Monogenic (Mendelian) Inheritance
A monogenic disorder is caused by a mutation or alteration in a single locus or gene in one or both members of a gene pair. Monogenic disorders are also called mendelian to signify that their transmission follows the laws of inheritance proposed by Gregor Mendel. Traditional modes of mendelian inheritance include autosomal dominant, autosomal recessive, X-linked, and Y-linked. Other monogenic patterns of inheritance include mitochondrial inheritance, uniparental disomy, imprinting, and trinucleotide repeat expansion, that is, anticipation (Guttmacher and Collins, 2002).
By age 25, about 0.4 percent of the population exhibits an abnormality attributed to a monogenic disorder, and 2 percent will have at least one such disorder during their lifetime.
It is important to emphasize that it is the phenotype that is dominant or recessive, not the genes. In some dominant diseases, for example, the normal gene may still be directing the production of normal protein, but the phenotype is determined by protein produced by the abnormal gene. Likewise, the heterozygous carrier of some recessive diseases may produce detectable levels of the abnormal gene product, but he or she does not display features of the disease because the phenotype is directed by the product of the normal co-gene. For example, erythrocytes from carriers of sickle-cell anemia contain about 30 percent hemoglobin S, however, because the remaining hemoglobin is A, these cells do not sickle under normal oxygen conditions.
Although transmission patterns of these diseases are consistent with mendelian inheritance, their phenotypes are strongly influenced by modifying genes and environmental factors. Some common single-gene disorders affecting adults are listed in Table 12-5.
Table 12-5. Some Common Single-Gene Disorders |Favorite Table|Download (.pdf)
Table 12-5. Some Common Single-Gene Disorders
Acute intermittent porphyria
Adult polycystic kidney disease
Antithrombin III deficiency
BRCA1 and BRCA2 breast cancer
Familial adenomatous polyposis
Hereditary hemorrhagic telangiectasia
Hypertrophic obstructive cardiomyopathy
Long QT syndrome
Neurofibromatosis type 1 and 2
von Willebrand disease
Congenital adrenal hyperplasia
Sickle cell anemia
Androgen insensitivity syndrome
Chronic granulomatous disease
Fragile X syndrome
Hemophilia A and B
Muscular dystrophy—Duchenne and Becker
Ocular albinism type 1 and 2
Autosomal Dominant Inheritance
If only one member of a gene pair determines the phenotype, that gene is considered to be dominant. An individual carrying a gene that causes an autosomal dominant disease has a 50-percent chance of passing on the affected gene with each conception. A gene with a dominant mutation generally specifies the phenotype in preference to the normal gene. That said, not all individuals will necessarily manifest an autosomal dominant condition the same way. Factors that affect the phenotype of an autosomal dominant condition include penetrance, expressivity, and occasionally, presence of co-dominant genes.
This term describes whether or not an autosomal dominant gene is expressed at all. A gene with some kind of recognizable phenotypic expression in all individuals has 100-percent penetrance. If some carriers express the gene but some do not, then penetrance is incomplete. This is quantitatively expressed by the ratio of those individuals with any phenotypic characteristics of the gene to the total number of gene carriers. For example, a gene that is expressed in some way in 80 percent of individuals who have that gene is 80-percent penetrant. Incomplete penetrance may explain why some autosomal dominant diseases appear to “skip” generations.
This term refers to the degree to which the phenotypic features are expressed. If all individuals carrying the affected gene do not have identical phenotypes, the gene has variable expressivity. Expressivity of a gene can range from complete or severe manifestations to only mild features of the disease. An example of a disease with variable expressivity is neurofibromatosis.
If alleles in a gene pair are different from each other, but both are expressed in the phenotype, they are considered to be co-dominant. A common example is the human major blood groups—because their genes are co-dominant, both A and B red-cell antigens can be expressed simultaneously in one individual. Another example is the several genes responsible for hemoglobinopathies. The individual with one gene directing production of sickle hemoglobin and the other directing production of hemoglobin C produces both S and C hemoglobins.
Increasing paternal age significantly increases the risk of spontaneous new mutations. These may result in offspring with autosomal dominant disorders, such as neurofibromatosis or achondroplasia (Friedman, 1981). Such new mutations may also result in offspring carrying X-linked conditions, and they may be a factor in early pregnancy loss. The incidence of new autosomal dominant mutations among newborns whose fathers are 40 years old is at least 0.3 percent. There is some evidence that paternal age also may affect the incidence of isolated structural abnormalities (McIntosh and colleagues, 1995).
Advanced paternal age is not associated with an increased risk for aneuploidy, probably because aneuploid sperm cannot fertilize an egg.
Autosomal Recessive Inheritance
A trait that is recessive is expressed only when both copies of the gene function identically. Thus, autosomal recessive diseases develop only when both gene copies are abnormal. Phenotypic alterations in gene carriers—that is, heterozygotes—usually are undetectable clinically but may be recognized at the biochemical or cellular level. For example, many enzyme deficiency diseases are autosomal recessive. The enzyme level in a carrier will be about half of normal, but because enzymes are made in great excess, this reduction usually does not cause disease. It does, however, represent a phenotypic alteration and can be used for screening purposes. Other recessive conditions do not produce any phenotypic changes in the carrier and can be identified only by molecular methods.
Unless they are screened for a specific disease, such as cystic fibrosis, carriers usually are recognized only after the birth of an affected child or the diagnosis of an affected family member (see Chap. 13, Familial Genetic Disease). A couple whose child has an autosomal recessive disease has a 25-percent recurrence risk with each conception. The likelihood that a normal sibling of an affected child is a carrier of the gene is two out of three. Thus, 1/4 of offspring will be homozygous normal, 2/4 will be heterozygote carriers, and 1/4 will be homozygous abnormal. Another way to look at this is that three of four children will be phenotypically normal, and two of these three will be carriers.
The carrier child will not have affected children, unless his or her partner is also a heterozygous carrier or is homozygous and has the disease. Because genes leading to rare autosomal recessive conditions have a low prevalence in the general population, the chance that a partner will be a gene carrier is low unless the couple is either related or is a member of an at-risk population (American College of Obstetricians and Gynecologists, 2004).
Inborn Errors of Metabolism
Most of these autosomal recessive diseases result from the absence of a crucial enzyme leading to incomplete metabolism of proteins, sugars, or fats. The metabolic intermediates that build up are toxic to a variety of tissues, resulting in mental retardation or other abnormalities.
This classic example of an autosomal recessive defect results from diminished or absent phenylalanine hydroxylase activity. Homozygotes are unable to metabolize phenylalanine to tyrosine. If the diet is unrestricted, incomplete protein metabolism leads to abnormally high phenylalanine levels that cause neurological damage and mental retardation. There also is hypopigmented hair, eyes, and skin because phenylalanine competitively inhibits tyrosine hydrolase, which is essential for melanin production. The disease affects 1 in 10,000 to 15,000 white newborns. There is tremendous geographical and ethnic variation, with incidences ranging from 5 to 190 cases per million.
PKU is notable for two reasons. First, it is one of the few metabolic disorders for which treatment exists. Homozygotes who ingest a phenylalanine-restricted diet can avoid many of the clinical consequences of the disease. Early diagnosis and limitation of dietary phenylalanine beginning in infancy are essential to prevent neurological damage. Accordingly, all states and many countries now mandate newborn screening for PKU, and about 100 cases per million births are identified worldwide. The special diet should be continued indefinitely, as patients who abandon the phenylalanine-restricted diet are reported to have a significantly lower IQ (Koch and co-workers, 2000).
The second reason is that women with PKU are at risk to have otherwise normal heterozygous offspring who sustain damage in utero as a result of being exposed to high phenylalanine concentrations during pregnancy. Phenylalanine readily crosses the placenta, and hyperphenylalaninemia has significant risk for miscarriage and for offspring with mental retardation, microcephaly, low birth weight, and congenital heart defects. For this reason, women with PKU should adhere to the phenylalanine-restricted diet if they are contemplating pregnancy, and then throughout pregnancy (Clarke, 2003). In the Maternal Phenylketonuria Collaborative Study, 572 pregnancies were followed over 18 years. Findings showed that maintenance of serum phenylalanine levels in the 160 to 360 μmol/L—2 to 6 mg/dL—range significantly reduced the risk of fetal abnormalities (Koch and colleagues, 2003; Platt and co-workers, 2000). The study further demonstrated that women who established optimal phenylalanine levels of 120 to 360 μmol/L between 0 and 10 weeks had children with mean IQ in the normal range at age 6 to 7 years (Koch and colleagues, 2003).
Two individuals are considered consanguineous if they have at least one ancestor in common. First-degree relatives share half of their genes, second-degree relatives share a fourth, and third-degree relatives—cousins—share one eighth. Because of the potential for shared deleterious genes, consanguineous unions are at increased risk to produce children with otherwise rare autosomal recessive diseases. They are also at increased risk to have offspring with multifactorial conditions that are subsequently discussed.
First-cousin marriages, the most frequent consanguineous mating, carry a twofold increased risk over background of abnormal offspring—4 to 6 percent if there is no family history of genetic disease. If one of the partners has a sibling with an autosomal recessive disease, the risk of affected offspring is many times higher than if he or she had chosen an unrelated partner.
Incest is defined as a sexual relationship between first-degree relatives such as parent and child or brother and sister and is universally illegal. Progeny of such unions carry the highest risk of abnormal outcome, and up to 40 percent of offspring are abnormal as a result of both recessive and multifactorial disorders (Friere-Maia, 1984; Nadiri, 1979).
X-Linked and Y-Linked Inheritance
Most X-linked diseases are recessive. Some of the best known examples are color blindness, hemophilia A, and Duchenne muscular dystrophy. When a woman carries a gene causing an X-linked recessive condition, each son has a 50-percent risk of being affected, and each daughter has a 50-percent chance of being a carrier.
Males carrying an X-linked recessive gene are usually affected because they lack a second X chromosome to express the normal dominant gene. When a male has an X-linked disease, none of his sons will be affected because they cannot receive the abnormal X-linked gene from him. Women carrying an X-linked recessive gene are generally unaffected by the disease it causes. In some cases, however, because of skewed lyonization—inactivation of one X chromosome in each cell—female carriers may have features of the condition. An example is a woman who has the gene for hemophilia A and who herself has bleeding tendencies (Plug and colleagues, 2006). Similarly, some female carriers of Duchenne muscular dystrophy may develop cardiomyopathy and conduction defects (Politano and colleagues, 1996). Identification of such symptoms may be valuable in caring for the pregnant woman and providing accurate prenatal diagnosis.
X-linked dominant disorders mainly affect females because they tend to be lethal in male offspring. Examples include focal dermal hypoplasia, vitamin D-resistant rickets, and incontinentia pigmenti.
The Y chromosome carries genes important for sex determination and a variety of cellular functions such as spermatogenesis and bone development. Deletion of genes on the long arm results in severe spermatogenic defects, whereas genes at the tip of the short arm are critical for chromosomal pairing during meiosis and for fertility.
Each human cell contains hundreds of mitochondria, each containing its own genome and associated replication system. In this sense, they behave autonomously. Mitochondria are inherited exclusively from the mother. Human oocytes contain approximately 100,000 mitochondria, but sperm contain only 100 and these are destroyed after fertilization. Each mitochondrion has multiple copies of a 16.5-kb circular DNA molecule that contains 37 unique genes. Mitochondrial DNA encodes peptides required for oxidative phosphorylation, as well as ribosomal and transfer RNAs.
Because mitochondria contain genetic information, their inheritance allows the transmission of genes from mother to offspring without the possibility of recombination. If a mitochondrial mutation occurs, it may segregate into a daughter cell during cell division and thus be propagated. If an oocyte containing largely mutated mitochondrial DNA is fertilized, the offspring may have a mitochondrial disease. Mitochondrial diseases have a characteristic transmission pattern—individuals of both sexes can be affected, but transmission is only through females.
As of April 2009, 26 mitochondrial diseases or conditions with known molecular basis were described in the OMIM website. Examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh syndrome, and interestingly, susceptibility to both aminoglycoside-induced deafness and chloramphenicol toxicity.
DNA Triplet Repeat Expansion—Anticipation
Mendel's first law states that genes are passed unchanged from parent to progeny. Barring the new mutations, this law still applies to many genes or traits. Certain genes, however, are unstable, and their size, and consequently their function, may be altered as they are transmitted from parent to child. This is manifested clinically by anticipation, a phenomenon in which disease symptoms seem to be more severe and to appear at an earlier age in each successive generation. Examples include fragile X syndrome and myotonic dystrophy, both of which are caused by expansion of a repeated trinucleotide segment of DNA. Examples of other DNA triplet (trinucleotide) repeat diseases are shown in Table 12-6.
Table 12-6. Some Disorders Caused by DNA Triplet Repeat Expansion |Favorite Table|Download (.pdf)
Table 12-6. Some Disorders Caused by DNA Triplet Repeat Expansion
Dentatorubral pallidoluysian atrophy
Fragile X syndrome
Kennedy disease—spinal bulbar muscular atrophy
This is the most common form of familial mental retardation and affects about 1 in 4000 males and 1 in 8000 females (American College of Obstetricians and Gynecologists, 2006). It is an X-linked disorder characterized by mental retardation that is borderline to severe. Males have an average IQ score of 35 to 45, whereas the IQ in females is generally higher (Nelson, 1995). Affected individuals also may have autistic behavior, attention-deficit/hyperactivity disorder—ADHD, as well as speech and language problems. The physical phenotype includes a narrow face with large jaw, long prominent ears, and macroorchidism in postpubertal males.
Fragile X is caused by expansion of a repeated trinucleotide DNA segment—CGG, that is, cytosine-guanine-guanine—at chromosome Xq27. When the CGG number reaches a critical size, the fragile X mental retardation 1 (FMR1) gene becomes methylated and thereby inactivated, and thus, FMR1 protein is not produced (Migeon, 1993). The number of repeats and the degree of methylation determines whether or not an individual is affected by the syndrome, as well as its severity (Cutillo, 1994). Clinically, four groups have been described:
Full mutation—more than 200 repeats
Premutation—61 to 200 repeats
Intermediate—41 to 60 repeats
Unaffected—fewer than 40 repeats
Males who have the full mutation typically have methylation of the FMR1 gene and full expression of the syndrome. In females, expression is variable, due to X-inactivation of the affected X chromosome.
Although individuals with premutations were initially considered to be normal, more recent research has been focused on three conditions that may manifest: late-onset neurodegenerative disorder with tremor and ataxia, particularly in males; premature ovarian failure in 20 to 30 percent of females; and autism or autistic-like behavior among children (Hagerman and Hagerman, 2004).
Whether a fetus will inherit the full mutation for fragile X syndrome depends on the gender of the transmitting parent and the number of CGG repeats in that parental gene. When transmitted by a male, the number of repeats usually remains stable—the premutation is transmitted without expanding to a full mutation. When transmitted by a female with a premutation, the FMR1 gene can expand during meiosis, particularly if the CGG repeat number exceeds 90. If a woman carries a premutation that increases in size as she transmits it to her offspring, then her child is at risk to have the full fragile X syndrome (Cutillo, 1994). If she carries an intermediate repeat number—41 to 60 repeats—expansion to a full mutation is unlikely.
Prenatal diagnosis of fragile X may be accomplished using Southern blot analysis and polymerase chain reaction to determine the CGG repeat number and the gene methylation status. These tests are discussed subsequently. Amniocentesis is preferred, because gene methylation status may not be reliably assessed from chorionic villi. It is reasonable to refer individuals with a history of mental retardation, developmental delay of unknown etiology, or autism for genetic evaluation because 2 to 6 percent will be determined to have fragile X (Curry and colleagues, 1997; Wenstrom and associates, 1999).
In this situation, both members of one pair of chromosomes are inherited from the same parent, instead of one member being inherited from each parent. Often, uniparental disomy does not have clinical consequences. Some exceptions are when it involves chromosomes 6, 7, 11, 14, or 15. These offspring are at increased risk for an abnormality that results from parent-of-origin differences in gene expression (Shaffer and colleagues, 2001). Although several genetic mechanisms may cause uniparental disomy, the most common is “trisomic rescue” as shown in Figure 12-8. After a nondisjunction event produces a trisomic conceptus, one of the three homologues may be lost. This will result in uniparental disomy for that chromosome in a third of cases.
Mechanism of uniparental disomy arising from trisomic “rescue.” A. In normal meiosis, one member of each pair of homologous chromosomes is inherited from each parent. B. If nondisjunction results in a trisomic conceptus, one homologue is sometimes lost. In a third of cases, loss of one homologue leads to uniparental disomy.
Isodisomy is the unique situation in which an individual receives two identical copies of one chromosome in a pair from one parent. This mechanism explains some cases of cystic fibrosis, in which only one parent is a carrier but the fetus inherits two copies of the same abnormal chromosome from that parent (Spence and co-workers, 1988; Spotila and colleagues, 1992). It also has been implicated in abnormal growth related to placental mosaicism (Robinson and colleagues, 1997).
This term describes the process by which certain genes are inherited in an inactivated or transcriptionally silent state at one of the parental loci in the offspring (Hall, 1990). This type of gene inactivation is determined by the gender of the transmitting parent and may be reversed in the next generation. Imprinting affects gene expression by epigenetic control; that is, it changes the phenotype by altering gene expression and not by permanently altering the genotype. When a gene is inherited in an imprinted state, gene function is directed by the co-gene inherited from the other parent, so imprinting exerts an effect by controlling the “dosage” of specific genes.
Selected diseases that can involve imprinting are shown in Table 12-7. A useful example includes two very different diseases that may be caused by microdeletion, uniparental disomy, or imprinting for the 15q11-q13 region of DNA:
Prader–Willi syndrome is characterized by obesity and hyperphagia; short stature; small hands, feet, and external genitalia; and mild mental retardation. In over 70 percent of cases, Prader-Willi is caused by microdeletion or disruption for the paternal 15q11-q13. The remainder of cases are due to maternal uniparental disomy or due to imprinting—with the paternal genes inactive (Online Mendelian Inheritance in Man, 2008).
Angelman syndrome includes normal stature and weight; severe mental retardation; absent speech; seizure disorder; ataxia and jerky arm movements; and paroxysms of inappropriate laughter. In approximately 70 percent of cases, Angelman syndrome is caused by microdeletion or disruption for the maternal 15q11-q13. In 2 percent, the syndrome is caused by paternal uniparental disomy, and another 2 to 3 percent are due to imprinting—with the maternal genes inactivated (Online Mendelian Inheritance in Man, 2008).
Table 12-7. Some Disorders That Can Involve Imprinting |Favorite Table|Download (.pdf)
Table 12-7. Some Disorders That Can Involve Imprinting
Depends on type
There are a number of other examples of imprinting important to obstetricians. A complete hydatidiform mole, which has a paternally derived diploid chromosomal complement, is characterized by the abundant growth of placental tissue with no fetal structures (see Chap. 11, Complete Hydatidiform Mole). Conversely, an ovarian teratoma, which has a maternally derived diploid chromosomal complement, is characterized by the growth of various fetal tissues but no placental structures (Porter and Gilks, 1993). It thus appears that paternal genes are vital for placental development, and maternal genes are essential for fetal development, but both must be present in every cell for normal fetal growth and development.
Multifactorial and Polygenic Inheritance
Polygenic traits are determined by the combined effects of more than one gene, and multifactorial traits are determined by multiple genes and environmental factors. Most inherited traits are multifactorial or polygenic. Birth defects caused by such inheritance are recognized by their tendency to recur in families, but not according to a mendelian inheritance pattern. The empirical recurrence risk for first-degree relatives usually is quoted as 3 to 5 percent. Multifactorial traits can be classified in several ways, but the most logical is to categorize them as continuously variable traits, threshold traits, or complex disorders of adult life.
Continuously Variable Traits
A trait is continuously variable if it has a normal distribution in the general population, such as height or head size. Abnormalcy for a trait is defined as a measurement greater than two standard deviations above or below the population mean. Continuously variable traits are believed to result from the individually small effects of many genes combined with environmental factors. They tend to be less extreme in the offspring of affected individuals, because of the statistical principle of regression to the mean.
These traits do not appear until a certain threshold is exceeded. Factors that create liability or propensity for the trait are normally distributed, and only individuals at the extreme of this distribution exceed the threshold and have the trait or defect. The phenotypic abnormality is thus an all-or-none phenomenon. Individuals in high-risk families have enough abnormal genes or environmental influences that their liability is close to the threshold, and in certain family members, the threshold is crossed. Cleft lip and palate and pyloric stenosis are examples of threshold traits.
Certain threshold traits have a predilection for one gender, indicating that males and females have a different liability threshold (Fig. 12-9). An example is pyloric stenosis, which is more common in males. If a female has pyloric stenosis, it is likely that she inherited even more abnormal genes or predisposing factors than are usually necessary to produce pyloric stenosis in males. The recurrence risk for her children or siblings is thus higher than the expected 3 to 5 percent. Her male siblings or offspring would have the highest liability, because they not only will inherit more than the usual number of predisposing genes but also are the more susceptible sex.
Schematic example of a threshold trait such as pyloric stenosis that has a predilection for males. Each gender is normally distributed, but at the same threshold, more males than females will develop the condition.
Finally, the recurrence risk of threshold traits is also higher if the defect is severe, again suggesting the presence of more abnormal genes or influences. For example, the recurrence risk after the birth of a child with bilateral cleft lip and palate is 8 percent, compared with only 4 percent for unilateral cleft lip without cleft palate (Melnick and associates, 1980).
Complex Disorders of Adult Life
These are traits in which many genes determine the susceptibility to environmental factors, with disease resulting from the most unfavorable combination of both. Examples include common disorders such as heart disease or hypertension. These are usually familial and behave as threshold traits, but with environmental influence as an important cofactor. In recent years, many specific gene mutations have been characterized that may cause these common conditions. For example, as of April 2009, the OMIM website listed more than 700 specific entries for “Diabetes.” In some diseases, the identity of the associated gene provides a clue to pathogenesis, whereas in others the related gene may simply serve as a disease marker.
Examples of Multifactorial or Polygenic Defects
Various birth defects and common diseases exhibit multifactorial or polygenic inheritance. These diseases have certain inherent characteristics that help to distinguish them from disorders with other modes of inheritance (Table 12-8). When assessing risks for a familial multifactorial trait, it is important to consider the degree of relatedness of the affected relative to the fetus, not the parents. An affected first-degree relative—parents or siblings of the fetus—results in a substantial risk increase, but risk declines exponentially with successively more distant relationships. Two examples are cardiac defects and neural-tube defects.
Table 12-8. Characteristics of Multifactorial Diseases |Favorite Table|Download (.pdf)
Table 12-8. Characteristics of Multifactorial Diseases
There is a genetic contribution
- No mendelian pattern of inheritance
- No evidence of single-gene disorder
Nongenetic factors are also involved in disease causation
- Lack of penetrance despite predisposing genotype
- Monozygotic twins may be discordant
Familial aggregation may be present
- Relatives are more likely to have disease-predisposing alleles
Expression more common among close relatives
- Becomes less common in less closely related relatives, fewer predisposing alleles
- Greater concordance in monozygotic than dizygotic twins
Structural heart anomalies are the most common birth defects worldwide, with an incidence of 8 per 1000 births. More than 100 genes believed to be involved in cardiovascular morphogenesis have been identified, including those directing production of various transcription factors, secreted proteins, extracellular proteins, and protein receptors (Olson, 2006; Weismann and Gelb, 2007). These gene products are likely involved in the development of specific cardiac tissues and structures. For example, folic acid and the methylene tetrahydrofolate reductase (MTHFR) mutation influence the development of cardiac defects (Wenstrom and co-workers, 2001). Importantly, periconceptional folic acid-containing multivitamin supplementation may reduce their incidence (Czeizel, 1998).
Observed recurrence risks for common congenital heart defects are shown in Table 12-9. If the exact nature of the defect is known, the most specific risk should be quoted when counseling. Otherwise, couples can be informed of the empirical risk of having a child with a cardiac defect. This is 5 to 6 percent if the mother has the defect and 2 to 3 percent if the father has the defect (Burn and associates, 1998). Specific defects, which may have recurrence risks four- to sixfold higher, include hypoplastic left heart, bicuspid aortic valve, and aortic coarctation (Lin and Garver, 1988; Nora and Nora, 1988).
Table 12-9. Recurrence Risk (Percent) for Congenital Heart Defects If Siblings or Parents Are Affected |Favorite Table|Download (.pdf)
Table 12-9. Recurrence Risk (Percent) for Congenital Heart Defects If Siblings or Parents Are Affected
Ventricular septal defects
Atrial septal defects
Isolated, that is, nonsyndromic, neural-tube defects are the second most common congenital structural abnormalities after cardiac defects. Their prenatal diagnosis and sonographic features are described in Chapter 13 and Chapter 16, Neural-Tube Defects, respectively.
Neural-tube defects are classic examples of multifactorial inheritance. Their development is influenced by environment, diet, physiological abnormalities such as hyperthermia or hyperglycemia, teratogen exposure, family history, ethnic origin, fetal gender, amnionic fluid nutrients, and various genes. Neural-tube defects associated with type 1 diabetes mellitus are more likely to be cranial or cervical-thoracic; with valproic acid exposure, lumbosacral defects; and with hyperthermia, anencephaly (Becerra and colleagues, 1990; Hunter, 1984; Lindhout and associates, 1992).
Hibbard and Smithells (1965) postulated more than 40 years ago that abnormal folate metabolism was responsible for many neural-tube malformations. Decades later, a thermolabile variant of the enzyme 5,10-methylene tetrahydrofolate reductase (MTHFR), which plays a key role in folate metabolism, was shown to be associated with neural-tube defects. This enzyme transfers a methyl group from folic acid to convert homocysteine to methionine. One abnormal form of MTHFR carries a mutation at position 677 of its gene and has reduced enzymatic activity. Folic acid supplementation likely works by overcoming this relative enzyme deficiency. Because some defects develop in fetuses with normal 677 C→T alleles, and because folic acid supplementation does not prevent all cases, other unknown genes or factors are presumed to be involved.
Without folic acid supplementation, the empirical recurrence risk after one affected child is 3 to 4 percent, and after two affected children it is 10 percent. With supplementation, the risk after one affected child decreases by 70 percent to less than 1 percent (Czeizel and Dudas, 1992; MRC Vitamin Study Research Group, 1991).
Importantly, prenatal folic acid supplementation in all women may also significantly decrease the incidence of first occurrences of neural-tube defects. Since 1998, the Food and Drug Administration has required fortification of cereal grain products calculated so that the average woman ingests daily an extra 200 μg of folic acid. In the United States, the incidence of neural-tube defects has decreased by a fourth following folic acid fortification (Centers for Disease Control and Prevention, 2004; De Wals and associates, 2003).