The Chromosomal House of Horrors

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To emphasize the troubling scientific and providential enigmas presented by human genetic disorders, and to illustrate the pervasive scope of conditions affected by pernicious genes, I will next describe briefly a few of the more common or gruesome afflictions from the morbid encyclopedia of the human genome. For each, mutations in one or more genes on a human chromosome result in the debilitating diseases mentioned.

Chromosome 1: hypophosphatasia This genetic defect in skeletal mineralization normally is transmitted as a recessive allele, and can result in symptoms that may include deformed bones and premature loss of deciduous teeth in children. Hypophosphatasia occurs throughout the world, but is notably prevalent in inbred Mennon-ite families in Manitoba, Canada. There is no established medical treatment.

Chromosome 2: precocious puberty The dominant allele for this condition is expressed only in males and results in an early onset of testosterone production. Affected boys generally show signs of puberty by the age of four years. This condition exemplifies the profound physiological consequences sometimes resulting from the smallest of genetic alterations. In the entire human genome of 3,000,000,000 nucleotide pairs, this form of precocious puberty is associated with a single nucleotide substitution!11

Chromosome 3: postanesthetic apnea The recessive mutation for this condition also involves a single nucleotide substitution that in this case leads to an alteration in nerve impulse transmissions in response to certain chemical stimuli. For homozygous individuals (whose cells possess two defective copies of the gene), a prolonged cessation of breathing may follow administration of a muscle relaxant during surgical anesthesia. Postanesthetic apnea is an example of a genetic condition that may not be a disorder at all under the normal circumstances in which humans evolved, but can become so under a modern environmental challenge. One in about 3,000 North American Caucasians is affected.

Chromosome 5: cri-du-chat syndrome Named after the unnerving "cry of the cat" wail by afflicted infants, this syndrome is among the most common (one in 50,000 births) of human genetic disorders attributable to a partial chromosomal deletion. The stricken are mentally retarded and have pronounced eye folds, a small face, and a prominent nasal bridge. Other medical complications from the disease often lead to death in infancy or early childhood.

Chromosome 6: Salla disease This disorder in the body's ability to process and store sialic acid produces noticeable symptoms of poor muscle tone and uncoordinated movements beginning at 6-9 months of age. Approximately one-third of patients never learn to walk, and an equal proportion lose the capacity to produce (but not to comprehend) words. Maturing individuals suffer retarded growth and mental function, and adult IQs are in the range of 20 to 40. Lifespan appears little shortened by the disease, and one man lived to the age of 72. Salla disease is concentrated in northeastern Finland, suggesting that the allele responsible probably traces genealogically to a single mutation that originated in this area.

Several other single-gene diseases have been uncovered in the Finnish population. Finland was colonized only about 2,000 years ago (seventy-five generations), and the population as recently as the late 1600s went through a severe decline. Historically, the Finns have mixed little with other populations, and the country has exceptional family records dating back over three centuries. These factors make the Finnish population a favorable target for molecular genetic studies.

Chromosome 7: cystic fibrosis (CF) According to northern European folklore, a child who when kissed on the forehead tastes salty is bewitched and soon must die. Excessive sweat is just one manifestation of cystic fibrosis, the most common fatal disorder attributable to an autosomal recessive allele in Caucasian populations (the incidence is one in about 2,500 live births). Thick mucous secretions, often life-threatening, obstruct the lungs of affected children. In a drama as compelling as the quest for the HD gene, another arduous molecular search came to fruition in 1989 with the identification of the offending CF gene, which encodes a protein that channels salt into and out of cells. This gene spans 230,000 nucleotide pairs in the long arm of chromosome 7. A nucleotide deletion that causes the protein product to lack a phenylalanine at position 508 appears to account for about 70 percent of the mutant CF chromosomes worldwide. However, more than five hundred sequence variants in this gene have been discovered, of which at least three hundred and fifty are thought also to produce the pathologic condition.

Chromosome 8: retinitis pigmentosa-1 Retinitis pigmentosa refers to a suite of genetic diseases characterized by degeneration of the eye's retina. First indicated by an inability to see well in poor light, the disease progresses through stages of narrowing tunnel vision to blindness by mid-life. This disorder exemplifies a common situation in which defects in many separate genes can produce similar or identical clinical symptoms, usually because each gene compromises a different step in the biochemical or developmental pathway leading to the disability. Genes implicated in various cases of retinitis pigmentosa have been mapped to chromosomes 3, 6, 7, 8, 11, 14, 16, and the X.

Another genetic disorder recently mapped to chromosome 8 causes individuals to senesce and die early, usually by age fifty. The gene responsible for Werner syndrome encodes a defective DNA helicase enzyme that in normal form appears to play a cellular role in the repair of DNA damages. The mutation leading to Werner syndrome has devastating effects: patients in their thirties typically show pronounced symptoms of old age, such as cataracts, osteoporosis, and heart disease. The Werner syndrome gene provides an unusually clear example of direct genetic control over the aging phenomenon itself.

Chromosome 9: xeroderma pigmentosum-1 This is another disease condition that can result from mutations in many separate genes, one of which is located near the tip of the long arm of chromosome 9. Affected patients show pronounced sensitivity to sunlight resulting in easily parched skin and extreme susceptibility to skin cancers. The median age of children with clinical onset of skin neoplasms is eight years. The disease stems from genetically-based failures in a cell's ability to repair DNA damages from ultraviolet light.

Chromosome 10: porphyria Disorders of porphyrin metabolism provide another example of a condition with a complex etiology that can involve mutations in any of several genes—in this case those involved in the body's ability to produce hemoglobin (the oxygen-carrying molecule in blood). Different forms of porphyria vary in the severity of symptoms, but all tend to be associated with anemia, insomnia, altered consciousness, and intractable pain. King George III, the English monarch during the American Revolution, displayed these symptoms that mystified his doctors but now are appreciated to have stemmed from acute intermittent porphyria, or AIP. The AIP disorder illustrates a general point about geneenvironment interactions: Many heritable disorders show variable symptomatic expression as a function of environmental circumstance. Some individuals with the defective AIP gene are asymptomatic throughout their lives. For others, attacks from AIP are intermittent, with debilitating episodes often associated with emotional anxiety or infectious illness. The especially nasty form of porphyria for which a mutated gene on chromosome 10 is responsible produces mutilating skin blisters and scars beginning in childhood.

Chromosome 14: Alzheimer disease This common progressive dementia of the elderly, affecting about four million U.S. citizens alone, is characterized by accumulations of amyloid (starch-like) plaques in the brain. Only 10 to 20 percent of Alzheimer cases are clearly familial, but because of the typical late onset of the disease many inherited cases may go unrecognized. Mutations in several protein-coding genes, notably one encoding an amyloid precursor protein on chromosome 21, are known to contribute to the development of the Alzheimer condition. A form of the disease associated with chromosome 14 shows relatively early onset, often before age sixty. Other genes implicated in familial forms of Alzheimer disease have been mapped to chromosomes 1 and 19, and to mitochondrial DNA.

Chromosome 15: Marfan syndrome This condition first was described in 1896 in a five-year-old girl, Gabrielle, who had disproportionately long limbs, spiderlike fingers (arachnodactyly), tall stature, curvature of the spine, and joint contractures of fingers and knees. Other conditions typically associated with Marfan syndrome include instability of the eye lens, pulmonary difficulties, and susceptibility to hernias. The disease occurs in one out of 10,000 individuals; 15 to 30 percent of these cases represent new mutations. In the late 1980s, molecular detective work identified the culprits, which proved to be mutant alleles of the fibrillin gene located near the middle of chromosome 15.

Chromosome 17: type 1 breast cancer About 180,000 women in the United States alone are diagnosed with breast cancer every year. Breast cancers have multifaceted etiologies that sometimes include a strong genetic component, as evidenced by the fact that at least 5-10 percent of cases come from families with an obvious history of the disease. In 1994, a BRCA-1 gene that accounts for about one-half of the inherited cases of breast cancer was mapped to chromosome 17. One mutation in this gene is found in relatively high frequency (1 percent) in Ashkenazi Jews whose forebears came from eastern Europe. Its presence increases by more than 80 percent the risk that a woman will develop breast cancer over her lifetime.

Chromosome 19: maple syrup urine disease This recessive disorder has a pan-ethnic distribution, with a mean worldwide frequency of one per 185,000 infants. The disease gets its name from the characteristic maple syrup odor of the patient's urine, which results from the abnormal accumulation of intermediate compounds from defective steps in the catabolic pathways for particular amino acids. The most severe form of this disorder results in neonatal brain disease and early death. Milder forms can be treated by dietary restrictions on the intake of amino acids that the body cannot process. Screening for maple syrup urine disease currently is conducted in about one-half of the states and a score of other countries.

Chromosome 20: fatal insomnia Many metabolic disorders are extremely rare. A case in point involved a report of a middle-aged man with sphincter disturbances and severe insomnia. Over the next nine months, the symptoms progressed to dreamlike mind states, tremors, coma, and death. Further inquiry revealed that two sisters of the patient and many relatives over three generations had died from similar symptoms. The disease otherwise was unknown. Fatal familial insomnia (FFI) soon was tracked metabolically to abnormalities of the thalamus portion of the forebrain. The gene responsible resides on chromosome 20, codes for a "prion" protein of uncertain function, and also is implicated in several other genetic diseases of the thalamus.

Chromosome 21: Down syndrome This genetic disorder involves a gross chromosomal aberration in which a patient carries three copies of a critical portion of chromosome 21, rather than the usual two. The condition lays claim to several firsts: the first chromosomal disorder to be defined clinically (in an 1866 paper by Down titled "Observation on an ethnic classification of idiots"); the first human disorder actually proven to be chromosomal in origin (in 1958); and the highest in frequency of the various forms of mental retardation (one in 700 live births). The physical and physiological hallmarks of Down syndrome include distinctive craniofacial and neurologic anomalies that stem ultimately from metabolic imbalances due to the extra gene copies and their protein products. Prenatal diagnosis via amniocentesis or serum screening is available, and is advised particularly for women thirty-five years and older where the risk to fetuses increases dramatically.

Chromosome 22: DiGeorge syndrome If a chromosomal duplication can produce medical disorders, it should come as no surprise that the partial or complete loss of a chromosome can do likewise. Cases in point involve DiGeorge syndrome and a related disease attributable to deletions or microdeletions (minimally 300,000 nucleotides long) of a DNA segment on chromosome 22. This disease complex is euphemistically known as CATCH-22. The "22" stands for the chromosomal location, and "CATCH" is an acronym to help physicians remember five hallmark symptoms: cardiac malformations, abnormal facial appearance, thymus gland defects, cleft palate, and hypocalcemia (low calcium levels in the blood).

X chromosome: All chromosomes discussed thus far are auto-somes, normally carried in pairs in the diploid somatic cells of both sexes. The full autosomal complement of humans is comprised of forty-four chromosomes total, or twenty-two autosomal pairs. The remaining two chromosomes, X and Y, are the sex chromosomes: Normal human females are XX, males are XY. A haploid egg of a female transmits one X chromosome to each child whereas a father's haploid sperm that fertilizes the egg carries either an X or a Y chromosome with equal probability, thereby deciding junior's gender.

The X chromosome is host to a plethora of genetic defects. For recessive disorders, the deleterious consequences often show higher incidences in males than in females. This is because a single defective copy of an X-chromosome gene in the XY male normally is sufficient to produce the disease whereas the joint occurrence of two defective copies is required for full disease symptoms in XX females.12 For similar reasons, the incidence of each dominant X-linked disorder is about two times higher in females than in males.

Diseases that are X-linked have characteristic transmission signatures through family pedigrees (see Figure 3.4). For example, because sons receive their X chromosome from mom, X-linked genetic diseases cannot be transmitted from father to son. Furthermore, daughters of affected fathers normally display clinical symptoms only when the defective X-linked allele is dominant (or, if recessive, on those rare occasions when the daughter receives a defective gene copy from mother also). Among the many X-linked diseases involving recessive alleles are particular forms of hemophilia, colorblindness, gout, G6PD deficiency (described later), and Duchenne muscular dystrophy. Vitamin-D-resistant rickets (a condition of soft, easily fractured bones) is an example of an X-linked disorder caused by a dominant allele.

One X-linked inborn error of metabolism, Lesch-Nyhan syndrome, is among the most horrific of all genetic disorders. This recessive ailment is characterized by neurologic dysfunctions that lead to compulsions for vomiting and self-mutilation. Affected children, always boys, exhibit obsessive and uncontrollable urges to harm themselves, for example by chewing away lips and fingers, scalding themselves with hot water, and stabbing faces and eyes with sharp objects. Although mentally retarded, these boys have bright and understanding eyes, feel the pain, and sadly remain aware of their uncontrollable condition. To protect themselves and others, affected children must be restrained physically, from infancy onward. Mothers sometimes are tortured further by guilt when they learn that they transmitted the defective X-linked gene to an affected son.

Figure 3.4 A linear, abbreviated pedigree for X-linked hemophilia through European royal families. Males with the disease are shown as filled squares. Queen Victoria of England (the granddaughter of King George III) apparently was the original heterozygous "carrier" (dot inside circle) for the mutant hemophilia allele, and passed the defective copy to several of her children and grandchildren. One daughter, Beatrice, introduced the allele to the Spanish royal family via marriage, as did a son to the Russian royal family. Viscount Trematon and Princes Alfonso and Gonzalo all died following automobile accidents.


In earlier times, children displaying the symptoms of Lesch-Nyhan syndrome were thought to be possessed by demons. Today, we know these demons intimately. They reside within the gene encoding hypoxanthine-guanine phosphoribosyltransferase (HGPRT), an enzyme involved in purine metabolism. The devils themselves usually are point mutations (single nucleotide substitutions) or other minute genetic lesions, the consequences of which are far out of proportion to their size. These genetic demons bedevil more than 2,000 American families alone.

Y chromosome: The Y chromosome is one of the smallest human chromosomes, with "only" 60 million nucleotide pairs. Its male-limited transmission means that any effects of Y-carried genes (of which there are relatively few) are confined to males.

The most fundamental of these effects is sex determination itself.

The gene responsible (originally named testis-determining factor or TDF) was identified recently and shown to be housed on the distal tip of the Y chromosome. Actually, TDF initiates a cascade of events in embryological development that culminates in production of a male. Any environmental or genetic factor that blocks testis differentiation can curtail male formation, leaving female-like "ground states." One such class of genetic defects, XY gonadal dysgenesis, maps to the TDF gene region itself. Affected patients show gradations of sexual ambiguity, ranging from phenotypic males with a micropenis to phenotypic females with a complete absence of male gonads and varying degrees of uterine development and female external genitalia.

The scientific quest for the TDF gene is of interest because it serves to introduce other forms of sex-chromosome anomaly. Early cytogenetic studies uncovered rare instances in which phenotypic males displayed the XX chromosomal constitution normally associated with females. Further analysis showed that these males actually did possess portions of the Y chromosome, but that these had been translocated to the short arm of one of their X's (probably via an abnormal meiotic event in production of their father's sperm). Examination of many such cases led to the identification of the smallest chromosomal transfer producing the XX male condition. This was the small distal tip of the Y. Individuals of XX constitution who possessed other regions of the Y chromosome remained phenotypically female.

Some other common genetic anomalies of sexual differentiation can be mentioned here. Females who carry a single X chromosome (an X0 genotype) display Turner syndrome. Symptoms include short stature, ovarian failure, webbed neck, swollen hands and feet, and constricted aorta. Turner syndrome occurs in an estimated 1-2 percent of all clinically recognized pregnancies, but 99 percent of the affected fetuses die before birth (making Turner syndrome the most common chromosomal anomaly reported in spontaneous abortions). In the general population, the incidence of Turner syndrome is about one per 5,000 female live births. Trisomy for the X (an XXX genotype) is even more common, about one per 1,000 females. The clinical symptoms are relatively mild but often include learning disabilities and partial infertility.

Some common abnormalities in sex chromosome configuration produce individuals who are phenotypically male. These include the XXY (Klinefelter syndrome) and XYY genotypic conditions, both of which occur with incidences of one in about 1,000 male live births. Patients with the former syndrome are tall, thin, and usually infertile; those with the latter show few indications and normally remain undiagnosed.

True hermaphroditism, in which individuals display both tes-ticular and ovarian development simultaneously, also is known in humans. One genetic route to hermaphroditism is XX/XY chimerism, wherein a double fertilization at the time of conception leads to a mixture of XX and XY fetal cells. The individual in effect is a dual embryo composed of two cell types, one genetically ear-marked as male and the other as female. Another route to hermaphroditism involves somatic cell mosaicism. Following the formation of a single fertilized egg that otherwise produces a Klinefelter (XXY) embryo, aberrant separation of sex chromosomes during mitotic cell divisions sometimes results in a mixture of XX and XXY somatic cells, with only the latter leading to testicular development.

Mitochondrial DNA: All genes discussed thus far occur in the cell's nucleus, a sort of command control center demarcated from the cell cytoplasm by a membrane semipermeable to the exchange of cellular products. Outside of this walled compound reside the cell's mitochondria with their own snippets of genetic material (mtDNA). Mitochondria are miniature power plants, generating energy for cellular functions through metabolic processes.13 Large numbers of mitochondrial power generators exist within each cell.

The cytoplasmic housing for mtDNA has important consequences for hereditary transmission and human diseases. When a tiny sperm and a comparatively huge egg unite, the cytoplasm (and mitochondria within it) in the resulting zygote come predominantly from the egg, and hence from the female parent. In other words, mtDNA is maternally transmitted.14 Furthermore, unlike the single copy of each nuclear gene that is inherited from each egg (and sperm) cell, large numbers of mitochondria coexist within an egg and are passed to the next generation. Thus, varying mixtures of different mitochondrial alleles sometimes co-inhabit an individual (a condition known as heteroplasmy), and if some of these genotypes prove defective metabolically, any clinical symptoms may vary along a continuum (or, sometimes, across a critical threshold) of severity influenced by the relative proportions of normal and abnormal mtDNA molecules.

Human mtDNA is a closed-circular molecule 16,569 nucleo-tides in length. Mutations can occur here as well as on the chromosomes in the cell's nucleus, and many are harmful. One example is Leber's hereditary optic neuropathy (LHON), a maternally inherited disease that results in rapid loss of central vision (due to optic nerve death) in young adults. A mutation at one nucleotide position in the mitochondrial ND4 gene causes production of an altered form of an enzyme (ubiquinone oxidoreductase) that leads to the disease. It is both impressive and disheartening that a genetic alteration so trivial can cause such debilitation.

Mitochondrial mutations (including those that arise during the lifetime of an individual) probably play an important role in degenerative disorders of the elderly.15 MtDNA is minuscule compared to the nuclear genome (less than 0.001 percent as big), but its crucial role in cellular energy production makes it a prime candidate for age-related dysfunctions. An accumulation of mtDNA damages in somatic cells may account in part for gradual declines in the cellular capacity to generate energy. These mtDNA damages often result from mutagenic saboteurs known as free radical molecules that occur in unusually high concentrations in mitochondria.16 Tissues and organ systems most affected by energy brownouts are those with high energy demands, such as the central nervous system, heart, skeletal muscle, pancreas, kidney, and liver. Mutations in nuclear genes are involved too, because many of the enzymes in the energy-generating pathways are nuclear encoded and imported into the mitochondrion where they interact with the mitochondrial gene products.

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