anemia, resulting from a mutation in the β-globin gene.

The terms dominant and recessive refer to phenotypes only and have their greatest application at the clinical level. At the gene level, dominance and recessiveness do not exist. Persons heterozygous for a recessive disorder may be clinically normal, but the reduced level of functional or immunoreactive protein is usually detectable analytically and may lead to other biochemical abnormalities that have no obvious effect on the person's health. In addition, patients homozygous for dominant mutations are usually more severely affected than are heterozygous patients, as is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality and is never seen. Huntington disease stands out as a major exception in that homozygous patients are not clinically different from heterozygous patients.

ETIOLOGY/PATHOGENESIS

Autosomal Recessive Inheritance

Autosomal recessive disorders occur when a person has defects in both copies of an autosomal gene (a gene that is located on any of the autosomes) (Figure 3.1B), resulting in “loss of function” (Figure 3.2A). If both copies of the gene have the same deleterious mutation, the defect is termed homozygous. If each copy of the gene has a different deleterious mutation, the defect is termed compound heterozygous. Each parent of an affected patient is typically a heterozygous carrier, and has one normal and one abnormal copy of the gene (Figure 3.1B). In most cases a normal copy of the gene can compensate for the defective copy; thus, heterozygous carriers are generally asymptomatic. When two carrier parents have offspring, statistically, one in four offspring should have the disease, two should be carriers, and one should be normal. Autosomal recessive disorders occur with increased frequency in offspring of consanguineous marriages or in isolated populations where an original “founder mutation” that occurs in one individual at some point in history is subsequently propagated throughout the population.

Autosomal Recessive Disorders

AR disorders are those that are clinically apparent only when the patient is homozygous for the disease (i.e., both copies of the gene are mutant). The following general principles of inheritance are recognized for AR disorders (see Figure 1-7, B):

The parents of affected children are clinically normal (i.e., carriers).

Assuming that the carrier frequency in the population is low, only siblings are affected, and vertical transmission does not occur; the pattern therefore tends to appear horizontal.

Consanguinity can be a factor. This can occur in outbred populations by mating between family members, or in inbred populations (e.g., the Amish) where the entire population is descended from a small number of ancestors.

Males and females are affected in equal proportions.

When both parents are heterozygous carriers of the mutation, 25% of their children are affected, 50% are carriers, and 25% are normal.

Every person is a carrier of AR mutations. Fortunately, the carrier frequency for most of these mutations is so low that the likelihood that carriers will have affected children is low.

Recessive mutations frequently involve enzymes, as opposed to regulatory and structural proteins. This is because 50% of the normal level of enzyme activity usually is sufficient for normal function. Complete enzyme deficiency produces an accumulation of one or more metabolites preceding the enzymatic block, such as the buildup of phenylalanine in phenylketonuria, and a deficiency of metabolites distal to the block. Either, or both, of these abnormalities may be responsible for the disease phenotype. Although many recessive disorders involve enzymes, two of the most common disorders with AR inheritance are cystic fibrosis, resulting from a mutation in a chloride channel, and sickle cell anemia, resulting from a mutation in the β-globin gene.

It is important to be aware that the terms dominant and recessive refer to clinical phenotypes only. At the gene level, “dominance” and “recessiveness” do not exist. Persons heterozygous for a recessive disorder may be clinically normal, but the reduced level of functional or immunoreactive protein can be detected analytically and may lead to other biochemical abnormalities that have no obvious effect on the person's health. For example, short chain acyl-coenzyme A dehydrogenase deficiency, a disorder of short chain fatty acid metabolism, is detected by newborn screening but appears to have no clinical consequences. Patients homozygous for dominant mutations usually are more severely affected than are heterozygous patients. This is true in familial hypercholesterolemia. In many cases, the homozygous condition results in embryonic lethality, and so it is never seen clinically. Huntington disease stands out as an exception in that homozygous patients are not clinically different from heterozygous patients, presumably because the gain of function effect of the triplet repeat mutation is not dose responsive.

Autosomal Recessive Inheritance

Autosomal recessive disorders are coded for by genes located on the nonsex chromosomes. In contrast to autosomal dominant inheritance, the heterozygote, who has one abnormal allele and one normal allele, does not differ clinically from a person homozygous for the normal gene. Rather, the person must be homozygous for the abnormal allele for the disease or trait to be expressed. In some cases, the person has two abnormal alleles of a certain gene, but each is abnormal in a different way. Such persons are referred to as compound heterozygotes. As described above for autosomal dominant disease, trinucleotide repeat expansions can also be the type of mutation causing autosomal recessive disease, such as Friedreich's ataxia.

For the disease to be present in the offspring, both parents must have one copy of an abnormal allele, and the risk of disease for each of their offspring, of either sex, is 25%. In autosomal recessive inheritance, the previous generations usually are not affected with the disease. Although the classic description of pedigrees for autosomal recessive inheritance includes two or more affected siblings, with today's small average family size of 2.4 children, it is not unusual for the disease to appear sporadically within the family. One cannot exclude autosomal recessive disease on the basis of a negative family history. In these cases it is sometimes necessary to rely on knowledge of the usual mode of inheritance of the disease. Although some diseases, such as CF, are always inherited in an autosomal recessive pattern, other clinically defined diseases may be inherited in one of several ways. For example, retinitis pigmentosa can be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive disease.

Even the same gene can have different mutations that act in a dominant or recessive fashion. For example, both autosomal dominant and autosomal recessive retinitis pigmentosa can be caused by different mutations in the rhodopsin gene.7 Furthermore, different mutations in the same gene can cause different clinical disorders. For example, mutations in the peripherin/RDS gene can cause autosomal dominant retinitis pigmentosa, as well as several types of macular dystrophy.5

For autosomal recessive diseases, the risk for an affected person to have an affected child is low, unless the disease is very common or the affected person marries a blood relative or a person also afflicted with the same autosomal recessive disease. However, even among couples who meet neither of these criteria, the risk is greater than the general population risk. For example, if one assumes that the carrier frequency of the gene for phenylketonuria (PKU) is 1 in 50 in the general population, the risk for healthy parents without a positive family history is 1/50 × 1/50 × 1/4 = 1/10,000. However, if a man has PKU, the risk for his children is 1 × 1/50 × 1/2 = 1/100. The risk for the affected man's healthy sister to have a child with PKU is 2/3 × 1/50 × 1/4 = 1/300.

There are some unusual mechanisms by which autosomal disease may occur, in which only one parent is a carrier for the gene defect. New mutations may occur, as has been documented at the molecular level. For example, a patient with spinal muscular atrophy type I was shown to be homozygous for the common deletion of exons 7 and 8 of the SMN1 gene. The mother was a carrier of the deletion, but the father was not. Nonpaternity was excluded, and it was concluded that the mutation had arisen by new mutation.52 In another type of situation, uniparental disomy for a chromosomal segment with an autosomal recessive gene defect was shown to cause “homoallelic” disease in a patient with a retinal dystrophy.40 Uniparental disomy refers to the inheritance of both of a pair of chromosomes or chromosomal segments from one parent rather than one from each parent. This can occur by various mechanisms, such as trisomic rescue, in which the zygote starts out with trisomy for a given chromosome, but the extra chromosome is lost early in subsequent cell divisions. Therefore, caution is always warranted in making presumptions about carrier status, particularly if prenatal diagnosis may be involved.

Autosomal Recessive

In autosomal recessive disorders (Figure 8-1B), individuals must have two disease alleles. Thus, both parents must either be affected or unaffected heterozygotes. If both parents are affected, all children will be affected. If both parents are unaffected heterozygotes, each child has a 25% chance of being affected and a 50% chance of being an unaffected heterozygous carrier of the disorder. Therefore, one fourth of the offspring of two unaffected heterozygotes will carry two defective copies of the gene and will be affected. Half of the offspring will be heterozygous carriers of the disorder. Because heterozygotes are not affected, clinical manifestations of disease are not seen in every generation. As in autosomal dominant disorders, males and females are equally affected by autosomal recessive disorders. Inborn errors of metabolism, cystic fibrosis, and sickle cell anemia are examples of autosomal recessive disorders. Common examples of cardiovascular diseases that are transmitted in an autosomal recessive manner include dilated cardiomyopathy, arrhythmogenic right-ventricular dysplasia, and homocysteinuria (Table 8-1).

Autosomal Recessive Disorders.

In autosomal recessive disorders, both alleles at a given gene locus must be mutated for an animal to be affected by the disorder. One mutated allele is provided by the sire and the other by the dam. Thus there is a 25% chance that each offspring from heterozygous parents will inherit both mutated alleles. Heterozygotes, with only one mutated allele, are clinically normal carriers of the trait. Homozygous animals usually have clinical disease, and the onset is usually early in life. Many of the mutated genes encode enzymes. Examples of autosomal recessive disorders in animals include lysosomal storage diseases (see E-Fig. 1-27 and Figs. 14-63 and 14-64), glycogen storage diseases (see Fig. 14-63) and mucopolysaccharidoses, and aminoacidopathies that affect organs such as the brain, spinal cord, skeletal muscle, liver, and kidney.

Autosomal Recessive

An autosomal recessive disorder becomes manifest only when an individual has two copies of the mutant gene. Most frequently each parent has one copy of the defective gene and is a carrier, and there is a 25% chance that both mutant genes will be passed on to their offspring. Male and female offspring will be equally likely to be affected. Fifty percent of the time the offspring will get one copy of the mutant gene from one parent and will be carriers, and 25% of the time the offspring will get two normal copies of the gene. Although autosomal recessive disorders are relatively uncommon, the carrier status in certain populations can be significant. For example, 1 in 25 people of northern European descent are carriers of cystic fibrosis.3 Genetic diseases more common among people of Asian and African descent are beta-thalassemia and sickle cell anemia, respectively.4,5

Wilson’s Disease

This AR disease results in systemic copper deposition, especially in brain and liver. Classic PD or parkinsonism with atypical features may occur. The presence of hepatic, extrapyramidal, or mood disorders in relatives of a patient with PD should lead to evaluation for Wilson’s disease, since treatment is highly effective. The causal gene a copper-transporting P-type adenosine triphosphatase (ATPase). Many mutations are responsible for disease, making genetic testing impractical. However, screening with serum ceruloplasmin, 24-h urinary copper, and slit lamp examination are straightforward.

Tyrosinemia type 2 (Richner-Hanhart syndrome)

This autosomal recessive disorder is caused by deficiency of tyrosine aminotransferase. It may present with ocular signs and symptoms as the initial manifestation in the first years of life with photophobia, pain, and conjunctival injection. There is a bilateral pseudodendritic keratitis which may lead to neovascularization and corneal scarring.77 Patients may have painful erosions and hyperkeratosis of the palms and soles, and cognitive impairment. Plasma tyrosine concentrations are extremely high and the eye and skin lesions probably result from the intracellular precipitation of tyrosine crystals. Dietary restriction of tyrosine and phenylalanine leads to resolution of these lesions.

Tyrosine concentrations are lower in tyrosinemia types 1 and 3. Type 1 patients treated with nitisinone sometimes complain of sore eyes.