CN1: Genetics II (Mendelian Disorder and Chromosomal Disorder) Flashcards

Question

Four major clinical types of osteogenesis imperfecta have been defined

Answer 1

○ Type I, the autosomal dominant form ○ Type 2, the perinatal lethal form ○ Type 3 with fractures present at birth ○ Type 4 with propensity to fractures but with normal sclera. ## Footnote Osteogenesis imperfecta shows clinical heterogeneity, reflecting even greater biochemical heterogeneity that results from heterogeneity in the types of alteration present in the genes for the pro 1 (I) and pro 2 (I) procollagen chains of the collagen molecule that is the major structural protein of bone and other fibrous tissues.

Answer 2

● The term anticipation is used for the apparent worsening and earlier onset of a disease in successive generations. ● The pattern is often observed in myotonic dystrophy families, but it can be explained by bias in ascertainment of the families rather than by any biological mechanism. ● Families with early-onset, more severe cases are more likely to be ascertained, but patients with mild, late-onset disease are more likely to have offspring. ● Examination of a family at a single point in time thus favors finding children with severe disease whose affected parents and grandparents have milder form.

Answer 3

● Many genetic diseases are not present at birth but manifest later in life, some at a characteristic age and others at variable ages throughout the life span. ● Genetic disorders are, of course, not necessarily congenital nor are congenital disorders necessarily genetic. ● To classify a disorder as genetic means that genes are plainly implicated in its etiology; to say that a disorder is congenital means only it is present at birth. ● Some genetic disorders have prenatal onset. ● Dysmorphic conditions of many kinds originate during embryological development, and are recognized postnatally as "birth defects". ● Some genetic diseases like phenylketonuria and galactosemia are expressed only postnatally or after birth. ● However, some genetic diseases may manifest at variable ages later, such as: ○ Tay-Sachs disease at 4 to 6 months ○ Neurofibromatosis at puberty ○ Huntington's chorea at a variable age of 15 to 65 years

Answer 4

● A trait which appears in only 1 sex is said to be sex-limited. ○ An example to illustrate this is testicular feminization. ○ In this condition, a male who has inherited the trait may be reared either as male or f emale since external genitalia are not obviously male at birth. ○ In either case the patient undergoes feminization at puberty. ● Sex-limited traits have to be differentiated from sex-influenced traits. ○ Traits are said to be sex-influenced when they are expressed in both sexes, but with widely varying frequencies. ○ Expressions of autosomal phenotypes with unequal expression in males and females are baldness, congenital adrenal hyperplasia, Legg-Calvé-Perthes disease, hemochromatosis, etc.

Answer 5

● Environment plays an important role in the manifestation of some hereditary diseases in which only a "tendency” is genetically transmitted. ● Here the person manifests the disease only if he encounters certain environmental conditions. ● For example, a person might have glucose-6-phosphate dehydrogenase deficiency but symptoms will not occur unless he takes in agents like fava beans, primaquine, acetanilamide, sulfonamides. ● In allergy, the tendency is inherited but it needs exposure to specific antigens for allergic manifestations like asthma and hives to occur.

Answer 6

● This is exemplified by hemolytic disease of the newborn, such as erythroblastosis fetalis. ● In this condition, both parents and infant have normal genes. ● The interaction of these normal genes, however, may lead to pathologic conditions which may be fatal to the baby.

Answer 7

Genetic disorder

Answer 8

Hereditary disorders

Answer 9

Mutations that affect the germ cell

Answer 10

Mutations that arise in somatic cells

Answer 11

Genome mutations

Answer 12

Chromosome mutations

Answer 13

Chromosomal mutations

Answer 14

Submicroscopic

Answer 15

Gene mutations

Answer 16

A single nucleotide base may be substituted by a different base --> POINT MUTATION

Answer 17

A single nucleotide base may be substituted by a different base --> POINT MUTATION

Answer 18

Frameshift mutations

Answer 19

○ **Genome mutation** - loss or gain of whole chromosome; monosomy, trisomy ○ **Chromosome mutation** - rearrangement of genetic material structural changes in the chromosome; changes in chromosome number or structure; most are incompatible with life ○ **Gene mutation** - partial or complete deletion of a gene or more often affect a single base; ■ Point mutation - missense, nonsense, silent ■ Frameshift mutation

Answer 20

● A point mutation (single base substitution) may alter the code in a triplet of bases and lead to the replacement of one amino acid by another in the gene product. ○ Because these mutations alter the meaning of the genetic code, they are often termed missense mutations. ● An excellent example of this type is the sickle mutation affecting the B-globin chain of hemoglobin. ○ Here the nucleotide triplet CTC (or GAG in messenger RNA [mRNA]), which codes for glutamic acid, is changed to CAC (or GUG in mRNA), which codes for valine (see Fig. 5-2). ● This single amino acid substitution alters the physicochemical properties of hemoglobin, giving rise to sickle cell anemia. ○ Besides producing an amino acid substitution, a point mutation may change an amino acid codon to a chain terminator, or stop codon (nonsense mutation). ○ Taking again the example of β-globin, a point mutation affecting the codon for glutamine (CAG) creates a stop codon (UAG) if U is substituted for C (Fig. 5.1). ○ This change leads to premature termination of β-globin gene translation, and the short peptide that is produced is rapidly degraded. ○ The resulting deficiency of β-globin chains can give rise to a severe form of anemia called β-thalassemia. ● Point mutations or deletions involving these regulatory sequences may interfere with binding of transcription factors and thus lead to a marked reduction in or total lack of transcription. ○ Such is the case in certain forms of hereditary hemolytic anemias. ○ In addition, point mutations within introns lead to defective splicing of intervening sequences. ○ This, in turn, interferes with normal processing of the initial mRNA transcripts and results in a failure to form mature mRNA transcripts. ○ Therefore, translation cannot take place, and the gene product is not synthesized.

Answer 21

● Small deletions or insertions involving the coding sequence lead to alterations in the reading frame of the DNA strand; hence they are referred to as frameshift mutations (see Figs. 5-3 and 5-4). ● If the number of base pairs involved is three or a multiple of three, frameshift does not occur (Fig. 5-6); instead an abnormal protein missing one or more amino acids is synthesized.

Answer 22

● Trinucleotide repeat mutations belong to a special category because these mutations are characterized by amplification of a sequence of three nucleotides. ● Although the specific nucleotide sequence that undergoes amplification differs in various disorders, almost all affected sequences share the nucleotides guanine (G) and cytosine (C). ● For example, in fragile X syndrome, prototypical of this category of disorders, there are 250 to 4000 tandem repeats of the sequence CGG within a gene called FMR-I. ● In normal populations, the number of repeats is small, averaging 29. ● It is believed that expansions of the trinucleotide sequences prevent normal expression of the FMR-I gene, thus giving rise to mental retardation. ● Another distinguishing feature of trinucleotide repeat mutations is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). ● These features, discussed in greater detail later, influence the pattern of inheritance and the phenotypic manifestations of the diseases caused by this class of mutations.

Answer 23

● To summarize, mutations can interfere with protein synthesis at various levels. ● Transcription may be suppressed with gene deletions and point mutations involving promoter sequences. ● Abnormal mRNA processing may result from mutations affecting introns or splice junctions, or both. ● Translation is affected if a stop codon (chain termination mutation) is created within an exon. ● Finally, some point mutations may lead to the formation of an abnormal protein without impairing any step in protein synthesis.

Answer 24

20,000 - 25,000 genes

Answer 25

Messenger RNA

Answer 26

1 of the 20 AA or a regulatory signal (s/a stop translation)

Answer 27

30,000-40,000

Answer 28

1000 bp (kilobases, kb) or 1,000,000 bp (megabases, mb)

Answer 29

2 to 12 um

Answer 30

(2) Germ cells (1) Somatic cells

Answer 31

Somatic cells

Answer 32

Germ cells

Answer 33

Homozygous

Answer 34

Heterozygous

Answer 35

Transcription of genes

Answer 36

Minimal promoter consisting of a TATA box and initiator sequences

Answer 37

Transcriptional termination

Answer 38

First lvl of regulatory ctrl

Answer 39

co-activators and co-repressors

Answer 40

Gene transcription

Answer 41

(1) Events that alter chromatin structure can enhance the access of transcription factors to DNA (e.g., histone acetylation opens chromatin structure and is correlated with transcriptional activation) (2) Post-translational modifications of transcription factors, s/a phosphorylation, can induce the assembly of active transcription complexes (3) Transcriptional activators can displace a repressor protein. This mechanism is particularly common during development when the pattern of transcription factor expression changes dynamically.

Answer 42

> X-inactivation | > Genomic imprinting

Answer 43

Epigenetic events

Answer 44

Histone and acetylation or protein dephosphorylation

Answer 45

Histone deacetylase activity

Answer 46

X-inactivation

Answer 47

Gene inactivation

Answer 48

1. Skipping of generation (Penetrance and Expressivity) 2. Pleiotropy 3. Genetic heterogeneity 4. Anticipation 5. Variable age of onset 6. Sex-limited traits 7. Environmental effects 8. Parental genetic factors

Answer 49

Reduced penetrance

Answer 50

Dominant gene

Answer 51

Double dose

Answer 52

Variable expressivity

Answer 53

Skipping of generation

Answer 54

Pleiotropic effects

Answer 55

Directs synthesis of a polypeptide chain

Answer 56

Lack of enz galactose 1-phosphate uridyl transferase

Answer 57

Heterogenous

Answer 58

Congenital deafness can be caused by genes located at different loci

Answer 59

Osteogenesis imperfecta

Answer 60

- Blue sclerae - Conductive hearing loss relatively early in life - Joint laxity - Defective dentition

Answer 61

Autosomal dominant form

Answer 62

Perinatal lethal form

Answer 63

With fractures present at birth

Answer 64

With propensity to fractures but with normal sclera

Answer 65

Anticipation

Answer 66

4-6 months

Answer 67

15-65 years

Answer 68

Testicular feminization

Answer 69

Teticular feminization

Answer 70

Sex-influenced

Answer 71

- Baldness - CAH (congenital adrenal hyperplasia) - Legg-perthe's dse - Hemochromatosis

Answer 72

Incompatibility of Parental Genetic Factors

Answer 73

Point mutation (single base substitution)

Answer 74

Missense mutation

Answer 75

Sickle mutation affecting the B-globulin chain of Hb

Answer 76

Nucleotide triplet CTC (GAG in mRNA)

Answer 77

Sickle cell anemia

Answer 78

1) chain terminator | 2) stop codon (nonsense mutation)

Answer 79

Marked reduction in or total lack of transcription

Answer 80

Point mutations within introns lead to defective splicing of intervening sequences

Answer 81

Frameshift mutations

Answer 82

NO; instead an abn CHON missing one or more AA is synthesized

Answer 83

Trinucleotide repeat mutations

Answer 84

Mental retardation

Answer 85

Dynamic (i.e., the degree of amplification increases during gametogenesis)

Answer 86

Abnormal mRNA processing

Answer 87

Transcription

Answer 88

Translation

Answer 89

Neil and Shull (1954) and Levitsky (1962): a. occurrence of dse in definitive numerical proportions in individuals related by descent b. failure of the dse to spread to related individuals c. onset of the condition at a characteristic age without a precipitating cause d. greater concordance in monozygotic twins e. presence of abn genetic material in chromosome f. ability to correlate the disorder w known genetically determined traits, the so-called marker association g. environmental exclusion of etiology of dse

Answer 90

1) recognizing that the condition is inherited; 2) identifying the pattern of inheritance; 3) clarifying the clinical nature of the disorder (e.g., understanding the risk of dse occurence in fam)

Answer 91

(1) Dis related to mutant genes of large effect (2) Dses w multifactorial (polygenic) inheritance (3) Chromosomal dis (4) Single-gene dis w non-classic patterns of inheritance

Answer 92

Disorders rel to mutant genes of large effect

Answer 93

Dses w multifactorial (polygenic) inheritance

Answer 94

Chromosomal disorders

Answer 95

Single-gene disorders w non-classic patterns of inheritance

Answer 96

Transmission Patterns (Classic forms)

Answer 97

Autosomal dominant disorder | - both males and females are affected, and both can transmit the condition

Answer 98

New mutations ## Footnote Many new mutations seem-to occur in germ cells of relatively older fathers

Answer 99

Variations in penetrance and expressivity

Answer 100

Incomplete penetrance

Answer 101

50% penetrance

Answer 102

Variable expressivity

Answer 103

Manifestations of neurofibromatosis type 1 range from brownish spots on the skin to multiple skin tumors and skeletal deformities

Answer 104

incomplete penetrance

Answer 105

Phenotype of px w Sickle cell anemia (mutation at B-globin locus)

Answer 106

Familial hypercholesterolemia

Answer 107

Dietary intake of lipids

Answer 108

Huntington dse

Answer 109

- Huntington dse - Neurofibromatosis 1 - Myotonic dystrophy - Tuberous sclerosis

Answer 110

Polycystic kidney dse

Answer 111

Familial polyposis coli

Answer 112

- vWD - Hereditary spherocytosis

Answer 113

- Marfan syndrome - Ehlers-Danlos syndrome - OI - Achondroplasia

Answer 114

- Familial hypercholesterolemia - Acute intermittent porphyria

Answer 115

Autosomal recessive disorders ## Footnote Autosomal recessive traits make up the largest category of mendelian disorders.

Answer 116

(1) trait doesn't usually affect the parents of the affected individual, but siblings may show the dse (2) siblings have 1 chance in 4 of having the trait (i.e., recurrence risk is 25% for each birth) (3) if the mutant gene occurs w a low frequency in the population, there is a strong likelihood that the affected individual (proband) is the product of a consanguineous marriage

Answer 117

- expression of defects tends to be more uniform than dominant - complete penetrance is common - onset is frequently early in life - although new mutations ass w recessive dis 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 mutated genes encode enz. In heterozygotes, equal amounts of normal and defective enz are synthesized. usually the natural "margin of safety" ensures that cells with half the usual complement of the enz fxn normally.

Answer 118

Autosomal recessive disorders

Answer 119

- CF - Phenylketonuria - Galactosemia - Homocystinuria - Lysosomal storage dse - a1-antitrypsin deficiency - Wilson dse - Hemochromatosis - Glycogen storage dse

Answer 120

Sickle cell anemia

Answer 121

CAH (congenital adrenal hyperplasia)

Answer 122

- Alkaptonuria - Ehlers-Danlos syndrome

Answer 123

- Neurogenic muscular atrophies - Friedrich ataxia - Spinal muscular atrophy

Answer 124

Infertile; hence there's no Y-linked inheritance ## Footnote ● 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.

Answer 125

X-linked recessive inheritance

Answer 126

Hemizygous for X-linked mutant genes

Answer 127

- an affected male doesn't transmit disorder to his sons, but all daughters are carriers. Sons of heterozygous women have 1 chance in 2 of receiving the mutant gene - the heterozygous female usually doesn't express the full phenotypic change bcs of the paired normal allele. Bcs of the random inactivation of 1 of the X chromosomes in the female, however, females have a variable proportion of cells in wc the mutant X chromosome is active

Answer 128

G6PD deficiency

Answer 129

G6PD def ## Footnote In the female, a proportion of the red cells may be derived from marrow cells with inactivation of the normal allele.

Answer 130

Hemizygous male

Answer 131

Females - bcs the proportion of defective red cells in heterozygous females depends on the random inactivation of one of the X chromosomes, however, the severity of the hemolytic rxn is almost always less in heterozygous women than in hemizygous men

Answer 132

○ They are caused by dominant disease-associated alleles on the X chromosome. ○ These disorders are transmitted by an affected heterozygous female to half her sons and half her daughters and by an affected male parent to all his daughters but none of his sons, if the female parent is unaffected. ○ **Vitamin D-resistant rickets** is an example of this type of inheritance.

Answer 133

Duchenne muscular dystrophy

Answer 134

- Hemophilia A and B - Chronic granulomatous dse - G6PD deficiency

Answer 135

- WAS (Wiskott-Aldrich syndrome) - Agammaglobulinemia

Answer 136

- Diabetes Insipidus - Lesch-Nyhan syndrome

Answer 137

Fragile-X syndrome

Answer 138

Huntington disease Neurofibromatosis 1 ## Footnote Only one mutated copy of the gene is needed for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.

Answer 139

Cystic Fibrosis Sickle Cell Anemia ## Footnote Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene (and are referred to as carriers).

Answer 140

X-linked dominant ## Footnote X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern. Females are more frequently affected than males, and the chance of passing on an X-linked dominant disorder differs between men and women.

Answer 141

X-linked hypophosphatemia

Answer 142

X-linked recessive

Answer 143

Duchenne muscular dystrophy Hemophilia A

Answer 144

Mitochondrial

Answer 145

Leber's hereditary optic neuropathy (LHON)

Answer 146

heart disease, diabetes, schizophrenia, and certain types of cancer

Answer 147

● When a genetic disorder is diagnosed in a family, family members often want to know the likelihood that they or their children will develop the condition. ● This can be difficult to predict in some cases because many factors influence a person's chances. ● One important factor is how the condition is inherited. For example: ○ A person affected by an autosomal dominant disorder has a 50-percent chance of passing the mutated gene to each child, There is also a 50-percent chance that a child will not inherit the mutated gene. ○ For an autosomal recessive disorder, two unaffected people who each carry one copy of the mutated gene (carriers) have a 25-percent chance with each pregnancy of having a child affected by the disorder. ○ There is a 75-percent chance with each pregnancy that a child will be unaffected. ○ The chance of passing on an X-linked dominant condition differs between men and women because men have one X and one Y chromosome, while women have two X chromosomes. ○ A man passes on his Y chromosome to all of his sons and his X chromosome to all of his daughters. ○ Therefore, the sons of a man with an X-linked dominant disorder will not be affected, and his daughters will all inherit the condition (Fig. 3b) ○ A woman passes on one or the other of her X chromosomes to each child. ○ Therefore, a woman with an X-linked dominant disorder has a 50-percent chance of having an affected daughter or son with each pregnancy (Fig. 3a) ○ Because of the difference in sex chromosomes, the probability of passing on an X-linked recessive disorder aiso differs between men and women. ○ The sons of a man with an X-linked recessive disorder will not be affected. and his daughters will carry one copy of the mutated gene (Fig. 4a). ○ With each pregnancy. a woman who carries an X-linked recessive disorder has a 50-percent chance of having sons who are affected and a 50% chance of having daughters who carry one copy of the mutated gene (Fig. 4b). ## Footnote ● It is important to note that the chance of passing on a genetic condition applies equally to each pregnancy. ○ For example, if a couple has a child with an autosomal recessive disorder, the chance of having another child with the disorder is still 25 percent (or 1 in 4). ○ Having one child with a disorder does not “protect" future children from inheriting the condition. ○ Conversely, having a child without the condition does not mean that future children will definitely be affected. ● Although the chances of inheriting a genetic condition appear straightforward, in some cases factors such as a person's family history and the results of genetic testing can modify those chances. ● In addition, some people with a disease-causing mutation never develop any health problems or may experience only mild symptoms of the disorder. ● If a disease that runs in a family does not have a clear-cut inheritance pattern, predicting the likelihood that a person will develop the condition can be particularly difficult. ● Because estimating the chance of developing or passing on a genetic disorder can be complex, genetics professionals can help people understand these chances and make informed decisions about their health.

Answer 148

50% chance passing to offspring

Answer 149

75% 25% - child affected by disorder

Answer 150

- Affected son - Affected daughter - Unaffected son - Unaffected daughter

Answer 151

- Unaffected son - Carrier son - Carrier daughter - Affected daughter

Answer 152

- Unaffected son - Unaffected daughter - Affected son - Affected daughter

Answer 153

- Unaffected son - Unaffected son - Affected daughter - Affected daughter

Answer 154

- Unaffected son - Unaffected son - Carrier daughter - Carrier daughter

Answer 155

- Unaffected son - Unaffected daughter - Affected son - Carrier daughter

Answer 156

Affected children

Answer 157

Unaffected children

Answer 158

**Nervous:** Huntington disease Neurofibromatosis Myotonic dystrophy Tuberous sclerosis **Urinary:** Polycystic kidney disease **GI:** Familial polyposis coli **Hematopoietic** Hereditary spherocytosis Von Willebrand disease **Skeletal** Marfan syndrome* Ehlers-Danlos syndrome (some variants)* Osteogenesis imperfecta Achondroplasia **Metabolic** Familial hypercholesterolemia* Acute intermittent porphyria

Answer 159

- formation of an abn CHON; or - reduction in the output of the gene product ## Footnote Mendelian disorders result from alterations involving single genes. ● Virtually any type of protein may be affected in single-gene disorders and by a variety of mechanisms. ● To some extent, the pattern of inheritance of the disease is related to the kind of protein affected by the mutation. ● The mechanisms involved in single-gene disorders can be classified into four categories: ○ Enzyme defects and their consequences ○ Defects in membrane receptors and transport systems ○ Alterations in the structure, function, or quantity of non enzyme proteins ○ Mutations remodeling in unusual reactions to drugs

Answer 160

Mutations ## Footnote In either case, the consequence is a metabolic block. Figure 5-6 provides an example of an enzyme reaction in which the substrate is converted by intracellular enzymes, denoted as 1, 2, and 3, into an end product through intermediates 1 and 2. In this model, the final product exerts feedback control on enzyme 1. A minor pathway producing small quantities of M1 and M2 also exists.

Answer 161

● **Accumulation of the substrate** ○ depending on the site of block, may be accompanied by accumulation of one or both intermediates. ○ Moreover, an increased concentration of intermediate 2 may stimulate the minor pathway and thus lead to an excess of M1 and M2. ○ Under these conditions tissue injury may result if the precursor, the intermediates, or the products of alternative minor pathways are toxic in high concentrations. ■ For example, in galactosemia, the deficiency of galactose-I-phosphate uridyltransferase leads to the accumulation of galactose and consequent tissue damage. ■ Excessive accumulation of complex substrates within the lysosomes as a result of deficiency of degradative enzymes is responsible for a group of diseases generally referred to as lysosomal storage diseases. ● **An enzyme defect can lead to a metabolic block and a decreased amount of end product that may be necessary for normal function.** ○ For example, a deficiency of melanin may result from lack of tyrosinase, which is necessary for the biosynthesis of melanin from its precursor, tyrosine. This results in the clinical condition called albinism. ○ If the end product is a feedback inhibitor of the enzymes involved in the early reactions (in Fig. 5-6 it is shown that the product inhibits enzyme 1), the deficiency of the end product may permit overproduction of intermediates and their catabolic products, some of which may be injurious at high concentrations. ■ A prime example of a disease with such an underlying mechanism is the Lesch-Nyhan syndrome. **● Failure to inactivate a tissue-damaging substrate** ○ best exemplified by a1-antitrypsin deficiency. ○ Individuals who have an inherited deficiency of serum a1-antitrypsin are unable to inactivate neutrophil elastase in their lungs. ○ Unchecked activity of this protease leads to destruction of elastin in the walls of lung alveoli, leading eventually to pulmonary emphysema.

Answer 162

● Many biologically active substances have to be actively transported across the cell membrane. ● This transport is generally achieved by one of two mechanisms-through: ○ **Receptor-mediated endocytosis** ■ exemplified by familial hypercholesterolemia ■ 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. **○ Transport protein** ■ In cystic fibrosis, the transport system for chloride ions in exocrine glands, sweat ducts, lungs, and pancreas is defective ■ By mechanisms not fully understood, impaired chloride transport leads to serious injury to the lungs and pancreas

Answer 163

● Genetic defects resulting in alterations of non enzyme proteins often have widespread secondary effects, as exemplified by sickle cell disease. ○ The hemoglobinopathies, sickle cell disease being one, all of which are characterized by defects in the structure of the globin molecule, best exemplify this category. ● In contrast to the hemoglobinopathies, the thalassemias result from mutations in globin genes that affect the amount of globin chains synthesized. ○ Thalassemias are associated with reduced amounts of structurally normal a-globin or B-globin chains. ● Other examples of genetically defective structural proteins include collagen, spectrin, and dystrophin, giving rise to osteogenesis imperfecta, hereditary spherocytosis, and muscular dystrophies, respectively.

Answer 164

● Certain genetically determined enzyme deficiencies are unmasked only after exposure of the affected individual to certain drugs. ● This special area of genetics, called pharmacogenetics, is of considerable clinical importance. ● The classic example of drug-induced injury in the genetically susceptible individual is associated with a deficiency of the enzyme G6PD. ○ Under normal conditions glucose-6 phosphate dehydrogenase (G6PD) deficiency does not result in disease, but on administration, for example, of the antimalarial drug primaquine, a severe hemolytic anemia results. ● In recent years an increasing number of polymorphisms of genes encoding drug-metabolizing enzymes, transporters, and receptors are being identified. In some cases, these genetic factors have major impact on drug sensitivity and adverse reactions. ● It is expected that advances in pharmacogenetics will lead to patient-tailored therapy, or “personalized medicine.”

Answer 165

- accumulation of substrate - an enz defect --> metabolic block and decreased amt of end product (e.g Lesch-Nyhan syndrome) - failure to inactivate a tissue-damaging substrate

Answer 166

Excess M1 and M2

Answer 167

a1-antitrypsin deficiency

Answer 168

Unchecked activity of protease

Answer 169

Familial hypercholesterolemia

Answer 170

- CF | - FH

Answer 171

- Sickle cell dse | - Hbopathies

Answer 172

Thalassemias

Answer 173

``` collagen = OI spectrin = Hereditary spherocytosis dystrophin = Muscular dystrophies ```

Answer 174

G6PD deficiency

Answer 175

Phenylketonuria

Answer 176

Tay-Sachs dse

Answer 177

Emphysema and liver dse

Answer 178

Vit D-resistant rickets

Answer 179

> Deletions: reduced amnt = a-thala > Defective mRNA processing: reduced amnt = B-thala > Pt mutations: abn structure = Sickle cell anemia

Answer 180

Marfan syndrome

Answer 181

Duchenne/Becker muscular dystrophy

Answer 182

Hereditary spherocytosis

Answer 183

Hemophilia A

Answer 184

Hereditary retinoblastoma

Answer 185

Neurofibromatosis type 1

Answer 186

- Marfan syn | - Ehlers-Danlos

Answer 187

- Familial hypercholesterolemia | - Vit D resistant rickets

Answer 188

- Lysosomal storage dse - Tay-Sachs dse (GM2 Gangliosidosis) - Niemann-Pick (Types A & B) - Mucopolysaccharidoses - Glycogen-storage dse - Alkaptonuria (Onchronosis)

Answer 189

● Normal growth and differentiation of cells are regulated by two classes of genes: proto-oncogenes and tumor suppressor genes, whose products promote or restrain cell growth. ● It is now well established that mutations in these two classes of genes are important in the pathogenesis of tumors. ● In the vast majority of cases, cancer-causing mutations affect somatic cells and hence are not passed in the germ line. ● In approximately 5% of all cancers, however, mutations transmitted through the germ line contribute to the development of cancer. ● Most familial cancers are inherited in an autosomal dominant fashion, but a few recessive disorders have also been described.

Answer 190

1. Genetic dominant fully penetrant 2. Incompletely penetrant 3. Polygenic 4. Multifactorial 5. Environmental

Answer 191

Multifactorial inheritance

Answer 192

Polygenic inheritance

Answer 193

Multifactorial traits ## Footnote Characteristics include the following: ○ There is a similar rate of recurrence (typically 3-5%) among all 1st-degree relatives (parents, siblings, offspring of the affected child). ■ It is unusual to find a substantial increase in risk for relatives related more distantly than 2nd degree to the index case. ○ The risk of recurrence is related to the incidence of the disease. ○ Some disorders have a sex predilection, as indicated by an unequal male:female incidence.

Answer 194

Females ## Footnote ■ Where there is an altered sex ratio, the risk is higher for the relatives of an index case in the less commonly affected sex. ■ The risk to the son of an affected female with infantile pyloric stenosis is 18% compared with the 5% risk for the son of an affected male. ■ The female has passed on a greater genetic susceptibility to her offspring. ○ The likelihood that both identical twins will be affected with the same malformation is less than 100% but much greater than the chance that both members of a nonidentical twin pair will be affected.

Answer 195

21-63% ## Footnote This distribution contrasts with that of mendelian inheritance, in which identical twins always share a disorder due to a single mutant gene.

Answer 196

○ The risk of recurrence is increased when multiple family members are affected; these instances are often the most problematic for distinguishing multifactorial from mendelian etiology. ■ A simple example is that the risk of recurrence for unilateral cleft lip and palate is 4% for a couple with one affected child and increases to 9% with two affected children. ○ The risk of recurrence may be greater when the disorder is more severe. ■ The infant who has long-segment Hirschsprung disease has a greater chance of having an affected sibling than the infant who has short-segment Hirschsprung disease.

Answer 197

● There are two types of multifactorial traits. ● One exhibits continuous variation, with normal defined by a statistical range, and outliers of that range, usually two standard deviations, are considered "abnormal" (intelligence, blood pressure, height, head circumference) ○ Offspring represent a modified average of their parents, with nutritional and environmental factors playing an important role. ● With other multifactorial traits, the distinction between normal and abnormal is clearer (pyloric stenosis, neural tube defects, congenital heart defects, and cleft lip, cleft palate) ○ There is postulated to be a distribution of liability due to genetic and nongenetic factors in the population. Individuals who exceed a threshold liability are affected by the trait. ● The balance between genetic and environmental factors is demonstrated by neural tube defects. Genetic factors are implicated by the increased recurrence risk for parents of an affected. ● In contrast to the mendelian disorders, many of which are uncommon, the multifactorial group includes some of the most common ailments to which humans are heirs. ● Examples of: ○ Cleft lip or cleft palate (or both) ○ Congenital heart disease ○ Coronary heart disease ○ Hypertension ○ Gout ○ Diabetes Mellitus ○ Pyloric stenosis ○ Neural tube defects

Answer 198

Nonidentical twin

Answer 199

Trinucleotide

Answer 200

● 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, discussed below. ● The proclivity to expand depends strongly on the sex of the transmitting parent. ○ In the fragile-X syndrome, expansions occur during oogenesis, whereas in Huntington disease they occur during spermatogenesis. ● From a mechanistic standpoint, the mutations can be divided into two groups: ○ In the first group of disorders, exemplified by fragile-X syndrome and myotonic dystrophy, the repeat expansions occur in noncoding regions ○ whereas in other disorders, such as Huntington disease, expansions occur in the coding regions.

Answer 201

● The vast majority of genes are located on chromosomes in the cell nucleus and are inherited in classical Mendelian fashion. ● There exist several mitochondrial genes, however, that are inherited in quite a different manner. ● 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; however, daughters but not sons transmit the DNA further to their progeny (Fig. 5.-28). ● Several other features apply to mitochondrial inheritance. They are as follows: ○ Human mtDNA contains 37 genes, of which 22 are transcribed into transfer RNAs and two into ribosomal RNAs. The remaining 13 genes encode subunits of the respiratory chain enzymes. ○ 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 mtDNA, and, typically, deleterious mutations of mtDNA affect some but not all of these copies. ○ Thus, tissues and, indeed, whole individuals may harbor both wild-type and mutant mtDNA, a situation called heteroplasmy. ○ It should be evident that a minimum number of mutant mtDNA must be present in a cell or tissue before oxidative dysfunction gives rise to disease. ■ This is called the "Threshold effect." ■ Not surprisingly, the threshold is reached most easily in the metabolically active tissues listed earlier. ○ 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. ● Diseases associated with mitochondrial inheritance are rare and, as mentioned earlier, many of them affect the neuromuscular system. ○ Leber hereditary optic neuropathy is a prototype of this type of disorder. ■ It is a neurodegenerative disease that manifests as a progressive bilateral loss of central vision. ■ Visual impairment is first noted between ages 15 and 35, and it leads eventually to blindness. ■ Cardiac conduction defects and minor neurologic manifestations have also been observed in some families.

Answer 202

● We all inherit two copies of each autosomal gene, carried on homologous maternal and paternal chromosomes. ○ In the past, it had been assumed that there is no functional difference between the alleles derived from the mother or the father. ○ Studies over the past two decades have 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 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. ● As with other instances of epigenetic regulation, imprinting is associated with differential patterns of DNA methylation at CC; nucleotides. ● Other mechanisms include histone H4 deacetylation and methylation. ○ Regardless of the mechanism, it is believed that such marking of paternal and maternal chromosomes occurs during gametogenesis, and thus it seems that from the moment of conception some chromosomes remember where they came from. ○ The exact number of imprinted genes is not known; estimates range from 200 to 600. ○ 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. ● As is often the case in medicine, genomic imprinting is best illustrated by considering two uncommon genetic disorders: ○ Prader Willi syndrome ○ Angelman syndrome

Answer 203

Proclivity to expand

Answer 204

Fragile-X syndrome

Answer 205

Huntington dse

Answer 206

``` tRNAs = 22 rRNAs = 2 ```

Answer 207

Heteroplasmy

Answer 208

Leber hereditary optic neuropathy

Answer 209

Prader Willi syndrome | Angelman syndrome

Answer 210

Prader Willi syndrome (deletion: band q12 long arm chr 15, del (l5) (q11.2q13)) ## Footnote ● In 65% to 70% of cases, an interstitial deletion of band q12 in the long arm of chromosome 15, del (15) (q11.2q13), can be detected. ● In most cases the breakpoints are the same, causing a 5-Mb deletion. ● It is striking that in all cases the deletion affects the paternally derived chromosome 15

Answer 211

Angelman syndrome

Answer 212

Prader Willi syndrome

Answer 213

Angelman syndrome ## Footnote ● In contrast with the Prader-WillI syndrome, patients with the l phenotypically distinct Angelman syndrome are born with a deletion of the same chromosomal region derived from their mothers. ● Patients with Angelman syndrome are also mentally retarded, but in addition they present with ataxic gait, seizures, and inappropriate laughter. ○ Because of their laughter and ataxia they have been referred to as "happy puppets." ○ A comparison of these two syndromes clearly demonstrates the parent-of-origin effects on gene function.

Answer 214

Prader Willi syndrome

Answer 215

Angelman syndrome

Answer 216

Prader Willi syndrome

Answer 217

- Assessment of methylation status marker genes | - FISH

Answer 218

Prader-Willi syndrome

Answer 219

Angelman syndrome

Answer 220

genomic imprinting ## Footnote which has 3 mechanisms involved: 1. Deletion 2. Uniparental Disomy 3. Defective Imprinting

Answer 221

● It is known that a gene or set of genes on maternal chromosome 15q12 is imprinted (and hence silenced), and thus the only functional allele(s) are provided by the paternal chromosome. ○ When these are lost as a result of a deletion, the person develops Prader Willi syndrome. ● Conversely, a distinct gene that also maps to the same region of chromosome 15 is imprinted on the paternal chromosome. ● Only the maternally derived allele of this gene is normally active. ○ Deletion of this maternal gene on chromosome 15 gives rise to the Angelman syndrome.

Answer 222

Uniparental Disomy ● Molecular - studies of cytogenetically normal patients with the Prader Willi syndrome (i.e., those without the deletion) have revealed that they have two maternal copies of chromosome 15. ● Inheritance of both chromosomes of a pair from one parent is called uniparental disomy. ○ The net effect is the same (i.e., the person does not have a functional set of genes from the [non imprinted] paternal chromosomes 15). ○ Angelman syndrome, as might be expected, can also result from uniparental disomy of paternal chromosome 15.

Answer 223

● In a small minority of patients (1% to 4%), there is an imprinting defect. In some patients with Prader-Willi syndrome, the paternal chromosome carries the maternal imprint, and conversely in Angelman syndrome, the maternal chromosome carries the paternal imprint (hence there are no functional alleles) ● The genetic basis of these two imprinting disorders is now being unraveled. ● In the Angelman syndrome, the affected gene is a ubiquitin ligase that is involved in catalyzing the transfer of activated ubiquitin to target protein substrates. ○ The gene, called UBE3A, maps within the 15q12 region, is imprinted on the paternal chromosome, and is expressed from the maternal allele primarily in specific regions of the brain. ○ The imprinting is tissue-specific in that UBE3A is expressed from both alleles in most tissues. ○ In approximately 10% of cases, Angelman syndrome occurs not as a result of imprinting but of a point mutation in the maternal allele, thus establishing a firm link between the UBE3A gene and Angelman syndrome. ● In contrast to Angelman syndrome, no single gene has been implicated in Prader Willi syndrome ○ Instead, a series of genes located in the 15q11.2-q13 interval (which are imprinted on the maternal chromosome and expressed from the paternal chromosome) are believed to be involved. ○ These include a gene that encodes small nuclear riboprotein N, which controls gene splicing and is expressed highly in the brain and heart. ○ Loss of small nuclear riboprotein N function is believed to contribute to Prader Willi syndrome. ● Molecular diagnosis of these syndromes is based on assessment of methylation status of marker genes and FISH. ● The importance of imprinting is not restricted to rare chromosomal disorders. ○ Parent-of-origin effects have been identified in a variety of inherited diseases, such as Huntington disease and myotonic dystrophy and in tumorigenesis. ● Genomic imprinting occurs when the phenotypic expression depends on the parent of origin for certain genes and chromosome segments whether the genetic material is expressed depends on the gender of the parent from whom it was derived.

Answer 224

Gonadal Mosaicism ## Footnote ● It was mentioned earlier that with every autosomal dominant disorder some patients do not have affected parents. ● In such patients the disorder results from a new mutation in the egg or the sperm from which they were derived; as such, their siblings are neither affected nor at increased risk of developing the disease. ● This is not always the case, however. In some autosomal dominant disorders, exemplified by osteogenesis imperfecta, phenotypically normal parents have more than one affected child. ● This clearly violates the laws of Mendelian inheritance. ● Studies indicate that gonadal mosaicism may be responsible for such unusual pedigrees. Gonadal mosaicism results from a mutation that occurs post zygotically during early (embryonic) development.

Answer 225

Gonadal Mosaicism ## Footnote ● If a mutation affects only cells destined to form the gonads, the gametes carry the mutation, but the somatic cells of the individual are completely normal. Such an individual is said to exhibit germ line (or gonadal) mosaicism. ○ A phenotypically normal parent who has germ line mosaicism can transmit the disease-causing mutation to the offspring through the mutant gamete. ○ Because the progenitor cells of the gametes carry the mutation, there is a definite 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.

Answer 226

Mosaicism ## Footnote ● Study of placental tissue from chorionic villus samples collected at or before the 10th week of gestation has shown that 2% or more of all conceptions are mosaic for a chromosome abnormality. With the exception of chromosomes 13, 18, and 21, complete autosomal trisomies are usually nonviable; the presence of a normal cell line may allow these other trisomic conceptions to survive to term. ● Depending on the point at which the new cell line arises during early embryogenesis, mosaicism may be present in some tissues but not in others. ● Germline mosaicism, which refers to the presence of mosaicism in the germ cells of the gonad, is associated with an increased risk for recurrence of an affected child.

Answer 227

Pallister-Killian Syndrome ## Footnote ● The syndrome is due to mosaicism for isochromosome 12p. The presence of the isochromosome 12p in cells gives four copies of 12p in the affected cells. ● The isochromosome 12p is preferentially cultured from fibroblasts and is seldom present in lymphocytes. ● The abnormalities seen in affected individuals probably reflect the presence of abnormal cells during early embryogenesis.

Answer 228

Hypomelanosis ## Footnote ● Abnormalities of the eyes, musculoskeletal system, and central nervous system may also be present. ● Patients with hypomelanosis of Ito have two genetically distinct cell lines. ● The mosaic chromosome anomalies that have been observed involve both autosomes and sex chromosomes and have been demonstrated in about 50% of patients. ● The mosaicism may not be visible in lymphocyte-derived chromosome studies; it is more likely to be found when chromosomes are analyzed from skin fibroblasts. ● The distinct cell lines may not always be due to observable chromosomal anomalies but to single gene mutations or other mechanisms.

Answer 229

● The **family history remains the most important screening tool for pediatricians in identifying a patient's risk for developing a wide range of diseases**, including multifactorial conditions, like diabetes and attention deficit disorder, to single-gene disorders such as osteogenesis imperfecta and cystic fibrosis. ○ Through a detailed family history the physician can ascertain the mode of genetic transmission and the risks to family members. Because not all familial clustering of disease is due to genetic factors, a family history can also identify common environmental and behavioral factors that influence the occurrence of disease. ○ The main goal of the family history is to identify genetic susceptibility, and the cornerstone of the family history is a systematic and standardized pedigree. ● For the practicing clinician, the family history remains an essential step in recognizing the possibility of a hereditary component. ○ When taking the history, it is useful to draw a detailed pedigree of the first-degree relatives (e.g., parents, siblings, and children), since they share 50% of genes with the patient. ○ The family history should include information about ethnic background, age, health status, and (infant) deaths. ○ Next, the physician should explore whether there is a family history of the same or related illnesses to the current problem. An inquiry focused on commonly occurring disorders such as cancers, heart disease, and diabetes mellitus should follow. ○ Because of the possibility of age-dependent expressivity and penetrance, the family history will need intermittent updating. ■ If the findings suggest a genetic disorder, the clinician will have to assess whether some of the patient's relatives may be at risk of carrying or transmitting the disease. ■ In this circumstance, it is useful to confirm and extend the pedigree based on input from several family members. ■ This information may form the basis for carrier detection, genetic counseling, early intervention, and prevention of a disease in relatives of the index patient.

Answer 230

● A pedigree provides a graphic depiction of a family's structure and medical history. ● The person providing the information is termed the proband, and is typically designated by an arrow. ● It is important when taking a pedigree to be systematic and use standard symbols and configurations (Fig. 80-1) so that anyone can read and understand the information. ● A three-generation pedigree should be obtained as an initial screen for every new patient to identify possible genetic disorders segregating within the family, the inheritance pattern, and the risk to the patient. The closer the relationship of the proband to the person in the family with the genetic disorder, the greater is the shared genetic complement. ● First-degree relatives, such as a parent, full sibling, or child, share 1/2 of their genetic information on average—first cousins share 1/8. ● Sometimes a disease in a more distant relative may create a greater risk; for that reason, a more extended pedigree may be needed to identify risk for certain disorders. ○ A history of a distant maternally related cousin with mental retardation due to fragile X syndrome may have little significance for the male infant you are examining, or it may mean that this child is at elevated risk for fragile X syndrome.

Answer 231

● Albinism is due to defects in the biosynthesis and distribution of melanin. ● Melanin is synthesized by melanocytes from tyrosine in a membrane-bound intracellular organelle, the melanosome. ● Melanocytes originate from the embryonic neural crest and migrate to the skin, eyes (choroids and iris), and hair follicles. ● The melanin in the eye is not secreted into the adjacent tissues, whereas the pigment in skin and hair follicles is secreted into the epidermis and the hair shaft. ● The rate of melanogenesis is very low in the eye and very high in the skin and hair. ● The biosynthetic pathway for melanin synthesis is not completely elucidated. ● Tyrosine is transported into the melanosome, where it is metabolized to dopa and dopaquinone by a single enzyme, tyrosinase (see Fig. 82-2). ○ This copper-containing enzyme is present only in the melanocytes. ○ Dopaquinone reacts with cysteine to make cysteinyl-dopa. The latter compound undergoes several poorly understood steps to form a yellow-red pigment called pheomelanin. ○ Dopaquinone may alternatively form eumelanin, a brown-black pigment, after several enzymatic and nonenzymatic reactions. ● Several genes have been found to be involved in melanogenesis (Table 82-1). However, only the product of the tyrosinase gene has been identified to date (tyrosinase enzyme). The products of other genes involved in melanin production are unknown.

Answer 232

Pheomelanin

Answer 233

**● Autosomal recessive trait** ○ Oculocutaneous (Generalized) albinism (OCA) ■ OCA Type 1 ■ OCA Type 2 ○ Hermansky-Pudlak syndrome ○ Chediak-Higashi syndrome **● X-linked** ○ Ocular albinism (OA) ■ OA Type 1 ■ OA Type 2 ■ OA3 – mild variant of OCA2 **● Autosomal dominant** ○ Localized albinism ■ Piebaldism ■ Waardenburg syndrome

Answer 234

a. Oculocutaneous (Generalized) albinism (OCA) b. Hermansky-Pudlak (HPS) c. Chediak Higashi (CHS)

Answer 235

Localized albinism: a. Piebaldism b. Warrdenburg syndrome

Answer 236

``` Ocular albinism (OA) = OA1 and OA2 (OA3 = Mild variant of OCA2) ```

Answer 237

● Notable example: oculocutaneous albinism ● The gene responsible for the trait is located on one of the non–sex chromosomes or autosomes. This means that both males and females have an equal chance of inheriting these genes and showing the trait, the term “recessive” refers to the way in which the gene is expressed. ● When two people who are carriers for the same gene have a child together, then the child has one out of four chances of getting two copies of the albinism gene and having albinism. ○ The child has one out of four chances of getting 2 copies of the normal gene and having normal pigment and not being a carrier. ○ The child has 2 out of 4 chances of getting one normal gene and one albinism gene and having normal pigment but being a carrier. ● Because autosomal recessive disorders result only when both alleles at a given gene locus are mutants, such disorders are characterized by the following features. ○ The trait does not usually affect the parents but siblings may show the disease. ○ Siblings have one chance in four of being affected (ie. the recurrence risk is 25% for each birth. ○ If the mutant gene occurs with a low frequency in the population, there is strong likelihood that the proband is the product of a consanguineous marriage.

Answer 238

● Notable example: ocular albinism ● X-linked means that the gene responsible for the disorder is located on the X chromosome. ● The term “recessive” means a person can carry one copy of an altered gene and not show the effects, if she has another unaltered copy. ● If a male carries one copy of an altered gene on his X chromosome, he does not carry an unaltered copy. As a result, he will show the effects of this gene. ● If a woman carries the gene responsible for X-linked ocular albinism, the risk for her to give birth to an affected son is 50% or one in two for each birth. ○ None of her daughters will be affected but for each birth of a daughter there is one-in-two chance that the daughter will be a carrier. ● Children of a man with X-linked ocular albinism will not have albinism, but all of his daughters will be carriers. ● These generalized risk figures for inheritance of an X-linked trait hold true in each and every pregnancy. They are not changed by the outcome of a previous pregnancy. ● All sex-linked disorders are X-linked; and almost all X-linked traits are recessive.

Answer 239

● This trait manifests in the heterozygous state, so at least one parent of an index case is usually affected, both males and females are affected, and both can transmit the condition. ● When an affected person marries an unaffected one, every child has a 50% chance of having the disease. ● With every autosomal dominant disorder, some 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. Their siblings are neither affected or at increased risk for developing the disease. ● Clinical features can be modified by reduced penetrance and variable expressivity ● In many conditions, the age at onset is delayed; symptoms and signs do not appear until adulthood.

Answer 240

● Clinical manifestations common in all forms of albinism are hypopigmentation of the skin and hair. ● Patients with involvement of the eyes may have strabismus, photophobia, decreased visual acuity, and the presence of ‘red reflex’. ○ The irides are translucent and pink in infancy and change to light blue or brown with age (note: irides are the medical term for irises). ○ Binocular vision is absent because of a decussation defect in which all optic nerve fibers from one eye completely cross to the other side at the chiasma. ○ Blindness and skin cancer are major late sequelae of albinism in its severe forms. ● Many clinical forms of albinism have been identified. Some of the seemingly distinct clinical forms are caused by different mutations of the same gene. ● Attempts to differentiate types of albinism based on the mode of inheritance, tyrosinase activity, or the extent of hypopigmentation have failed to yield a comprehensive classification. The following classification is based on the distribution of albinism in the body (see Table 82-1). **Oculocutaneous Generalized Albinism (OCA)** ● Lack of pigment is generalized, affecting skin, hair and eyes. Two genetically distinct forms exist: OCA Type 1 and OCA Type 2. ○ The lack of pigmentation is more severe in patients with OCA Type 1, than in those with OCA Type 2. ○ Both conditions are inherited as an autosomal recessive trait. **Type 1 (tyrosinase-deficient) OCA** ● The genetic defect is in the gene encoding for the tyrosinase enzyme. This gene is located on the long arm of chromosome 11. ○ Many mutant alleles have been identified. ○ Most affected individuals are compound heterozygotes. ○ A number of mutations render the enzyme completely inactive (tyrosinase negative). ● These individuals have the most severe form of albinism. ○ Lack of pigment in the skin, hair, and eyes is evident at birth and remains unchanged throughout life. ● Some mutations result in enzymes with some residual activity. These individuals, although completely depigmented at birth, are capable of developing some pigment with age (yellow OCA). ○ There is minimal tyrosinase activity in these patients, as evidenced by the ability of a plucked hair bulb to form minimal amounts of pigments when incubated with tyrosine. **Type 2 (tyrosinase-positive) OCA** ● This is the **most common form of generalized albinism.** It is particularly common in **African blacks.** ● These individuals demonstrate some pigmentation of the skin and eyes at birth and continue to collect pigment throughout their lives. ○ The hair is yellow at birth and may become darker with age. The tyrosinase activity in the plucked hair bulb is normal. ● The defect is in the p gene, which is located on the long arm of chromosome 15. This gene produces the p protein, which is involved in the transport of tyrosine across the melanosome membrane. ● Patients with Prader-Willi and Angelman syndromes who have deletion of chromosome 15 also have this form of albinism. **Hermansky–Pudlak Syndrome** ● This is a tyrosinase-positive oculocutaneous albinism associated with platelet dysfunction (owing to the absence of platelet-dense bodies) and an accumulation of a ceroid-like material in tissues. ○ The degree of albinism is variable. ○ The condition is most prevalent in Puerto Rico (frequency about 1 per 2,000). ● Bleeding tendencies, often manifested as epistaxis, and a prolonged bleeding time are common. The ceroid-like material is histochemically similar to that found in neuronal ceroid-lipofuscinosis. ● The accumulation of this material in tissues results in restrictive lung disease, inflammatory bowel disease, kidney failure, and cardiomyopathy during the third or fourth decade of life. ● The basic defect is thought to be a membrane abnormality involving melanosomes, lysosomes, and platelet-dense bodies. **Chediak–Higashi Syndrome** ● Patients with this rare autosomal recessive condition have partial albinism and susceptibility to infection with the presence of giant peroxidase-positive lysosomal granules in granulocytes. ● These patients have a reduced number of melanosomes, which are abnormally large (macromelanosomes). ● Patients who survive early childhood may develop a lymphofollicular malignancy. **Ocular Albinism (OA)** ● Albinism is limited to the eyes. All the eye findings of albinism (see above) are present. ● Skin and hair color are within normal limits but are usually lighter than those in nonaffected siblings. ● Hair bulb tyrosinase activity is positive. At least three forms of this condition (OA1, OA2, and OA3) have been reported. ○ Only the X- linked recessive form (OA1) has been segregated as a separate entity. ○ OA2, which was thought to be an autosomal recessive trait, is now known to be inherited as an X-linked condition and, likely, is a form of OA1. ○ OA3, which has been known as the autosomal recessive ocular albinism, is now known to be a mild variant of type 2 oculocutaneous albinism (OCA2). **Ocular Albinism 1 (OA1 Nettleship–Falls Type)** ● In this form only the hemizygous male has the complete manifestation. Some abnormal pigmentation of the retina may be present in heterozygote carriers. ● The gene for this condition is located on the short arm of the X chromosome. An X-linked ocular albinism with late-onset sensorineural deafness has been reported. **Localized Albinism** ● This disorder is characterized by localized hypopigmentation of skin and hair, which may be present at birth or develop with time. **Piebaldism** ● In this autosomal dominant inherited condition, the individual is usually born with a white forelock. The underlying skin is depigmented. ● In addition, there are usually white macules on the face, trunk, and extremities. The white hair lock and the depigmented underlying skin are devoid of melanocytes. ● Mutations in the KIT gene (tyrosine kinase receptor) have been shown in affected patients. **Waardenburg Syndrome** ● In this syndrome, lateral displacement of inner canthi, broad nasal bridge, heterochromia of irides and sensorineural deafness are associated with a white forelock. ● This is inherited as an autosomal dominant trait. ● Two types of this syndrome, types I and II, have been identified. Patients with type I have displacement of inner canthi, while type II patients have normal inner canthi. ● Mutation in PAX3 gene is the cause of type I Waardenburg syndrome.

Answer 241

● It is usually possible to determine the type of albinism present with a careful history of pigment development and an examination of the skin, hair and eyes. ○ The only type of albinism that has white hair at birth is OCA 1. ○ Individuals with other types of OCA will have some hair pigment at birth, although it may be very slight in amount. It can be difficult to tell if the hair is completely white or very lightly pigmented in a very young child, and changes in pigment over time will usually help clarify the OCA type present. ● The most accurate test for determining the specific type of albinism is a gene test. ○ A small sample of blood is obtained from the affected individual and the parents as a source of DNA, the chemical that carries the genetic code of each gene. ○ By a complex process, a genetic laboratory can "sequence" the code of the DNA, to identify the changes (mutations) in the gene that cause albinism in the family. ○ The test is useful only for families that contain individuals with albinism, and cannot be performed practically as a screening test for the general population. ● Researchers have analyzed DNA of people with albinism and found the changes that cause albinism, but these changes are not always in exactly the same place, even for a given type of albinism. Therefore the tests for the gene may be inconclusive. ● None of the tests available are capable of detecting all of the mutations of the genes that cause albinism, and responsible mutations cannot be detected in a small number of individuals and families with albinism. ● The test can be used to determine if a fetus has albinism. For this purpose a sample would be obtained by amniocentesis, a procedure which involves using a needle to draw fluid from the uterus, at 16 to 18 weeks gestation. Those considering such testing should be aware that given proper support children with albinism can function well and have normal life spans.

Answer 242

- The eye needs melanin pigment to develop normal vision. People with albinism have impairment of vision bcs the eyes doesn't have normal amt of melanin pigment during development - skin needs pigment for protection from sundamage, and people with albinism often sunburn easily. In tropical areas, many people with albinism who do not protect their skin get skin cancers. ● Vision problems in albinism result from abnormal development of the retina and abnormal patterns of nerve connections between the eye and the brain. It is the presence of these eye problems that defines the diagnosis of albinism. Therefore the main test for albinism is simply an eye examination. ● There are several less common types of albinism which involve other problems also such as mild problems with blood clotting, or problems with hearing. ● Albinism may cause social problems, because people with albinism look different from their families, peers, and other members of their ethnic group. ● Growth and development of a child with albinism should be normal and intellectual development is normal. ○ Developmental milestones should be achieved at the expected age. ○ General health of a child and an adult with albinism is normal, and the reduction in melanin pigment in the skin, hair and the eyes should have no effect on the brain, the cardiovascular system, the lungs, the gastrointestinal tract, the genitourinary system, the musculoskeletal system, or the immune system. Life span is normal.

Answer 243

● People with albinism, whether it involves the eyes alone or involves the skin and the hair, often have several problems: ○ People with albinism are not "blind," but their visual acuity is not normal, and cannot be corrected completely with glasses. Extreme farsightedness or near-sightedness, and astigmatism are common (see definitions below) and correction with glasses can improve acuity in many people with albinism. ○ Corrected visual acuity ranges from 20/20 (can see at 20 feet what should be seen at 20 feet; normal) to 20/400 (see at 20 feet what should be seen at 400 feet; legally blind). Normal or near-normal vision is unusual, however, even when glasses are worn. ○ Nystagmus, which is an involuntary movement of the eyes back and forth. Many people with albinism learn to use a head tilt or turn that decreases the movement and may improve vision. ○ Strabismus, which means that the eyes do not fixate and track together. Despite this condition, people with albinism do have some depth perception, although it is not as sharp as when both eyes can work together. ○ Sensitivity to light, which is called photophobia. The iris allows "stray" light to enter the eye and cause sensitivity. Contrary to a common idea, this sensitivity does not limit people with albinism from going out into the sunlight. ● Iris color is usually blue/gray or light brown (Diagram 1) It is a common notion that people with albinism must have red eyes, but in fact the color of the iris varies from dull gray to blue to brown. (A brown iris is common in ethnic groups with darker pigmentation). ○ Under certain lighting conditions, there is a reddish or violet hue reflected through the iris, which has very little pigment. This reddish reflection comes from the retina, which is the surface lining the inside of the eye. This reddish reflection is similar to that which occurs when a flash photograph is taken of a person looking directly at the camera, and the eyes appear red. ○ With some types of albinism the red color can reflect back through the ins as well as through the pupil. ● One major eye abnormality in albinism involves lack of development of the fovea (foveal hypoplasia) (Diagram 2). ○ The fovea is a small but most important area of the retina in the inside of the eye. The retina contains the nerve cells that detect the light entering the eye and transmit the signal for the light to the brain. ○ The fovea is the area of the retina which allows sharp vision, such as reading, and this area of the retina does not develop in albinism. It is not known why the fovea does not develop normally with albinism, but it is related to the lack of melanin pigment in the retina during development of the eye. ○ The developing eye seems to need melanin for organizing the fovea. ● The major abnormality of the eye in albinism involves the development of the nerves that connect the retina to the brain. ○ People with albinism have an unusual pattern for sending nerve signals from the eye to the brain (Diagram 3). ○ The nerve connections from the eye to the vision areas of the brain are organized differently from normal (see Diagram 3). ○ This unusual pattern for nerve signals probably prevents the eyes from working well together, and causes reduced depth perception. ● Strabismus is also related to the altered development of the optic nerves. The strabismus in albinism is usually not severe and tends to alternate between involving the right and the left eye.

Answer 244

● Various optical aids are helpful to people with albinism, and the choice of an optical aid depends on how a person uses his or her eyes in jobs, hobbies, or other usual activities. ○ Some people do well using bifocals which have a strong reading lens, prescription reading glasses, or contact lenses. Others use handheld magnifiers or special small telescopes. ○ Some use bioptics, glasses which have small telescopes mounted on, in, or behind their regular lenses, so that one can look through either the regular lens or the telescope. ○ Newer designs of bioptics use smaller light-weight lenses. Some states allow the use of bioptic telescopes for driving. ● Optometrists or ophthalmologists who are experienced in working who have people with low vision can recommend various optical aids. Clinics should provide aids on trial loan, and provide instruction in their use. ● In the United States, people with albinism live normal life spans and have the same types of general medical problems as the rest of the population. ○ The lives of people with Hermansky-Pudlak syndrome can be shortened by lung disease or other problems. In tropical countries, those who do not use skin protection may develop life-threatening skin cancers. ○ If they use appropriate skin protection, such as sunscreen lotions rated 20 or higher, and opaque clothing, people with albinism can enjoy outdoor activities even in summer. ● People with albinism are at risk of isolation, because the condition is often misunderstood. ○ Social stigmatization can occur, especially within communities of color, where the race or paternity of a person with albinism may be questioned ○ Families and schools must make an effort not to exclude children with albinism from group activities. ○ Contact with others with albinism or who have albinism in their families is most helpful. NOAH can provide the names of contacts in many regions of the country. Classroom aids for helping children with albinism: ● Ophthalmologists and optometrists can help people with albinism compensate for their eye problems, but they cannot cure them. ● For help with visual acuity, eye doctors experienced in low vision can prescribe a variety of devices. ○ No one device can serve the needs of all persons in all situations, since different occupations and hobbies require the use of vision in different ways. ○ Young children may simply need glasses, and older children can sometimes benefit from bifocal glasses. ○ Low vision clinics may prescribe telescopic lenses mounted on glasses, sometimes called bioptics, for close-up work as well as for distant vision. ○ Recently smaller and lighter telescopes have been developed; however, ordinary glasses or bifocals with a strong reading correction may serve well for many people with albinism. ● For nystagmus, treatments to control nystagmus have included biofeedback, contact lenses, and surgery. ● The most promising may be eye muscle surgery that reduces the movement of the eyes; however, vision may not improve in all cases due to other associated eye abnormalities. ● People with albinism may find ways of reducing nystagmus while reading, such as placing a finger by the eye, or tilting the head at an angle where nystagmus is dampened. ● For strabismus, ophthalmologists prefer to treat infants starting at about six months of age, before the function of their eyes has developed fully. ○ They may recommend that parents patch one eye to promote the use of the non-preferred eye. In other cases, the alignment of the eyes improves with the wearing of glasses. ○ Correction of strabismus by surgery or by injection of medicine into the muscles around the eyes does not completely correct the problem with both eyes fixing on one point. ● Preschool evaluations allow parents and teachers to form an Individual Education Plan for the child. The use of Braille is not necessary, and, if a trial of Braille is given, children with albinism will read the dots visually ● Children with albinism often prefer to read with a head tilt and usually hold the page close to the eyes. Occasionally it can be difficult to get them to use their glasses, as they do not notice significant improvement in their vision when glasses are used. Furthermore, use of glasses or books with large print can be difficult because of peer pressure. Classroom aids for helping children with albinism: ● High contrast written material: Children with albinism have a hard time reading worksheets and papers that are light or low contrast. Black on white high contrast material is better. ● Large-type textbooks: The school can usually obtain large type editions from the publishers of their regular textbooks. ○ Because children with albinism often have difficulty keeping track of their place on the page while shifting back and forth between a textbook and a worksheet, it may help to allow them to write in the textbook. ○ Worksheets may need to be copied on a machine that enlarges print size. ○ Children with albinism do not always need large-type materials, however, and large types should not substitute for poor optical visual aids. Use of audio tapes may be preferable to voluminous reading. ● Copies of the teacher's board notes: The child with low vision can read the notes close-up while classmates read the board. ● Various optic devices: Hand-held monoculars, telescopic lenses mounted over eye glasses, video enlargement machines (closed circuit TV), and other types of magnifiers may help some people with albinism. ● Computers: Children with albinism should begin key-boarding skills early, since computers with software for large character screen display can help greatly with writing projects. ● Prescription of appropriate classroom visual aids requires teamwork of the student, parent, classroom teacher, vision resources teacher, and an optometrist or ophthalmologist experienced in working with persons with low vision. How Much Time Can a Person with Albinism Stay in the Sun? ● Most people with albinism do not tan, and they burn easily on exposure to the sun. ○ People with albinism who develop increasing amounts of hair and skin pigment as they get older may not be bothered by the sun, and may tan with sun exposure. ○ If sun exposure produces a sunburn, then the skin must be protected to prevent burning and damage. ● Sunburn is skin damage from exposure to ultraviolet light, which is a part of sunlight that is not visible to the human eye. ○ Redness develops 2 to 6 hours after exposure to ultraviolet light, and sunburn may not turn completely red until as long as 24 hours after the exposure. ○ As a result a sunburn can worsen after a person leaves the sun. Prolonged sun exposure in a person who does not tan well is associated with the development of skin cancer. This can be prevented with correct protection of the skin from the ultraviolet radiation of the sun. ● It is difficult to state a general rule for the number of hours in the sun that people with albinism can tolerate, since the intensity of the ultraviolet light varies a great deal, depending upon the time of day and year, and the environmental conditions.

Answer 245

● One person in 17,000 in the USA has some type of albinism. Albinism affects people from all races. ● In the Philippines, there is no statistics on its incidence but it is very uncommon among Filipinos.

Answer 246

DIAGNOSIS: OSTEOGENESIS IMPERFECTA ● Osteoporosis, a feature of both inherited and acquired disorders, classically demonstrates fragility of the skeletal system and a susceptibility to long bone fractures or vertebral compressions from mild or inconsequential trauma. ● Osteogenesis imperfecta (OI) (brittle bone disease), the most common genetic cause of osteoporosis, is a generalized disorder of connective tissue caused by defects in type I collagen. ● The spectrum of Ol is extremely broad, ranging from a form that is lethal in the perinatal period to a mild form in which the diagnosis may be equivocal in an adult.

Answer 247

● All types of osteogenesis imperfecta are caused by structural or quantitative defects in type I collagen, the primary component of the extracellular matrix of bone and skin. ● In about 10% of clinically indistinguishable cases, no biochemical defect of collagen protein can be demonstrated. It is not clear whether these cases represent limitations in biochemical detection or genetic heterogeneity of the disorder.

Answer 248

The collagen structural mutations cause Ol bone to be globally abnormal. The bone matrix contains abnormal type I collagen fibrils and relatively increased levels of types III and V collagen. In addition, several noncollagenous proteins of bone matrix are found in reduced amount. The hydroxyapatite crystals deposited on this matrix are poorly aligned with the long axis of fibrils.

Answer 249

● Type I collagen is a heterotrimer, composed of two a1(1)- chains and one a2(1)-chain. The chains are synthesized as procollagen molecules with short globular extensions on both ends of the central helical domain. The helical domain is composed of uninterrupted repeats of the sequence Gly-X-Y, where gly is glycine, X is often proline, and Y is often hydroxyproline. ○ The presence of glycine at every third residue is crucial to helix formation then proceeds linearly in a carboxyl to amino direction. Concomitant with helix assembly and formation, the chains are glycosylated at lysine residues. ● The collagen structural defects are of two types: 85% are point mutations causing substitutions of glycine residues by other amino acids, 12% are single exon splicing defects. The clinically mild type I Ol has a quantitative defect with mutations that cause on a1 (1) allele to be functionally null. These patients make a reduced amount of normal collagen. ● The relationship between genotype and phenotype remains elusive for the structural mutations. Lethal and nonlethal mutations occur with about equal frequency on both chains. ○ For a2(1) mutations, lethal and nonlethal mutations occur in alternating regions along the chain. ○ For mutations on the a1(1)-chain, no model adequately predicts phenotype. ● Osteogenesis imperfecta is an autosomal dominant disorder. A minority of Ol cases with apparent recessive inheritance are due to parental mosaicism and are also dominant. ● Mutations in the COL1A1 and COL1A2 genes cause osteogenesis Imperfecta. ● The COL1A1 and COL1A2 genes make proteins that areused to assemble larger molecules called type I collagen. This type of collagen is the most abundant protein in bone, skin, and other connective tissue (the type of tissue that provides structure and strength to the body). Mutations in the COL1A1 or COL1A2 gene either reduce the amount of collagen produced or cause collagen molecules to be defective. These changes weaken the body's connective tissue, particularly the bones, causing the signs and symptoms of osteogenesis imperfecta. ● In cases without mutations in the COL1A1 or COL1A2 genes, the cause of the disorder is unknown.

Answer 250

● Osteogenesis imperfecta is an autosomal dominant disorder that occurs in all racial and ethnic groups. The incidence of Ol that is detectable in infancy is about 1 in 20,000. There is a similar incidence of the mild form type I OI ● This condition affects as many as 1 in 10,000 individualsworldwide.

Answer 251

● Most cases of osteogenesis imperfecta involve a dominant mutation. When a gene with a dominant mutation is paired with a normal gene, the faulty gene "dominates" the normal gene. In Ol, a dominant genetic defect cause one of two things to occur: ○ Dominant altered gene directs cells to make an altered collagen protein. Even though the normal gene directs cells to make normal collagen, the presence of altered collagen causes Type II, III, or IV OI. These types result from a problem with the quality of collagen. ○ The dominant altered gene fails to direct cells to make any collagen protein. Although some collagen is produced by instructions from the normal gene, there is an overall decrease in the total amount of collagen produced, resulting in Type I OI. This type results from a problem with the quantity of collagen. ● When a mutation is dominant, a person only has to receive one faulty gene to have a genetic disorder. This is the case with most people who have Ol: they have one faulty gene for type 1 collagen, and one normal gene for type I collagen. **Recessive Inheritance** ● With recessive inheritance, both copies of a gene must be defective for a person to have a genetic disorder. This occurs when both parents carry a single altered copy of the gene. ● The parents do not have the genetic disorder (because they have only one faulty gene), but they are carriers of the disorder. With each pregnancy, there is a 25 percent chance that the child will receive two altered genes, one from each parent. In this case, the child would have the genetic disorder. ● There is a 50 percent chance that the child will receive only one altered gene, in which case he or she will be a carrier (like his or her parents), but not have the disorder.

Answer 252

Most researchers now agree that recessive inheritance rarely causes osteogenesis imperfecta. OSTEOGENESIS IMPERFECTA IN FAMILIES ● There are essentially three scenarios that occur to cause a child to be born with osteogenesis imperfecta. **Direct Inheritance from a Parent** ● A person with Ol has two genes for type 1 collagen- one gene is faulty, the other is normal. Each time that person conceives a child, he or she passes on one of the two genes to the child. Therefore, there is a 50 percent chance that his or her child will inherit the faulty gene. ● If the child inherits the faulty gene, he or she will have the same type of Ol as the parent. However, the child may be affected in different ways than the parent (e.g, the child's number of fractures, level of mobility, stature, etc. may not be identical to his or her parent's). ● If the parent with Ol passes on his or her normal gene to a child, that child will not have Ol and cannot pass on the disorder to his or her own children. **A New Dominant Mutation** ● About 25 percent of children with Ol are born into a family with no history of the disorder. That is, a child is born with a dominant genetic mutation that causes Ol, yet neither parent has Ol. ● This occurs when the child has a "new" or "spontaneous" dominant mutation. The gene spontaneously mutated in either the span or the egg before the child's conception. Now that the child has a dominant gene for Ol, he or she has a 50 percent chance of passing the disorder on to his or her children, as explained above. ● As far as we know, nothing the parents did caused a spontaneous mutation to occur. There are no known environmental, dietary, or behavioral triggers for this type of mutation. ● In most cases, when a family with no history of Ol has a child with Ol, they are not at any greater risk than the general population for having a second child with Ol. (For the exception to this rule, see "Mosaicism" below). In addition, unaffected siblings of a person with Ol are at no greater risk of having children with Of than the general population. **Mosaicism** ● In studies of families into which infants with Ol Type (the perinatal lethal form) were born, it was found that most of the babies had a new dominant mutation in a collagen gene. ○ However, in some of these families, more than one infant was born with Ol. ○ Previously, researchers had seen this recurrence as evidence of recessive inheritance of this form of Ol. ○ More recently, however, researchers have concluded that the rare recurrence of Ol in a previously unaffected family is more likely due to a phenomenon called mosaicism. ● Studies suggested that the mutation, instead of occurring in an individual sperm or egg, occurred in a percentage of the cells that give rise to a parent's multiple sperm or eggs. ○ Thus, although the parent is not affected by the disorder, the mutation present in a percentage of his or her reproductive cells can result in more than one affected child. ○ It is estimated that 2 to 4 percent of families into which an infant with Ol Type is born are at risk of having another affected child because of this problem with sperm or eggs. **When Both Parents Have Osteogenesis Imperfecta** ● If two people with Ol have a child, there is a 75% chance that the child will inherit one or both Ol genes, as follows: ○ There is a 25% chance the child will inherit only the mother's Ol gene (and the father's unaffected gene). ○ A 25% chance the child will inherit only the father's Ol gene (and the mother's unaffected gene). ○ A 25% chance the child will inherit both parents' Ol genes. ● Because this situation has been uncommon, the outcome of a child inheriting two Ol genes is hard to predict. It is likely (even if both parents have mild OI) that the child would have a severe, possibly lethal, form of the disorder.

Answer 253

● Ol has the triad of fragile bones, blue sclerae, and early deafness. Ol was once divided into "congenital," the forms detectable later in childhood; this did not account for the variability of Ol. The current classification divides Ol into four types based on clinical and radiographic criteria. **Type 1 Osteogenesis Imperfecta** ● “mild” type ● This form is sufficiently mild that it is often found in large pedigree. Many type I families have blue sclerae, recurrent fractures in childhood, and presenile hearing loss (30- 60%). ● Both types I and IV are divided into A and B subtypes, depending on the absence (A) or presence (B) of dentinogenesis imperfecta. ● Other possible connective tissue abnormalities include easy bruising. joint laxity, and slight short stature compared with family members. ● Fractures result from mild to moderate trauma and decrease after puberty. **Type 2 Osteogenesis Imperfecta** ● “perinatal lethal” type ● These infants may be stillborn or die in the 1 yr. of life. Birth weight and length are small for gestational age. ● There is extreme fragility of the skeleton and other connective tissues. ● There are multiple intrauterine fractures of long bone, which have a crumpled appearance on roentgenograms. ● There is striking micromelia and bowing of extremities; the legs are held abducted at right angles to the body in the "frog-leg position." ● Multiple rib fractures create a beaded appearance and the small thorax body size with enlarged anterior andposterior fontanelles. ● Sclerae are dark blue-gray. **Type 3 Osteogenesis Imperfecta** ● “progressive deforming” type ● This is the severest nonlethal form of Ol and results in significant physical disability. Birth weight and length are often low normal. ● There are usually in utero fractures. ● There is relative macrocephaly and triangular facies (Fig. 704-1). ● Postnatally, fractures occur from inconsequential trauma and heal with deformity. ● Disorganization of the bone matrix results in a "popcorn" appearance at the metaphyses (Fig. 704-2). ● The rib cage has flaring at the base, and pectal deformity is frequent. ● Virtually all type III patients have scoliosis and vertebral compression. ● Growth falls below the curve by the first year, all type III patients have extreme short stature. ● Scleral hue ranges from white to blue. **Type 4 Osteogenesis Imperfecta** “moderately severe” type ● Patients with type IV OI may present at birth with in utero fractures or bowing of lower long bones. ● They may also present with recurrent fractures after ambulation. ● Most children have moderate bowing even with infrequent fractures. ● Type IV children require orthopedic and rehabilitation intervention, but they are usually able to attain community ambulation skills. ○ Fracture rates decrease after puberty. Radiographically, they are osteoporotic and have metaphyseal flaring and vertebral compressions. ● Type IV patients have moderate short stature. Scleral hue may be blue or white.

Answer 254

● The diagnosis is confirmed by collagen biochemical studies using fibroblasts cultured from a skin punch biopsy. ○ Most collagen structural mutations cause a delay in helix formation, which results in over modification of chains and the presence of broad or delayed bands on protein electrophoresis. ○ In type I OI, the reduced amount of type I collagen results in an increase in the type III:type I collagen ratio detected by protein electrophoresis. ○ Molecular techniques can identify the particular collagen mutation. This allows family members to be diagnosed using leukocyte DNA. ● Severe OI can be detected prenatally by level II ultrasonography as early as 16 weeks of gestation. OI and thanatophoric dysplasia may be confused. ○ Fetal ultrasonography may not detect type IV OI and rarely detects type I OI. ○ For recurrent cases, chorionic villus biopsy can be used for biochemical or molecular studies in appropriate cases. ● In the neonatal period, the normal to elevated alkaline phosphatase levels present in OI distinguish it from hypophosphatasia.

Answer 255

● The morbidity and mortality of OI are cardiopulmonary. ○ Recurrent pneumonias and transient cardiac failure occur in childhood and cor pulmonale is seen in adults. ● Neurologic complications include basilar invagination, brain stem compression, hydrocephalus, and syringohydromyelia. ○ Most types III and IV children have basilar invagination, but brain stem compression, hydrocephalus and syringohydromyelia. - Most types III and IV children have basilar invagination is best detected w spiral CT of the craniocervical jxn

Answer 256

- there is no curative tx for OI. For severe nonlethal OI, active physical rehab in the early years allows children to attain a higher fxnal lvl than orthopedic mgmt alone ○ Type I and some type IV children are spontaneous ambulators. ○ Type III and severe type IV children benefit from long leg plastic braces, gait aids, and a program of swimming and conditioning. ○ Severely affected individuals require a wheelchair for community mobility but can acquire transfer and self-care skills. ● Orthopedic management of Ol is aimed at fracture management and correction of deformity to enable function. ○ Fractures should be promptly splinted or cast; Ol fractures heal well, and cast removal should be aimed at minimizing immobilization osteoporosis. ○ Correction of long bone deformity requires an osteotomy procedure and placement of an intramedullary rod. ● Treatments with calcium or fluoride supplements or calcitonin do not improve Ol. ○ Growth hormone improves bone histologic characteristics in growth-responsive children (usually types I and IV). ● Intravenous bisphosphonate treatment given each month may improve bone density and decrease bone turnover and new fractures. ○ Bone marrow (mesenchymal cell) transplantation is an experimental approach to Ol. ○ Ol teens may require psychological support with body image issues.

Answer 257

● Ol is a chronic condition that limits both life span and functional level. ○ Infants with type II Ol usually die within months to a year of life. ○ An occasional child with radiographic type II and extreme growth deficiency may survive to the teen years. ○ Type III Ol individuals have a reduced life span with clusters of mortality from pulmonary causes in early childhood, the teen year, and the 40s. ○ Types IV and I Ol are compatible with a full life span. ● Individuals with type III Ol are usually wheelchair-dependent. ○ With aggressive rehabilitation, they may attain transfer skills and household ambulation. ○ Type IV Ol children usually attend community ambulation skills either independently or with gait aids.