Genetics Inherited genetic disease is of tremendous importance in clinical medicine.

Except as marked or noted in lecture, this is mastery-level material at the recall level. You should be able to:

define all the terms given in this handout list the modes of inheritance, molecular pathogenesis (when applicable), and distinctive clinical features of all the major genetic disorders use this knowledge to talk to patients or the families about these diseases

QUIZBANK Developmental abnormalities (all); Metabolic #'s 5-8, 25-41, 117 KEY IDEAS AND TERMS * "An organism is the genes' way of making more genes." Today, no life-scientist seriously doubts that the tremendous diversity and success of living creatures is due, at least in part, to natural selection for and against genes that have been randomly altered. Since most mutations probably confer no advantage or disadvantage (Nature 354: 114, 1991), random drift ("the molecular clock") also plays an important role in changing the sequences. * A species is a breeding population that can produce fertile offspring among its members, but not outside its group. We know that new species arise as a result of reproductive isolation; members of the ancestral populations have become separated by geography and/or niche. The molecular mechanisms that underlie micro-evolution (i.e., loss of the ability to interbreed) must be the result of genetic drift in an isolated population, so that at least one enzyme no longer meshes with its distant cousins. We look forward to learning the details, but obviously this is a long way off. Along with Rudolf Virchow (Nature 427: 487, 2004), your lecturer considers "race" an antiscientific, outdated social construct that we might do well to forget about. The ability to evolve, and to select helpful genes, is basic to the survival of life on earth. Humankind pays a price for the tendency of the genes to keep changing. The cost is borne by the "less fit", especially the 7% (estimates vary, and this doesn't include "polygenic inheritance") of people with significant genetic disease, and by those who care for them. Most embryonic and early fetal wastage is probably due to genetic and chromosomal problems, and even today, we don't know how common these losses really are.

You know about genes, alleles, chromosomes (autosomal and sex), mitosis and meiosis, haploid and diploid cells (exact multiples of the haploid number are euploid; others are aneuploid), mutations (and the environmental problems that cause them), centromeres, and the basic biology of nucleic acids. You also understand classic Mendelian and sex-linked inheritance, homozygosity, heterozygosity, hemizygosity, and consanguineous mating. If any of these terms are unfamiliar, please review. If you don't know what restriction fragment length polymorphism is all about, ask a molecular diagnostician -- it's important. Remember that germ line mutations are present in the sperm or the egg, while somatic mutations are acquired after fertilization. Notice that if two normal parents give birth to a child with achondroplasia, one of them either had a somatic mutation involving the germinal epithelium, or a mutation involving just a single gamete. Certain diseases of the genes can result only from post-zygotic, somatic mutations. These include McCune-Albright's syndrome (rare) and the fullyexpressed malignant phenotype (all too common).

Hutchinson-Gilford progeria ("accelerated aging") is apparently always caused by a de novo mutation in a sperm (Science 300: 1995, 2003). More about this later. Progeria child Vertical transmission of a mutation occurs from parent to child. Horizontal transmission of a mutation occurs within a single organism as a clone of mutated cells (as in tumors, and such mosaics as McCune-Albright's). As we will soon see, diseases of DNA are really of two types -- inherited disease (vertical transmission) and tumors (horizontal transmission). Nowadays, we call only the first "genetic disease". The genetic code translates nucleic acid base pair triplets (codons) into animo acids for a protein sequence. It is almost (not exactly: Comp. Bio. Phys. 106: 89, 1993; J. Mol. Evo. 34: 331, 1992) constant across nature, and entirely constant for the nuclei of the higher creatures. (* This is one more piece of evidence that evolution has occurred on the grand scale, since the code is apparently arbitrary.) Restriction enzymes (endonucleases): Enzymes, mostly from bacteria, that cleave ("digest") DNA at specific sequences. * EcoR1, still the "champ", cleaves at GAATTC. Denatured DNA: single-stranded DNA

Exon: the portion of the gene that is transcribed onto mRNA, for translation into protein sequences. Intron: the rest of the DNA in the gene under discussion. Gene probe: a single-stranded nucleic acid sequence, labeled with radio-isotope, used to identify a specific complementary sequence Southern blotting: using probes to search for particular DNA sequences, on digested DNA samples that have been digested using restriction enzymes and the fragments separated by electrophoresis. Invented by Dr. Southern. Northern blotting: searching for m-RNA by a technique similar to Southern blotting. Named by some wag in imitation of "Southern". Western blotting: searching for a protein, using electrophoretic methods Dot blotting: like Northern and Southern blotting, only without using electrophoresis In-situ hybridization: using probes to detect nucleic acid sequences within cells, without destroying the cells themselves. Polymerase chain reaction: a technique to identify very small quantities (perhaps even a single copy) of a particular DNA sequence in a sample. This has many uses, ranging from the most sensitive and specific AIDS test to a way of telling whether a leukemia is completely cured (Lancet 344: 348, 1994). Classical genetic research: define the biochemical abnormality, then isolate the protein, sequence it, and identify the gene. How we cloned the hemoglobin S gene. "Functional cloning." Reverse genetic research (positional cloning): locate the affected chromosome, sequence until you find the gene, then deduce the protein sequence ("the predicted protein") and find it, and finally figure out its function. Duchenne's muscular dystrophy, cystic fibrosis, and Li-Fraumeni disease were all successfully approached in this way. "Positional cloning." Pseudogene: a DNA sequence, once useful (we may suppose) or else transferred from a real gene, and homologous to active genes in us or in related organisms, but now genetically inactive. Pseudogenes left over from evolution would constitute the ultimate "vestigial structures". Genetic disease: almost impossible to define. My best shot is, "a disease that is determined, more or less, the moment the egg is fertilized." ("You made the first mistake, you picked the wrong parents.") Entities such as sickle cell disease and Huntington's chorea develop when, and only when, a particular gene is defective. Yet even sickle cell disease is modified by the presence or absence of thalassemia genes. Cystic fibrosis, a

simple mendelian problem, varies in severity depending on which of more than a dozen alleles has been inherited. Identical twins are 100% concordant for type II diabetes, which is polygenic, and the course of the disease is influenced by environmental factors. Diseases like lupus, high blood pressure, alcoholism, and schizophrenia show obvious familial tendencies, even in siblings raised apart, yet many identical twins are spared. The variability in particular diseases from person to person reflects, in part, our varying genetic heritage. A handful of diseases, outstandingly McCune-Albright syndrome, KlippelTrenaunay, Ollier/Maffucci, and Proteus syndrome, are genetic diseases that cannot be inherited, but that always result from a mutation early in embryogenesis. Even the "Big Robbins" example of automobile accidents as a process in which "the environment totally determines the nature of disease" ignores the obvious genetic factors in alcoholism. (Rabies or gonorrhea would be better examples.) Notice that the above definitions of "genetic disease" ignore the other, equally important, "acquired genetic diseases", i.e., tumors, in which defective genes are propagated and accumulate within clones of cells in a single organism. We now talk about inherited genetic disease ("vertical transmission") and neoplastic genetic disease ("lateral transmission"). Much more about this soon. Hereditary disease: "Genetic disease", with the exception of those rare ones you can't inherit. Familial disease: Definitions vary. "Diseases that cluster within families" can include classic genetic diseases, polygenic disease, mysterious things (more on "SIDS" later in the course), heritable viruses, nutritional stuff, environmental stuff ("Is that lead paint peeling from the walls?"), and, of course, behavioral stuff -- the child-abuse cycle, obesity ("Clean your plate!"), etc., etc. Congenital disease: a disease present at birth. Note that sickle cell disease and Huntington's chorea, both genetic, are not symptomatic at birth, and that various traumas and infections acquired in utero are congenital but not genetic. Transgenic mice: mice developed from fertilized eggs in which the genetic material was manipulated. Knockout mice have had genes deleted, which is tricky. Chromosomal aberration ("cytogenetic aberration"): diseases in which there are the wrong number of copies of some or all of a chromosome, sufficient to detect using

classic karyotyping. About 1% of newborns, and maybe 50% of spontaneous abortions, possess an abnormal karyotype. G-banding (from "Giemsa" stain): a technique that visualizes bands on chromosomes, improving our ability to localize genes and recognize minor karyotypic problems. Standard cytogenetic terminology names a karyotype for the number of chromosomes, a list of the sex chromosomes, and mention of any extra ("+") or deleted ("-") chromosomes. Abnormalities of individual chromosomes are designated by "p" for the short arm, "q" for the long arm, and mention of the numbered regions shown by G-banding. Imprinting: Genes and chromosomes sometimes differ slightly depending on whether they were acquired from Mom or Dad. A hot topic right now. Uniparental disomy: Non-mendelian inheritance in which two copies of a gene or chromosome were inherited from the same parent. Triplet (trinucleotide) repeat mutations: Genes rendered abnormal by the amplification of CG-rich units. This is the usual mechanism of mutation in fragile-X disease, Huntington's, and myotonic dystrophy, and a few others. Unlike more familiar syndromes, these diseases get worse from generation to generation as the amplification continues (anticipation or Sherman's paradox, long-noted in myotonic dystrophy, means the disease appears sooner in the son than in the father). Mutant genes of large effect: diseases caused by a single defective gene. Most are Mendelian disorders, either autosomal or sex-linked. We are now discovering diseases caused by mutated mitochondrial genes. * It is simply wrong to think of all mutations as just rendering a gene ineffective. The old pseudoscientist's complaint, "How can a mutation give rise to something useful?" is now abundantly invalidated by studies of the origins of modern genes from mutations (base-pair substitutions, recombinations, even frame-shifts; see Nature 306: 203, 1983) of genes that once did something else. Sex-limited inheritance: diseases inherited independent of the sex-chromosomes, but that can ordinarily express themselves only in one sex or the other. The prime example is male baldness -- a woman must usually take exogenous testosterone in order to go bald. Polygenic inheritance: diseases that are caused or significant modulated by several different abnormal genes Multifactorial etiology: despite "Big Robbins", this may mean either "caused by several abnormal genes" or "requiring both abnormal genes and an abnormal environment".

Lyonization: Inactivation, early in embryogenesis, of all but one of the Xchromosomes in each cell. Once lyonization has occurred, the same X-chromosome will be inactivated in all of that cell's progeny, where it will be the Barr body (or bodies, for those with more than two X's), or sex chromatin (visible on buccal smear), until oogenesis is required again. microRNA genes do not code for proteins, but for short RNA sequences that block other messenger RNA's.

Note that the entire chromosome is not inactivated. (If the second X were totally inactive, then XO's, XXY's, and XXXX's would be phenotypically normal. * The Kallmann's syndrome gene (no olfactory nerves, no gonadotropins, all because of defective neuronal migration, see NEJM 326: 1752, 1992), located on X (with an inactive counterpart on Y), is expressed whether or not the chromosome is lyonized (Nature 383: 529, 1991). Lyonization may be lucky or unlucky. For example, female identical twins with one X-chromosome carrying color blindness may be discordant for color blindness (Am. J. Hum. Genet. 51: 291, 1992). If the X's are discordant for skin color (for whatever reason), you will end up spotted (Arch. Derm. 129: 1460, 1993). Whenever X's differ in some significant way, the woman is a "functional mosaic" (in contrast to a "genomic mosaic", caused by a somatic mutation). * Transcription of a gene from the inactivated X: Nature 351: 325, 1991. By the way, we're still puzzled about the actual molecular biology of lyonization itself. The gene XIST produces an RNA that ties up the lyonized chromosome, and methylation of cytosines also seems to be involved (Nature 368: 154, 1994, others). Pseudo-autosomal inheritance: The tips of the short arms of chromosomes X and Y are homologous, and a few genes (* notably blood group Xg) are located here (Am. J. Hum. Genet. 51: 1172, 1992). Somatic mosaicism: when all cells in a person do not have essentially the same genetic makeup. This can result from a mutation in one cell during the early stages of embryogenesis, or even from fusion of two fertilized eggs to produce one person (i.e., a chimera -- * ponder that!, fortunately, it's rare.) Chimerism may also result from blood exchange between fraternal twins, and the person has two people's bone marrow. Future blood bankers: these patients will probably have two different blood types. Somatic mosaicism probably underlies many (if not most) birthmarks (for example Lancet 345: 596, 1995). People living comfortably with a "forme fruste" of some dreadful classic lethal disease may be mosaics (for example,

Am. J. Hum. Genet. 46: 591, 1990). It's also the basis of tumorigenesis (more about this later). Functional mosaicism is the result of lyonization, as explained above. All about mosaics: Arch. Derm. 129: 1460, 1993 (why a dermatologist?) Germinal mosaicism means that a mother who is not affected by a particular mutation has transmitted it more than once as if she were; i.e., the eggs arose from a mutant clone. Penetrance: the chance that someone with the gene (or genes) for a condition will express the condition. Variable expressivity: a term for an allele that causes widely different degrees of abnormality in different people. Balanced polymorphism: the heterozygote enjoys an advantage that has allowed selection for the gene, making the homozygous condition common. The prime example is sickle cell disease, in which the heterozygote enjoys immunity to malaria . Cystic fibrosis, Gaucher's, and probably others are probably also balanced polymorphisms. Pleiotropism: one mutant gene produces several effects Genetic heterogeneity: the same effect can be produced by mutations at several sites. For example, there are several different loci at which two defective genes will produce an albino, there are at least two genes that produce adult polycystic kidney disease, there are at least seven ways to get xeroderma pigmentosum, there are multiple dominant and recessive forms of retinitis pigmentosa (Am. J. Hum. Genet. 53: 80, 1993; Nat. Genet. 23: 217, 1999, lots more), there are about a dozen known ways to get Ehlers-Danlos syndrome, there are several dozen deafness syndromes, etc., etc. * My favorite example, right now, is Leigh's syndrome, a progressive brain disease of young children in which there is defective cytochrome oxidase in the mitochondria. Sounds straightforward -- except that the cytochrome oxidase complex is coded by at least 13 different genes, some in the nucleus and some in the mitochondria. (For starters, three different ways to get Leigh's are described in Ped. Res. 26: 260, 1989, J. Ped. 116: 84, 1990, and Neurology 39: 697, 1989). Probably there are many, many alleles here, and many Leigh's cases could even be polygenic. Dermatoglyphics: examining the lines on the palms and soles, and the fingerprint ridge patterns. A fascinating game that has yielded many interesting correlations, none of any clinical utility. For a nice review, see J. Invest. Dermatol. 43: 261, 1970. (* P.S. As a pathology resident, I used to check the lengths of the "life lines" on autopsy patients' palms, to see how long they had lived. Sorry, no obvious correlation.)

* Genetic load: the frequency of deleterious recessive mutations in a population. An important concept in biology. In populations with high genetic load (i.e., most humans), matings of near relatives is likely to result in defective newborns. By contrast, in populations with low genetic load (i.e., lab animals, many wild populations), inbreeding is not a hazard. Frequent inbreeding does reduce genetic load in the long run. Remember that Cleopatra ("the most beautiful woman in history", they say) was the offspring of several sequential brother-sister matings. CYTOGENETIC DISORDERS Aneuploidy results form failure of homologous chromosomes to move into separate progeny cells. This may be from nondisjunction during the first meiotic division, or anaphase lag in any other cell division. Rules: (1) Autosomal monosomy or no "X" chromosome causes early loss of the embryo. (2) All trisomies except trisomy 21 produce infants who will usually die during the first few months of life; around half of early spontaneous abortions has a trisomy. (3) Unless a parent carries a balanced translocation, or when advanced parental age is a factor, there is no real tendency for these problems to recur. Beyond this, given the present limitations of our knowledge, the common chromosomal disorders present a memory task for medical students. Chromosomal breaks and rearrangements should be familiar to you. Deletions indicate loss of part of a chromosome, either "terminal" or "interstitial". Several curious birth defects are caused by microdeletions, i.e., loss of a few adjacent genes. As you would expect, not all patients with these defects have the same phenotypes (why?) Translocations are common; most are reciprocal translocations between two chromosomes. Unless genes are damaged in the process, the patient is likely to be normal, but will produce lots of abnormal gametes. * "Robertsonian translocation" is a reciprocal translocation involving two acrocentric chromosomes, producing a tiny chromosome that is lost and a very large chromosome. * "Isochromosomes" result from faulty chromosome division. The products are a chromosome with two long arms, and a chromosome with two short arms.

* "Inversions" involve two breaks in the same chromosome, with the portion between being re-incorporated backwards. * "Ring chromosomes" result from deletions at both ends of a chromosome, with subsequent fusion of their ends. Obviously, this chromosome is not going to take a normal role in mitosis. There are several fragile chromosome syndromes (better, "chromosome instability syndromes"). "Big Robbins" lists Bloom's syndrome (* small jaw, red blotches on face, short stature), Fanconi's anemia (* gene cloned: Nature 356: 763, 1992), and ataxia-telangiectasia; there are several others. Not surprisingly, these patients have high risk for cancer. Trisomy 21: Down's syndrome (Lancet 361: 1281, 2003) Although Down's syndrome is very common, we don't understand the reason that the extra chromosome 21 causes so many problems. * We do know that the full expression requires the presence of 21q22. The genes for superoxide dismutase, amyloid beta ("Alzheimer's amyloid" -- hmmm) and the oncogene ets-2 are all here. It affects around 1 child in 700. Advanced maternal age is grave risk factor. Maybe 1 in 25 live births to mothers over 45 have Down's. In only 20% of cases is the extra chromosome of paternal origin. Most parents are cytogenetically normal, though occasionally one has a balanced translocation 95% have three separate 21's; 4% have a translocation; 1% are mosaics and less severely affected. (Advanced maternal age is only a risk factor for the first group -- why?) There are now five markers for Down's, all usable during the first trimester (-fetoprotein, pregnancy-associated protein A, hCG, free beta chain of hCG, and unconjugated estriol); levels tell risk: NEJM 338:955, 1998. Pediatricians look for several signs. Don't expect to see them all:

flattened face open mouth, big tongue with no central crease slanting palpebral fissures and epicanthic folds ("mongolism") mental retardation (IQ 25-50) hypoplasia of the middle phalanx of the little fingers / fifth finger clinodactyly lack of muscle tone at birth ("floppy baby") low-set or funny-looking ears single palmar crease ("simian crease") radiographic abnormalities (middle phalanges, pelvis) "Brushfield's spots" on iris heart defects (40%, notably endocardial cushion defects)

gentle, shy demeanor

The condition is usually obvious at birth. Likely future health problems include:

hypothyroidism (untreated, doesn't help intellectual function) conductive hearing loss (untreated, doesn't help learning) bad respiratory infections (we don't know why) various leukemias (very common in these children; also other cancers; nobody knows why Arch. Int. Med. 163: 705, 2003) Alzheimer's disease (always develops in patients surviving to age 40 or so)

Management of these children and young adults requires great understanding. Puberty compounds their adjustment problems. Half are dead by age 30, but many make it to age 50 or beyond. * Medical history buffs: Dr. Down, an Englishman of Victorian times, was among the first and most ardent advocates of higher education for women. Neuroanatomy of Down's: Neurology 44: 1039, 1994. Other cytogenetic autosomal problems Trisomy 18 is Edward's syndrome. Remember tiny jaw ("micrognathia"), overlapping fingers, rocker-bottom feet, and cysts of the choroid plexus visible on ultrasound before birth (beware: these last are by no means specific, and are common enough in normal unborn children: Ob. Gyn. 90: 191, 1997). * These children usually simply stop breathing shortly after birth. Activists' attempts to keep these children alive (Arch. Dis. Child. 75: F38, 1996) seem particularly cruel and futile. Trisomy 13 is Patau's syndrome. Remember tiny head ("microcephaly"), arhinencephaly ("abnormal limbic system"), tiny eyes ("microphthalmia"), polydactyly, and scrambled viscera. Sometimes there is only one cerebral hemisphere ("holoprosencephaly") or even a single eye ("cyclops"); * Trisomy 9 Deletion of the short arm of chromosome 5 (i.e., 5p-) is cat-cry ("cri du chat", "Is there a cat in the nursery?") syndrome. Children are usually severely retarded with severe behavioral problems, but some are less affected and some survive into adulthood. J Postgrad Med. 42: 86, 1996; Arch. Dis. Child. 75: 448, 1996. Velocardiofacial syndrome ("Shprintzen syndrome") was identified as a microdeletion of 22q11 in 1993. Because it is extremely common (about 1 person in 3000), it's worth remembering.

Kids generally have

hypernasal speech; at least some degree of cleft palate (this is the most common genetic reason for this common problem); various cardiac abnormalities (* VSD, tetralogy, right-sided aortic arch); many (but by no means all) have early onset (around age 12) of the major mental illnesses as teens (schizophrenia, bipolar disorder, major depression); * catechol O-methyl transferase is located in the deleted portion * wide, long nose, high at the top; * little chin; * narrow palpebral fissures; * short stature, slender fingers and extremities * bland affect, poor socialization, poor coordination. * learning disabilities (these have been characterized specifically);

More on velocardiofacial syndrome: Am. J. Psych. 153: 1541, 1996; J. Ped. 123: 406, 1993). * Deletion of 22q11 is the rule in DiGeorge's (Am. J. Hum. Genet. 51: 964, 1992). Isochromosome 12p mosaicism (Am. J. Med. Genet. 47: 241, 1993) produces Pallister-Killian, etc., etc., etc. Prader-Willi and Angelman syndromes: a major mystery of contemporary genetics. Read all about it in Am. J. Med. Genet. 32: 285 & 514, 1989; 33: 66, 1989; 35: 319, 1990. These two syndromes have been well-characterized for several decades. Each affects one child out of a few thousand. Prader-Willi patients are a little bit dull, typically have crossed eyes and almond-shaped epicanthic folds, hypotonia (i.e, these are floppy babies), small hands and feet, growth delay, short stature, and hypogonadism (low gonadotropins, not much puberty; some doctors give testosterone to selected PraderWilli's, as in J. Ped. 114: 325, 1989). They overeat, incorrigibly stealing and hiding food, and become very obese ("the commonest known cause of genetic obesity": NEJM 326: 807, 1992, no longer true of course; "1 person in 10,000": NEJM 326: 1599, 1992, both good reading). Described as generally docile and even "cute", they are also said to be prone to outbursts of extreme violence. (* Do you remember the fat kid in "Full Metal Jacket"?) Major psychosis develops in many of these people in early adult life (Lancet 359: 135, 2002. * There's an albinism gene here, and the kids tend to be fair-complected (NEJM 330: 529, 1994).

Angelman patients, or "happy (?) puppets", are severely retarded, with microcephaly and huge jaws. They have jerky, puppet-like movements, and laugh a lot (though apparently not in response to pleasure). * The neuropathology has recently been described for the first time: Neurology 41: 416, 1991. These two very distinct diseases are controlled by the same locus (15q11-13). Prader-Willi patients lack the normal gene from their father. A Prader-Willi child has inherited Dad's mutant (typically deleted) gene, or else got two normal chromosome 15's from Mom and no chromosome 15 from Dad (Nature 342: 281, 1989). Angelman patients lack the normal gene from their mothers. So far, Angelman patients have inherited Mom's gene deletion. (* Mouse gene at the same locus gives light pigmentation, and both types of kid tend to be fair-complected: Science 257: 1121, 1992). Puzzle that out! Parental imprinting of chromosomes is a hot topic, especially in the study of tumors. * There's a familial Angelman, too, same locus; if the bad gene comes from Dad, the child is sick, if the bad gene comes from Mom the child is normal; in other words, this version doesn't produce Prader-Willi. Am. J. Hum. Genet. 53: 140, 1993. The gene is now cloned, and has to do with ubiquitin-related disposal of damaged proteins in the brain; it's only transcribed from the maternal chromosome: Nat. Genet. 15: 70 & 74, 1997. * News: Beckwith-Wiedemann syndrome victims (hypoglycemic, big tongue, asymmetric body, big kids with a propensity for getting tumors) have both their 11p15's (IGF2 and WT2 are here) from their fathers (i.e., the gestation was a trisomy, but a cell line discarded Mom's chromosome). Am. J. Path. 154: 635, 1999. * Common autism gene only affects you if you got it from Mom: Am. J. Hum. Genet. 60: 928, 1997. * Note also that Wilms tumors, which lose alleles at the 11p13 position, generally lose Mom's rather than Dad's. (Read all about it: Nature 351: 665, 1991; Lancet 338: 413, 1991). * (Brachmann-Cornelia) De Lange syndrome: An important, relatively common (maybe 1:15,000 births; there's a national organization) genetic disorder.

Affected children have small heads, hirsutism, a single bushy eyebrow, a small upturned nose, and a down-turning upper lip. Many have deformed upper extremities. Most are very retarded, and most succumb to infections early in life. The genetics is just now being sorted out. The first locus (NIBPL) has a mutation in about half of the cases (discovery Nat. Gen. 36: 63, 2004); a second was discovered in a gene belonging to the same complex (Nat. Gen. 38: 528, 2006). Because of imprinting, a man usually cannot transmit the disease, though it has happened (Hum. Mut. 27: 731, 2006). Probably lots of people are mosaics. The recurrence rate if Mom has had a Cornelia de Lange baby is about 3%. Other microdeletion syndromes: * Rubinstein-Tabyi (funny face, short thumbs, sometimes retarded) and Miller-Dieker are the prototypes. In each, a few adjacent genes are lost. Wait for more. Sex chromosomal disorders (* history of the sex chromosomes: Science 251: 1031, 1991) Rules: (1) A Y-chromosome is necessary and sufficient to make a phenotypic male, provided the body can also make and use testosterone. Well, usually -- it's actually the "testis determining factor" gene that is usually present on the Y and usually not present on the X. (2) The more extraneous X-chromosomes, the more abnormal the person. (3) You will usually miss the diagnosis at birth, and may only make it late in adult life. Klinefelter's syndrome This occurs when a man has more than one X chromosome (i.e., 47,XXY, 48,XXXY, etc.). One man in about 850 is affected. The etiology is unknown, but advanced maternal age contributes. At puberty, the typical features generally appear. They include small testes, long arms and legs, often smallish penis. Klinefelter patients generally are high-voiced, not very hairy, and (the big payoff!) rarely go bald.

Because the Leydig cells do not function well, serum gonadotropins are high, Leydig cells are hyperplastic, plasma testosterone is low, and (for some reason) estrogens are high, with about half getting gynecomastia. The seminiferous tubules are always underdeveloped to some degree. Many Klinefelter men have libidos and ejaculations, and many others don't. (The higher the testosterone level, the more "maleness" and also, apparently, the higher the level of function and the more normal the appearance: Abstract from Humangenetik 26: 61, 1975.) In any case, almost all of these men are sterile, and Klinefelter's syndrome is a consideration whenever a couple is having difficulty having a child. XXY guys average lower IQ's than XY's, and psychologists talk about specific learning handicaps and "diminished economic striving", but they are seldom retarded. XXY's are slightly over-represented in prison populations, but the impact of the karyotype disappears when one controls for low IQ, and violent XXY's are rare (Arch. Gen. Psych. 41: 93, 1984). Most Klinefelter's men are pleasant, easy-to-like guys. XYY syndrome ("supermale") Around one male in 1000 has an extra Y chromosome. This is still "controversial" but won't be resolved in today's political climate. On the average, these guys are taller (Klin. Ped. 36: 39, 1997), have worse acne, have higher average hFSH, hLH, and testosterone (this has held up nicely), and allegedly average slightly lower IQ's (this point's very questionable), than XY's. * These kids don't make great athletes; they are wiry rather than bulky, and tend to be poorly coordinated. Pectus, squint, and elbows turned a bit farther out than most other guys are supposedly common features as well. When first discovered, it was hypothesized that XYY men would exhibit more anti-social and impulsive (i.e., "typically male" according to the ideology of the times) behavior than other men (* popularized in the "penal colony for XYYs" in Aliens 3). This remains controversial. * Richard Speck, the vile murderer of eight student nurses, was tall and had acne; he defended himself at trial saying he was an XYY, which he actually was not. This contributed to the "guy with the most acne on the prison basketball team" stereotype; of course the XYY defense -- even if the perpetrator has it -- is

long-discredited (Ciba Foundation Symposium 194: 248, 1996). One study (Arch. Gen. Psych. 41: 93, 1984) noted (1) these men average substantially higher testosterone levels, and are slightly over-represented in prison populations; (2) among tall men of any karyotype, the rate of conviction, especially for violent crimes, correlates surprisingly well with plasma testosterone levels, with little additional contribution from karyotype; results of psychological tests correlate poorly with all these variables; (3) the typical XYY's crime is wife-beating; (4) the differences between XYY's and their XY counterparts are anything but striking. (XYY's found before birth are being followed, and this claim, which I made in 1984, is now being confirmed: Prenatal Diagnosis 17: 363, 1997). By the time you are ready for practice, perhaps we'll know exactly what the extra Y does. You can find plenty of accounts of individual kids with developmental delay / behavior problems who turn out to be XYY's. And you'll find "series" of patients in which most of the XYY's have behavior problems. This is a classic example of drawing faulty conclusions from a selected patient population. Until somebody shows that kids who are karyotyped as part of a fishing expedition to explain behavior problems are MUCH more likely than the 1-in-a-thousand to turn out to be XYY, I conclude that the relationship is dubious at best. Indeed, the largest study indicates that the frequency is the same as in the general population -- indicating XYY is NOT a measurable risk factor for mental retardation or major character problems (Genetic Counseling 6: 197, 1995). If it's a minor risk factor for minor problems (as suggested in the big Danish study in Birth Defects 26: 209, 1990) -- who cares? * The current work on XYY and mental/physical problems is totally unimpressive -- small sample statistics ("five kids instead of three, out of 2000"), anecdotes ("a single person with both XYY and schizophrenia"; "a single person with both XYY and teenaged lymphoma"). One group tried to quantitate the supposed angular facial features of XYY men (Arch. Oral. Bio. 42: 579, 1997). The one prospective study of Swedish children incidentally discovered during a "let's screen all the new babies" fad showed only a minor impact on behavior -- despite the fact that their parents had almost certainly been told about the "criminal gene". The study's "findings" result mostly from the presence of a single XYY career criminal... and the authors couldn't find even one XYY who had committed a crime with a weapon: Psych. Med. 29: 953, 1999. Pretty slim pickings.

* Part of "political correctness" nowadays forbids geneticists to "impose their own values" on parents. Before I set up my, I get 1-2 E-mails a month from distraught parents who know they're going to have an XYY boy "and the doctor wouldn't tell us the right thing to do". I care more about people than about pseudoethics, so I'll be straight with you -- I am satisfied that there is no reason to abort a child for being XYY, or to be overly worried or designate him as "special" or "different". Acne's treatable, and tall is fun. I think there won't be any serious work on XYY and behavior in the near future. In the meantime, Doc, PLEASE exercise caution before predicting that "the extra Y will affect behavior". Turner's syndrome This is the result of monosomy for the short arm of the X chromosome. About 1 out of every 2000 women are affected. Of these, around half are XO, and the remainder either have an isochromosome of the long arm of X, or have partial deletion of the short arm of X, or are mosaics. * Oddly, maybe 10% of spontaneous abortions would have been a Turner's, and 99% of XO conceptions spontaneously abort (Nature 351: 406, 1991). The major problem is failure of feminization at adolescence. Patients have "webbed neck", "shield-shaped chest", and "cubitus valgus" (elbows turned out). However, most patients are not diagnosed until the teens (if then). They fail to menstruate (i.e. "primary amenorrhea" -- Turner's is the most common identifiable cause) or develop secondary sex characteristics. Almost all of the oocytes disappear by age 2, and patients have only "streak ovaries". As "Big Robbins" puts it, "menopause occurs before menarche". Rarely, lymph channels fail to form properly, and lymphedema of the hands and feet makes the diagnosis apparent at birth. Or an alert clinician notes the "webbed neck" or "shield-shaped chest" of the patient. Another common problem in these patients is coarctation of the aorta.

* Psychologists talk about curious spatial perceptual problems in Turner's patients, etc. * A male or non-XO female with Turner-like features has "Noonan syndrome". Some are XY/XO mosaics; others have mutant PTPN11 (this is quite common, the commonest gene for congenital heart disease. Update Nat. Med. 10: 849, 2004; Nat. Genet. 39: 1007, 2007; the nearby RAF-1 may do the same thing Nat. Genet. 39: 1013, 2007). Multi-X females ("super-female") Around one woman in 1000 has three or more X-chromosomes. Most 47,XXX women are normal, though supposedly they are a bit slower than their sibs. The 48,XXXX woman are usually mildly retarded, and 49,XXXXX produces severe disability. Hermaphrodites and intersex states: This is complicated. Learn these terms: Genetic sex (really, chromosomal sex) is determined by the presence ("male") or absence ("female") of the Y-chromosome. The terminology needs changing now that we've discovered "testis determining factor", the presence or absence of which should soon define genetic sex. Occasional men have testis-determining factor gene, or something like it, on the X-chromosome, and the dudes are 46, XX (J. Clin. End. Met. 76: 690, 1993, J. Urol. 149: 126, 1993). Occasional women are XY's with a mutated testis determining factor gene (Hum. Genet. 88: 471, 1992; gene is now called SRY, sex-determining region on Y: Nature 372: 525, 1994). * Of course, these curiosities will run in the family. By the way, this is the answer to the old creationist's objection "How could the mechanism of sex determination change?" The gene for maleness left the autosome shortly after we branched off from duckbilled platypuses (Genomics 15: 317, 1993). Gonadal sex is determined by the histology of the gonads, i.e., whether there are little eggs and follicles (), or little tubules and Leydig cells (), or both (true hermaphrodite), or neither (?). "Streak gonads" without the distinctive features of either sex are characteristic of Turner's syndrome (XO people) and * Swyer's syndrome (XY people who have problems with testis determining factor or its receptor).

Some guys have their testes vanish during fetal life ("vanishing testis syndrome"). They'll never be dads, but hormone replacement turns them into fully-sexual men when the time comes. Ductal sex is determined by whether the muellerian (male) or wolffian (female) ducts developed. (* Remember that the embryonic testis's Sertoli cells produces "muellerian regression factor"). Phenotypic sex ("genital sex" -- the use of the latter term may invite misunderstanding) is determined by the external genitalia (male? female? can't be sure?) True hermaphrodites, as noted above, have both ovarian and testicular tissue. Very, very rare. The majority are 46,XX's with translocation of the Y to another chromosome, while most of the rest are XX/XXY mosaics or XY's who have lost testis determining factor from a clone of cells during embryogenesis (for the latter, see Am. J. Hum. Genet. 52: 578, 1993). Pseudohermaphrodites have disparity between gonadal and phenotypic sex. A female pseudohermaphrodite has a penis and ovaries, usually because of exposure to male hormones before birth. The usual problem is a glitch in glucocorticoid synthesis, in which steroids are shunted into male pathways. The "penis" is really a big clitoris (but aren't they all...?) A male pseudohermaphrodite has a vulva and testes. The infant may have a problem with testosterone biosynthesis, but normal sensitivity to testosterone, so pubic and axillary hair develop when the "woman" reaches puberty. * Three such patients recently proved to lack 5--reductase 2 (the enzyme that reduces testosterone to its active dihydrotestosterone form in the genital area: Nature 354: 159, 1991). Or the infant may lack testosterone receptors. This is testicular feminization (dumb name), a common problem often inherited on the X-chromosome. These "women" usually have no axillary or pubic hair, and of course, they don't menstruate. A sensitive article: Lancet 337: 33, 1991. "Muellerian regression factor" ensures that neither type will have a uterus or oviducts, and the "groin testes" should be removed because they tend to turn cancerous.

Don't confuse any of the above with gender dysphoria ("transsexualism" -- a boy insists he is a girl, a man wants to be a woman or has even had a "sex-change" operation; less often, vice versa; Lancet 338: 603, 1991), transvestism (liking to wear the clothing of the opposite sex) or homosexuality/bisexuality. Studying chromosomes and genes has contributed exactly nothing to our understanding of these states of mind. * The "conventional wisdom" has been to raise kids with ambiguous genitalia as girls (i.e., life is extremely difficult for a man with a oneinch erect penis), and to operate early for cosmetic reasons. The wisdom of surgery seems dubious, since at least some of these kids insist (without being told) that they are really boys, and grow up into angry men. There are activists, etc., etc. * In the 1970's, the Left redefined gender to mean gender-role, i.e., your culturally-defined role as a male or female, in order to emphasize the primacy of wicked cultural stereotyping over any biological differences. If you read left-wing rhetoric, knowing this will help you understand it. ("Did you hear about the postmodernist gangster? He made you an offer that could mean anything you wanted it to mean!") What's the real sex? Unless someone is a parent (the ultimate proof of maleness or femaleness), it all depends on your definitions. Would anybody want to say that gorgeous --- ---, who supposedly has testicular feminization, is "really a man"....? * Life birth of a non-mosaic tetraploid child: Arch. Path. Lab. Med. 127: 1612, 2003. INTRODUCING THE MENDELIAN DISORDERS Enzyme defects cause substrates to accumulate (i.e., the storage diseases, alkaptonuria), and/or prevent formation of a good end product (albinism, red hair, other white people) perhaps even with accumulation of unwholesome precursors (Lesch-Nyhan), and/or fail to inactivate something bad (i.e., 1-protease inhibitor deficiency) Defects in receptors and transport systems produce various malabsorption syndromes, urinary wasting syndromes, unresponsiveness to hormones, problems mobilizing lipoproteins, and so forth. Altered non-enzyme proteins include altered structure and function (hemoglobinopathies, collagen problems), and abnormal quantities (the prime example is the thalassemia family) Altered responses to drugs you'll study in "Pharm". If you lack G6PD, you get hemolytic anemia from various oxidizing drugs, fava beans, and so forth. Some people are "slow acetylators" of certain drugs, etc., etc.

AUTOSOMAL DOMINANT DISEASES Rules: When a person has only one good gene where most people have two, the person can expect to make 50% as much of the good protein as do most other people. Sometimes, that isn't enough. Therefore, the known autosomal dominant diseases fall into five categories. (1) Problems with the quantity or arrangement of large structural proteins (2) Problems with regulator proteins and receptors, that permit relatively good quality of life. (3) Deficiency in proteins that are in short supply even in health. (4) Anti-oncogene deletion syndromes, in which a "second hit" on the normal allele of a normal cell turns it to a tumor cell. More about this last category later. (5) The mutant gene makes a harmful protein ("gain of function"). Today, the best-understood of these are the prion-related diseases, in which an altered protein begins a terrible chain reaction that can even be transmitted to genetically normal creatures, even across species lines. The common autosomal dominant diseases do not kill or disable until the patient has had a good chance of having a family. Why? Hint: Most genetic diseases do not result from new mutations. The major exceptions are Von Recklinghausen's neurofibromatosis and achondroplastic dwarfism (both are genes with very high mutation rates). The autosomal dominant disorders are mostly of variable penetrance and/or expressivity (why?). Two doses of a bad autosomal dominant gene produces some severe exaggeration of the single-dose syndrome, or else death in the womb. Obviously, consanguinity does not play a role in autosomal dominant disease. The major autosomal dominant disorders that you'll meet in this course: Structural proteins (or the proteins that guide their arrangement):

Marfan's syndrome (any of several connective tissue proteins) Many Ehlers-Danlos variants, and plain old familial doublejointnedness (any of several connective tissue proteins) Hereditary spherocytosis (any of several red cell membranestrengtheners) The not-so-bad kinds of epidermolysis bullosa (abnormal keratin in intermediate fibers: Cell 66: 1301, 1991; Science 254: 1202, 1991)

Familial hypertrophic cardiomyopathy (any of several heart muscle proteins) Familial psoriasis (* probably amphiregulin, an autocrine growth factor for keratinocytes) Achondroplastic dwarfism (* fibroblast growth factor receptors, maybe others)

Hereditary hemorrhagic telangiectasia (several are known) Common ichthyosis (filaggrin) Hereditary autoimmune lymphoproliferation (mutant fas, the apoptosis trigger): Ann. Int. Med. 130: 591, 1999; Ped. Clin. N.A. 47: 1291, 2000. Osteogenesis imperfecta (usually collagen)

Treacher-Collins (variably malformed face, "Johnny Handsome", gene on 5q cloned and product "Treacle" identified: Nature Genetics 12: 130, 1996). The mechanism during embryogensis identified (from Stowers): Nat. Med. 14: 115 & 125, 2008.

Waardenburg's (deafness, different-colored eyes, white forelock; gene Am. J. Hum. Genet. 52: 455, 1993). * Fibrodysplasia ossificans (funny toes, ectopic bone; mutation is bone morphogenetic protein 4: NEJM 335: 555, 1996) * Saethre-Chotzen, another common Johnny Handsome syndrome, results from a mutant TWIST DNA transcription factor: Nat. Genet. 15: 36, 1997; exists in fruit flies and mice too.

Receptor / channel problems:

Familial hypercholesterolemia (LDL receptor) Benign familial tremor (presumptive) Glucocorticoid-suppressible aldosteronism (ACTH turns on aldosterone) The ion channel problems (periodic paralysis syndromes, myotonia congenita syndromes, malignant hyperthermia susceptibility syndromes) * Autosomal dominant cerebellar ataxia: the mutation is in the voltagegated calcium channel. Nat. Genet. 15: 62, 1997. * Narcolepsy: Watch these. Hypocretin receptor 2 and preprohypocretin genes; variable expressivity. Lancet 355: 39, 2000; Cell 98: 365, 1999; Nat. Med. 6: 991, 2000. Williams's syndrome: Deleted elastin gene. Elfin face, mental retardation, sometimes hypercalcemia in infancy.

* Cutis laxa -- elastin or fibulin (Am. J. Hum. Genet. 72: 998, 2003) Darier's calcium pump (Nat. Genet. 21: 271, 1999; patients have epidermal cells that tend both to keratinize abnormally and to separate too easily)

Short-supply protein deficiency syndromes

Von Willebrand's disease (VIII-R) Maturity onset diabetes of the young (glucokinase; see Nature 356: 721, 1992) Acute intermittent porphyria

Tumor genes:

Retinoblastoma gene syndrome Neurofibromatosis I & II Familial polyposis coli (including its variant Gardner's syndrome)

Lynch's hereditary non-polyposis colon cancer Multiple endocrine neoplasia syndrome I, IIa & IIb Li-Fraumeni cancer syndrome Tuberous sclerosis Von Hippel-Lindau disease Peutz-Jegher's syndrome * LEOPARD syndrome (PTPN11; J. Med. Genet. 39: 571, 2002) Adult polycystic kidney disease

Harmful proteins / "gain of function"

Prion diseases (PrP mutation that lets the protein give rise to prions) Hereditary amyloidosis (transthyretin/prealbumin, a mutant form that is amyloidogenic) Huntington's disease ("Huntington's chorea"; gene cloned Science 260: 28, 1993; Cell 72: 971, 1993; Br. Med. J. 307: 391, 1993; defective "huntingtin" accumulates and damages the cells) The non-Friedreich's dominant ataxias (defective "ataxin", any of 3 loci, accumulates and damages the cells) Familial dysplastic nevus syndrome (? the melanin generates, rather than protects from, free radicals) Familial amyotrophic lateral sclerosis (superoxide dismutase: Nature 362: 59, 1993); generates neurotoxin (NEJM 331: 1091, 1996); weird interactions with other proteins: Nat. Genet. 15: 91, 1997. Familial myopathies (bad actin: Nat. Genet. 23: 208, 1999) Hereditary pancreatitis (mutant trypsinogen)

The common thrombophilias (hypercoagulability problems, MUCH underrecognized):

Antithrombin III deficiency Protein S deficiency Protein C deficiency Factor V Leiden

Molecular biology unknown:

Pelger-Huet's non-disease (presumptive) Stein-Leventhal (??)

If you want, you could consider the common heterozygote semi-maladies "beta-thalassemia minor", "sickle cell trait", "hemoglobin C trait", and "onedose familial hemochromatosis" to be autosomal dominant conditions. We won't argue. The -thalassemias are even more special, since the loci are double and the severity of the illness depends on whether one has inherited one ("-thal minima"), two ("-thal minor"), three ("hemoglobin H disease"), or four ("hydrops fetalis") bad genes. Don't worry about these yet. Marfan's syndrome This is a heterogeneous group of genetic disorders with connective tissue problems. It is a physical diagnostician's delight. Marfan patients are tall, with very long extremities. The arm span exceeds the height. Joints are hyper-extensible (try extending the thumb to touch the wrist; patients say they are "double-jointed"). The chest is usually somewhat deformed, and the face may look funny. The bone structure is slim, the muscles are wiry, and patients are generally slender. The suspensory ligaments of the lens are often lax, and an ophthalmologist may diagnose "ectopia lentis", which is almost pathognomonic. The globe is long and the cornea flat, so patients tend to be very nearsighted. The central portion of the thoracic aorta's media suffers breakdown of its fibers ("cystic medial necrosis", a misnomer), creating a loose channel through which blood may extravasate ("aortic dissection", kills about 1/3 of "true marfan people". As the patient gets older, the aortic valve ring becomes lax, and the valve becomes incompetent. Severe heart failure results. Marfan types also generally have the trivial "Barlow's mitral valve". The most common Marfan locus is a protein that is woven around elastin (Nature 352: 279, 330, 334, & 337, 1991).

* Congenital contractural arachnodactyly maps to the fibrillinlike gene on chromosome 5: NEJM 326: 905, 1992). Variants and semi-marfan types abound -- around a hospital, string beans like your lecturer (especially when he had TB and weighed 135 lb) occasionally get asked, "Are you a marfanoid?" (Probably not, unless you count all us skinny, nearsighted folks with Barlow valves.) You'll need to decide for yourself whether the athletic, physically powerful, but funny-looking Abraham Lincoln could have been a "marfan" (seems less-than-classic), or had some variant connective tissue anomaly (seems likely).

We can hope that finding the remaining gene(s) will further clarify the nature of marfanism. In the meantime, there are two classical "models": (1) Lathyrism, caused by feeding sweet peas to turkeys and resulting in fatal aortic dissection, results from beta-aminopropionitrile inhibiting lysine oxidase, which cross-links collagen and elastin fibers. (2) Menke's kinky hair disease (* a rarity on the X-chromosome), which prevents normal handling of copper, prevents function of lysine oxidase. Of course, lysine oxidase structure and function, and the genes for collagen types I, II, and III are all normal in Marfan's patients. * Oddly, advanced paternal age seems to be linked to new Marfan's mutations. Stay tuned -- the study of Marfan's syndrome may yield insights into the secrets of why we're built differently. "Marfan variants" are numerous. (* I have friends from two different families with "probable Stickler's syndrome"; one family is deaf, the other friend is a physician-athlete. Stickler's results from a premature termination codon on the type II procollagen gene: Am. J. Hum. Genet. 52: 39, 1993; Am. J. Hum. Genet. 53: 55, 1993.) Ehlers-Danlos syndrome ("human pretzels") is a family of variably-inherited diseases that leave a person with poorly-woven collagen.

Typical cases have overly-extensible (even "cigaret-paper") skin that gets hurt easily and heals poorly, and very overly-mobile joints that often slip out of place. * The following is presented only to give you an idea of the great variety of different problems that can result in very similar clinical syndromes.... type I and type II: Classic Ehlers-Danlos, with lax joints and stretchy skin. Mutated type V collagen (globby stuff that shapes and stabilizes type I collagen): Am. J. Hum. Genet. 60: 547, 1997. type IV: various problems with type III collagen ("reticulin"); colon and arteries often rupture (review NEJM 342: 673, 2000). Type VI: reduced lysyl hydroxylase (autosomal recessive), ruptured corneas, detached retinas Type VII: inability to turn type I procollagen into collagen. Distinct but closely related "torn skin" syndrome: Am. J. Hum. Genet. 51: 253, 1992. type IX: X-linked copper problem awaiting characterization, a copper problem Familial hypertrophic cardiomyopathy ("sudden death during gym class", "Reggie Lewis's disease", etc., etc.) is due, in at least half of cases, to missense (i.e., singlebase substitutions) in key portions of the beta-cardiac myosin chain (NEJM 326: 1108, 1992). There are other mutations (troponin, myosin binder: NEJM 338: 1249, 1998). Familial hypercholesterolemia "The most common mendelian disorder", with estimates of its frequency ranging from "Big Robbins"'s conservative 1 in 500 to "minor forms" that maybe explain "why some healthy-living people run higher LDL's than others". (Homozygotes with the really bad alleles die in their teens.) To make a complicated story short (and extremely oversimplified), we think most of these patients lack enough good apoprotein B-100 ("LDL") receptors. Therefore, they have trouble with: (1) hepatic clearance of VLDL leftovers ("IDL's") for recycling, leaving them in the plasma to turn into LDL's (2) hepatic clearance of LDL's from the plasma, leaving high plasma LDL levels (3) receptor-mediated uptake of LDL's by other cells (do you remember "coated pits"?), leaving more around to be taken up by the mononuclear phagocytes by their receptor-independent method.

You recall that receptor-mediated LDL uptake is tightly-regulated, but that non-receptor-mediated LDL uptake is chaotic, and leads to lipid-bloated cells. Dysregulated uptake of LDL's by macrophage clusters leads to "xanthomas", masses of lipid-laden cells. Dysregulated uptake of LDL's by phagocytes of the arterial intima probably causes atherosclerosis. The classic autosomal dominant disease features plasma cholesterol levels of around 300-500 mg/dL, tendon xanthomas, and precocious atherosclerosis (with strokes, heart attacks, and so forth). Classic familial hypercholesterolemia features 50% reduction in B-100 apoprotein receptor effectiveness. This can be due to absence of receptors (most common), receptors that don't bind LDL, or (rarely) receptors that don't work once LDL is bound. * Animal model for defective LDL receptors: the Watanabe rabbit (Science 256: 772, 1992.) The genetics are more complex than cited above, and "familial high cholesterol" is clearly heterogeneous. One gene ("for both high cholesterol and high triglycerides") has been found at 11q23-24 (apolipoprotein city; Nature 349: 161, 1991). Stay tuned for the discovery of alleles. The second attempt to cure a genetic disease using recombinant gene therapy was directed against LDL receptor deficiency (in the Watanabe rabbit, of course). A retrovirus is used to introduce the good gene into cultured liver cells, that are then re-introduced into the rabbit. This has now worked in a human being (Science 260: 926, 1993; JAMA 269: 837, 1993). * Other important, less-common lipoprotein defects are mutant apolipoprotein B-100 and mutant apolipoprotein E; the latter produces the famous "type III hyperlipoprotienemia (remnant disease)". All about genetic defects in lipoprotein metabolism: JAMA 265: 78, 1991. The apo-E deficient mouse: Science 258: 468, 1992. Stein-Leventhal syndrome is a mysterious very common woman's problem. The combination is:

amenorrhea (typically, she stops having periods) hyperandrogenism (high testosterone, high other-androgens, and of course hirsutism, i.e., a man's body-hair pattern, i.e., some beard, and some coarse hair at least approaching the belly button) no other obvious cause (i.e., she's not taking gym steroids or suffering from a testosterone-producing tumor or a glitch in her adrenal steroid metabolism)

Stein-Leventhal women also usually have:

relative tissue resistance to insulin; big ovaries with thick fibrous capsules ("polycystic ovaries"; the cysts are follicles that could not rupture).

Nobody understands Stein-Leventhal, but it appears to travel as a dominant condition with variable penetrance. You can treat it by manipulating hormones, and sometimes this seems to cure it. The male phenotype seems to be the super-hairy guy who goes bald early. NEJM 333: 853, 1995; Clin. Encodr. 38: 653, 1993. Since we haven't covered tumors yet, we'll look at anti-oncogene deletion syndromes under "Neoplasia". Understanders: It is nearly certain that many "sporadic" birth defects represent "second hits" in people inheriting a single autosomal gene for dysmorphism. A cell in the embryo is hit at the opposite, normal allele, and a body part develops abnormally. One such case is known in the mouse (Ds; Am. J. Hum. Genet. 52: 866, 1993). Finding these in humans (as the cause of birthmarks) is only a matter of time. * Love may be blind, but it is evidently not anosmic. Since the HLA molecules combine with captured invaders to present their antigens to the immune system, in an ever-changing world it's desirable that people should have a variety. Of course, it's also good to marry non-relatives. And indeed, people tend to marry people with different HLA types more than you'd expect by chance. HLA type Is an important contributor to your individual musk, and in one study, women preferred the dirty Tshirts of unknown men whose HLA types differed from them (Proc. Roy. Soc. Lond. 260: 245, 1995). This finding is now pretty robust (Am. J. Hum. Genet. 61: 494, 1997), and the "electronic nose" (a computerized odor-detector) can tell your HL-A's apart (Proc. Nat. Acad. Sci. 98: 9249, 2001). AUTOSOMAL RECESSIVE DISEASES Rules: Many body proteins are in such abundant supply that if a person has only half as much of that protein (i.e., has one good gene where most people have two), there is no obvious problem. However, if a person has no good gene where most people have two, the person is sick. Therefore, the known autosomal recessive diseases are either (1) deficiencies or defects in highly specialized proteins (enzymes, transport proteins), or (2) hemoglobinopathies requiring more than one dose of a gene In contrast to autosomal dominant diseases, autosomal recessive diseases:

often result from consanguineous matings. are often apparent at, or shortly after, birth; have unknown mutation rates;

generally show complete penetrance (if there are several alleles, expressivity may vary; the most conspicuous exception is 1-protease inhibitor deficiency); Unaffected siblings have a 2/3 chance of being carriers. If you can't explain this, please go back to your basics.

If the autosomal recessive disease is particularly common (worldwide, or in an ethnic group), it's likely that the heterozygote state confers a significant advantage on its carrier. Examples: Sickle cell and some other hemoglobinopathy carriers resist malaria. Hemochromatosis carriers have much less trouble maintaining body iron stores. Cystic fibrosis carriers are much more resistant to gram-negative intestinal infections. No one has a clue as to why Ashkenazi Gaucher's carriers have an advantage, but they must, since five different mutations have gained a foothold (Proc. Nat. Acad. Sci. 90: 5384, 1993). Here are the major autosomal recessive disorders that you'll meet in this course: Deficiencies or defects in highly specialized proteins Known proteins

Cystic fibrosis ("mucoviscidosis") Phenylketonuria (8 alleles: NEJM 324: 1232, 1991). All 50 states screen for hemoglobinopathies, PKU, congenital hypothyroidism, and galactosemia. Galactosemia Adenosine deaminase deficiency (immunodeficiency) Biotinidase deficiency (rare brain disorder, treatable with big doses of biotin; widely screened-for today) Maple syrup urine disease (leucine, isoleucine, and valine are neurotoxic; widely screened-for today) 1-protease inhibitor ("antitrypsin") deficiency Common albinism The lysosomal storage diseases (except Fabry's and Hunter's) Most glycogen storage diseases Alkaptonuria (* the first human disease discovered to be autosomal recessive) Really bad von Willebrand's variants Abetalipoproteinemia (missing apoprotein B; spiny red cells, malabsorption): JAMA 270: 865, 1993; one gene Nature 364" 291, 1993

* The bad kind of epidermolysis bullosa (bad type VII collagen, therefore bad anchoring fibers: Science 256: 799, 1992) pyrin (familial mediterranean fever)

Various inborn errors of hormone metabolism Friedreich's ataxia (loss of function of frataxin gene, causing accumulation of iron in the mitochondria; * Friedreich's was once mistakenly considered dominant) Chediak-Higashi (immunodeficiency, * LYST gene) hereditary fructose intolerance (aldolase B) homocystinuria (cystathione synthetase). hereditary tyrosinemia (fumarylacetoacetate hydrolase) Various inborn errors of hormone metabolism metachromatic leukodystrophy (arylsulfatase A) Krabbe's (galactosylceramidase) the renal tubular ion-transport diseases (* Getelman's, * Bartter's, * Liddle's) Limb-girdle muscular dystrophy (* sarcoglycans: NEJM 336: 618, 1997) Mevalonate kinase deficiency -- high IgD and episodes of acute phase reaction (figure that one out! Nat. Genet. 22: 121 & 178, 1999) Most hypophosphatasias -- deficient alkaline phosphatase (skeletal abnormalities, raised phosphoethanolamine and pyrophosphate -- Clin. Sci. 94: 203, 1998). * Thiamine resistance (gene Nat. Genet. 22: 300 & 305, 1999) Progressive spinal muscular atrophy ("Werdnig-Hoffman floppy baby") -- gene is SMN "survival motor neurons" Hum. Mol. Gen. 9: 341, 2000. Wilson's hepatolenticular degeneration (defective copper pump, * gene is ATP7B) Tangier (no HDL, heterozygotes at a disadvantage too; Nat. Gen. 22: 316, 347 & 352, 1999; Nat. Genet. 24: 192, 2000; gene is ABC1 cholesterol transporter)

Major hemoglobin problems

Sickle cell anemia Hemoglobin C disease beta-thalassemia major Three and four-dose -thalassemia syndromes Combinations of the above

Carriers of most recessive traits can be detected by molecular biologists, who'll find, for example, "only 50% of normal enzyme activity", or "50% of the protein migrating abnormally", or "restriction fragment length polymorphism".

Albinism: inability to synthesize melanin, our protective brown pigment. Albinism involving eyes, hair and skin indicates homozygosity for defective genes at any one of twelve or so autosomal loci. (* A form of albinism limited`(to the eyes is X-linked). The best-understood form is deficiency in tyrosinase. The other ("tyrosinase positive") forms are poorly-understood, and often form only part of complex genetic syndromes. Regardless of the enzyme defect, patients with classic albinism suffer from light-sensitive eyes and skin, skin cancers, and eye cancers. Alkaptonuria ("ochronosis"): lack of homogentisic acid oxidase Homogentisic acid's nonenzymatic breakdown products ("alkapton", black stuff) accumulates in the urine and cartilages (check those ears). Articular cartilage wears out early, causing precocious arthritis of the spine and big joints. Lysosomal storage diseases: Lots and lots of these are known. They result from failure of catabolism of large molecules within lysosomes. The molecular lesions include lack of enzymes, mutant inactive enzymes, improperly-packaged enzymes, enzymes lacking necessary activators or protectors, lack of helper proteins, or lack of proteins to move digested material out of the lysosomes. Tay-Sachs disease ("amaurotic familial idiocy"): lack of hexosaminidase A, causing accumulation of GM2-ganglioside. The prototype gangliosidase deficiency. Around one Ashkenazic person in 30 is a carrier. Neurons, including those in the retina, are particularly affected. "Ashkenazic" denotes an ethnic group, mostly of the Jewish faith, mostly from Eastern Europe. Babies seem normal at birth, but become retarded, blind ("amaurotic"), uncoordinated, and limp. The brain and head enlarge abnormally, due to accumulation of lipid. Death occurs within a few years. The "cherry red spot" on the macula of the eye is actually the normal color, and the rest of the retina is too white because of the lipid accumulation. Light microscopy shows ballooned neurons, which ultimately die off. Electron microscopy shows lamellar lipid masses in lysosomes. Tay Sach's ballooned neurons

Natural selection at work: Tay-Sachs heterozygotes enjoy extra resistance to tuberculosis (Lancet 341: 214, 1993). Niemann-Pick disease: lack of any one of several proteins required to break down sphingomyelin molecules Classic type A (no sphingomyelinase) features extensive accumulations of sphingomyelin and cholesterol in neurons and the body's fixed phagocytes, notably liver and spleen. Patients die in early childhood. By contrast, adults with type B have large livers and spleens but no CNS involvement clinically. Pathologists see lipid-laden, foamy-looking affected cells. Electron microscopy shows lamellar lipid masses ("zebra bodies", other forms). * Medical history buffs: Pathology boasts two Dr. Picks: Louis Pick described this disease, Arnold Pick discovered Pick's disease of the brain. Gaucher's disease: the genes Science 256: 794, 1992; mouse Nature 357: 407, 1992): lack of glucocerebrosidase. The most common lysosomal storage disease. type I Gaucher's disease ("adult type") results from subtotal deficiency of glucocerebrosidase. It is very common in many communities, and one Ashkenazic person in twelve is a carrier. It is compatible with a long, basically healthy life. Patients have massively enlarged spleens (30 kg or more), and large livers and lymph nodes. Most of these glucocerebrosides are probably from normal breakdown of old blood cells. Patients develop pancytopenia (decreased numbers of circulating red cells, neutrophils, and platelets). This reflects both bone marrow involvement and an overactive spleen ("hypersplenism"). Skeletal problems (bone pain, fractures) result from the marrow being packed with ever-expanding cells. (For more about this see Orthop. Clin. N.A. 15: 765, 1984; Medicine 64: 310, 1985). Pathologists see "Gaucher cells", huge reticuloendothelial cells bloated with glucocerebroside. Since glucocerebroside is not lipid, affected cells are not "foamy"; instead, the good texture comparison is to crumpled tissue paper. (* Old-timers compared it to "watered silk", which is hard to find nowadays. Future pathologists: If you notice loaded cells in the alveoli, it's probably Gaucher's.)

type II Gaucher's disease ("infantile type") resembles type I, except that the mutation is different (NEJM 316: 570, 1987) and neurons are progressively destroyed (nobody knows exactly how, since the storage is extra-neuronal). These children have progressive mental retardation and die after a few years. This is not an ethnic disease. type III Gaucher's disease is of intermediate severity, and causes progressive dementia beginning in the teenaged years. * Roundsmanship: If you suspect Gaucher's disease but have no biopsy material yet, order a serum L-tartrate-resistant acid phosphatase and a serum angiotensin-converting enzyme. Gaucher cells elaborate lots of both. * "Alglucerase", the replacement enzyme for Gaucher's disease, is available but costs $380,000 per year (Proc. Nat. Acad. Sci. 90: 5384, 1993). Uh-huh. We learn with hope of the prospect of real gene therapy: J. Hep. 30(S1): 1, 1999.

The mucopolysaccharidoses Problems degrading glycosaminoglycans ("mucopolysaccharides", such as heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate, and/or others). These include the very severe Hurler's syndrome ("gargoyle" children with progressive mental retardation) to the variable Sanfilippo (severely mental deterioration, near normal-looking) and Morquio (dwarves with bad aortic valves and normal intelligence) syndromes.

Ian Michael Smith (left) Actor with Morquio's

Hunter's (MPS-II) is sex-lined, but all the others are autosomal recessives. Expect mild to severe accumulation of mucopolysaccharides in the spleen, liver, etc.; * In some syndromes, the coronary arterial intima is also progressively narrowed, leading to myocardial infarcts. Pathologists see PAS-positive material in affected cells. Zebra bodies, which include lipid, may be seen in normal lysosomes when the brain is involved. Hurler's baby; abdomen protrudes because of large liver and spleen * Medical history buffs: The brilliant Dr. Gertrude Hurler was one of the first female physicians in Germany.

* This is as good a place as any to list the other inborn errors of metabolism that chiefly affect the brain. Except as noted, they are autosomal recessives. Don't learn these just now; save them for later. Metachromatic leukodystrophy: deficiency of arylsulfatase A; galactosyl sulfatide accumulates; brain deteriorates after infancy. * Alleles: NEJM 324: 18, 1991. Krabbe's globoid cell leukodystrophy: deficiency of galactocerebroside B galactosidase; galactocerebroside accumulates; brain deteriorates in infancy. Adrenoleukodystrophy ("Lorenzo's oil", etc.): a family of diseases, some X-linked, with problems breaking down long-chain fatty acids; both white matter and adrenal cortical problems. Glycogen storage diseases: The clinical application of a "Biochemistry" unit. type I (Von Gierke's disease, glucose-6-phosphatase deficiency): Patients have big livers and most of the problems are due to hypoglycemia. A mild disease. Von Gierke's disease, severe, with glycogen in the heart Von Gierke's disease involving kidney, histologic view; clear glycogen in proximal tubular epithelium Von Gierke's disease, intracytoplasmic glycogen appears clear Von Gierke's patient with hepatomegaly producing protuberant abdomen type II (Pompe's disease, lysosomal glucosidase deficiency, "acid maltase" deficiency): Patients have involvement of all organs, and die young of heart disease. * A mild adult version exists (NEJM 315: 694, 1986). * type III (Cori's disease, limit dextrin disease, de-branching enzyme deficiency); Rare, patients have liver storage problems. See Ann. Int. Med. 116: 896, 1992. * type IV (branching enzyme deficiency): accumulation of abnormal glycogen in all organs, including the brain; death in infancy. Liver transplants for this disease: NEJM 324: 39, 1991. Type V (McArdle's disease, muscle glycogen phosphorylase deficiency): Patients are poor athletes, and get bad cramps and muscle damage when they try. Glycogen is deposited beneath the sarcolemma. * Type VI (liver glycogen phosphorylase deficiency): Big liver, hypoglycemia, mild disease * Type VII (muscle phosphofructokinase deficiency): Poor athletes, like type V; NEJM 324: 364, 1991.

* Type VIII (liver glycogen phosphorylase kinase deficiency): Big liver, hypoglycemia, mild disease I-cell disease ("mucolipidosis II") is among the most popular biochemistry exam items. It is a storage disease in which several different enzymes are lacking in lysosomes. Along with its milder allele "Pseudo-Hurler", it results from lack of Nacetylglucosamine phosphotransferase. This is the enzyme responsible for picking up the mannose-6-phosphate-tagged enzymes that are destined to go into the lysosomes. As you'd expect, these children store several different breakdown products, hence "mucolipidosis". "I" refers to inclusions in the cells of these children. SEX-LINKED DISEASES Chromosomes X and Y have only a short homologous regions at the tip of the short arm. (This is the locus for pseudo-autosomal inheritance, seen only in uncommon disorders. This portion of X does not lyonize.) We await the definitive identification of any common genetic defect on the Xchromosome that is not overridden by a normal allele on another X-chromosome (a real "X-linked dominant"). The best candidate for such a gene is one for manic-depression (J. Med. Genet. 36: 585, 1999), but it remains unidentified. The one well-known X-linked dominant disorder is familial vitamin D resistant rickets, an uncommon phosphate-wasting problem. * Rett syndrome (MECP2) is autosomal dominant. It causes a neurodegenerative syndrome and a movement disorder (continuously wringing the hands) beginning around age 5 months in affected girls (Lancet 356: 830, 2000). Males with the allele die in utero or have a much more severe encephalophaty. * There are also a few exotic skin diseases that are mostly lethal to the male fetus. Most problems on the X-chromosome require one dose ("dominant" for hemizygous men), two doses ("recessive") for women. Rules: X-linked diseases:

affect all males with the gene affect a woman only if (1) she had two affected X-chromosomes, i.e., she had an affected father and a carrier mother (possible if we're just dealing with color blindness, most unlikely if we're dealing with

Duchenne's muscular dystrophy); (2) she suffers from really unfortunate lyonization; (3) the disease is expressed when individually lyonized cells are affected (i.e., G6PD deficiency, in which half the red cells hemolyze and half don't; or some cases of fragile X syndrome); (4) she has Turner's syndrome (XO) or testicular feminization (XY). generally produce many affected family members, once the new mutation has been propagated.

The only two conditions known to be carried on the Y-chromosome are: (1) being a man ("testis determining factor": Nature 351: 325, 1991). (2) having lots of hair grow on your ears when you get old. Actually, even this one isn't true (Eur. J. Hum. Genet. 12: 1077, 2004). (3) Some mutations that render a guy almost completely infertile (Gene 321: 25, 2003, Am. J. Med. Genet. 41: 814, 2004; others). These are passed father-to-son. We get our Y-chromosomes exclusively via the male line, just as we get our mitochondria exclusively by the female line. * Adam, our common male ancestor, seems to have lived in Africa (if you accept some straightforward assumptions): Science 251: 378 & 379, 1991. Eve did too, around 135,000 years ago (Ph. Tr. Royal Soc. London 337: 167, 1992). More about the recent African origins of contemporary humankind: Nat. Gen. 13: 154, 1996. * What's worse, it seems that the coalescence time for the Y's is considerably shorter than the coalescence time for the X's. See Nature 378: 376 & 378, 1995. Any ideas how this could be? (HINT: "Like it or not, we are the descendants of the men who won wars.") * The Neanderthals apparently buried their children (Nature 377: 585, 1995), practiced cannibalism (Science 286: 128, 1999), and may have used the same musical scale as we do (Sci. Am. 277: 28, 1997). Right now it looks as if they were a separate species (Nature 412: 534, 2001 morphology, Nature 404: 453, 2000), i.e., we exterminated them (Am. J. Hum. Genet. 55: 760, 1994; Am. J. Hum. Genet. 59: 185, 1996) * If we're to believe one new study, about 8% of men in the regions of Asia that were part of the Mongol empire are male-line descendants of Genghis Khan (Am. J. Hum. Genet. 72: 717, 2003). * Microdeletions on "Y" probably account for a few percent of cases of male infertility: NEJM 336: 534, 1997. The major sex-linked disorders that you'll meet in this course:

Known proteins

Hemophilia A (factor VIII deficiency) Hemophilia B (factor IX deficiency) G6PD deficiency ("favism"; several alleles) Lesch-Nyhan syndrome Duchenne's muscular dystrophy (Jerry's kids) Emery-Dreifuss muscular dystrophy Pelazaeus-Merzbacher disease (demyelination; proteolipid protein: Neurology 50: 1749, 1998) Chronic granulomatous disease (neutrophil defect) Hunter's mucopolysaccharidosis Properdin deficiency (neisseria infections); Fabry's disease Common red-green color-blindness (one of the pigments is mutated into having a peak absorption near the same as one of the others) Testicular feminization (common type) * Nephrogenic diabetes insipidus (hADH receptor in collecting duct; Nature 357: 336, 1992) * An allele for monoamine oxidase A that correlates strikingly with horribly aggressive misbehavior (Science 260: 1722, 1993; Science 262: 580, 1993; for writing this paper, the author was smeared by prominent Leftists as a "Nazi!" doing grave harm to his career: Science 264: 653, 1994). Anyway, the finding that monoamine oxidase A alleles correlate with violence is now robust: Science 297: 752 & 851, 2002. * Mencke's kinky hair (a real "kink" in copper metabolism; gene APT7A cloned Nature 361: 98, 1993; update NEJM 385: 605, 2008) Bruton's agammaglobulinemia (special tyrosine kinase required for Bcell development) "David the Bubble Boy"'s immunodeficiency (* SCIDX1) X-linked adrenoleukodystrophy (* peroxisome membrane protein, very long chain acyl-coenzyme A synthetase)

Fragile X chromosome Fabry's disease (* "angiokeratoma corporis diffusum universale"; deficiency of the enzyme alpha-galactosidase A) Ceramide trihexoside accumulates in blood vessels and elsewhere; especially involved are the renal glomeruli (look for big foam cells here). There is also some brain involvement, and the peripheral nerve involvement makes this the most painful of the storage diseases. * "Angiokeratomas" ("tumors of vessels with keratin") are rough, red bumps. Don't confuse these with the smaller, similar-looking angiokeratomas that are common on the scrotums of many older men. * Replacement enzyme therapy: Lancet 358: 601, 2001. It seems to work: Lancet 374: 1986, 2009.

Fabry's, lamellar bodies on electron microscopy

Fragile X syndrome (* Martin-Bell syndrome): see Am. Fam. Phys. 39(5): 185, 1989; JAMA 271: 536, 1994 (deep stuff), or Am. J. Med. Genet. 30(1-2), whole issue. Fragile X foundation: Box 300233, Denver, Colorado 80203. Screening: Br. Med. J. 305: 265, 1992. Around half of cases of familial mental retardation now appear due to a single genetic defect, detectable using cytogenetics, in which a defective gene at Xq27.3 presents as discontinuity seen on G-banding. * Fragile X protein has to do with synapse morphology, and affected people have long-skinny dendritic spines and small buttons (Proc. Nat. Acad. Sci. 94: 540, 1997). The syndrome is almost as common as Down's; around 1 guy in 1500 has it. Affected men have IQ's in the 35-50 range, and distinctively large testes (the only reliable physical finding, though there may be other abnormalities: "big ears, big upper jaw, big testicles"). By the way, about a third of heterozygous women are also retarded (Am. J. Hum. Genet. 52: 884, 1993). It turns out the problem isn't lyonization, but the severity of the mutation (JAMA 271: 507, 1994). Deep stuff. * Molecular biology: Nature 349: 624, 1991; JAMA 271: 536, 1994. Surprisingly, not every guy with the abnormal sequence is affected; the defective DNA must also be tagged with methyl-cytosines (Science 251: 1236, 1991). The gene that gets turned off is FMR1. Its product is FMRP, and you can test for the absence of this thing using an antibody (cheapo; Lancet 345: 1147, 1995). * Medical history buffs: Julia Bell, an English physician who characterized this illness, began her career as a major astronomer. In the future, look for other "fragile site" diseases. This may go a long way to explaining "polygenic inheritance", "variable expressivity", spotted animals, etc. (Ideas: Lancet 338: 289, 1991). fragile-X guy (long maxilla) fragile-X guy Lesch-Nyhan is already partly familiar to you from Biochemistry's discussion of gout, but this is only part of the story of this grisly disease. The neuropathology (i.e., why these kids chew off their body parts) has been clarified. There is a profound lack of dopaminergic terminals and cells (NEJM 334: 1568, 1996).

MITOCHONDRIAL INHERITANCE (Lancet 379: 1825, 2012) We are just beginning to discover diseases that are carried in the extranuclear DNA of the mitochondria. Of course, we get our mitochondria, with their genes, only from our mothers. (* We believe paternal transmission is vanishingly rare; first proven case in a human NEJM 347: 576, 2002.) Obviously, a variable number of mitochondria in various family members are affected, and the severity seems to depend (at least in the case of myoclonus epilepsy; see below) on the overall % of involved mitochondria. * The mitochondrial genome follows the old routes of trafficking in female slaves: Am. J. Hum. Genet. 72: 1058, 2003. Important: All these diseases are progressive, and affect cells non-uniformly. Different cells bear widely variable numbers of bad mitochondria. What is clearly happening is that the mutation gives the bad mitochondria a growth advantage over their normal counterparts. The first cloned mitochondrial disease gene was the one for Leber's hereditary optic atrophy (Science 242: 1427, 1988; Sci. Am. 259(4): 32, Oct. 88; NEJM 320: 1300 & 1331, 1989; Am. J. Hum. Genet. 51: 378, 1992; another problem with cytochrome oxidase); progressive visual impairment. The name's worth remembering because it made history. Soon afterwards, it became clear that most cases of Kearns-Sayre disease (progressive external ophthalmoplegia, retinal pigmentation, heart block, cerebellar ataxia) and progressive external ophthalmoplegia (without the other stigmata of K-S diseases) were found to be caused by various deletions of the mitochondrial genome (NEJM 320: 1293, 1989; Science 244: 346, 1989). Mitochondrially-inherited illnesses are progressive, i.e., not apparent at birth, but eventually causing disability. Every mitochondrion, of course, has many copies of its genome, and probably the "bad" loops somehow overgrow the "good" loops over the course of time. For more on this idea, see Am. J. Hum. Genet. 48: 649, 1991. Myoclonus epilepsy with ragged red fibers is inherited maternally. The cause was found in 1990 to be due to a mutation in the lysine transfer RNA gene (Cell 61: 931, 1990; see also Lancet 2: 1253, 1988); the "ragged red fibers" look that way because of proliferated, dysfunctional mitochondria packed around their edges. * MELAS ("mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes") results from a disastrous mutation in a leucine transfer RNA gene (Nature 351: 194 & 236, 1991; the mutation Proc. Nat. Acad. Sci. 89: 4221, 1992; a variant: Lancet 338: 143, 1991.) * More: a deafness-and-diabetes mutation on tRNA(Leu(UUR)): Diabetes 43: 746, 1994.

Other "mitochondrial diseases" (notably the other "mitochondrial myopathies with ragged red fibers" and Leigh's) are coded (at least in most cases) by the nuclear DNA. * Pearson's: J. Clin. Invest. 86: 1601, 1991. * We are just now linking particular tumors to mutated mitochondria DNA (more about this under "Kidney"). All about the mitochondrial genome in health: Ann. Rev. Cell. Bio. 4: 289, 1988. Maternal inheritance is a near-synonym for "mitochondrial inheritance", but you must rule out an infectious organism that can only be passed from person to person across the placenta. ("* But mitochondria are really...."; see Nature 364: 358, 1993. Nobody questions nowadays that cyanobacteria gave rise to chloroplasts, and the biologists tell us that mitochondria sure seem a lot like purple bacteria.) * Wolfram's disease, an autosomal recessive disease on chromosome 4, causes loss of DNA from the mitochondria. Nobody knows how. J. Clin. Invest. 97: 1570, 1996. POLYGENIC DISORDERS (much better term than "Big Robbins's" "multifactorial inheritance") Diseases and conditions in which heredity clearly plays a dominant role, but for which there is clearly no single gene, include:
o

alcoholism (Br. Med. J. 303: 72, 1991)

asthma (the search for loci: Nat. Genet. 23: 241, 1999)

atherosclerosis

attention-deficit disorder /hyperactivity (Science 301: 160, 2003)

baldness and hirsutism (Clin. End. 38: 653, 1993) / Stein-Leventhal

breast cancer risk

common eye problems

autism (it's now obvious: Lancet 362: 1133, 2003)

cleft palate

diabetes mellitus (type I, type II)

high blood pressure

idiopathic gout

pyloric stenosis

schizophrenia

obesity (i.e., appetite out-of-synch with bodyweight)

familial combined hyperlipidemia ("my triglycerides and LDL both run high", the mouse model is two loci: Science 275: 391, 1997)

lots and lots of other things

Telling polygenic disorders from "single-gene diseases with incomplete penetrance" or "genetic diseases modified by environment" or "genetic heterogeneity" is a tricky business. Evidence for "polygenic inheritance" of a particular disease includes: (1) Adoption studies demonstrate that "nature" is more important than "nurture" for this disease. (2) There is no classic pattern of inheritance in most large kindreds. (3) Parents and sibs are at some (approximately the same) increased risk;

(4) The sicker the index patient, the greater the risk to the near-kin; (5) The more sibs that are affected, the greater the risk to the next baby; (6) Diseases are of variable severity, and minor or even trivial cases can be found. (7) Because the disease is caused by "piling up of several abnormalities", environment modifies the full expression of most of these diseases, and identical twins of patients, while at high risk, are not invariably affected. (The closest we have to an exception: type II diabetes) Heredity obviously plays a role in height, build, looks, coloration, voice, and masculine hair distribution-loss pattern. Most people would admit that intelligence ("defined to be what is measured by IQ tests", sorry; despite ideology see Nature 367: 591, 1994), personality (whatever that is), and tendency to gain fat (i.e., appetite), along with certain aptitudes, depend at least in part on one's genetic background. Our knowledge of the actual genes is minimal. Be extremely skeptical about "scientific studies" of such things, especially when race is an issue, or the writer sounds very confident. More plausible are studies that find a single locus that seems to modify several "distinct polygenic diseases" (a "Beavis and Butt-Head" D2 dopamine receptor variant that correlates with nastiness: JAMA 266: 1793, 1991; Arch. Gen. Psych. 49: 157, 1992). Right now, watch the genetics of obesity -- it's probable that many, if not most, overweight folks have a defective leptin receptor in the brain (NEJM 332: 679, 1996), its expression modified (probably) by other genes. GENETIC DISEASES THAT ARE NEVER INHERITED Sounds impossible, but isn't. Rules: 1. A fertilized egg with the disease is non-viable. 2. All patients with these diseases have a post-zygotic mutation involving only some of their cells, and express their conditions variably depending on where affected cells may be. There's at least three so far:
o o o

McCune-Albright's polyostotic dysplasia Proteus syndrome (the disease that actually affected the "elephant man"; Arch. Derm. 133: 77, 1997). * the obscure Schimmelpenning-Feurerstein-Mims syndrome, with skin hamartomas and eye and brain problems (Clin. Genet. 50: 393, 1996) Stay tuned for more.

By the way: Creutzfeldt-Jakob's (prions) is a disease that produces an infectious particle that can be propagated to healthy people. There is a genetic subtype that generates infectious, transmissible prions. By the way: Neoplasms are the great acquired genetic disease. More about this soon.
this knowledge. Know your stuff yourself.