Genetic Disorders and Developmental Abnormalities A34-A38

Question 1

A/34. Diagnosis of genetic diseases

genetic disease terms:

penetrance,

expressivity

Answer 1

Diagnosing genetic diseases:

1. Karyotyping and Banding (Giemsa staining)
   
   • Polysomies (polyploidies are alway lethal)
   • Large deletions, translocations, insertions, duplication.
   • p - short arm q - long arm. (p comes first, q is second, gets bigger)
2. Karytyping and FISH,
   
   1. to look for exactly two of each region and that they are inthe expected locations.
3. Family History
4. Infant Blood screening for high or low levels of proteins, hormones, lipoproteins ormetabolites found in deficiencies, - phenylketonuria causing high blood levels of phenylalanine. - hypothyroidism
5. GWAS - Genome Wide Association Screening. Array based studies screening for gene polymorphisms associated with certain diseases. Via DNA or mRNA hybridization.
6. DNA sequencing or PCR test for specific suspected gene polymorphisms or repeats.
7. Body characteristics.

Penetrance: The % of patients having a genetic mutation that display symptoms, phenotype..

Expresssivity: Out of the patients that have the disease, how severe is it.

Question 2

A/35. Autosomal dominant disorders

Answer 2

Autosomal dominant disorders may be caused by mutations of a single gene, or may be caused by mutation to one of many different genes -Genetic heterogeneity.

They may also be pleitropic, as in Marfan syndrome, in which the fibrillin is mutated and causes skeletal, cardiac, and visual defects.

Modifier genes which may not be mutated themselves, can alter the severity of a disease even if it its known genetic defect is dominant, and may affect the penetrance/expressivitiy of disorders that used to be thought of more simply. Sometimes a known “autosomal dominant gene” may have reduced penetrance.

Not all individuals have the same severity of an autosomal dominant defect, variable expressivity.

Enzyme defects are less common in autosomal dominant heterozygous defects, because these can be compensated. Usually they are regulators of metabolic pathays or key structural proteins.

Some autosomal dominant disorders:

• Marfan syndrome - Fibrillin mutation. very long limbs and fingers. flexible joints, and most importantly, increased risk of mitral valve prolapse and aortic aneurysm
• Familial hypercholesterinemia - LDL receptor mutation
• Ehler Danlos syndrome - Collagen mutation.
• Huntington’s disease - CAG repeats in the huntingtin gene, severe neurology disorders.

Question 3

A/36. Autosomal recessive and X-linked disorders

Autosomal recessive disorders

Answer 3

Because both alleles are required for a recessive disorder, there is less variable penetrance of autosomal recessive disorders (as long as the person is homozygous). Many of them are 100% penetrant.

Rapid onset.

• Cystic Fibrosis - CFTR Chloride channel, prevents Cl secretion, preventing H20 secretion.
  
  • Bronchitis, Bronchiectasia
  • Pancreatitis
  • Meconium illeum blockage of illeus in newborns, because of the excessive viscocity of the meconium (the very first poop)
• Phenylketonuria - Phenylalanine hydroxylase
  
  • _​_phenylalanie accumulation, causing sever retardation by 6 months
• Tay-Sachs disease - Hexosaminidase,
  
  • _​_ganglioside accumulation
  • lysosomal storage disease
• SCID - adenosine deaminase
  
  • _​_dATP accumulates in all cells,
  • Inhibits ribonucleotide reductase
  • Prevents DNA synthesis, preventing cell division.
• Alpha- Beta-Thalassemia - hemoglobin
  
  • _​_Defect in either one of the four alpha chain genes
  • Or in the single Beta chain gene - less
  • Cause varying degrees of Microcytic anemia or hypoxia due to impaired hemoglobin oxygen binding/releasing ability.
• Sickle cell anemia - hemoglobin
  
  • _​_causes hgb aggregation and rupture of RBCs.
  • sickle shape also damages spleen over time.
• Galactosemia
• Lysosomal stoarge diseases
  
  • ​Tay Sachs
  • Gaucher disease - Glucosylceramidase. glucosylceramide accumulation
    
    • Can cause hepatosplenomegaly and bone disorders 99%
    • Or can cause those in addition to severe CNS impairment
  • Neimann-Pick disease: Sphingomyelinase deficiency.
    
    • Hepatosplenomegaly
    • Severe CNS defects.
  • Pompe’s disease: Lysosomal storage disorder of glycogen, lysosomal acid hydrolase disorder. Cardiac and skeletal muscle defects.
• ​​Glycogen storage diseases
  
  • ​McArdles
  • G-6-Pase
  • Debranching enzyme

Question 4

A/36. Autosomal recessive and X-linked disorders

X-linked recessive disorders.

Answer 4

Duchenne-Becker muscular dystrophy - Dystrophin gene inactivating mutation/deletion.

• Dystrophin is needed for normal muscle function, by anchoring the sarcomere to the cll membrane. These indivudals have skeletal and cardiac muscle problems.
• Variable size of muscle fibers,
• Degeneration/necrosis in muscle
• Adipose infiltration
• Delayed walking, skeletal muscle weakness
• Pulmonary weakness causes dcreased ventilation, infection, pulmonary inssuficiencies.

Hemophelia A - Factor VIII both hemophelias are errors of the intrinsic pathway.

Hemophilia B - Factor IX

Fragile X syndrome - FMRP fragile-x mental retardation protein 3 nucleotides (CGG) repeat in the FMR1 gene, leading to gene silencing. FMRP is highly expressed everywhere, but highest in the brain, causing severe mental retardation.

Question 5

A/37. Cytogenetic disorders

Terminology of chromosomal numbers,

how do most chromosomal additions/deletions occur?

Answer 5

Cytogenetic disorders = Chromosomal changes. Number or large structural deletions, mutation, inverstions, cyclic chromosome formation.

terms:

Euploid: is any exact multiple of the haploid number.

Diploid: what all somatic cells are. 46 chromosomes.

Polyploid: 3n 4n etc.

Aneuploid: any thing that is not an exact multiple. Chromosome deletions/duplications result in aneuploidy.

Usually results from Nondisjunction of homologous pairs in Meiosis 1 (four chromosomes go to one cell) or in meiosis 2 (2 go to one cell).

Mosaicism: When a non-disjunction occurs early in the blastocyst, and there are multiple populations of cells in the same person. Usually occurs in the sex chromosomes, but not in autosomes.

Robertsonian translocation, aka centric fusion. The two long arms of chromosomes join, and so do two of the short arms, forming one very long chromosome and one very short one. The short one is then usually degraded/lost. Rsulting in aneuploidy.

Question 6

A/37. Cytogenetic disorders

What are the structural abnormalities and how do they occur.

Answer 6

Translocation. Reciprocal translocation may not be harmful, but if the translocation disrupts a gene or forms a new fusion gene it can be very damaging.

Robertsonian translocation, aka centric fusion. Occurs between two Acrocentric chromosomes, which have the centrosome very near to one end, ie one very long arm and one very short one. The two long arms of chromosomes join, and so do two of the short arms, forming one very long chromosome and one very short one. The short one is then usually degraded/lost. Rsulting in aneuploidy.

Isochromosomes: When the chromosomes divide down a horizontal axis instead of vertically. Creating one with two long arms and one with two short arms. most common one is X chromosome long arm isochromosome. In females, This generates Trisomy of the long arm and monosomy of the short arm.

Inversion: Can be Para-centric not involving the centrosome, or Peri-centric, inversion around the centrosome.

Deletion: deletions involving the centrosome delete the whole chromosome/are lethal.

Ring chromosomes: are a type of deletion. Loss of both ends of the long and short arms, and then they are fused.

Duplication

Insertion

Question 7

A/37. Cytogenetic disorders

What are the 3 most common Autosomal Aneuploidies

Answer 7

Trisomy 21 - Maternal age is a very large risk factor. 1/25 chance if mother is over 45.

Trisomy 18 - Edward’s Syndrome

• Severe retardation, Heart defects, Renal malformations, low ears, short neck, very small mouth, Fingers overlap, very large occipital skull. Very severe and usually lethal within 1 year.

Trisomy 13- Patau Syndrome:

• Extra fingers. Cleft lip/palate. Small eyes, small skull, micropthalmia, microcephaly. Cardiac defects and Renal defects. Also very severe and lethal within 1 year.

Question 8

A/37. Cytogenetic disorders

22q11.2 deletion syndromes

Answer 8

Spectrum of disorders resulting from various sized deletions around this locus.

• Congenital heart disease, palate and facial abnormalities, developmental delay, thymic hypoplasia (low T cell immunity), parathyroid hypoplasia (hypocalcemia).
• Causes DiGeorge syndrome: when patients have T cell immunodeficiency and hypocalcemia as dominant features.
• Have high risk for bipolar or schizophrenia development.

Question 9

A/37. Cytogenetic disorders

Sex chromosome abnormalities

Answer 9

Klinefelter syndrome (gelder syndrome) - Males with multiple X chromosomes

• Hypogonadism and infertility are main characteristics.
• May involve other feminizing characteristics.

Turner syndrome - XO or X-X with short arm deletion, or mosiac with XX, and XO.

• Webbed neck, hairline
• Stunted growth
• But NO mental retardation
• Hypogonadism
• Delayed or absent puberty

Question 10

A/38. Single-gene disorders with atipical patterns of inheritance.

Answer 10

1. Fragile X Syndrome
2. Huntington’s disease
3. Mitochondrial DNA mutations
   
   • Affect skeletal muscle, heart, brain - areas of highest oxidative metabolism.
4. Impaired gene imprinting syndromes
   
   • Prader-Willi syndrome
   • Angelman syndrome

Fragile-X Syndrome: Caused by a trinuleotide repeat in the FMR gene. normally about 50, affected people have 200-4000 repeats. More severe in males, as it is X-linked.

Atypical inheritance:

1. 20% of males that genetically have these repeats are clinically normal.They are called Carrier Males, and transmit the disease on to their grandsons, via their daughters.
2. Affected Females are very common in this disease, as many as 50% of females with one fragile X chromosome may be mentally retarded
3. Amplification of severity, with each generation it is passed on.

Huntington’s Syndrome:

1. CAG repeats, likely cause a neurotoxic gain of function of the protein. Because Knockouts are lethal. Severe neural problems.

Leber hereditary optic neuropathy:

1. ​Progressive blindness due to impairment and progressive degeneration of the CNS visual center.

Prader-Villi syndrome and Angelmann syndrome

1. In the normal state, there are two genes between the q11 and q13 regions, one of which is paternally imprinted, and the other is maternally imprinted.
2. In Prader-Villi syndrome: The paternal allele is deleted, resulting essentially in a knockout of the maternally imprinted gene, and normal expression of the paternally imprinted one
3. In Angelmann syndrome: the maternal allele is deleted, so there is a knockout of the gene that is paternally imprinted, and normal expression of the maternally imprinted one.

• Angelman syndrome, the laughing puppet one, seizures and ataxia.
• Prader-Willi, Obese, short, hypotonic, hypogonadism.
• Both: mental retardation.