Single-gene disorders are caused by a defective or mutant allele at a single gene locus and follow mendelian patterns of inheritance. Single-gene disorders are primarily disorders of the pediatric age group. Less than 10% manifest after puberty and only 1% after the reproductive years.
Single-gene disorders are characterized by their patterns of transmission, which usually are obtained through a family genetic history. The patterns of inheritance depend on whether the phenotype is dominant or recessive and whether the gene is located on an autosomal or sex chromosome. In addition to disorders caused by mutations of genes located on the chromosomes located within the nucleus, another class of disorders with a maternal pattern of inheritance involves the mitochondrial genome.
Virtually all single-gene disorders lead to formation of an abnormal protein or decreased production of a gene product. The disorder can result in a defective enzyme or decreased amounts of an enzyme, defects in receptor proteins and their function, alterations in nonenzyme proteins, or mutations resulting in unusual reactions to drugs. Table 7.1 lists some of the common single-gene disorders and their manifestations.
Autosomal Dominant Disorders
In autosomal dominant disorders, a single mutant allele from an affected parent is transmitted to an offspring regardless of sex. The affected parent has a 50% chance of transmitting the disorder to each offspring (Fig. 7.1). The unaffected relatives of the parent or unaffected siblings of the offspring do not transmit the disorder. In many conditions, the age of onset is delayed, and the signs and symptoms of the disorder do not appear until later in life, as in Huntington chorea.
Autosomal dominant disorders also may manifest as a new mutation. Whether the mutation is passed on to the next generation depends on the affected person’s reproductive capacity. Many autosomal dominant mutations are accompanied by reduced reproductive capacity; therefore, the defect is not perpetuated in future generations. If an autosomal defect is accompanied by a total inability to reproduce, essentially all new cases of the disorder will be due to new mutations. If the defect does not affect reproductive capacity, it is more likely to be inherited.
Although there is a 50% chance of inheriting a dominant genetic disorder from an affected parent, there can be wide variation in gene penetration and expression. When a person inherits a dominant mutant gene but fails to express it, the trait is described as having reduced penetrance. Penetrance is expressed in mathematical terms: a 50% penetrance indicates that a person who inherits the defective gene has a 50% chance of expressing the disorder. The person who has a mutant gene but does not express it is an important exception to the rule that unaffected persons do not transmit an autosomal dominant trait. These people can transmit the gene to their descendants and so produce a skipped generation. Autosomal dominant disorders also can display variable expressivity, meaning that they can be expressed differently among people. Polydactyly or supernumerary digits, for example, may be expressed in either the fingers or the toes.
The gene products of autosomal dominant disorders usually are regulatory proteins involved in rate-limiting components of complex metabolic pathways or key components of structural proteins such as collagen. Two disorders of auto-somal inheritance, Marfan syndrome and neurofibromatosis (NF), are described in this chapter.
Marfan Syndrome. Marfan syndrome is an autosomal dominant disorder of the connective tissue, which gives shape and structure to other tissues in the body and holds them in place. The basic biochemical abnormality in Marfan syndrome affects fibrillin I, a major component of microfibrils found in the extracellular matrix. These microfibrils form the scaffolding for the deposition of elastin and are considered integral components of elastic fibers. Fibrillin I is coded by the FBNI gene, which maps to chromosome 15q21. Over 100 mutations in the FBNI gene have been found, making genetic diagnosis unfeasible. The prevalence of Marfan syndrome is estimated to be 1 per 5000. Approximately 70% to 80% of cases are familial and the remainder are sporadic, arising from new mutations in the germ cells of the parents.
Marfan syndrome affects several organ systems, including the eyes; the cardiovascular system, specifically correlated highly with aortic aneurysms; and the skeletal system (bones and joints). There is a wide range of variation in the expression of the disorder. People may have abnormalities of one, two, or more systems. The skeletal deformities, which are the most obvious features of the disorder, include a long, thin body with exceptionally long extremities and long, tapering fingers, some-times called arachnodactyly or spider fingers; hyperextensible joints; and a variety of spinal deformities, including kyphosis and scoliosis (Fig. 7.2). Chest deformities, pectus excavatum (i.e., deeply depressed sternum) or pigeon chest deformity, often are present and may require surgery. The most common eye disorder is bilateral dislocation of the lens due to weakness of the suspensory ligaments. Myopia and predisposition to retinal detachment also are common, the result of increased optic globe length due to altered connective tissue support of ocular structures. However, the most life-threatening aspects of the disorder are the cardiovascular defects, which include mitral valve prolapse, progressive dilation of the aortic valve ring, and weakness of the aorta and other arteries. Dissection and rupture of the aorta may lead to premature death. In women, the risk of aortic dissection is increased in pregnancy.
The diagnosis of Marfan syndrome is based on major and minor diagnostic criteria that include skeletal, cardiovascular, and ocular deformities. There is no cure for Marfan syndrome. Treatment plans include echocardiograms and electrocardiograms to assess the status of the cardiovascular system, periodic eye examinations, and evaluation of the skeletal system, especially in children and adolescents. The risks associated with participation in sports depend on which organ systems are involved.
Neurofibromatosis. Neurofibromatosis is a condition that causes tumors to develop from the Schwann cells of the neurological system. There are at least two genetically and clinically distinct forms of the disorder:
• Type 1 NF (NF-1), also known as von Recklinghausen disease
• Type 2 bilateral acoustic NF (NF-2)
Both of these disorders result from a genetic defect in a tumor suppressor gene that regulates cell differentiation and growth. The gene for NF-1 has been mapped to the long arm of chromosome 17 and the gene for NF-2 to chromosome 22.
Type 1 NF is a common disorder, with a frequency of 1 in 4000 that affects people of all races. In more than 90% of people with NF-1, cutaneous and subcutaneous neurofibromas develop in late childhood or adolescence. The cutaneous neurofibromas, which vary in number from a few to many hundreds, manifest as soft, pedunculated lesions that project from the skin. They are the most common type of lesion, often are not apparent until puberty, and are present in greatest density over the trunk (Fig. 7.3). The subcutaneous lesions grow just below the skin. They are firm and round and may be painful. Plexiform neurofibromas involve the larger peripheral nerves. They tend to form large tumors that cause severe disfigurement of the face, overgrowth of an extremity, or skeletal deformities such as scoliosis. Pigmented nodules of the iris (Lisch nodules), which are specific for NF-1, usually are present after 6 years of age. They do not present any clinical problem but are useful in establishing a diagnosis. If a person presents with sudden visual loss and no radiological findings or increased intracranial pressure, it is a warning of possible increased tumor growth in the central nervous system (CNS). A second major component of NF-1 is the presence of large (usually ≥15 mm in diameter), flat cutaneous pigmentations, known as café au lait spots. They are usually a uniform light brown in whites and darker brown in people of color, with sharply demarcated edges. Although small single lesions may be found in normal children, larger lesions or six or more spots larger than 1.5 cm in diameter suggest NF-1. A Wood lamp, which uses ultraviolet light, can be used to detect lighter spots. The skin pigmentations become more evident with age as the melanosomes in the epidermal cells accumulate melanin.
Children with NF-1 are also susceptible to neurologic complications. There is an increased incidence of learning disabilities, attention deficit disorders, and abnormalities of speech among affected children. Complex partial and generalized tonicclonic seizures are a frequent complication. Malignant neoplasms are also a significant problem in people with NF-1. One of the major complications of NF-1, occurring in 3% to 5% of people, is the appearance of a neurofibrosarcoma in a neurofibroma, usually a larger plexiform neurofibroma. NF-1 is also associated with increased incidence of other neurogenic tumors, including meningiomas, optic gliomas, and pheochromocytomas.
Type 2 NF is characterized by tumors of the acoustic nerve. Most often, the disorder is asymptomatic through the first 15 years of life. This type of NF occurs less frequently at a rate of 1 in 50,000 people. The most frequent symptoms are headaches, hearing loss, and tinnitus. There may be associated intracranial and spinal meningiomas. The condition is often made worse by pregnancy, and oral contraceptives may increase the growth and symptoms of the tumors because many neurofibromas express progesterone receptors. People with the disorder should be warned that severe disorientation may occur during diving or swimming underwater, and drowning may result. Surgery may be indicated for debulking or removal of the tumors.
Autosomal Recessive Disorders
Autosomal recessive disorders are manifested only when both members of the gene pair are affected. In this case, both parents may be unaffected but are carriers of the defective gene. Autosomal recessive disorders affect both sexes. The occurrence risks in each pregnancy are one in four for an affected child, two in four for a carrier child, and one in four for a normal (noncarrier, unaffected), homozygous child (Fig. 7.4). Consanguineous mating (mating of two related people), or inbreeding, increases the chance that two people who mate will be carriers of an autosomal recessive disorder.
With autosomal recessive disorders, the age of onset is frequently early in life. In addition, the symptomatology tends to be more uniform than with autosomal dominant dis- orders. Furthermore, autosomal disorders are characteristically caused by loss-of-function mutations, many of which impair or eliminate the function of an enzyme. In the case of a heterozygous carrier, the presence of a mutant gene usually does not produce symptoms because equal amounts of normal and defective enzymes are synthesized. This “mar- gin of safety” ensures that cells with half their usual amount of enzyme function normally. By contrast, the inactivation of both alleles in a homozygote results in complete loss of enzyme activity. Autosomal recessive disorders include almost all inborn errors of metabolism. Enzyme disorders that impair catabolic pathways result in an accumulation of dietary substances (e.g., phenylketonuria [PKU]) or cellular constituents (e.g., lysosomal storage diseases). Other disorders result from a defect in the enzyme-mediated synthesis of an essential protein (e.g., the cystic fibrosis transmembrane conductance regulator in cystic fibrosis). Two examples of autosomal recessive disorders that are not covered elsewhere in this book are PKU and Tay-Sachs disease.
Phenylketonuria. PKU is a rare autosomal recessive metabolic disorder that affects approximately 1 in every 10,000 to 15,000 infants in the United States. The disorder is caused by a deficiency of the liver enzyme phenylalanine hydroxylase, which allows toxic levels of the amino acid, phenylalanine, to accumulate in tissues and the blood.12 If untreated, the disorder results in mental retardation, microcephaly, delayed speech, and other signs of impaired neurologic development.
Because the symptoms of PKU develop gradually and would be difficult to assess, policies have been developed to screen all infants for abnormal levels of serum phenyl- alanine. It is important that blood samples for PKU screening be obtained at least 24 hours after birth to ensure accuracy.
Infants with the disorder are treated with a special diet that restricts phenylalanine intake. The results of dietary therapy of children with PKU have been impressive. The diet can prevent mental retardation as well as other neurodegenerative effects of untreated PKU. However, dietary treatment must be started early in neonatal life to prevent brain damage. Infants with elevated phenylalanine levels (>10 mg/dL) should begin treatment by 7 to 10 days of age, indicating the need for early diagnosis. Evidence suggests that high levels of phenylalanine even during the first 2 weeks of life can be very harmful to the infant. Recent research regarding trials of sapropterin dihydrochloride in managing mild-to- moderate PKU shows potential promise, but more outcome data are needed.
Tay-Sachs Disease. Tay-Sachs disease is a variant of a class of lysosomal storage diseases, known as the gangliosidoses, in which there is failure to break down the GM2 gangliosides of cell membranes. Tay-Sachs disease is inherited as an autosomal recessive trait and occurs ten times more frequently in offspring of Eastern European (Ashkenazi) Jews compared to the general population.
The GM2 ganglioside accumulates in the lysosomes of all organs in Tay-Sachs disease, but is most prominent in the brain neurons and retina. Microscopic examination reveals neurons ballooned with cytoplasmic vacuoles, each of which constitutes a markedly distended lysosome filled with gangliosides. In time, there is progressive destruction of neurons within the brain substance, including the cerebellum, basal ganglia, brain stem, spinal cord, and autonomic nervous system. Involvement of the retina is detected by ophthalmoscopy as a cherry-red spot on the macula.
Infants with Tay-Sachs disease appear normal at birth but begin to manifest progressive weakness, muscle flaccidity, and decreased attentiveness at approximately 6 to 10 months of age. This is followed by rapid deterioration of motor and mental function, often with development of generalized seizures. Retinal involvement leads to visual impairment and eventual blindness. Death usually occurs before 4 to 5 years of age. Analysis of the blood serum for the lysosomal enzyme, hex- osaminidase A, which is deficient in Tay-Sachs disease, allows for accurate identification of genetic carriers for the disease. Although there is no cure for the disease, evidence suggests that the development of recombinant human lysosomal (beta)-hexosaminidase A may be helpful in assisting some people with Tay-Sachs disease to have a higher quality of life.
X-Linked Recessive Disorders
Sex-linked disorders are almost always associated with the X, or female, chromosome, and the inheritance pattern is predominantly recessive. Because of the presence of a normal paired gene, female heterozygotes rarely experience the effects of a defective gene, whereas all males who receive the gene are typically affected. The common pattern of inheritance is one in which an unaffected mother carries one normal and one mutant allele on the X chromosome. This means that she has a 50% chance of transmitting the defective gene to her sons, and her daughters have a 50% chance of being carriers of the mutant gene (Fig. 7.5). When the affected son procreates, he transmits the defective gene to all of his daughters, who become carriers of the mutant gene. Because the genes of the Y chromosome are unaffected, the affected male does not transmit the defect to any of his sons, and they will not be carriers or transmit the disorder to their children. X-linked recessive disorders include glucose-6-phosphate dehydrogenase deficiency, hemophilia A, and X-linked agammaglobulinemia.
Fragile X Syndrome
Fragile X syndrome is a single-gene disorder that causes intellectual disability. The mutation occurs at the Xq27 on the fragile site and is characterized by amplification of a CGG repeat. The disorder, which affects approximately 1 in 1250 males and 1 in 2500 females, is the most common form of inherited intellectual disability. As with other X-linked disorders, fragile X syndrome affects boys more often than girls.
Pathogenesis. The fragile X gene has been mapped to the long arm of the X chromosome, designated the FMR1 (fragile X mental retardation 1) site. The gene product, the fragile X mental retardation protein (FMRP), is a widely expressed cytoplasmic protein. It is most abundant in the brain and testis, the organs most affected by the disorder. Each gene contains an introduction or promoter region and an instruction region that carries the directions for protein synthesis. The promoter region of the FMR1 gene contains repeats of a specific CGG (cytosine, guanine, guanine) triplet code that, when normal, controls gene activity. The mechanism by which the normal FMR1 gene is converted to an altered, or mutant, gene capable of producing disease symptoms involves an increase in the number of CGG repeats in the promoter region of the gene. Once the repeat exceeds a threshold length, no FMRP is produced, resulting in the fragile X phenotype. People without fragile X syndrome have between 6 and 40 repeats. A gene with 55 to 200 repeats is generally considered a permutation and one with more than 200 repeats, a full mutation.
The inheritance of the FMR1 gene follows the pattern of X-linked traits, with the father passing the gene on to all his daughters but not his sons. Approximately 20% of males who have been shown to carry the fragile X mutation are clinically and cytogenetically normal. Because these male carriers transmit the trait through all their daughters (who are phenotypically normal) to affected grandchildren, they are called transmitting males.
Clinical Manifestations and Diagnosis. Affected boys are intellectually disabled and share a common physical phenotype that includes a long face with large mandible and large, everted ears. Hyperextensible joints, a high-arched palate, and mitral valve prolapse, which are observed in some cases, mimic a connective tissue disorder. Some physical abnormalities may be subtle or absent. Because girls have two X chromosomes, they are more likely to have relatively normal cognitive development, or they may show a learning disability in a particular area, such as mathematics.
Diagnosis of fragile X syndrome is based on mental and physical characteristics. DNA molecular tests can be done to con- firm the presence of an abnormal FMR1 gene. Because the manifestations of fragile X syndrome may resemble those of other learning disorders, it is recommended that people with intellectual disability of unknown cause, developmental delay, learning disabilities, autism, or autism-like behaviors be evaluated for the disorder. Fragile X screening is now often offered along with routine prenatal screening to determine if the woman is a carrier.