Robbins and Cotran Chapter 5

What are the potential consequences of an enzyme creation defect

-Accumulation of the substrate with possible accumulation of one or both intermediates. Could cause injury from toxicity. (ex- galactosemia, deficiency in galactose-1-phosphate uridyltransferase, leads to galactose accumulation. Also, this is what happens in lysosomal storage diseases) -Can have metabolic block and decreased amount of end product necessary for normal function (ex- lack of tyrosinase casues lack of biosynthesis of melaninsm and consequent albinism). May have overproduction of intermediates and their catabolic products -Failure to inactivate tissue-damaging substrate (ex- α 1 -antitrypsin deficiency means you can't inactivate neutrophil elastase in lungs -> destruction of elastin in walls of lung alveoli -> pulmonary emphysema

How is LDL cleared by the liver

-LDL binds to coated pits in plasma membrane, is internalized as coated vesicle, and fuses with lysosome and is degraded. Pit is recycled back to surface (this is regulated by PCSK9, which can bind to LDL receptors on hepatocyes and cause their degredation after endocytosis) -Apoprotein part is hydrolyzed to AAs, cholesteryl esters broken down to free cholesterol. -This free cholesterol, in turn, crosses the lysosomal membrane to enter the cytoplasm, where it is used for membrane synthesis and as a regulator of cholesterol homeostasis. The exit of cholesterol from the lysosomes requires the action of two proteins, called NPC1 and NPC2 (see "Niemann-Pick Disease Type C").

Familial Hypercholesterolemia

-Most common cause- Mutation in gene encoding LDL receptors -> inadequate removal of plasma LDL by liver -Less common cause- mutation in ApoB (ligand for LDL receptor on LDL particle) and PCSK9 (reduces expression of LDL receptors by downregulation their recycling and consequent degradation in lysosomes) -Heterozygotes with FH due to mutation in the LDLR gene possess only 50% of the normal number of high-affinity LDL receptors because they have only one normal gene. Homozygotes have virtually no normal LDL receptors. See in both defective LDL clearance and increased LDL synthesis (IDL, the immediate precursor of plasma LDL, also uses hepatic LDL receptors (apoB/E receptors) for its transport into the liver. In FH, impaired IDL transport into the liver secondarily diverts a greater proportion of plasma IDL into the precursor pool for plasma LDL.) -See also mutant ApoB gene so there's reduced binding of LDL, as well as activating mutation in PCSK9 gene so there are greatly reduced LDL recptors due to increased degredation -See also makred increase in scavenger receptor-mediated traffic of LDL cholesterol in macrophages and vacular wall (explains appearance of xanthomas)

What can happen when there's a mutation in a noncoding sequence

-Mutation in promoter/enhancer sequences may interfere with binding of transcription factor and lead to reduction/absence of trascription. -Point muctations within introns may lead to defective splicing of intervening sequences so mRNA transcripts can't be normally processed (so mature mRNA doesn't form, translation doesn't take place, and gene product is not synthesized)

Differentiate different kinds of PCR

-Sanger- single PCR product mixed with DNA polymerase and nucleotides -Next-gen sequencing- uses primers for many different genomic regions. More sensitive than Sanger. -Single-base primer extension- use for identifying mutation at specific nucleotide position. Add primer one base upstream of target. Very sensitive -Restriction fragment length analysis- digest DNA with endonucleases (restriction enzymes) and cut at specific sequence and normal and mutant PCR products yield fragments of different sizes Amplicon length analysis- detects mutants that affect DNA length rtPCR- use flurophore indicators to detect sequences in real time. Use to monitor frequence of cancer cells bearing genetic lesions or infectious load of certain viruses

What are the three broad classifications of human genetic disorders

1) Disorders related to mutation in single genes with large effects- mutations highly penetrant, usually follow classic Mendelian pattern of inheretence and are called Mendelian disorders 2) Chromosomal disorders- alterations in autosomes and sex chromosomes. Uncommon but high penetrance 3) Complex multigenic disorders- most common diseases. Aka polymorphisms. No single gene is necessary or sufficient to produce disease (diabetes mellitus, hypertension, etc.) To these three well-known categories must be added a heterogeneous group of single-gene disorders with nonclassic patterns of inheritance. This group includes disorders resulting from triplet-repeat mutations, those arising from mutations in mitochondrial DNA (mtDNA), and those in which the transmission is influenced by genomic imprinting or gonadal mosaicism

Why is there maternal inheritance of mitochondria

A feature unique to mtDNA is maternal inheritance. This peculiarity exists because ova contain numerous mitochondria within their abundant cytoplasm, whereas spermatozoa contain few, if any. Hence the mtDNA complement of the zygote is derived entirely from the ovum. Thus, mothers transmit mtDNA to all their offspring, male and female; daughters, but not sons, transmit the DNA further to their progeny Because mtDNA encodes enzymes involved in oxidative phosphorylation, mutations affecting these genes exert their deleterious effects primarily on the organs most dependent on oxidative phosphorylation such as the central nervous system, skeletal muscle, cardiac muscle, liver, and kidneys. Each mitochondrion contains thousands of copies of mtDNAs, and typically deleterious mutations of mtDNA affect some, but not all, of these copies. Thus tissues and, indeed, individuals may harbor both wild-type and mutant mtDNA, a situation called heteroplasmy. A minimum number of mutant mtDNAs must be present in a cell or tissue before oxidative dysfunction gives rise to disease. This is called the "threshold effect." During cell division, mitochondria and their contained DNA are randomly distributed to the daughter cells. Thus when a cell containing normal and mutant mtDNA divides, the proportion of the normal and mutant mtDNA in daughter cells is extremely variable. Therefore the expression of disorders resulting from mutations in mtDNA is quite variable.

What are some examples of defective transport systems and receptors

A genetic defect in a receptor-mediated transport system is exemplified by familial hypercholesterolemia (FH), in which reduced synthesis or function of LDL receptors leads to defective transport of LDL into the cells and secondarily to excessive cholesterol synthesis by complex intermediary mechanisms. In cystic fibrosis the transport system for chloride and bicarbonate ions in exocrine glands, sweat ducts, lungs, and pancreas is defective. By complex mechanisms not fully understood, impaired anion transport leads to serious injury to the lungs and pancreas

Define terms: ring chromosome, inversion, paracentric, pericentri, isochromosome

A ring chromosome is a special form of deletion. It is produced when a break occurs at both ends of a chromosome with fusion of the damaged ends. Ring chromosomes do not behave normally in meiosis or mitosis and usually result in serious consequences. Inversion refers to a rearrangement that involves two breaks within a single chromosome with reincorporation of the inverted, intervening segment. An inversion involving only one arm of the chromosome is known as paracentric. If the breaks are on opposite sides of the centromere, it is known as pericentric. Inversions are often fully compatible with normal development. Isochromosome formation results when one arm of a chromosome is lost and the remaining arm is duplicated, resulting in a chromosome consisting of two short arms only or of two long arms.

What is pleiotropism vs genetic heterogeneity

A single mutant gene may lead to many end effects, termed pleiotropism; conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity). Sickle cell anemia is an example of pleiotropism. In this hereditary disorder, not only does the point mutation in the gene give rise to HbS, which predisposes the red cells to hemolysis, but also the abnormal red cells tend to cause a logjam in small vessels, inducing, for example, splenic fibrosis, organ infarcts, and bone changes.

Important X-linked disorder facts

All sex-linked disorders are X-linked, and almost all are recessive. Several genes are located in the male-specific region of Y; all of these are related to spermatogenesis. Males with mutations affecting the Y-linked genes are usually infertile, and hence there is no Y-linked inheritance. Males are said to be hemizygous for X-linked mutant genes. An affected male does not transmit the disorder to his sons, but all daughters are carriers. A heterozygous female usually does not express the full phenotypic change because of the paired normal allele. Because of the random inactivation of one of the X chromosomes in the female, however, females have a variable proportion of cells in which the mutant X chromosome is active. Thus it is remotely possible for the normal allele to be inactivated in most cells, permitting full expression of heterozygous X-linked conditions in females. An illustrative condition is glucose-6-phosphate dehydrogenase (G6PD) deficiency. Transmitted on the X chromosome, this enzyme deficiency, which predisposes to red cell hemolysis in patients receiving certain types of drugs ( Chapter 14 ), is expressed principally in males. In females, a proportion of the red cells may be derived from precursors with inactivation of the normal allele. Such red cells are at the same risk for undergoing hemolysis as the red cells in hemizygous males. Thus, females are not only carriers of this trait but also are susceptible to drug-induced hemolytic reactions.

What is a trinucleotide-repeat mutation

Amplication of a sequence of three nucleotides. Almost all affected sequences share nucleotides guanine (G) and cytosine (C). Another distinguishing feature of trinucleotide-repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). Fragile X syndrome has CGG repeat in FMR1 (familial mental retardation 1)

How does trisomy or monosomy happen

Any exact multiple of the haploid number of chromosomes (23) is called euploid. If an error occurs in meiosis or mitosis and a cell acquires a chromosome complement that is not an exact multiple of 23, it is referred to as aneuploidy. The usual causes for aneuploidy are nondisjunction and anaphase lag. When nondisjunction occurs during gametogenesis, the gametes formed have either an extra chromosome (n + 1) or one less chromosome (n − 1). Fertilization of such gametes by normal gametes results in two types of zygotes—trisomic (2n + 1) or monosomic (2n − 1). In anaphase lag, one homologous chromosome in meiosis or one chromatid in mitosis lags behind and is left out of the cell nucleus. The result is one normal cell and one cell with monosomy.

Pathway of Glycogen Metabolism

Asterisks mark the enzyme deficiencies associated with glycogen storage diseases. Roman numerals indicate the type of glycogen storage disease associated with the given enzyme deficiency. Types V and VI result from deficiencies of muscle and liver phosphorylases, respectively.

What is mitophagy and why is it important

Autophagy is essential for turnover of mitochondria by a process termed mitophagy. This serves as a quality control system whereby dysfunctional mitochondria are degraded. If there's a lysosomal enzyme deficiency: accumulation of macromolecules in lysosome -> reduced rate of lysosomes processing organelles -> persistence of dysfunctional and leaky mitochondria with poor calcium-buffering capacity and altered membrane potentials in the lysosomes. Damaged mitochondria generate free radicals and release molecules that trigger the intrinsic pathway of apoptosis. Impaired autophagy gives rise to secondary accumulation of autophagic substrates including ubiquitinated and aggregate-prone polypeptides such as α-synuclein and Huntingtin protein.

Relevant facts about autosomal dominant disorders

Autosomal dominant disorders are manifested in the heterozygous state, so at least one parent of an index case is usually affected; With every autosomal dominant disorder, some proportion of patients do not have affected parents. Such patients owe their disorder to new mutations involving either the egg or the sperm from which they were derived

Important facts about autosomal recessive disorders

Autosomal recessive traits make up the largest category of Mendelian disorders. They occur when both alleles at a given gene locus are mutated. • Although new mutations associated with recessive disorders do occur, they are rarely detected clinically. Since the individual with a new mutation is an asymptomatic heterozygote, several generations may pass before the descendants of such a person mate with other heterozygotes and produce affected offspring. • Many of the mutated genes encode enzymes. In heterozygotes, equal amounts of normal and defective enzyme are synthesized. Usually the natural "margin of safety" ensures that cells with half the usual complement of the enzyme function normally.

Different class mutations for LDL receptors

Class I mutations are relatively uncommon and lead to a complete failure of synthesis of the LDL receptor protein (null allele). Class II mutations are fairly common; they encode LDL receptor proteins that accumulate in the endoplasmic reticulum because their folding defects make it impossible for them to be transported to the Golgi complex. Class III mutations affect the ApoB binding site of the receptor; the mutant LDL receptors reach the cell surface but fail to bind LDL or do so poorly. Class IV mutations encode LDL receptors that are synthesized and transported to the cell surface efficiently. They bind LDL normally, but they fail to localize in coated pits, and hence the bound LDL is not internalized. Class V mutations encode LDL receptors that are expressed on the cell surface, can bind LDL, and can be internalized; however, the pH-dependent dissociation of the receptor and the bound LDL fails to occur. Such receptors are trapped in the endosome, where they are degraded, and hence they fail to recycle to the cell surface. Class VI mutations result in the failure of initial targeting of the LDL receptor to the basolateral membrane. (So I stops it at synthesis, II stops it at transport, III stops it at binding, IV stops it at clustering, V stops it at recycling. These mutations disrupt the receptor's synthesis in the endoplasmic reticulum, transport to the Golgi complex, binding of apoprotein ligands, clustering in coated pits, and recycling in endosomes. Not shown is class VI mutation, in which initial targeting of the receptor to basolateral membrane fails to occur. Each class is heterogeneous at the DNA level.)

What is the difference between penetrance and expressivity

Clinical features can be modified by variations in penetrance and expressivity. Some individuals inherit the mutant gene but are phenotypically normal. This is referred to as incomplete penetrance. Penetrance is expressed in mathematical terms. Thus 50% penetrance indicates that 50% of those who carry the gene express the trait. In contrast to penetrance, if a trait is seen in all individuals carrying the mutant gene but is expressed differently among individuals, the phenomenon is called variable expressivity. (can be affected by other genes or environmental factors like dietary intake)

What alterations can be made to protein-coding genes other than mutations

Coding genes also can undergo structural variations, such as copy number changes— amplifications or deletions —or translocations that result in aberrant gain or loss of protein function. In many instances, pathogenic germline alterations involve a contiguous portion of a chromosome rather than a single gene, such as in the 22q microdeletion syndrome. Cancers often contain somatically acquired structural alterations, including amplifications, deletions, and translocations. The so-called Philadelphia chromosome—translocation t(9;22) between the BCR and ABL genes in chronic myeloid leukemia- is a classic example

How does normal cholesterol metabolism work

Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa and travel by way of the gut lymphatics to the blood. These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat. The chylomicron remnants, rich in cholesterol, are then delivered to the liver. Some of the cholesterol enters the metabolic pool (to be described), and some is excreted as free cholesterol or as bile acids into the biliary tract. The endogenous synthesis of cholesterol and LDL begins in the liver ( Fig. 5.6 ). The first step in this process is the secretion of very-low-density lipoprotein (VLDL) from the liver into the blood. VLDL particles are rich in triglycerides, but they contain lesser amounts of cholesteryl esters. In addition, they carry apolipoproteins ApoB, ApoC, and ApoE on their surface. In the capillaries of adipose tissue and muscle, the VLDL particle undergoes lipolysis and is converted to VLDL remnant, also called intermediate-density lipoprotein (IDL). Compared with VLDL, IDL particles have reduced content of triglycerides and an increase in cholesteryl esters. ApoC is lost, but ApoB and ApoE are retained. After release from the capillary endothelium, the IDL particles have one of two fates. Approximately 50% of newly formed IDL is rapidly taken up by the liver by receptor-mediated transport. The receptor responsible for the binding of IDL to the liver cell membrane recognizes both ApoB and ApoE. It is called ApoB/E, or more commonly the LDL receptor, because it is also involved in the hepatic clearance of LDL (described later). In the liver cells, IDL is recycled to generate VLDL. The IDL particles not taken up by the liver are subjected to further metabolic processing that removes most of the remaining triglycerides and ApoE, yielding ApoB carrying cholesterol-rich LDL particles.

Ehlers-Danlos Syndrome

EDSs comprise a clinically and genetically heterogeneous group of disorders that result from some mutations in genes that encode collagen, enzymes that modify collagen, and less commonly other proteins present in the extracellular matrix; tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of EDS (hyperextensible, hypermotile). Can see rupture of colon, large arteries, ocular fragility, diaphragmatic hernia. the best characterized is the kyphoscoliosis type , the most common autosomal recessive form of EDS. It results from mutations in the PLOD1 gene encoding lysyl hydroxylase, an enzyme necessary for hydroxylation of lysine residues during collagen synthesis. Affected patients have markedly reduced levels of this enzyme. Because hydroxylysine is essential for intermolecular and intramolecular cross-linking of collagen fibers, a deficiency of lysyl hydroxylase results in the synthesis of collagen that lacks normal structural stability. The vascular type of EDS results from abnormalities of type III collagen. This form is genetically heterogeneous because at least three distinct types of mutations affecting the COL3A1 gene encoding collagen type III can give rise to this variant. Some affect the rate of synthesis of pro-α1 (III) chains, others affect the secretion of type III procollagen, and still others lead to the synthesis of structurally abnormal type III collagen. In two forms of EDS—arthrochalasia type and dermatosparaxis type—the fundamental defect is in the conversion of type I procollagen to collagen. This step in collagen synthesis involves cleavage of noncollagen peptides at the N terminus and C terminus of the procollagen molecule. This is accomplished by N-terminal-specific and C-terminal-specific peptidases. The defect in the conversion of procollagen to collagen in the arthrochalasia type has been traced to mutations that affect one of the two type I collagen genes, COL1A1 and COL1A2 . As a result, structurally abnormal pro-α1 (I) or pro-α2 (I) chains that resist cleavage of N-terminal peptides are formed. Finally, in the classic type of EDS, molecular analysis suggests that genes other than those that encode collagen may also be involved. In close to 90% of cases, mutations in the genes for type V collagen ( COL5A1 and COL5A2 ) have been detected.

How do you treat lysosomal storage disease

Enzyme replacement therapy, substrate reduction theapy, molecular chaperone therapy (giving exogenous competitive inhibitor that can bind to mutant enzyme and act as foldindg template so enxyme is properly folded and degredation is prevented)

What do trinucleotide repeat mutations cause

Expansion of trinucleotide repeats is an important genetic cause of human disease, particularly neurodegenerative disorders.The causative mutations are associated with the expansion of a stretch of trinucleotides that usually share the nucleotides G and C. In all cases the DNA is unstable, and an expansion of the repeats above a certain threshold impairs gene function in various ways. See loss of function of affected gene, toxic gain of function by alteration of protein structure, or toxic gain of function mediated by RNA. Those affecting coding regions usually involve CAG repeats coding for polyglutamine tracts in the corresponding proteins (see progressive neurodegeneration from polyglutamine expansion toxic gain of function). The aggregates may suppress transcription of other genes, cause mitochondrial dysfunction, or trigger the unfolded-protein stress response and apoptosis. A morphologic hallmark of these diseases is the accumulation of aggregated mutant proteins in large intranuclear inclusions.

What is FISH

FISH uses DNA probes that recognize sequences specific to particular chromosomal regions. To perform FISH, large fragments of cloned genomic DNA spanning up to 200 kb are labeled with fluorescent dyes and applied to metaphase chromosome preparations or interphase nuclei that are pretreated so as to "melt" the genomic DNA. The probe hybridizes to its homologous genomic sequence and thus labels a specific chromosomal region that can be visualized under a fluorescent microscope Can detect numeric abnormalities of chromosomes (aneuploidy), subtle microdeletions, complex translocations, and gene amplification (like HER2 for breast cancer and NMYC for neuroblastomas)

What is FMRP

FMRP selectively binds mRNAs associated with polysomes and regulates their intracellular transport to dendrites. Unlike other cells, in neurons, protein synthesis occurs both in the perinuclear cytoplasm and in dendritic spines. Newly made FMRP translocates to the nucleus, where it assembles into a complex containing mRNA transcripts that encode presynaptic and postsynaptic proteins. The FRMP-mRNA complexes are then exported to the cytoplasm, from where they are trafficked to dendrites near neuronal synapses FRMP is a translation regulator. At synaptic junctions, FMRP suppresses protein synthesis from the bound mRNAs in response to signaling through group I metabotropic glutamate receptors (mGlu-R). Thus a reduction in FMRP in FXS results in increased translation of the bound mRNAs at synapses. This leads to an imbalance in the production of proteins at the synapses resulting in loss of synaptic plasticity—the ability of synapses to change and adapt in response to specific signals. Synaptic plasticity is essential for learning and memory.

What is fragile X syndrome

FXS is the most common genetic cause of intellectual disability in males and overall the second most common cause after Down syndrome. It results from a trinucleotide expansion mutation in the familial mental retardation 1 (FMR1) gene. Its name derives from an inducible cytogenetic abnormality in the X chromosome within which the FMR1 gene maps. The cytogenetic alteration was discovered as a discontinuity of staining or as a constriction in the long arm of the X chromosome when cells are cultured in a folate-deficient medium. Because it appears that the chromosome is "broken" at this locale, it was named as a fragile site. Males have marked intellectural disability and macro-orchidism. FXS affects males predominatly The molecular basis of intellectual disability and other somatic changes is related to loss of function of the fragile X mental retardation protein (FMRP), the product of FMR1 gene. As mentioned earlier, the normal FMR1 gene contains up to 55 CGG repeats in its 5′ untranslated region. When the trinucleotide repeats in the FMR1 gene exceed approximately 230, the DNA of the entire 5′ region of the gene becomes abnormally methylated. Methylation also extends upstream into the promoter region of the gene, resulting in transcriptional suppression of FMR1. The resulting absence of FMRP is believed to cause the phenotypic changes.

What is Tay-Sachs Disease

GM2 Gangliosidoses due to a hexosaminidase alpha-subunit deficiency. G M2 gangliosidoses are a group of three lysosomal storage diseases caused by deficiency of the enzyme β-hexosaminidase resulting in an inability to catabolize G M2 gangliosides. There is relentless motor and mental deterioration, resulting in motor incoordination and intellectual disability leading eventually to muscular flaccidity, blindness, and increasing dementia. Sometime during the early course of the disease, the characteristic, but not pathognomonic, cherry-red spot appears in the macula of the eye in almost all patients.

What is Gaucher Disease

Gaucher disease refers to a cluster of autosomal recessive disorders resulting from mutations in the gene encoding glucocerebrosidase. It is the most common lysosomal storage disorder. The affected gene encodes glucocerebrosidase, an enzyme that normally cleaves the glucose residue from ceramide. As a result of the enzyme defect, glucocerebrosides accumulate principally in phagocytes but in some subtypes also in the central nervous system. Glucocerebrosides are continually formed from the catabolism of glycolipids derived mainly from the cell membranes of senescent leukocytes and red cells. It is clear now that the pathologic changes in Gaucher disease are caused not just by the burden of storage material but also by activation of macrophages and the consequent secretion of cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF). Glucocerebrosides accumulate in massive amounts within phagocytic cells throughout the body in all forms of Gaucher disease. The distended phagocytic cells, known as Gaucher cells, are found in the spleen, liver, bone marrow, lymph nodes, tonsils, thymus, and Peyer patches. With the electron microscope the fibrillary cytoplasm can be resolved as elongated, distended lysosomes, containing the stored lipid in stacks of bilayers. In contrast to other lipid storage diseases, Gaucher cells rarely appear vacuolated, but instead have a fibrillary type of cytoplasm likened to crumpled tissue paper. PAS-positive. Mutation of the glucocerebrosidase gene is the most common known genetic risk factor for development of Parkinson disease. The diagnosis in homozygotes can be made by measurement of glucocerebrosidase activity in peripheral blood leukocytes or in extracts of cultured skin fibroblasts. The enzyme assay cannot identify heterozygotes because the levels of glucocerebrosidase are difficult to distinguish from those in normal cells. Replacement therapy with recombinant enxymes is the mainstay for treatment.

What are CpG islands

Gene expression frequently correlates negatively with the level of methylation of DNA, particularly of cytosine residues in CG dinucleotide-rich promoter regions known as CpG islands. As discussed earlier in the section on genomic imprinting, increased methylation of CpG islands is associated with decreased gene expression and is accompanied by concomitant alterations of histone methylation and acetylation. Diagnosis of an increasing number of diseases involves the analysis of promoter methylation—for example, FXS, in which hypermethylation results in FMR1 silencing. Methylation analysis is also essential in the diagnosis of Prader-Willi syndrome and Angelman syndrome. To detect DNA methylation can treat genomic DNA with sodium bisulfite, a chemical that converts unmethylated cytosine to uracil, which acts like thymine in downstream reactions. Methylated cytosines are protected from modification and remain unchanged. After treatment, it is then straightforward to discriminate the unmethylated (modified) DNA from the methylated (unmodified) DNA by DNA sequencing.

What determines gonadal vs ductal sex

Genetic sex is determined by the presence or absence of a Y chromosome. Gonadal sex is based on the histologic characteristics of the gonads. Ductal sex depends on the presence of derivatives of the müllerian or wolffian ducts. Phenotypic, or genital, sex is based on the appearance of the external genitalia. The term true hermaphrodite implies the presence of both ovarian and testicular tissue. In contrast, a pseudohermaphrodite represents a disagreement between the phenotypic and gonadal sex.

Glycogen Storage Diseases (glycogenoses)

Glycogen synthesis begins with the conversion of glucose to glucose-6-phosphate by the action of a hexokinase (glucokinase). A phosphoglucomutase then transforms the glucose-6-phosphate to glucose-1-phosphate, which, in turn, is converted to uridine diphosphoglucose. A highly branched, large polymer is then built, containing many glucose molecules linked together by α-1,4-glucoside bonds. The glycogen chain and branches continue to be elongated by the addition of glucose molecules mediated by glycogen synthetases. During degradation, distinct phosphorylases in the liver and muscle split glucose-1-phosphate from the glycogen until about four glucose residues remain on each branch, leaving a branched oligosaccharide called limit dextrin. This can be further degraded only by the debranching enzyme. In addition to these major pathways, glycogen is also degraded in the lysosomes by acid alpha-glucosidase. If the lysosomes are deficient in this enzyme, the glycogen contained within them is not accessible to degradation by cytoplasmic enzymes such as phosphorylases.

What are the 3 major subgroups of gycogenoses

Hepatic forms- ex.- deficiency of glucose-6-phosphate (aka von Gierke disease, type 1 glycogenosis). Other examples include deficiencies of liver phosphorylase and debranching enzyme, both involved in the breakdown of glycogen. In all these disorders, glycogen is stored in many organs, but hepatic enlargement and hypoglycemia dominate the clinical picture. Myopathic forms- skeletal muscles use glycogen and predominant source of energy. ATP generated by glycolysis and lactate forms. If the enzymes that fuel the glycolytic pathway are deficient, glycogen storage occurs in the muscles and is associated with muscular weakness due to impaired energy production. Examples in this category include deficiencies of muscle phosphorylase (McArdle disease, or type V glycogenosis), muscle phosphofructokinase (type VII glycogen storage disease). See muscle cramps after excercise and no rise in lactate from exercise. See myocardial fibers full of glycogen -Glycogen storage diseases associated with (1) deficiency of acid alpha-glucosidase (acid maltase) and (2) lack of branching enzyme do not fit into the hepatic or myopathic categories. They are associated with glycogen storage in many organs and death early in life. Acid alpha-glucosidase is a lysosomal enzyme, and hence its deficiency leads to lysosomal storage of glycogen (type II glycogenosis, or Pompe disease ) in all organs, but cardiomegaly is the most prominent feature

Describe karyotyping

Human somatic cells contain 46 chromosomes—22 homologous pairs of autosomes and two sex chromosomes, XX in the female and XY in the male. The study of chromosomes— karyotyping —is the basic tool of the cytogeneticist. The usual procedure to examine chromosomes is to arrest dividing cells in metaphase with mitotic spindle inhibitors (e.g., N -diacetyl- N -methylcolchicine [colcemid]) and then to stain the chromosomes. In a metaphase spread, the individual chromosomes take the form of two chromatids connected at the centromere. A karyotype is obtained by arranging each pair of autosomes according to length, followed by sex chromosomes. A variety of staining methods have been developed that allow identification of individual chromosomes on the basis of distinctive and reliable patterns of alternating light and dark bands. The one most commonly used involves a Giemsa stain and is hence called G banding.

What is the Lyon hypothesis

In 1961, Mary Lyon outlined the idea of X-inactivation, now commonly known as the Lyon hypothesis. It states that (1) only one of the X chromosomes is genetically active, (2) the other X chromosome of either maternal or paternal origin undergoes heteropyknosis and is rendered inactive, (3) inactivation of either the maternal or the paternal X chromosome occurs at random among all the cells of the blastocyst on or about day 5.5 of embryonic life, and (4) inactivation of the same X chromosome persists in all the cells derived from each precursor cell. The molecular basis of X inactivation involves a unique gene called XIST, whose product is a lncRNA that is retained in the nucleus, where it "coats" the X chromosome that it is transcribed from and initiates a gene-silencing process by chromatin modification and DNA methylation. The XIST allele is switched off in the active X chromosome. Although it was initially thought that all the genes on the inactive X chromosome are "switched off," it is now established that many genes escape X inactivation. Molecular studies suggest that 30% of genes on Xp and a smaller number (3%) on Xq escape X inactivation. Furthermore, although one X chromosome is inactivated in all cells during embryogenesis, it is selectively reactivated in oogonia before the first meiotic division. Thus, it seems that both X chromosomes are required for normal growth as well as oogenesis. he tips of short and long arms of X and Y chromosomes have regions of homology that recombine during meiosis and are therefore inherited as autosomal loci. For this reason they are called pseudoautosomal regions. These genes also escape X inactivation. These mechanisms ensure that males and females have equivalent doses of genes that map on X and Y chromosomes.

Looking at mRNA for cancer

In some instances, cancer cells bearing particular chromosomal translocations are detected with greater sensitivity by analyzing mRNA (e.g., the BCR-ABL fusion transcript in CML). The principal reason for this is that most translocations occur in scattered locations within particular introns, which can be very large, complicating detection by PCR amplification of DNA. Since introns are removed by splicing during the formation of mRNA, PCR analysis is possible if RNA is first converted to complementary DNA (cDNA) by reverse transcriptase. Real-time PCR performed on cDNA is the method of choice for monitoring residual disease in patients with CML and certain other hematologic malignancies

What is primary accumulation

Inherited deficiency of functional lysosomal enzyme -> incomplete catabolism of substrate -> accumulation of partially degraded incoluble metabolite within lysosomes (called primary accumulation). Lysosomes become stuffed and large and numerous enough to interfere with normal cell functions

Key Concepts for lysosomal storage diseases

Inherited mutations leading to defective lysosomal enzyme functions gives rise to accumulation and storage of complex substrates in the lysosomes and defects in autophagy resulting in cellular injury. • Tay-Sachs disease is caused by an inability to metabolize G M2 gangliosides due to lack of the α-subunit of lysosomal hexosaminidase. G M2 gangliosides accumulate in the central nervous system and cause severe intellectual disability, blindness, motor weakness, and death by 2 to 3 years of age. • Niemann-Pick disease types A and B are caused by a deficiency of sphingomyelinase. In the more severe type A variant, accumulation of sphingomyelin in the nervous system results in neuronal damage. Lipid also is stored in phagocytes within the liver, spleen, bone marrow, and lymph nodes, causing their enlargement. In type B, neuronal damage is not present. • Niemann-Pick disease type C is caused by a defect in cholesterol transport and resultant accumulation of cholesterol and gangliosides in the nervous system. Affected children most commonly exhibit ataxia, dysarthria, and psychomotor regression. • Gaucher disease results from lack of the lysosomal enzyme glucocerebrosidase and accumulation of glucocerebroside in mononuclear phagocytic cells. In the most common, type I variant, affected phagocytes become enlarged (Gaucher cells) and accumulate in liver, spleen, and bone marrow, causing hepatosplenomegaly and bone erosion. Types II and III are characterized by variable neuronal involvement. Gaucher disease has a strong association with Parkinson disease. • MPSs result in accumulation of mucopolysaccharides in many tissues including liver, spleen, heart, blood vessels, brain, cornea, and joints. Affected patients in all forms have coarse facial features. Manifestations of Hurler syndrome include corneal clouding, coronary arterial and valvular deposits, and death in childhood. Hunter syndrome is associated with a milder clinical course.

Commonly used cytogenic terminology for karyotypes

Karyotypes are usually described using a shorthand system of notations in the following order: total number of chromosomes is given first, followed by the sex chromosome complement, and finally the description of abnormalities in ascending numerical order. For example, a male with trisomy 21 is designated 47,XY,+21 . Notations denoting structural alterations of chromosomes and their corresponding abnormalities are described later. The short arm of a chromosome is designated p (for petit), and the long arm is referred to as q (the next letter of the alphabet). In a banded karyotype, each arm of the chromosome is divided into two or more regions bordered by prominent bands. The regions are numbered (e.g., 1, 2, 3) from the centromere outward. Each region is further subdivided into bands and sub-bands, and these are ordered numerically as well (see Fig. 5.17 ). Thus the notation Xp21.2 refers to a chromosomal segment located on the short arm of the X chromosome, in region 2, band 1, and sub-band 2.

Klinefleter Syndrome

Klinefelter syndrome is best defined as male hypogonadism that occurs when there are two or more X chromosomes and one or more Y chromosomes. Klinefelter syndrome can be attributed to two major factors: (1) aneuploidy and the impact of increased gene dosage by the supernumerary X and (2) the presence of hypogonadism. here is increased incidence of type 2 diabetes and the metabolic syndrome that gives rise to insulin resistance.. Patients with Klinefelter syndrome have a 20- to 30-fold higher risk of developing extragonadal germ cell tumors, mostly mediastinal teratomas. Klinefelter syndrome is an important genetic cause of reduced spermatogenesis and male infertility. (XXY). See high FSH and low testosterone. They have extra copy of Short-stature HomeobOX (SHOX) gene/ See CAG long repeats

Mucopolysaccharidoses

MPSs are a group of closely related syndromes that result from genetically determined deficiencies of enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans). Chemically, mucopolysaccharides are long-chain complex carbohydrates that are linked with proteins to form proteoglycans. They are abundant in extracellular matrix, joint fluid, and connective tissue. Enzymes cleave terminal sugars from the polysaccharide chains disposed along a polypeptide or core protein. In the absence of enzymes, these chains accumulate within lysosomes. The accumulated mucopolysaccharides are generally found in mononuclear phagocytic cells, endothelial cells, intimal smooth muscle cells, and fibroblasts throughout the body. Common sites of involvement are thus the spleen, liver, bone marrow, lymph nodes, blood vessels, and heart. Microscopically, affected cells are distended and have apparent clearing of the cytoplasm to create so-called balloon cells. Under the electron microscope, the clear cytoplasm can be resolved as numerous minute vacuoles. These are swollen lysosomes containing a finely granular periodic acid-Schiff-positive material that can be identified biochemically as mucopolysaccharide.

Where are the genes that are testis-specific and involved in spermatogenesis

MSY region, harboring 75 protein coding genes. All of these are believed to be testis-specific and are involved in spermatogenesis. In keeping with this, all Y chromosome deletions are associated with azoospermia

Main points for Marfan Syndrome and Ehlers-Danlos Syndromes

Marfan Syndrome • Marfan syndrome is caused by a mutation in the FBN1 gene encoding fibrillin, which is required for structural integrity of connective tissues and regulation of TGF-β signaling. • The major tissues affected are the skeleton, eyes, and cardiovascular system. • Clinical features may include tall stature, long fingers, bilateral subluxation of lens, mitral valve prolapse, aortic aneurysm, and aortic dissection. Ehlers-Danlos Syndromes • There are several variants of EDS, all characterized by defects in collagen synthesis or assembly. Each of the variants is caused by a distinct mutation involving one of several collagen genes or genes that encode other ECM proteins like tenascin-X. • Clinical features may include fragile, hyperextensible skin vulnerable to trauma; hypermobile joints; and ruptures involving the colon, cornea, or large arteries. Wound healing is poor.

Relevant Marfan Syndrome facts

Marfan syndrome is a disorder of connective tissues, manifested principally by changes in the skeleton, eyes, and cardiovascular system. Most are familial with autosomal dominant inheritance. Inherited defect in fibrillin-1 (extracellular glycoprotein). There are two fundamental mechanisms by which loss of fibrillin leads to the clinical manifestations of Marfan syndrome: loss of structural support in microfibril-rich connective tissue and excessive activation of transforming growth factor (TGF)-β signaling. Fibrillin fibrils provide scaffold on which tropoelastin is deposited to form elastic fibers. Fibrillin occurs in two homologous forms, fibrillin-1 and fibrillin-2, encoded by two separate genes, FBN1 and FBN2, mapped on chromosomes 15q21.1 and 5q23.31, respectively. Mutations of FBN1 underlie Marfan syndrome; mutations of the related FBN2 gene are less common (congenital contractural arachnodactyly) ibrillin-1 controls the bioavailability of TGF-β. Reduced or altered forms of fibrillin-1 give rise to abnormal and excessive activation of TGF-β, since normal microfibrils sequester TGF-β. Excessive TGF-β signaling, in turn, leads to inflammation, has deleterious effects on vascular smooth muscle development, and increases the activity of metalloproteases, causing loss of extracellular matrix. See life-threatening cardiovascular lesions like aortic dissetion, floppy valves, and mitral regurg from lenghtened chordae tendineae. The variable expression of the Marfan defect is best explained on the basis of the many different mutations that affect the fibrillin locus, which number around 1000. This genetic heterogeneity also poses formidable challenges in the diagnosis of Marfan syndrome.

What is Niemann-Pick Disease Type C

Mutation in NPC1 (membrane bound) and/or NPC2 (soluble). Primary defect in nonenzymatic lipid transport. Inhibits transport of free cholesterol from the lysosomes to the cytoplasm. Clincally heterogenous disorder.

Why is next gen sequencing better than Sanger sequencing

NGS, by contrast, is well suited to analysis of heterogeneous DNA samples due to the application of three common basic principles ( Fig. 5.33 ). • Spatial separation. At the beginning of the procedure, individual DNA molecules are physically isolated from each other in space. The specifics of this process are platform-dependent. • Local amplification. After separation, the individual DNA molecules are amplified in place using a limited number of PCR cycles. Amplification is necessary so that sufficient signal can be generated to ensure detection and accuracy. • Parallel sequencing. The amplified DNA molecules are then simultaneously sequenced by the addition of polymerases and other reagents, with each spatially separated and amplified original molecule yielding a "read" corresponding to its sequence. Sequence reads from NGS instruments are generally short, less than 500 bp.

What are niemann-pick disease types A and B

Niemann-Pick disease types A and B are two related disorders that are characterized by lysosomal accumulation of sphingomyelin due to an inherited deficiency of sphingomyelinase. Type A is a severe infantile form with extensive neurologic involvement, marked visceral accumulations of sphingomyelin, and progressive wasting and early death within the first 3 years of life. In contrast, patients with type B disease have organomegaly but generally no central nervous system involvement. Patients usually survive into adulthood. Although this disease is typically inherited as an autosomal recessive, heterozygotes who inherit the mutant allele from the mother can develop Niemann-Pick disease. See hepatosplenomegaly

What is mosaicism

Occasionally, mitotic errors in early development give rise to two or more populations of cells with different chromosomal complement in the same individual, a condition referred to as mosaicism . Mosaicism can result from mitotic errors during the cleavage of the fertilized ovum or in somatic cells. Mosaicism affecting the sex chromosomes is relatively common. In the division of the fertilized ovum, an error may lead to one of the daughter cells receiving three sex chromosomes, whereas the other receives only one, yielding, for example, a 45,X/47,XXX mosaic. All descendant cells derived from each of these precursors thus have either a 47,XXX complement or a 45,X complement. Such a patient is a mosaic variant of Turner syndrome, with the extent of phenotypic expression dependent on the number and distribution of the 45,X cells. Autosomal mosaicism seems to be much less common than that involving the sex chromosomes. An error in an early mitotic division affecting the autosomes usually leads to a nonviable mosaic due to autosomal monosomy.

What is a missense mutation and what is an example thereof

Point mutation that alters triplet code and replacement of one amino acid, thereby changing sequence of encoded protein. If the substituted AA is similar to original it's called a conservative missense mutation. A nonconservative missense mutation causes replacement of normal AA with biochemically differnt one. Example is sickle mutation affecting beta-globin chain of hemoglobin. A point mutation can also cause stop codon and become a nonsense mutation. Can make peptide short and rapidly degraded

Prader-Willi vs Angelman syndrome

Prader-Willi syndrome is characterized by intellectual disability, short stature, hypotonia, profound hyperphagia, obesity, small hands and feet, and hypogonadism.In contrast to Prader-Willi syndrome, patients with the phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. Patients with Angelman syndrome also have intellectual disability, but in addition they present with microcephaly, ataxic gait, seizures, and inappropriate laughter. UBE3A gene absence in Angelmann. SNORP family of noncoding molecules in Prader-Willi Molecular diagnosis of these syndromes is based on assessment of methylation status of marker genes and FISH.

What is a robertsonian translocation

Robertsonian translocation (or centric fusion), a translocation between two acrocentric chromosomes. Typically the breaks occur close to the centromeres of each chromosome. Transfer of the segments then leads to one very large chromosome and one extremely small one. Usually the small product is lost (see Fig. 5.18 ); however, because it carries only highly redundant genes (e.g., ribosomal RNA genes), this loss is compatible with a normal phenotype. Robertsonian translocation between two chromosomes is encountered in 1 in 1000 apparently normal individuals. The significance of this form of translocation also lies in the production of abnormal progeny, as discussed later with Down syndrome.

Describe sickle cell trait vs anemia

Sickle cell anemia is caused by substitution of normal hemoglobin (HbA) by hemoglobin S (HbS). When an individual is homozygous for the mutant gene, all the hemoglobin is of the abnormal, HbS, type, and even with normal saturation of oxygen the disorder is fully expressed (i.e., sickling deformity of all red cells and hemolytic anemia). In the heterozygote, only a proportion of the hemoglobin is HbS (the remainder being HbA), and therefore red cell sickling occurs only under unusual circumstances, such as exposure to lowered oxygen tension. This is referred to as the sickle cell trait to differentiate it from full-blown sickle cell anemia.

What is imprinting

Studies have now provided definite evidence that, at least with respect to some genes, important functional differences exist between the paternal allele and the maternal allele. These differences result from an epigenetic process called imprinting. In most cases, imprinting selectively inactivates either the maternal or the paternal allele. Thus, maternal imprinting refers to transcriptional silencing of the maternal allele, whereas paternal imprinting implies that the paternal allele is inactivated. Imprinting occurs in the ovum or the sperm, before fertilization, and then is stably transmitted to all somatic cells through mitosis. Imprinting is associated with differential patterns of DNA methylation at CG nucleotides. Although imprinted genes may occur in isolation, more commonly they are found in groups that are regulated by common cis -acting elements called imprinting control regions.

What is gonadal mosaicism

Studies indicate that gonadal mosaicism may be responsible for such unusual pedigrees. Such mosaicism results from a mutation that occurs postzygotically during early (embryonic) development. If the mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the individual are completely normal. A phenotypically normal parent who has gonadal mosaicism can transmit the disease-causing mutation to the offspring through their mutated gametes. Because the progenitor cells of the gametes carry the mutation, there is a possibility that more than one child of such a parent would be affected. Obviously the likelihood of such an occurrence depends on the proportion of germ cells carrying the mutation.

Classic example of genetically determined adverse drug reactions

The classic example of drug-induced injury in the genetically susceptible individual is associated with a deficiency of the enzyme G6PD. Under normal conditions, G6PD deficiency does not result in disease, but on administration, for example, of the antimalarial drug primaquine, a severe hemolytic anemia results

What are the subcategories of lysosomal storage diease

The ever-expanding number of lysosomal storage diseases can be divided into rational categories based on the biochemical nature of the accumulated metabolite, thus creating such subgroups as glycogenoses, sphingolipidoses (lipidoses), mucopolysaccharidoses (MPSs), and mucolipidoses (see Table 5.6 ).

Down's syndrome

Trisomy 21 in 95% of individuals (chromosome count 47). The most common cause of trisomy and therefore of Down syndrome is meiotic nondisjunction. In about 4% of cases of Down syndrome the extra chromosomal material derives from the presence of a robertsonian translocation of the long arm of chromosome 21 to another acrocentric chromosome (e.g., 22 or 14). Approximately 1% of patients with Down syndrome are mosaics, having a mixture of cells with 46 or 47 chromosomes. See abnormal immune responses (most severe affecting T-cell functions); trisomy 21 has high risk of leukemia development, see mitochondrial dysfunction

Turner Syndrome fun facts

Turner syndrome results from complete or partial monosomy of the X chromosome and is characterized by hypogonadism in phenotypic females. It is the most common sex chromosome abnormality in females. Because 99% of conceptuses with an apparent 45,X karyotype are nonviable, many authorities believe that there are no truly nonmosaic Turner syndrome patients. These patients are at a higher risk for development of a gonadal tumor (gonadoblastoma). See amenorrhea. From abnormality in paternal gametogenesis.Haploinsufficiency of SHOX in Turner syndrome is believed to give rise to short stature. Klinefelter has excess SHOX and that's why they're tall

What is whole exome sequencing

WES is a more expansive type of targeted sequencing, in which hundreds of thousands of custom probes are used to enrich for the roughly 1.5% of the genome that consists of protein-encoding exons prior to NGS. It is not routinely used in the evaluation of suspected germline disorders, but has led to some wonderful success stories, allowing physicians to deliver answers and even therapies for children with orphan diseases who had suffered through prolonged and unsuccessful diagnostic odysseys. WES is also used in oncology to perform a very broad analysis, mostly in the research setting.

How are lysosomal enzymes made

lysosomal enzymes (or acid hydrolases, as they are sometimes called) are synthesized in the endoplasmic reticulum and transported to the Golgi apparatus. Within the Golgi complex they undergo a variety of posttranslational modifications including the attachment of terminal mannose-6-phosphate groups to some of the oligosaccharide side chains. The phosphorylated mannose residues serve as an "address label" that is recognized by specific receptors found on the inner surface of the Golgi membrane. Lysosomal enzymes bind these receptors and are thereby segregated from the numerous other secretory proteins within the Golgi. Subsequently, small transport vesicles containing the receptor-bound enzymes are pinched off from the Golgi and proceed to fuse with the lysosomes. Thus the enzymes are targeted to their intracellular abode, and the vesicles are shuttled back to the Golgi. Genetically determined errors in this remarkable sorting mechanism may give rise to one form of lysosomal storage disease. Large molecules that lysosomes break down come from metabolic turnover of organelles (autophagy) or are acquired from outside by phagocytosis (heterophagy)

What are the 4 categories of mechanisms for single-gene disorders

the mechanisms involved in single-gene disorders can be classified into four categories: (1) enzyme defects and their consequences; (2) defects in membrane receptors and transport systems; (3) alterations in the structure, function, or quantity of nonenzyme proteins; and (4) mutations resulting in unusual reactions to drugs.

Name common patterns of autosomal dominant diseases arising from deleterious mutations

understanding the reasons why particular loss-of-function mutations give rise to dominant versus recessive disease patterns requires an understanding of the biology. Many autosomal dominant diseases arising from deleterious mutations fall into one of a few familiar patterns: 1. Diseases involved in regulation of complex metabolic pathways that are subject to feedback inhibition. 2. Key structural proteins, such as collagen and cytoskeletal elements of the red cell membrane (e.g., spectrin). In some cases, especially when the gene encodes one subunit of a multimeric protein, the product of the mutant allele can interfere with the assembly of a functionally normal multimer (like for collagen). In this instance the mutant allele is called dominant negative because it impairs the function of a normal allele.

What four separate processes are affected by released intracellular cholesterol

• Cholesterol suppresses cholesterol synthesis within the cell by inhibiting the activity of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which is the rate-limiting enzyme in the synthetic pathway. • Cholesterol activates the enzyme acyl-coenzyme A:cholesterol acyltransferase, favoring esterification and storage of excess cholesterol. • Cholesterol suppresses the synthesis of LDL receptors, thus protecting the cells from excessive accumulation of cholesterol. • Cholesterol upregulates the expression of PCSK9, which reduces recycling of LDL receptors and causes degradation of endocytosed LDL receptors. This provides an additional mechanism of protecting the cells from excessive accumulation of cholesterol.

Key concepts for cytogenic disorders involving autosomes

• Down syndrome is associated with an extra copy of genes on chromosome 21, most commonly due to trisomy 21 and less frequently from translocation of extra chromosomal material from chromosome 21 to other chromosomes or from mosaicism. • Patients with Down syndrome have severe intellectual disability, flat facial profile, epicanthic folds, cardiac malformations, higher risk of leukemia and infections, and premature development of Alzheimer disease. • Deletion of genes at chromosomal locus 22q11.2 gives rise to malformations affecting the face, heart, thymus, and parathyroids. The resulting disorders are recognized as DiGeorge syndrome (thymic hypoplasia with diminished T-cell immunity and parathyroid hypoplasia with hypocalcemia) and velocardiofacial syndrome (congenital heart disease involving outflow tracts, facial dysmorphism, and developmental delay).

Key concepts for genomic imprinting

• Imprinting involves transcriptional silencing of the paternal or maternal copies of certain genes during gametogenesis. For such genes, only one functional copy exists in the individual. Loss of the functional (not imprinted) allele by deletion gives rise to diseases. • In Prader-Willi syndrome there is deletion of band q12 on the long arm of paternal chromosome 15. Genes in this region of maternal chromosome 15 are imprinted, so there is complete loss of their functions. Patients have intellectual disability, short stature, hypotonia, hyperphagia, small hands and feet, and hypogonadism. • In Angelman syndrome there is deletion of the same region from the maternal chromosome, and genes on the corresponding region of paternal chromosome 15 are imprinted. These patients have intellectual disability, ataxia, seizures, and inappropriate laughter.

Key concepts for cytogenetic disorders involving sex chromosomes

• In females, one X chromosome, maternal or paternal, is randomly inactivated during development (Lyon hypothesis). • In Klinefelter syndrome, there are two or more X chromosomes with one Y chromosome as a result of nondisjunction of sex chromosomes. Patients have testicular atrophy, sterility, reduced body hair, gynecomastia, and eunuchoid body habitus. It is the most common cause of male sterility. • In Turner syndrome, there is partial or complete monosomy of genes on the short arm of the X chromosome, most commonly due to absence of one X chromosome (45,X), mosaicism, or deletions involving the short arm of the X chromosome. Short stature, webbing of the neck, cubitus valgus, cardiovascular malformations, amenorrhea, lack of secondary sex characteristics, and fibrotic ovaries are typical clinical features.