Autosomal Dominant Diseases

Question 1

Achondroplasia

Answer 1

Autosomal Dominant
Gene: Point mutation in the FGFR-3 gene
Symptoms: short-limbed dwarfism, characteristic face structure, and radiological features of the spine
Homozygotes are more severely affected-do not survive infancy

Question 2

Huntington disease

Answer 2

Autosomal Dominant
Gene: HD or huntington
HD is a trinucleotide repeat expansion disease
Symptoms: progressive dementia, choreic movements, and late age onset (30s-40s)

Question 3

Neurofibromatosis Type 1

Answer 3

Autosomal Dominant
Gene: NF1 (neurofirbomin-1)
nonsense mutation-introduce stop codon
Symptoms: cafe-au-lait spots, neurofibromas, Lisch nodules in the eye, and learning disabilities
highly variable in severity

Question 4

Marfan syndrome

Answer 4

Autosomal Dominant
Gene: FBN1 (fibrillin), involved in formation of elastic fibers in connective tissue
Symptoms: disproportionate tall stature, arachnodactyly, skeletal abnormalities, and serious cariovascular problems. Severity is variable and symptoms may be delayed.

Question 5

Familial hypercholesterolemia (FH)

Answer 5

Autosomal Dominant
Gene: LDL receptor gene, loss-of-function mutation
Symptoms:
Heterozygous: elevated LDL; deposition of cholesterol in the tendons and skin and later in life, in the arteries. Increased risk of cardiovascular disease and early MI
Homo: similar but much earlier and more extreme, LDL is higher, death due to MI is common in childhood

Question 6

Hurler Syndrome

Answer 6

Autosomal Recessive
Type of mucopolysacaridosis-a lysosomal storage disorder

Gene: alpha-L-iduronidase
enzyme catalyses the breakdown of glycosaminoglycans; deficiency results in a build up of glycosaminoglycan in lysosomes

Symptoms: progressive intellectual disability, skeletal abnormalities, short stature, corneal clouding and course facial features, deafness, heart and joint problems

Treatment: targeted enzyme replacement therapy (Aldurazyme), hematopoietic stem cell transplant (good success if used <2.5 years), combo therapy

Question 7

Tay-Sachs

Answer 7

Autosomal Recessive lysosomal strage disorder

Gene: hexosaminidase A (hexA)
Lack of hexoaminidases leads to build up of GM2 gangliosides causing neuron damage
Can be caused by various mutations:
-4-base insertion causes a frameshift and a premature stop codon
-point mutation that alters the proper splicing of mRNA

Question 8

Cystic fibrosis

Answer 8

Autosomal Recessive affecting lung function and digestive system

Gene: CFTR
Most common mutation: deletion of three nucleotides within the coding region-loss of a single AA (in-frame mutation)
CFTR is a chloride channel-mutation prevents the channel from reaching the plasma membrane-sticky mucus builds up

Question 9

Sickle Cell Disease

Answer 9

Autosomal recessive that alters the shape of RBCs
Mutation: missence mutation causes the incorporation of a wrong AA into the beta-globin protein
Clumped Hb

Question 10

Beta-Thalassemia

Answer 10

Autosomal recessive affecting hemoglobin

Gene: B-globin gene

Mutation: large number of different point mutations can cause and result in a decrease in production of B-globin
can affect:
Transcriptional levels of the gene
Splicing of the gene
AA sequence of the coding region
Stability of the protein

Question 11

Hereditary Hemochromatosis

Answer 11

Autosomal recessive
Gene: HFE (high iron)

Mutation: in most cases a single missense mutation
Homozygotes absorb 2-4 times the normal amount of iron
Delayed onset (about 30 years); not sex-linked but adult males are more affected

Treatment: blood letting

Question 12

Lesch-Nyhan Syndrome

Answer 12

X-linked recessive disease
Gene: HGPRT involved in the salvage pathway of purines
Physio: recyles 90% of purines
Patho: Purines that normally would be recycled are now degraded->overproduction of uric acid
Symptoms: premature gout from the uric acid, kidney stones, decreased production of dopamine in the brain, low IQ, spastic cerebral palsy, dystonia, self-mutilation and aggressive behavior

Question 13

Duchenne muscular dystrophy

Answer 13

X-linked recessive
Gene: dystrophin, present in muscle fibers
without frameshifts results in milders forms of diseases such as Becker muscular (protein partially active)
Symptoms: progressive weakness and muscle loss; high serum creatine; Gowers sign

Question 14

Hemophilia B

Answer 14

X-linked recessive
bleeding disorder
Gene: factor IX
Cause: point mutation in 5’ untranslated region (promoter)

Question 15

Rett Syndrome

Answer 15

X-linked dominant
Gene: methyl-CpG binding protein (MeCP2) which controls the expression of genes important in brain function
Symptoms: some autistic behaviors, seizures, gait ataxia, and heart rhythm and breathing abnormalities
Variation can be seen in females due to skewed X-inactivation patterns
Lethal to males

Question 16

Fragile X syndrome

Answer 16

X-linked dominant
Gene: FMR1 gene affects fragile X mental retardation protein which is involved in cognitive development
Symptoms: intellectual disability, distintive facial appearance
Anticipation observed due to trinucleotide expansion
More severe in males, milder in females

Question 17

Langer mesomelic dysplasia and Leri-Weill dyschondrosteosis

Answer 17

Mutation in the pseudoautosomal region of Y chromosome SHOX gene
Bone growth disorders

Question 18

Swyer syndrome

Answer 18

(46, XY gonadale dysgenesis)
Y-linked
Mutation in the SRY gene
A genotypic male will develop as a female with additional problems related to sex characteristics and fertility

Question 19

46, XX (male) testicular disorder of sex development

Answer 19

Y-linked
Translocation of the SRY gene onto an X chromosome
Individuals develop as male but with symptoms similar to Klinefelter syndrome