Autosomal recessive disorders

Question 1

Characteristics of Autosomal Recessive (AR) Disorders

Answer 1

a) Phenotype expressed only in people who have two mutant alleles of the same gene.
b) Both parents of an affected child are obligated carriers of the disease-causing allele(s).
c) Men and women are usually equally affected.
d) Horizontal pedigree (affected individuals are usually siblings).
e) Carriers are usually undetected, thus the birth of the first affected child is usually unexpected.
The recurrence risk is 1 in 4 (25%) for each unborn child of the same couple.
f) The probability of an unaffected sibling being a carrier is 2/3.
g) The majority of mutant allele(s) are present in carriers instead of patients.
h) Sometimes with a higher frequency within people of a small group (high-risk group).
i) Increased incidence of parental consanguinity for a child affected by a rare AR disorder.

Question 2

Allelic heterogeneity

Answer 2

the existence of multiple mutant alleles of a single gene.

Question 3

Compound heterozygote

Answer 3

one who carries two different mutant alleles of the same gene.

Question 4

Parental consanguinity

Answer 4

parents sharing one or more common ancestors.

Question 5

high-risk group –

Answer 5

a population with higher-than-expected risk for a particular AR disease.

Question 6

PKU phenotype

Answer 6

Microcephaly and profound mental retardation if untreated during infancy. Neurobehavioral symptoms such as seizure, tremor, and gait disorders are common. High phenylalanine and low tyrosine levels in the plasma because the conversion from Phe to Tyr is impaired. High levels of phenylalanine metabolites in urine and sweat gives a characteristic “mousy” odor.

Question 7

Newborn PKU screening

Answer 7

1. Guthrie test
2. mass spec
3. timing of test is important to remove phenylalanine from diet

Question 8

guthrie test

Answer 8

thienylalanine inhibits the growth of the bacterium Bacillus subtilis and that such inhibition can be overcome by a high level of phenylalanine in the blood sample of a PKU baby.

assay

Question 9

PKU mass spec

Answer 9

for pku

Question 10

pku gene

Answer 10

PAH gene is at chromosome 12q22-24

Question 11

α1-Antitrypsin Deficiency (ATD) a. Phenotypes

Answer 11

20-fold increased risk of developing emphysema,

late-onset,

80- 90% of deficient individuals will develop disease symptoms.

Many develop liver cirrhosis

increased risk of liver carcinoma due to the accumulation of a misfolded α1-AT mutant protein in the liver.

Question 12

The main target of SERPINA1 is ______

Answer 12

elastase

Question 13

α1-antitrypsin also called

Answer 13

ATT or SERPINA1

Question 14

The SERPINA1 gene is on chromosome

Answer 14

The SERPINA1 gene is on chromosome 14 (14q32.13)

Question 15

a1-antitrypsin alleles

Answer 15

The Z allele (Glu342Lys) encodes a misfolded protein that aggregates in the endoplasmic reticulum (ER) of liver cells, causing damage to the liver in addition to the lung.

The S allele (Glu264Val) expresses an unstable protein that is less effective.

Question 16

Z allele

Answer 16

Glu342Lys

Question 17

S allele

Answer 17

Glu264Val

Question 18

Tach sachs biochemical defects

Answer 18

T-S is a lysosomal storage disease. Inability to degrade GM2 ganglioside results in up to 300-fold accumulation of this sphingolipid inside swollen lysosomes in neurons of the central nervous system. A defective hexosaminidase A (HexA) needed for in metabolizing GM2 is responsible for T-S. HexA is a heterodimer of αβ, which are encoded by the HEXA and HEXB genes, respectively. Although HexA is a ubiquitous enzyme, the impact of T-S is primarily in the brain where most of GM2 ganglioside is synthesized.

Question 19

Ba:

Answer 19

wild type

Question 20

Bs

Answer 20

sickle cell anemia mutant allele

Question 21

Bc

Answer 21

hemoglobin C disease mutation

Question 22

PKU phenotypes

Answer 22

High phenylalanine level in the blood.

High levels of phenylalanine metabolites in the urine.

Hyperactivity and epilepsy.

Mental retardation and microcephaly.

Question 23

PKU biochem

Answer 23

Defects in PAH (phenylalanine hydroxylase) (>98%)

Defects in the PAH cofactor BH4 (tetrahydrobiopterin) (1~2%)

Question 24

PKU maternal effect problem

Answer 24

PKU women are low phd diet in pregnancy
increased risk of miscarriage
congenital phenylalanin level in maternal circulation

Question 25

PKU maternal effect casue

Answer 25

elevated phenylalanien level in maternal circulation

Question 26

ATD biochemical

Answer 26

Deficiency in a1-antitrypsin (SERPINA1, AAT), a protease inhibitor

mutations in a1-AT (SERPINA1) gene.

Question 27

tay sachs symptoms

Answer 27

Loss of voluntary movement.
Seizure.
Mental retardation.
Vegetative state.

Question 28

Gm2 ganglioside degradaion requires

Answer 28

3 proteins

Question 29

Tay sachs screening

Answer 29

1. carrier screening higher in high risk populations
2. prenatal diagnosis when both parents are carriers
3. enzymatic activity test
4. DNA test