Autosomal Recessive Disorders

Question 1

Characteristics of Autosomal Recessive (AR) Disorders: Phenotype expressed only in people who have _______

Answer 1

two mutant alleles of the same gene

Question 2

Characteristics of Autosomal Recessive (AR) Disorders: Both parents of an affected child are _______

Answer 2

obligated carriers of the disease-causing allele(s)

Question 3

Characteristics of Autosomal Recessive (AR) Disorders: Men and women are usually _______

Answer 3

equally affected

Question 4

Characteristics of Autosomal Recessive (AR) Disorders: Horizontal pedigree (affected individuals are usually _______).

Answer 4

siblings

Question 5

Characteristics of Autosomal Recessive (AR) Disorders: Carriers are usually _______, thus the birth of the first affected child is usually _______. The recurrence risk is _______ for each unborn child of the same couple.

Answer 5

undetected
unexpected
1 in 4 (25%)

Question 6

Characteristics of Autosomal Recessive (AR) Disorders: The probability of an unaffected sibling being a carrier is _______.

Answer 6

2/3

Question 7

Characteristics of Autosomal Recessive (AR) Disorders: The majority of mutant allele(s) are present in _______

Answer 7

carriers instead of patients

Question 8

Characteristics of Autosomal Recessive (AR) Disorders: Sometimes with a higher frequency within people of a _______ (high-risk group).

Answer 8

small group

Question 9

Characteristics of Autosomal Recessive (AR) Disorders: Increased incidence of _______ for a child affected by a rare AR disorder

Answer 9

parental consanguinity

Question 10

Allelic heterogeneity

Answer 10

the existence of multiple mutant alleles of a single gene.

Question 11

Compound heterozygote

Answer 11

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

Question 12

Parental consanguinity

Answer 12

parents sharing one or more common ancestors.

Question 13

high-risk group

Answer 13

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

Question 14

Phenylketonuria: Phenotypes

Answer 14

ATD patients have a 20-fold increased risk of developing emphysema, with more severe symptoms among smokers. This disorder is late-onset, especially in non-smokers, but 80- 90% of deficient individuals will eventually develop disease symptoms. Many patients also develop liver cirrhosis and have increased risk of liver carcinoma due to the accumulation of a misfolded α1-AT mutant protein in the liver

Question 15

Phenylketonuria: Frequency

Answer 15

α1-antitrypsin deficiency is a common genetic disorder among Northern European Caucasians. Disease frequency is 1/2,500, carrier frequency ~1/25. The most common normal (wild-type) allele, the M allele, occurs with a frequency of 95%; thus 90% (0.952 =0.9025) of white Europeans have M/M genotype. Most ATD diseases are associated with two mutant alleles, the Z and S alleles. Individuals with Z/Z genotype have only 10-15% of normal α1-AT activity and account for most cases of the disease. Individuals with S/S genotype have 50-60% of normal α1-AT activity and usually do not express disease symptoms. Z/S compound heterozygotes have 30-35 % of normal α1-AT activity and may develop emphysema.

Question 16

Phenylketonuria: Biochemical defects

Answer 16

α1-antitrypsin (ATT or SERPINA1) is made in the liver and secreted into plasma. SERPINA1 is a member of serpins (serine protease inhibitor), which are suicide substrates that bind and inhibit specific serine proteases. The main target of SERPINA1 is elastase, which is released by neutrophils in the lung. When left unchecked, elastase can destroy the connective tissue proteins (particularly elastin) of the lung, causing alveolar wall damage and emphysema.

Question 17

Phenylketonuria: Molecular basis

Answer 17

The SERPINA1 gene is on chromosome 14 (14q32.13). There are ~20 different mutant alleles, although the Z & S alleles account for most of the disease cases. 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 18

Phenylketonuria: Screening

Answer 18

Sequence specific oligonucleotide probes can be used to distinguish the M, Z and S alleles in a target population and provide accurate prenatal diagnosis.

Question 19

Phenylketonuria: Environmental factors (Ecogenetics)

Answer 19

Smoking accelerates the onset of emphysema in ATD patients. Tobacco smoke damages the lung, prompting the body to send more neutrophils to the lung for protection. More neutrophils release more elastase, causing more severe lung damage.

Question 20

Phenylketonuria: Treatment

Answer 20

Two approaches of delivering human SERPINA1 to the pulmonary epithelium are being studied: intravenous infusion and aerosol inhalation.

Question 21

Tay-Sachs disease (GM2 gangliosidosis type I): Phenotypes

Answer 21

T-S is an inherited disorder that progressively destroys neurons in the brain and spinal cord. The most common form of T-S is an early-onset, fatal disorder apparent in infancy. T-S infants appear normal until the age of 3-6 months, when early symptoms such as muscle weakness, decreased attentiveness, and increased startle response appear. As the disease progresses, the T-S children experience symptoms of neurodegeneration including seizures, vision and hearing loss, diminishing mental function, and paralysis. An eye abnormality called “cherry-red spot” is a characteristic of T-S. Children of T-S usually live only till 3-4 years of age.

Question 22

Tay-Sachs disease (GM2 gangliosidosis type I): Frequency

Answer 22

The Ashkenazic Jewish population is at 100-fold higher risk for T-S (~1/3,600) than the general population (~1/360,000). Other high-risk groups for T-S are certain French- Canadian communities of Quebec, the Old Order Amish community in Pennsylvania, and the Cajun population of Louisiana

Question 23

Tay-Sachs disease (GM2 gangliosidosis type I): Biochemical defects

Answer 23

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 24

Tay-Sachs disease (GM2 gangliosidosis type I): Molecular basis

Answer 24

Over 100 HEXA mutations are known. The most common mutant allele (~80%) in the Ashkenazi Jewish population is a 4 bp insertion in exon 11 of HEXA, causing a frameshift and a premature stop codon in the coding sequence of the gene (i.e. it’s a null allele).

Question 25

Tay-Sachs disease (GM2 gangliosidosis type I): Screening

Answer 25

• Enzymatic activity assay
• Carrier Screening
• Prenatal screening
• DNA testing

Question 26

Tay-Sachs disease (GM2 gangliosidosis type I): Other forms of T-S

Answer 26

Juvenile and adult-onset forms of T-S are very rare with milder symptoms appearing in childhood, adolescence, or adulthood; the patients have decreased HexA activity

Question 27

Sandhoff disease (GM2 gangliosidosis type II)

Answer 27

presents the same neurological symptoms as T-S. Sandhoff disease patients have defects in both Hexosaminidase A and Hexosaminidase B (HexB); Hex B is a homodimer of ββ. T-S is caused by a defective α subunit; only HexA activity is affected. Sandhoff disease is caused by a defective β subunit; both HexA and HexB activities are affected. The α subunit gene HEXA and the β subunit gene HEXB reside on chromosomes #15 and #5, respectively.

Question 28

AB-variant of Tay-Sachs

Answer 28

is a rare form of T-S in which both HexA and HexB are normal but GM2 accumulates due to a defect in the GM2 activator protein (GM2-AP), which facilitates interaction between the lipid substrate and the HexA enzyme (α subunit) within the cell. Note: HexA and HexB refer to the two enzymes; HEXA and HEXB refer to two genes encoding the α and β subunit, respectively.

Question 29

Enzymatic activity assay

Answer 29

both HexA and HexB enzymes are present in the serum. Their activities can be distinguished in such assays because only HexA is inactivated by heat

Question 30

Carrier Screening

Answer 30

primarily among Ashkenazi Jewish population, the enzyme test has 97% accuracy because carriers have lower HexA enzyme levels in the blood.

Question 31

Prenatal screening

Answer 31

the enzyme test can also be performed on cultured amniotic fluid cells to detect T-S fetus when both parents are known to be carriers. Notably, this screening has reduced the number of T-S cases by about 95% over the past 30 years.

Question 32

DNA testing

Answer 32

The tests currently available can detect about 95% of carriers in the Ashkenazi Jewish population and about 60% of carriers among non-Jewish individuals. Therefore, some carriers will be missed by DNA test alone.