MONOGENIC CHARACTERS AND DISEASES

Question 1

MONOGENIC DISORDERS WITH CLASSIC MENDELIAN INHERITANCE ARE DOMINANT AND RECESSIVE IN WHAT?

Answer 1

DOMINANT = structural defects
RECESSIVE = enzyme defects (1 normal allele is enough to maintain normal enzyme as enzymes are produced in excess)

Question 2

DISCUSS AUTOSOMAL DOMINANT

Answer 2

-gene on autosome
-manifests in a heterozygote (Aa → A)
-one parent is affected (heterozygote) = 50% children are effected heterozygotes and 50% children will be healthy
-both parents are affected (heterozygotes) = 25% children will be affected homozygotes, 50% children will be affected heterozygotes and remaining 25% of children will be healthy
-not dependent on sex
-occurs in each generation
-vertical pedigree character – in each generation there is an effected member
-healthy parents have healthy children (exceptions are mutations and incomplete penetrance)

Question 3

DISCUSS AUTOSOMAL RECESSIVE

Answer 3

-gene on autosome
-manifests only in a recessive homozygote (aa)
-if both parents are carriers then they will have 25 % children effected, 25 % healthy and 50 % carriers
-horizontal pedigree character – healthy individual has a sudden sick child
-more frequent in consanguinities (incest / occurs in siblings)
-not dependent on sex

Question 4

EXPLAIN X LINKED RECESSIVE

Answer 4

• male = hemizygote (only one X chromosome)
• impossible transmission from father to son
• men are either sick (sick man -> 100% healthy children, but all daughters are carriers) or healthy
• women can be sick, carrier (50% sick sons, 50% carrier daughters) or healthy
  -disease occurs every second generation (women carriers transfers the
  disease to their son, who is then sick, transfers it to his daughter, she is a carrier but appears healthy -> disease skipped a generation
  -this type of heredity looks like incomplete penetrance
  -if one woman is sick (and suspects that the mutation did not form de novo)
  -> father had to be sick and mother carrier
  -> all sons will be sick and all daughter will be carriers
  -disease can never be carried from father to son, men are sick only through the female line
  -daughters of sick men are always carriers

Question 5

DISCUSS X LINKED DOMINANT

Answer 5

-very rare
-females affected more than males
-gene on X chromosome
-manifests in a heterozygote (XX → only one X is affected → sick)
-effected man + healthy woman -> healthy sons, sick daughters

Question 6

LACTOSE INTOLERANCE

Answer 6

-AD
-affects 10% caucasians
-mutation of lactose-hydroxylase
-frequency of >1/2000

Question 7

ADULT POLYCISTIC KIDNEY DISEASE

Answer 7

-AD
-Mutation of gene PKD1 - 16. chromosome (85%) or PKD2 on 4. chromosome (15%)
->Both genes regulate intracellular concentration of Ca2+
-Treatment through dialysis and kidney transplant
-Child type also exists - autosomal recessive, very rare
-Frequency 1/1000

Question 8

NEUROFIBROMATOSIS TYPE 1 (NF1, von Recklinghausen disease)

Answer 8

-AD
-NF1, Ch17
-Nerve defects
-Frequency = 1/3000
-Mutation in tumour suppressor gene -> predisposition to tumours; epilepsy
-Half of patients have a de novo mutation
-First symptoms are café au lait spots on skin, yellow spots on iris (not dangerous, but important for diagnosis)
benign tumours of PNS and malignant tumours of CNS; then follows a neurofibroma (tumour), which causes
organ failure and death

Question 9

TUBEROUS SCLEROSIS

Answer 9

-AD
-Nerve defects
-Mutation in gene TSC1 on 9. chromosome or TSC2 on 16. chromosome
-Both genes slow down cell division, without them there is a build-up of benign tumours almost everywhere
-Symptoms differ depending on the location of formation, often there is however a change of behavioural character, intelligence, discorded learning, epilepsy, lumps on the skin, heart failure, kidney failure, pulmonary cysts and sometimes internal bleeding

Question 10

HUNTINGTINS DISEASE

Answer 10

-AD
-Nerve defects
-Dynamic mutation – non-Mendelian inheritance
- Mutation of Huntingtin gene on 4. chromosome
-neurodegenerative disease, progressive dementia with involuntary muscle contractions
-manifestations at around 50 years of age, earlier manifestation is through paternal transmission

Question 11

HEREDITARY SPHEROCYTOSIS

Answer 11

-AD
-RBC defects
-frequency 1/5 000
-Mutation of genes coding for cytoskeletal proteins and erythrocyte membranes
-anaemia, enlargement of spleen, increased number of underdeveloped erythrocytes, gallstones, osteoporosis

Question 12

OSTEOGENESIS IMPERFECTA

Answer 12

-AD
-Skeletal defects
- frequency 1/5 000
-Disorders of connective tissue, specifically genes of collagen, which leads to frequent fractures, lens deformities and hearing loss

Question 13

EHLERS-DANOS SYNDROME

Answer 13

-AD
-Skeletal defects
-Also, collagen disorder but a different type of collagen
-Many versions of disease can include fragility and elasticity of skin, hypermobility of joints

Question 14

MARFAN SYNDROME

Answer 14

-AD
-Skeletal defects
-Mutation of gene FBN1 on 15. Chromosome which causes the production of fibrillin for elastic connective tissue
-Can also be a mutation de novo – risk increases with the age of father
-pleiotropy - disorders of more than one system – in this case the skeleton, cardiovascular system and eyes
-> skeleton – spider man – long fingers (arachnodactyly) and other deformities
-> heart – improper closing of mitral valve (blood flows from atrium to ventricle nonstop) and weak walls of blood vessels, which the aorta may not handle and break (which is often the cause of death of this syndrome); aneurysm of aorta
-> eyes – ectopia lentis; retinal detachment

Question 15

ACHONDROPLASIA

Answer 15

-AD
-Skeletal defects
-Mutation of gene for the fibroblast growth factor receptor (FGFR) which causes an undeveloped cartilage = short
stature
-Because bones growth through the ossification of cartilage; no cartilage à no growth
-Head is disproportionally large compared to body, spine is curled, maximal height is 110cm
-In 80 % of patients the disease is formed de novo
-affects the proximal segment of limbs (e.g. humerus bone) -> shortest
-hot spot = site of frequent mutation

Question 16

FAMILIAL ADENOMATOUS POLYPOSIS COLI (FAPC)

Answer 16

-AD
-Mutation of tumor suppressor genes
-APC gene - Ch5
-Deletion of normal allele à hypomethylation of DNA -> activation of oncogene -> deletion of P53 -> cancer = cancer everywhere
-Treated by preventive removal of effected part of intestine

Question 17

RETINOBLASTOMA

Answer 17

-AD
-Mutation of tumor suppressor gene
-retinal cancer
-hereditary retinoblastoma – manifests early, tumours are frequent and in both eyes
-sporadic retinoblastoma – manifests later, only one tumour

Question 18

VITAMIN D RESISTANCE RICKETS

Answer 18

-Practically no longer exists nowadays
-Kidneys have an impaired ability to reabsorb phosphate, which causes abnormal ossification
-X-linked dominant

Question 19

HAEMOPHILIA

Answer 19

-X linked coagulation defects
-No coagulation due to no or insufficient formation of coagulation factors (total 12) VIII or IX
-First signs manifest when the concentration of coagulation factors decreases below 10% of standard level, under 1% is considered severe
-Pathological phenotype – less than 5 % coagulation factor
-Spontaneous bleeding post mild traumas, bleeding into joints and GIT (bleeding into large joints -> arthrosis -> hemarthrosis)
- haemophilia A - frequency 1/5 000 men; deficiency of coagulation factor VIII
-haemophilia B - frequency 1/35 000 men; deficiency of coagulation factor IX
- Haemophilia C, AR (4. chromosome), very rare and deficiency of coagulation factor

Question 20

DALTONISM

Answer 20

-X linked recessive
-mutation in gene coding for rhodopsin (red-green colour-blindness)

Question 21

NON SPECIFIC X LINKED MENTAL RETARDATION

Answer 21

-X linked recessive
-frequency 1/2 000 men

Question 22

FRAGILE X SYNDROME

Answer 22

-X linked recessive
-frequency 1/4 000 men, belong to dynamic mutations (non-Mendelian), mental retardation

Question 23

X LINKED MUSCULAR DYSTROPHY

Answer 23

Duchenne and Becker muscular dystrophy (DMD a BMD) – diseases have a different site of deletion of the same gene
-Progressive muscular atrophy, affects mainly men
-mutated gene for dystrophin, which leads to the breakdown of muscle fibre, cause of death is usually heart failure
-> dystrophin has the longest gene and several tissue specific promotors
-> ensure the attachment to the extracellular fibres – ensure the communication between the inside and outside
-muscular fibres die and are replaced by connective tissue
-problems walking from a young age, begin to walk later, cannot jump, need support when standing up
Duchenne - frequency 1/3 500 men
-> Upper variant – effects the dystrophin connection site for actin
-> Manifestation in early childhood, death around 20 years old
-> Muscle fibrosis
-> 33 % mutation de novo
Becker - frequency 1/20 000 men
-> Milder variant, disease effects sites in the central region of the protein, where it is hidden, onset at 11 years

Question 24

PRIMARY HEMOCHROMATOSIS (bronze diabetes)

Answer 24

-AR
-frequency 1/400
-mutation gene HFE on 6. chromosome
-> very low penetrance
-> accumulation of iron in tissues- liver (cirrhosis), heart (cardiomyopathy), skin (bronze colour due to the build-up of iron under the skin) and pancreas (low of ability to produce insulin -> diabetes)
-signs – gender dependent – women have easier symptoms – do not eat as much red meat (which is high in iron) and loose blood (and thus even iron) through menstruation

Question 25

CYSTIC FIBROSIS

Answer 25

-most common AR disease
-delta F508, CFTR gene, Ch7
-frequency of 1/2500
-Most common lethal AR disease in Caucasians (every 25th is a heterozygote)
-Mutation in gene coding for chloride ion channel found in cytoplasmic membrane
-Defected export of chloride and water, which leads to increased viscosity of mucus, which then blocks the lower respiratory airways and eventually leads to death, either due to suffocation or bacterial infections at around 30
years old
-During the middle ages, heterozygotes had an evolutionary advantage against some dehydrating diseases (cholera)
-Severity depends on location and type of mutation

Question 26

ALPHA1-ANTITRYPSIN DEFICIENCY

Answer 26

-AR
-α1-antitrypsin is an inhibitor of elastase, which is a cleaving enzyme
-when there is low concentration of α1-antitrypsin, then elastase cleaves and destroys the lungs, causes emphysema = destruction of lung tissue
-cigarettes significantly worsen the prognosis, encourage the production of elastase

Question 27

CONGENITAL ADRENAL HYPERPLASIA

Answer 27

-AR
-frequency 1/10 000
-Steroid metabolism defects
-Loss of enzyme involved in the biosynthesis of steroid hormones
-When there is no aldosterone and cortisol, the there is a massive loss of salt (untreated leads to death)
- If there is no 21-hydroxyláase, then common precursors are transformed into androgens, which results in masculinization of women and premature puberty in men
- Due to the fact that the body is missing steroid, the body starts to produce large amounts of ACTH (brain is trying to encourage the production of steroids from the adrenal glands) which leads to excessive bilateral enlargement
of adrenal glands
-Treated with by giving mineralocorticoids and glucocorticoids

Question 28

PHENYLKETONURIA

Answer 28

-AR
-Amino acid defects
-frequency of 1/10,000
-Deficiency of enzyme phenyl-alanine hydroxylase, which transforms phenylalanine into tyrosine
-Phenylalanine accumulates in blood and its metabolites destroy the myelin sheaths of nerves in CNS
-Children have muscular hypertonicity and convulsions, they also develop severe mental retardation
-Typically, blonde + blue eyes + light skin (because of tyrosine deficiency, tyrosine is involved in the synthesis of melanin)

Question 29

SMITH-LEMLI-OPITZ SYNDROME

Answer 29

-AR
-Lipid metabolism defects
-frequency 1/10 000
-Deficiency of enzyme 7-dehydrocholesterolreductase which catalyses the last step in cholesterol synthesis
-behavioural abnormalities, brain, heart, kidney, genital, polydactyly abnormalities

Question 30

TAY SACHS

Answer 30

-AR
-lysosomal enzyme defects
-most common in Ashkenazi jews due to interbreeding and close community
-enzyme hexosaminidase; progressive neurological dysfunction

Question 31

GAUCHER DISEASE

Answer 31

-AR
-lysosomal enzyme defects
-most common in Ashkenazi jews due to interbreeding and close community
-enzyme β-glucosidase; anaemia, hyperplasia of liver and pancreases neurological complications

Question 32

NIEMANN PICK DISEASE

Answer 32

-AR
-Lysosomal enzyme defects
-enzyme sphingomyelinase; epilepsy, hyperplasia of liver and pancreas, cirrhosis of liver

Question 33

MUCOPOLYSACCHARIDOSES

Answer 33

-AR
-lysosomal enzyme defects
-disorders of many enzymes involved in mucopolysaccharide metabolism
-There is a whole spectrum of symptoms for each concrete enzyme; in general, however the following symptoms occur : k chronic and progressive multi system failure both physical and mental

Question 34

GALACTOSEMIA AND FRUCTOSE INTOLERANCE

Answer 34

-AR
-Saccharide metabolism defects
-Disorders in the utilization of monosaccharides, relatively preventable and curable symptoms (both mental and physical)

Question 35

VON GIERKE OR POMPE DISEASE

Answer 35

-AR
-Glycogen storage defects
-Hepatic (von Gierke disease) or Muscle (Pompe disease)
-Excessive accumulation leading to hypoglycaemia

Question 36

SICKLE CELL ANAEMIA

Answer 36

-AR
-RBC defects
-defect of β-subunit, heterozygotes have an advantage against malaria, formation of abnormal haemoglobin HbS

Question 37

ALPHA THALASSEMIA

Answer 37

-AR
-RBC defects
-missing α –subunit of haemoglobin

Question 38

BETA THALASSEMIA

Answer 38

-AR-RBC defects
-missing B - subunit of haemoglobin

Question 39

WHEN DOES NEW BORN SCREENING OCCUR?

Answer 39

48-72 hours after birth, blood taken from heel and examined for genetic disorders
-18 disorders examined

Question 40

WHAT DISEASES ARE EXAMINED DURING NEW BORN SCREENING?

Answer 40

1: congenital hypothyroidism (CH) – congenital decreased thyroid function
2: congenital adrenal hyperplasia (CAD)
3: cystic fibrosis (one exception – we cannot cure but control the symptoms)
-> 8 disorders of amino acid metabolism
-phenylketonuria
-leucinosis (maple syrup urine disease) – disorder of BCAA metabolism
-citrullinemia type I- deficit of arginosuccinate synthase
-argininemia - deficit of arginase
-homocystinuria from cystathionine beta synthase deficiency
-homocystinuria from methylenetetrahydrofolate reductase deficiency
-glutaric aciduria type I
-isovaleric aciduria
-> 6 disorders of fatty acid metabolism
-medium chain acyl-CoA dehydrogenase deficiency
-very long chain acyl-CoA dehydrogenase deficiency (VLCAD deficiency)
-long chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHAD deficiency)
-carnitine palmitoyl transferase I deficiency (CPT I deficiency)
-carnitine palmitoyl transferase II deficiency (CPT II deficiency)
-carnitine-acyl-carnitine translocase deficiency (CACT deficiency)
-hereditary disorders of vitamin transformation
-biotinidase deficiency (BTD)

Question 41

WHAT DOES HOLANDRIC INHERITANCE MEAN?

Answer 41

Y linked

Question 42

WHAT ARE CHROMOSOME ABERRATIONS?

Answer 42

change in the number of chromosomes
or by changes in the chromosomal structure

EG:
- Klinefelter’s syndrome: 47, XXY.
- Edward’s Syndrome (Trisomy 18): 47, XY +18.
- Down’s syndrome (mongolism): 47, XY, +21; or 47, XX, +21.

Question 43

EXPLAIN TRANSLOCATION

Answer 43

transfer of chromosome segments to make a non-homologous chromosome

Question 44

WHAT IS A KARYOTYPE?

Answer 44

image which shows the sum of all chromosome information in an individual cell
-image rearranged so that chromosomes are lined up in pairs, beginning with autosomes and ending in sex chromosomes

Question 45

LI FRAUMENI

Answer 45

AD
-cancer causing
-mutation in TP53 gene
-chromosome 17

Question 46