Genetic Disorders Chart.docx

**Genetic Disorders** Inheritance Patterns +-----------------------+-----------------------+-----------------------+ | **Autosomal | **Autosomal | **X-linked | | Dominant** | Recessive** | Recessive** | | |...

**Genetic Disorders** Inheritance Patterns +-----------------------+-----------------------+-----------------------+ | **Autosomal | **Autosomal | **X-linked | | Dominant** | Recessive** | Recessive** | | | | | | **(one parent is | **(both parents' | | | typically affected)** | genes are defective, | | | | but they aren't | | | | personally affected, | | | | often from | | | | consanguineous | | | | marriage)** | | +-----------------------+-----------------------+-----------------------+ | 1. Huntington | 1. Cystic fibrosis | 1. Duchenne muscular | | Disease | | dystrophy | | | 2. Phenylketonuria | | | 2. Myotonic | (PKU) | 2. Hemophilia A & B | | dystrophy | | | | | 3. Galactosemia | 3. Glucose-6-phospha | | 3. Marfan syndrome | (cataracts) | te | | | | dehydrogenase | | 4. Ehlers-Danlos | 4. ⍺₁-antitrypsin | deficiency (G6PD) | | (stretchy skin) | deficiency | | | | | 4. Agammaglobulinemi | | 5. Familial | 5. Glycogen storage | a | | hypercholesterole | diseases | | | mia | | 5. Wiskott-Aldrich | | | 6. Ehlers-Danlos | syndrome | | 6. Chromosome | (others) | | | 22q11.2 deletion | | 6. Fragile X | | syndrome | 7. Tay- Sachs | syndrome | | | | | | | 8. Thalassemia | | +-----------------------+-----------------------+-----------------------+ **Chromosomal Disorders** +-----------+-----------+-----------+-----------+-----------+-----------+ | **Chromos | **Turner | **Klinefe | **Down | **Prader- | **Angelma | | ome | syndrome* | lter | Syndrome* | Willi | n | | 22q11** | * | syndrome* | * | syndrome* | syndrome* | | | | * | | * | * | +-----------+-----------+-----------+-----------+-----------+-----------+ | Deletion | Monosomy | Males | **Trisomy | **Materna | **Paterna | | of a | X: | have an | 21** | l** | l** | | small | ***45X*** | extra X | | uniparent | uniparent | | piece of | | ***(47, | (Three of | al | al | | **chromos | 2nd X is | XXY)*** | 21 | disomy of | disomy of | | ome | altered/m | | chromosom | chromosom | chromosom | | 22 at | issing | More | es) | e | e | | region | | estrogen | | 15; | 15; | | 11**, | Failure | and low | *Robertso | deletion | deletion | | including | to | testerone | nian | of band | of q12 on | | the | develop | = soft | transloca | q12 on | maternal | | DiGeorge | normal | body and | tion* | paternal | chromosom | | chromosom | secondary | boobies | of the | chromosom | e | | al | sex | | long arm | e | | | region | character | Male | of | 15 | | | (DGCR). | istic | infertili | chromosom | | | | | | ty | e | | | | (DiGeorge | | and low | 21 to | | | | syndrome | | sperm | another | | | | and | | | chromosom | | | | Velocardi | | | e | | | | ofacial | | | (e.g., 22 | | | | syndrome) | | | or 14). | | | +-----------+-----------+-----------+-----------+-----------+-----------+ **X-LINKED RECESSIVE DISORDERS** X-linked recessive disorders are caused by mutations in genes on the X chromosome. Example: **G6PD Deficiency (affects blood cells)**: Common in males; carrier females may show mild symptoms depending on X-chromosome inactivation. +-----------------------+-----------------------+-----------------------+ | **Characteristics:** | **Females** | **Males** | | | | | | - **Males: Affected | - **Females have | - **Males have only | | if they inherit a | two X | one X chromosome | | mutant gene on | chromosomes, so | and | | their single X | they usually do | are hemizygous fo | | chromosome. They | not express the | r | | cannot pass the | full phenotype of | X-linked genes, | | disorder to sons, | an X-linked | so they will | | but all daughters | recessive | express the | | become | disorder because | disorder if they | | carriers.** | the normal allele | inherit the | | | on the second X | mutant gene.** | | - **Females: | chromosome | | | Usually carriers | compensates for | - **An affected | | and less affected | the mutant one.** | male does not | | due to a second | | transmit the | | normal X | - **Heterozygous | disorder to his | | chromosome, but | females (carriers | sons (who inherit | | can show mild | ) | his Y | | symptoms due to | have a 50% chance | chromosome), but | | random | of passing the | all his daughters | | inactivation of | mutant gene to | will | | one X chromosome | their sons, who | be carriers (sinc | | (lyonization).** | may be affected, | e | | | and a 50% chance | they inherit his | | | of passing the | X chromosome with | | | carrier status to | the mutant | | | their | gene).** | | | daughters.** | | | | | - **Always express | | | - **Due to random | the disorder if | | | X-chromosome | they inherit the | | | inactivation (lyo | mutant gene, | | | nization), | since they lack a | | | some cells in | second X | | | heterozygous | chromosome to | | | females may | provide a normal | | | inactivate the | copy of the | | | normal X | gene.** | | | chromosome, | | | | leading to | | | | partial | | | | expression of the | | | | disorder.** | | | | | | | | - **Usually do not | | | | express the | | | | disorder fully | | | | due to the | | | | presence of a | | | | second, normal | | | | allele. However, | | | | they can exhibit | | | | mild symptoms if | | | | some of their | | | | cells inactivate | | | | the normal X | | | | chromosome.** | | +-----------------------+-----------------------+-----------------------+ **Genetic Mutations** Trinucleotide-Repeat Mutations - Accumulation of aggregated mutant proteins in large intranuclear inclusions +-----------------------+-----------------------+-----------------------+ | **Fragile X | **Myotonic | **Huntington | | Syndrome** | Dystrophy** | Disease** | +-----------------------+-----------------------+-----------------------+ | - Loss of gene | - Gene: ***DMPK*** | - Toxic gain of | | function | (myotonic | function by | | (transcription | dystrophy protein | altered protein | | silencing) | kinase) | | | | | - Gene: ***HTT*** | | - RNA-mediated | - \[CTG\] | | | toxicity | | - \[CAG\] | | (tremor/ataxia) | | | | | | | | - Gene: ***FMRI | | | | (FRAXA)*** | | | | | | | | - \[CGG\] | | | +-----------------------+-----------------------+-----------------------+ Anticipation -- \# of repeated DNA sequences (trinucleotide repeats) tends to increase when the gene is passed from one generation to the next. Enzyme Deficiencies +-----------------------+-----------------------+-----------------------+ | **Tay-Sachs Disease** | **Marfan Syndrome** | **Familial | | | | Hypercholesterolemia* | | | | * | +-----------------------+-----------------------+-----------------------+ | Deficiency of | Mutations in **FBN1** | Mutations in the | | **hexosaminidase A** | - defect in | **LDLR** (85%) gene. | | - excessive | fibrillin-1 | | | accumulation of | (extracellular | - **APOB** (5-10%) | | certain fats | glycoprotein | | | (gangliosides) in the | essential for | - **PCSK9** (1-2%) | | brain and nerve cells | connective tissue) | | | | | Elevated low-density | | - Leads to | Defect in fibrillin-1 | lipoprotein | | progressive | → abnormal activation | cholesterol (LDL-C) - | | dysfunction of | of **TGF-β** (tissue | atherosclerotic | | the CNS | overgrowth and | plaque deposition in | | (lysosomal | instability in CV | the coronary arteries | | storage disease) | system) | and proximal aorta | | | | | | - Failure to | | | | breakdown | | | | GM2-ganglioside - | | | | abnormal | | | | accumulation in | | | | brain and nerve | | | | cells | | | +-----------------------+-----------------------+-----------------------+ **FRAGILE X SYNDROME** (Monosmy X) Genetic mutation: - Cognitive impairment - **[\[CGG\]]** repeat expansion in *familial mental retardation 1 (FMR1), causing deficiency of the FRMP protein* that leads to abnormal synapse development - Mutations on the **X chromosome** (from mom) Clinical Presentation: - Tremor/ataxia (fragile x-associated) - Primary ovarian failure (in granulosa cells and ovarian stromal cells) due to toxic gain of function by the abnormal *FMR1 mRNA* - Epilepsy - Aggressive behavior - Autism spectrum disorder/ADHD - Affects MALES **Phenylketonuria:** Learn about the enzyme deficiency responsible for phenylketonuria and its genetic implications. - ***Autosomal recessive disorder*** - Severe deficiency of the enzyme ***[phenylalanine hydroxylase (PAH)]*** leading to hyperphenylalaninemia - Mutations in both ***PAH (on chromosome 12)*** alleles to develop disease -- inability to convert *phenylamine into tyrosine* +-----------------------------------------------------------------------+ | - 1/3 of kids cannot walk | | | | - 2/3 cannot talk | | | | - Seizures | | | | - Decreased pigmentation of hair and skin | | | | - MUSTY ODOR | | | | - Eczema | +-----------------------------------------------------------------------+ - Restricting phenylalanine intake early in life to avoid intellectual disability - Usually by 6 months, severe intellectual disability becomes evident - **Maternal PKU** occurs when women with phenylketonuria (PKU) have high levels of phenylalanine due to stopping dietary restrictions in adulthood. - **Effects on Children**: 75-90% risk of intellectual disability and microcephaly; 15% risk of congenital heart disease, even if the child is a heterozygote. - **Cause**: Teratogenic effects of high phenylalanine or its metabolites crossing the placenta. - **Prevention**: Strict dietary phenylalanine restriction **before conception and throughout pregnancy** to prevent fetal anomalies. **Necrotizing Enterocolitis:** Study the risk factors and clinical course of necrotizing enterocolitis. **Risk Factors:** - Higher risk in more premature and lower birth weight infants (especially \