Genetics

Question 1

Polymorphism

Answer 1

Refers to the existence of more than one “normal” allele (form) of a gene. Polymorphism can also refer to SNP’s (single nucleotide polymorphs), which are the most common form of this phenomenon.

Question 2

Pleiotropism

Answer 2

Refers to the ability of a single gene mutation to have more than one phenotypic affect.
Marfan syndrome is another disorder in which a single gene mutation can cause many different phenotypic changes.
The gene mutation causing Neurofibromatosis 1, for example, can cause pigment changes in the skin (café au lait macules), neurofibromas and Lisch nodules.

Question 3

Genetic Heterogeneity

Answer 3

Refers to the ability of different gene mutations to cause the same phenotypic change.
Childhood deafness is another example and can be caused by 16 different types of autosomal recessive mutations.
Retinitis pigmentosa, caused by abnormal retinal pigmentation, can be caused by several different, unique gene mutations.

Question 4

Huntington disease

Answer 4

AD disorder, gain-of-function mutation

Question 5

Autosomal Dominant Disorders - Nervous System

Answer 5

Neurofibromatosis (von Recklinghausen disease)
Huntington disease*
Myotonic dystrophy*
Tuberous sclerosis (Bourneville’s disease)

Question 6

Autosomal Dominant Disorders - Skeletal

Answer 6

Marfan syndrome
Ehlers-Danlos syndrome*
Osteogenesis imperfecta
Achondroplasia

Question 7

Autosomal Dominant Disorders Gastrointestinal

Answer 7

Familial polyposis coli

Question 8

Autosomal Dominant Disorders Hematopoietic

Answer 8

Hereditary spherocytosis

von Willebrand disease

Question 9

Autosomal Dominant Disorders Metabolic

Answer 9

Familial hypercholesterolemia

Acute intermittent porphyria

Question 10

Autosomal Dominant Disorders Urinary System

Answer 10

Adult (Autosomal Dominant) polycystic kidney disease

Question 11

Neurofibromatosis Type 1

Answer 11

(von Recklinghausen disease) Autosomal dominant disorder - Up to 50% are new mutations. Results from defect of NF-1 gene which is found on chromosome 17q11. NF-1 is a tumor suppressor gene producing the protein neurofibromin.
Clinical Findings: Neurofibromas (multiple) malignant nerve tumors in ~3% of patients, cafe au lair macules 90%, Lisch nodules >94%

Question 12

Marfan Syndrome

Answer 12

Autosomal Dominant
Due to defective fibrillin protein. Fibrillin gene found on chromosome 15. Fibrillin, together with elastin, provides stability to elastic tissue.
Clinical features:
Aortic dilatation -> aortic valve incompetence
Cystic medial necrosis -> aortic dissection
Mitral valve prolapse
Increased stature and arachnodactyly
Dislocated lens (ectopia lentis)
Premature aging changes; mucopolysaccharide deposition often pronounced.

Question 13

Ehlers-Danlos Syndrome

Answer 13

Autosomal dominant disorder
Heterogenous group of disorders that result from various defect in collagen synthesis or structure (12 variants) of collagen IV, VI, VII
Mode of inheritance encompasses all 3 Mendelian patterns
Clinical Findings:
Very stretchable skin and hypermobile joints (contortionists)
Abnormal connective tissues are more easily injured and healing is delayed/abnormal

Question 14

Pleiotropism

Answer 14

Refers to the ability of a single gene mutation to have more than one phenotypic affect.
Marfan syndrome is another disorder in which a single gene mutation can cause many different phenotypic changes.
The gene mutation causing Neurofibromatosis 1, for example, can cause pigment changes in the skin (café au lait macules), neurofibromas and Lisch nodules.

Question 15

Genetic Heterogeneity

Answer 15

Refers to the ability of different gene mutations to cause the same phenotypic change.
Childhood deafness is another example and can be caused by 16 different types of autosomal recessive mutations.
Retinitis pigmentosa, caused by abnormal retinal pigmentation, can be caused by several different, unique gene mutations.

Question 16

Huntington disease

Answer 16

AD disorder, gain-of-function mutation

Question 17

Autosomal Dominant Disorders - Nervous System

Answer 17

Neurofibromatosis (von Recklinghausen disease)
Huntington disease*
Myotonic dystrophy*
Tuberous sclerosis (Bourneville’s disease)

Question 18

Autosomal Dominant Disorders - Skeletal

Answer 18

Marfan syndrome
Ehlers-Danlos syndrome*
Osteogenesis imperfecta
Achondroplasia

Question 19

Autosomal Dominant Disorders Gastrointestinal

Answer 19

Familial polyposis coli

Question 20

Autosomal Dominant Disorders Hematopoietic

Answer 20

Hereditary spherocytosis

von Willebrand disease

Question 21

Autosomal Dominant Disorders Metabolic

Answer 21

Familial hypercholesterolemia

Acute intermittent porphyria

Question 22

Autosomal Dominant Disorders Urinary System

Answer 22

Adult (Autosomal Dominant) polycystic kidney disease

Question 23

Neurofibromatosis Type 1

Answer 23

(von Recklinghausen disease) Autosomal dominant disorder - Up to 50% are new mutations. Results from defect of NF-1 gene which is found on chromosome 17q11. NF-1 is a tumor suppressor gene producing the protein neurofibromin.
Clinical Findings: Neurofibromas (multiple) malignant nerve tumors in ~3% of patients, cafe au lair macules 90%, Lisch nodules >94%

Question 24

Neurofibromatosis Type 2 (NF-2)

Answer 24

Much less frequent than Type 1. Gene found on chromosome 22 and produces the protein merlin. Also a tumor suppressor gene.
Clinical findings:
Bilateral acoustic neuromas
Multiple meningiomas
May have neurofibromas and café au lait macules
No Lisch nodules

Question 25

Marfan Syndrome

Answer 25

Autosomal Dominant Due to defective fibrillin protein. Fibrillin gene found on chromosome 15. Fibrillin, together with elastin, provides stability to elastic tissue. Clinical features: Aortic dilatation -> aortic valve incompetence Cystic medial necrosis -> aortic dissection Mitral valve prolapse Increased stature and arachnodactyly Dislocated lens (ectopia lentis) Premature aging changes; mucopolysaccharide deposition often pronounced.

Question 26

Familial Hypercholesterolemia

Answer 26

Autosomal dominant disorder Results from a defective LDL receptor, an important regulator in cholesterol metabolism May be the most frequent Mendelian disorder; estimated to occur in 1 in 500 Clinical manifestations result from high levels of total and LDL cholesterol Five distinct types of mutations can cause this entity Clinical Manifestations: Xanthelasma - lipid accumulations around the eye Xanthomas

Question 27

Autosomal Recessive Disorders Metabolic

Answer 27

``` Cystic fibrosis PKU Galactosemia Homocystinuria Lysosomal storage diseases Alpha-1-antitrypsin deficiency Wilson disease Hemochromatosis Glycogen storage diseases ```

Question 28

Cystic fibrosis (CF)

Answer 28

Pathophysiologic lesion is a defect in c-AMP-regulated ion transport across apical membranes of affected epithelial cells. The most common fatal autosomal recessive disease affecting the Caucasian population The CF gene has been localized to a single locus on the long arm of chromosome 7 The gene product is a protein called CF transmembrane conductance regulator (CFTR), which is a chloride channel that fails to be activated by c-AMP Heterozygous states may have a relative resistance to diarrheal diseases, especially cholera The impairment of transport here is failure of resorption of chloride through the duct epithelial cells.

Question 29

CF Respiratory airway and pancreatic duct cells

Answer 29

In these systems, there is a failure to transport chloride into the lumen of the airways and ducts. This is coupled with increased sodium resorption, the combination of which greatly decreases the water content in the lumens of these systems resulting in thick, viscid secretions which are difficult to clear. The viscid secretions lead to obstruction with parenchymal destruction. In the lungs, this also predisposes to infection; in particular a propensity to become infected with mucoid strains of Pseudomonas.

Question 30

CF Pancreas

Answer 30

Early on there is cystic dilatation and direct plugging of the exocrine glands and ducts with inspissated (thickened or congealed) eosinophilic secretions. Acinar atrophy with rupture, inflammation and progressive fibrosis ensues. Later, there is extensive fatty and fibrous replacement of the exocrine pancreas with relative sparing of the islet cells, although they may ultimately become involved as well and cause secondary diabetes mellitus

Question 31

CF Lungs

Answer 31

Show plugging of the submucosal tracheal mucous glands and ducts. The bronchioles often become distended with thick mucus, often associated with marked hyperplasia and hypertrophy of the mucus-secreting cells and inflammation. Atelectasis and emphysema ensue. Superimposed infections give rise to severe chronic bronchitis and bronchiectasis, and, in many cases, lung abscesses develop.

Question 32

CF Liver

Answer 32

Liver involvement follows the same basic pattern of duct involvement as in the pancreas. Early on, there is bile duct hyperplasia with mucus plugging of the bile canaliculi. Focal biliary cirrhosis is characteristic, but diffuse hepatic nodularity is seen only in a small percentage of patients.

Question 33

Alkaptonuria

Answer 33

Autosomal recessive disorder Results from lack of homogentisic oxidase causing build-up of homogentisic acid Large amount excreted in urine which causes urine to turn black upon standing Ochronosis: homogentisic acid binds to collagen in tissues imparting black-blue pigmentation to these tissues Seen especially over ears, nose and cheeks Arthropathies occur

Question 34

Autosomal Recessive Disorders Endocrine

Answer 34

Congenital adrenal hyperplasia

Question 35

Autosomal Recessive Disorders Skeletal

Answer 35

Ehlers Danlos syndrome (some variants) | Alkaptonuria

Question 36

Autosomal Recessive Disorders Neural

Answer 36

Friedreich ataxia* Neurogenic muscular atrophies Spinal muscular atrophy

Question 37

Sickle Cell Anemia

Answer 37

The mutated allele is recessive, meaning it must be inherited from each parent for the individual to have Sickle Cell disease. This is a type of missense point mutation. Inheritance of a single mutant allele results in Sickle Cell trait ≈ 60% Hemoglobin A and 40% Hemoglobin S (protective against malaria.

Question 38

Phenylketonuria (PKU)

Answer 38

Autosomal recessive disorder Affects people of Scandinavian descent; rarely seen in African or Jews Due to a severe lack of phenylalanine hydroxylase causing hyperphenylalaninemia and PKU. Unable to convert phenylalanine to tyrosine due to phenylalanine hydroxyls (PAH); results in metabolites that are excreted in the urine and sweat, producing a characteristic “mousy” odor. Infants are normal at birth, but within a few weeks develop increasing plasma levels of phenylalanine and toxic metabolites Seizures, eczema and decreased pigmentation of hair and skin (due to the lack of tyrosine, which is largely produced from phenylalanine) often accompany the mental retardation

Question 39

Maternal PKU

Answer 39

``` Anomalies can include Cardiac defects Microcephaly Low birth weight Mental retardation Slow development Language deficits ```

Question 40

Galactosemia

Answer 40

Autosomal recessive disorder Deficiency in ability to convert galactose to glucose – deficient in galactose-1-phosphate urydil transferase May clinically result in hepatomegaly/ hepatic steatosis with jaundice, cataracts, non-specific CNS changes, failure to thrive, vomiting and diarrhea May be prevented by early removal of galactose from the diet (until at least age 2)

Question 41

Tay-Sachs Disease

Answer 41

Autosomal Recessive Disorder Results from mutations affecting hexosaminidase enzyme complex A deficiency of hexosaminidase A alpha subunit causes GM2-ganglioside accumulations in the neurons of CNS and ANS Blindness with retinal cherry red spot Most common in Jews of Eastern European origin

Question 42

Niemann-Pick Disease

Answer 42

Results from the accumulation of sphingomyelin and cholesterol. Affected NPC-1 gene controls cholesterol trafficking. Types A, B and C (C is most common type) Types A and B common in Eastern European Jews Type A is the severe infantile form and is associated with the following: Neuronal death with resultant brain shrinkage Retinal cherry red spot Hepatosplenomegaly and lymphadenopathy Death at 1-3 years of age Heterogeneous clinically Hydrops fetalis and still births Neonatal hepatitis Chronic form with progressive neurologic damage

Question 43

Gaucher Disease

Answer 43

Characterized by mutations involving the glucocerebrosidase gene, resulting in decreased levels or activity of this enzyme – leading to accumulations of glucocerebrosides Type I: (99%) Involves the mononuclear phagocytes in body but not the CNS Spleen and skeletal changes common Seen in Eastern European Jews

Question 44

Hunter/Hurler Syndromes

Answer 44

``` Mucopolysaccharidoses - MPS I - MPS VII All autosomal recessive, except Hunter syndrome which is X-linked recessive Common features include Coarse facial features Clouding of the corneas Joint stiffness Mental retardation ```

Question 45

Glycogenoses

Answer 45

``` Result from some metabolic defect in the synthesis or catabolism of glycogen Hepatic type (von Gierke disease, type I) Myopathic type (McArdle syndrome, type V) Miscellaneous types (Pompe disease, type II) ```

Question 46

Pompe Disease

Answer 46

Deficiency of lysosomal acid maltase, therefore both a glycogen storage and lysosomal storage disorder Lysosomal accumulation of glycogen in multiple organs, especially the heart Early death

Question 47

Alkaptonuria

Answer 47

Autosomal recessive disorder Results from lack of homogentisic oxidase causing build-up of homogentisic acid Large amount excreted in urine which causes urine to turn black upon standing Ochronosis: homogentisic acid binds to collagen in tissues imparting black-blue pigmentation to these tissues Seen especially over ears, nose and cheeks Arthropathies occur

Question 48

X-Linked Recessive Disorders Musculoskeletal

Answer 48

Duchenne Muscular Dystrophy | Becker Muscular Dystrophy

Question 49

X-Linked Recessive Disorders Hematopoietic

Answer 49

Hemophilia A & B Glucose-6-phosphate dehydrogenase deficiency Chronic granulomatous disease

Question 50

X-Linked Recessive Disorders Neural

Answer 50

Fragile X syndrome*

Question 51

X-Linked Recessive Disorders Metabolic

Answer 51

Lesch-Nyhan syndrome | Diabetes insipidus

Question 52

Multifactorial Inheritance

Answer 52

Disorders or defects associated with multifactoral inheritance includes cleft lip/palate, congenital heart disease, coronary heart disease, hypertension, gout, diabetes mellitus and pyloric stenosis

Question 53

Mosaicism

Answer 53

defined as the presence of two or more populations of cells with different genotypes in a single individual

Question 54

Trisomy 21

Answer 54

Clinical findings: Flat facial profile Oblique palpebral fissures Epicanthic folds Congenital heart disease (40%), especially endocardial cushion defects Acute leukemia (10-20X increased risk) GI atresia, Alzheimer disease (in patients older than 40), and immunodeficiencies

Question 55

Klinefelter Syndrome

Answer 55

Male hypogonadism that occurs when there are two or more X chromosomes and at least one Y chromosome (needed for the male phenotype). 1:660 male births 82% are of the “classic” form; 47,XXY Slightly low IQ, increased risk of mental retardation with additional copies of the X chromosome Atrophic testes, hypospadias, cryptorchidism, infertility, gynecomastia, female distribution of fat and skeletal abnormalities Increased breast cancer and autoimmune disorders

Question 56

XYY Males

Answer 56

47,XYY or 48,XYYY etc. 1:1000 live-born males Phenotypically normal except may be tall and have increased acne Normal intelligence

Question 57

Turner Syndrome

Answer 57

Results from complete or partial monosomy of the X chromosome Characterized primarily by hypogonadism in phenotypic females Other phenotypic changes can also be present Clinical findings: Short stature Coarctation of aorta Edema Cystic hygromas Webbing of the neck Broad (shield) chest with widely spaced nipples Streak ovaries Nevi Primary amenorrhea (causes up to 1/3 of all cases of primary amenorrhea) Infantile genitalia Hypothyroidism (50%) Insulin resistance - can cause a form of diabetes mellitus

Question 58

Triplet Repeat Mutations

Answer 58

Fragile X syndrome (CGG) Myotonic dystrophy Friedrich ataxia (GAA) Huntington disease (CAG)

Question 59

Fragile X Syndrome

Answer 59

Prototype of diseases in which the mutation is characterized by a long repeating sequence of 3 nucleotides. CGG is the trinucleotide repeat at this location FMR-1 (familial mental retardation-1 gene), located on the X chromosome, is the gene involved Named Fragile X syndrome because the triple repeats give the X chromosome a “broken” appearance on G banding. FMR-1 protein is widely expressed, but most highly in the brain and testes, possibly explaining the syndromes most common features. In the brain, FMRP complexes with mRNA to form mRNP-FMRP complexes, which are transported down the axons and regulate transcription of specific mRNA’s. Characteristic phenotype: Long face with large mandible, large, everted ears, and macroorchidism (large testis) in 90% of post-pubertal males

Question 60

Mitochondrial Mutations

Answer 60

Mitochondrial DNA is maternally inherited mtDNA encodes for genes necessary for oxidative phosphorylation Therefore, mutations affect organs most dependent on oxidative phosphorylation, including the CNS, skeletal muscle, cardiac muscle, liver and kidneys

Question 61

Leber Hereditary Optic Neuropathy

Answer 61

Mitochondrial Mutations

Question 62

Genomic Imprinting

Answer 62

Selective inactivation of either the maternal or paternal allele, e.g. maternal imprinting refers to transcriptional silencing of the maternal allele Prader-Willi syndrome Angelman syndrome

Question 63

Prader-Willi syndrome

Answer 63

Chromosome 15 partial deletion with loss of expression of seven genes (paternal) 1 in 10,000 to 1 in 25,000 live births Signs and symptoms Poor muscle tone with weak cry and poor suckling Lack of eye coordination and almond shaped eyes Excessively sleepy Hyperphagia with obesity and diabetes Short stature with extreme flexibility Hypogondaism Learning disabilities

Question 64

Angelman syndrome

Answer 64

``` Chromosome 15 partial deletion (Maternal) 1 in 10,000 to 1 in 20,000 live births Signs and symptoms Movement disorder/ataxia Developmental delays Speech impairment Seizures with characteristic EEG changes Hypopigmented skin Sleep disturbances and hyperactive tendon reflexes ```