Autosomal Recessive Disorders Flashcards
Characteristics of Autosomal Recessive (AR) Disorders: Phenotype expressed only in people who have _______
two mutant alleles of the same gene
Characteristics of Autosomal Recessive (AR) Disorders: Both parents of an affected child are _______
obligated carriers of the disease-causing allele(s)
Characteristics of Autosomal Recessive (AR) Disorders: Men and women are usually _______
equally affected
Characteristics of Autosomal Recessive (AR) Disorders: Horizontal pedigree (affected individuals are usually _______).
siblings
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.
undetected
unexpected
1 in 4 (25%)
Characteristics of Autosomal Recessive (AR) Disorders: The probability of an unaffected sibling being a carrier is _______.
2/3
Characteristics of Autosomal Recessive (AR) Disorders: The majority of mutant allele(s) are present in _______
carriers instead of patients
Characteristics of Autosomal Recessive (AR) Disorders: Sometimes with a higher frequency within people of a _______ (high-risk group).
small group
Characteristics of Autosomal Recessive (AR) Disorders: Increased incidence of _______ for a child affected by a rare AR disorder
parental consanguinity
Allelic heterogeneity
the existence of multiple mutant alleles of a single gene.
Compound heterozygote
one who carries two different mutant alleles of the same gene.
Parental consanguinity
parents sharing one or more common ancestors.
high-risk group
a population with higher-than-expected risk for a particular AR disease.
Phenylketonuria: Phenotypes
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
Phenylketonuria: Frequency
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.
Phenylketonuria: Biochemical defects
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.
Phenylketonuria: Molecular basis
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.
Phenylketonuria: Screening
Sequence specific oligonucleotide probes can be used to distinguish the M, Z and S alleles in a target population and provide accurate prenatal diagnosis.
Phenylketonuria: Environmental factors (Ecogenetics)
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.
Phenylketonuria: Treatment
Two approaches of delivering human SERPINA1 to the pulmonary epithelium are being studied: intravenous infusion and aerosol inhalation.
Tay-Sachs disease (GM2 gangliosidosis type I): Phenotypes
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.
Tay-Sachs disease (GM2 gangliosidosis type I): Frequency
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
Tay-Sachs disease (GM2 gangliosidosis type I): Biochemical defects
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.
Tay-Sachs disease (GM2 gangliosidosis type I): Molecular basis
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).