Genetic Disorders: Alpha1 Antitrypsin and Abetalipoproteinemia

Hepatotoxicity (liver damage)

Isolated high triglycerides due to the liver producing too much VLDL.

Fibrates (fenofibrate, gemfibrozil)

Muscle pain (myopathy)

Decreased myopathy risk

Pancreatitis and abdominal pain

Fructokinase deficiency; asymptomatic

Aldolase B deficiency; severe presentation

Leads to jaundice, cirrhosis, and hypoglycemia (low blood sugar) in Hereditary Fructose Intolerance

Avoid table sugar (sucrose)

Milder; infantile cataracts, galactose in urine

GALT deficiency, severe presentation; liver problems, mental impairment

Galactose is converted to galactitol by aldolase reductase, causing cataracts.

Stop breastfeeding for infants

E.coli infections are a concern in neonates with classic galactosemia

Co-dominant, not recessive.

Produced in the liver; sequestered there.

Breaks down elastase; build-up of elastase causes emphysema.

Hepatic cirrhosis; pan-acinar emphysema.

Smoking increases elastase activity, worsening emphysema.

Misfolded glycoprotein aggregation; endoplasmic reticulum accumulation and hepatocyte death causes cirrhosis; increased elastase in lungs leads to emphysema.

Deficiency of ApoB-48 and ApoB100.

Decreased fat absorption; increased steatorrhea.

Decreased absorption of fat-soluble vitamins (A, E).

Acanthocytes (spur cells).

Converts glucose to sorbitol and galactose to galactitol.

Osmotic injury to cells, leading to neuropathy and cataracts.

Cataracts are from galactitol, not sorbitol; other symptoms are due to a different enzyme.

Lack of homogentistic oxidase (needed to break down tyrosine to fumarate).

Urine becomes dark/black upon standing.

Painful joints; orochronosis (blue/black/brown connective tissue).

Different imprinting of chromosome 15.

Maternal imprinting or uniparental disomy.

Obesity, mental impairment, hyperphagia.

Paternal imprinting or uniparental disomy.

Mental impairment, happy disposition.

NADPH oxidase deficiency; inability to create reactive oxygen intermediates to kill microbes.

Catalase-positive organisms (e.g., Candida, Serratia, etc.).

A technique used to identify individuals based on variations in their DNA, particularly VNTRs (Variable Number of Tandem Repeats).

Used to detect single nucleotide polymorphisms (SNPs) in DNA.

A method used to determine the order of nucleotides (A, T, C, G) in DNA.

Used to measure mRNA levels by converting mRNA to cDNA, then amplifying it with PCR.

Enzyme-Linked Immunosorbent Assay, a sensitive test used for screening.

Detects antigens by coating the plate with antibodies.

Detects antibodies by coating the plate with antigen.

Leads to night blindness, increased infections, skin issues, and susceptibility to measles.

Can cause high intracranial pressure, birth defects, and dry skin.

Can treat certain cancers/leukemias by inducing differentiation of cancer cells.

A cofactor for glutathione peroxidase, an enzyme that converts hydrogen peroxide into water.

Causes anosmia, dysgeusia, decreased wound healing, & acrodermatitis enteropathica.

Leads to dry beriberi (neuropathy), wet beriberi (cardiomyopathy), and Wernicke-Korsakoff syndrome.

Brain disorder caused by thiamine deficiency, characterized by ataxia, confusion, and ophthalmoplegia.

A cofactor for oxidation/reduction reactions involving FAD/FADH2, crucial in the TCA cycle.

A cofactor for oxidation/reduction reactions, improves lipid profiles (HDL, VLDL).

Can cause flushing, hyperglycemia, and gout.

Abnormal exchange of chromosome segments, often associated with specific cancers (leukemia).

A genetic disorder affecting collagen synthesis due to a defect in lysyl oxidase activity.

Inherited maternally, characterized by ragged red fibers, visual/hearing problems, hypotonia, and lactic acidosis.

Presence of more than one type of mitochondrial DNA in a single individual, contributing to variable disease severity.

Not all individuals with a pathogenic gene variant develop the associated condition.

Even individuals with the same disease-causing genotype may have different disease presentations.

Mitochondrial disorder with seizures, ataxia, hearing loss, and myopathy.

Genetic disorder causing a buildup of phenylalanine due to a deficiency in phenylalanine hydroxylase or tetrahydrobiopterin.

Subtype of PKU where phenylalanine hydroxylase is deficient.

Subtype of PKU where tetrahydrobiopterin is deficient.

If a pregnant mother has PKU, she has to watch her diet to prevent phenylalanine entering the baby's system.

Group of neurocutaneous disorders including NF1, NF2, TSC, VHL, and Sturge-Weber syndrome.

Autosomal dominant disorder on chromosome 17, characterized by neurofibromas, café au lait spots, and Lisch nodules.

Autosomal dominant disorder on chromosome 22, characterized by bilateral acoustic schwannomas.

Autosomal dominant disorder impacting the function of TSC1 and TSC2 genes, presenting with skin lesions and organ-based abnormalities.

Autosomal dominant disorder on chromosome 3 characterized by hemangioblastomas in multiple organs, primarily the brain, retina, and kidneys.

X-linked recessive disorder impacting FMR1 gene, resulting in physical and mental developmental issues.

Autosomal dominant disorder on chromosome 4, resulting in progressive neurological and cognitive dysfunction.

Autosomal recessive disorder on chromosome 9, characterized by a range of neurological and muscular issues.

Autosomal dominant disorder on chromosome 19, resulting in muscle weakness, inability to relax muscles, and other features.

Group of inherited metabolic disorders affecting the urea cycle, causing elevated ammonia levels.

Inherited disorder impacting pyrimidine synthesis, resulting in increased orotic acid in the body.

DNA analysis technique used for identification of specific DNA sequences.

RNA analysis technique used for identification of specific RNA sequences.

Protein analysis technique used for detection of specific proteins from cell or tissue samples.

Increased serotonin synthesis depletes tryptophan, reducing niacin production. Niacin deficiency leads to pellagra (dementia, dermatitis, diarrhea).

Lifestyle changes are the initial approach; niacin is the most effective treatment, but only after lifestyle changes.

Essential for coenzyme-A (CoA) reactions. Deficiency causes adrenal insufficiency and burning feet syndrome.

Isoniazid (TB treatment) depletes B6. B6 deficiency can cause seizures (due to decreased GABA).

B6 is a cofactor for cystathionine synthase. Used in treating homocysteinuria.

Crucial for heme production; deficiency leads to sideroblastic anemia.

Vitamin B6 is necessary for various decarboxylase reactions, including those involved in heme synthesis.

Vitamin B6 is required for niacin synthesis.

Vitamin B6 is necessary for hepatic transaminase reactions.

Essential for decarboxylase reactions, including those that convert pyruvate to oxaloacetate, acetyl-CoA to malonyl-CoA, and propionyl-CoA to methylmalonyl-CoA.

Consumption of raw egg whites, due to avidin binding to B7, can cause deficiency.

Dietary folate (B9) is converted to tetrahydrofolate (THF) in the body.

Dark green leafy vegetables are a good source of folate (B9).

Folate deficiency can cause elevated Mean Corpuscular Volume (MCV) in blood tests.

Deficiencies in B9 (folate) and B12 can cause megaloblastic anemia and hypersegmented neutrophils.

Maternal folate deficiency (B9) during pregnancy can lead to neural tube defects in the developing fetus.

Antiepileptic drugs like phenytoin, valproic acid, and carbamazepine can impair folate absorption, leading to deficiency.

Vitamin B12 is involved in converting homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA.

Elevated serum methylmalonyl-CoA levels suggest B12 deficiency.

Urine test that shows purple/blue/magenta color indication in patients with cystinuria and homocystinuria.

Autosomal recessive genetic disorder located on chromosome 7.

A cAMP-regulated and ATP-gated chloride channel crucial for fluid balance in the lungs and other organs.

Mutation causing misfolded CFTR protein retention in the endoplasmic reticulum (ER).

Increased activation of the epithelial sodium channel (ENaC) leading to fluid imbalance.

Diagnosis method using sweat chloride testing (accurate than genotyping).

Different alleles causing the same cystic fibrosis disease.

Nasal transepithelial potential difference (TEPD) less than 40 mV in CF patients.

Pseudomonas infections (more common after 10 years) and Staphylococcus aureus (more common before 10 years).

Nasal polyps, bronchiectasis, clubbing, malabsorption, vitamin deficiencies (ADEK and B12), diabetes mellitus, and infertility (congenital bilateral absence of vas deferens).

Failure to pass meconium (first stool) in newborns with CF.

N-acetylcysteine, guaifenesin, and ivacaftor (targets misfolded CFTR).

Inherited disorder causing immotile cilia (impaired function).

Situs inversus (mirror-image organ arrangement) and chronic respiratory infections.

Presence of sperm in sample suggests Kartagener syndrome.

Meiotic non-disjunction, robertsonian translocation (14q;21q), or post-fertilization errors leading to mosaicism.

Increased risk of Down syndrome with advancing maternal age (35+).

Epicanthal folds; slanted palpebral fissures, flat facies, and heart defects (AVSD, ostium primum ASD, mitral/tricuspid regurg, pulmonary HTN).

Failure of neural crest cell migration potentially contributing to heart malformations.

Tracheoesophageal fistula, duodenal atresia, Hirschsprung disease, ALL, AML, hypothyroidism, eustachian tube dysfunction, and early-onset Alzheimer's disease.

Increased nuchal translucency, decreased PAPP-A, and increased beta-hCG.

Decreased AFP, estriol, and inhibin A; increased beta-hCG.

Low-set ears, micrognathia, prominent occiput, clenched hands, rocker-bottom feet, omphalocele, and Meckel diverticulum with gut malrotation.

Decreased AFP, estriol, beta-hCG, and inhibin A.

Holoprosencephaly, cleft lip/palate, and polydactyly.

Flattened facies and elongated philtrum (upper lip indentation).

Mutations in the dystrophin gene (DMD).

Cytoskeletal protein stabilizing the muscle fibers and acting as a connecting molecule to the extracellular matrix.

Dystrophin binds to a protein called beta-dystroglycan.

Duchenne is more severe than Becker; Becker has a later onset.

Characteristic way of standing up, using hands to push up on legs. In Duchenne muscular dystrophy.

Appearance of enlarged muscles due to fat and fibrous tissue buildup. In Duchenne and Becker muscular dystrophy.

Substances that disrupt the proton gradient in the inner mitochondrial membrane, increasing oxygen consumption.

2,4-Dinitrophenol, ethanol, aspirin, thermogenin

Inhibits electron transfer to oxygen in the electron transport chain.

Fe3+ hemoglobin cannot bind oxygen; blood appears chocolate brown.

Bright red lips/face/nail beds due to CO binding to hemoglobin.

Hyperbaric oxygen therapy.

Hyperchylomicronemia due to LPL or ApoC-II deficiency.

Hypercholesterolemia due to LDL receptor deficiency.

Hypercholesterolemia and hypertriglyceridemia stemming from LDL receptor and VLDL issues.

Remnant accumulation due to ApoE deficiency.

Hypertriglyceridemia from VLDL overproduction.

Statins inhibit HMG-CoA reductase, increasing LDL receptor expression, and decreasing cholesterol production.

LPL typically positioned on endothelial cell surfaces.

Co-dominant; not recessive.

Produced and sequestered in the liver.

Breaks down elastase, preventing emphysema.

Hepatic cirrhosis and pan-acinar emphysema.

Smoking increases elastase activity, worsening emphysema.

Misfolded protein aggregates, endoplasmic reticulum accumulation leading to hepatocyte death, and increased elastase in lungs causing emphysema.

Deficiency of ApoB-48 and ApoB100.

Decreased fat absorption, leading to increased steatorrhea.

Decreased absorption of fat-soluble vitamins, such as A and E.

Acanthocytes (spur cells).

Converts glucose to sorbitol and galactose to galactitol.

Causes osmotic injury leading to complications like neuropathy and cataracts.

Lack of homogentistic oxidase, needed to break down tyrosine to fumarate.

Urine turns dark/black upon standing.

Painful joints and orochronosis (blue/black/brown connective tissue).

A genetic disorder causing an inability of neutrophils to kill microorganisms due to defects in NADPH oxidase.

A diagnostic test for CGD that measures the ability of neutrophils to produce reactive oxygen species in response to stimulation.

Interferon-gamma, a treatment for CGD.

An enzyme found in the granules of myelocytes and neutrophils that gives sputum its color and is released during leukemia.

Structures seen in acute myeloid leukemia (AML) composed mainly of myeloperoxidase.

A major structural protein found in skin, bone, dentin, and cornea, crucial for late wound repair.

A genetic disorder affecting collagen type I, leading to multiple fractures, blue sclerae, and conductive hearing loss.

A disorder characterized by abnormally dense bones, due to decreased osteoclast activity.

A collagen type that primarily exists in cartilage, nucleus pulposus, and vitreous body, important for supporting connective tissues.

A genetic disorder characterized by defective Type II collagen, leading to progressive deafness and ocular problems.

A collagen type present in granulation tissue (early wound healing), blood vessels, and fetal tissue, forming retiulin.

A group of genetic disorders affecting collagen synthesis, leading to hyperelastic skin, joint hypermobility, and increased risk of vascular issues.

A collagen type forming the basement membranes of various tissues, including the glomerulus and alveoli.

A genetic disorder affecting collagen type IV, typically X-linked, presenting with kidney problems, ear/eye problems (specifically in males).

An autoimmune disorder where autoantibodies target type IV collagen in the glomerular basement membrane.

A multi-step process involving gene transcription, translation, modification, and crosslinking of glycine-rich proteins.

A genetic disorder affecting the reabsorption of cystine in the kidneys, leading to the formation of hexagonal cystine stones.

Liver damage (hepatotoxicity)

High triglycerides from liver overproduction of VLDL; isolated high triglycerides

Fibrates (fenofibrate, gemfibrozil) are most effective

Reduces muscle pain (myopathy) risk

Pancreatitis and abdominal pain

Fructokinase deficiency; asymptomatic

Aldolase B deficiency, severe; liver problems (jaundice, cirrhosis), low blood sugar

Avoid sucrose (table sugar)

Milder; cataracts, galactose in urine

GALT deficiency, severe; liver and mental issues

Converted by aldose reductase, leading to cataracts

Stop breastfeeding

Sepsis is a concern in infants

An enzyme that requires biotin (vitamin B7) for its function.

Enzyme that converts oxaloacetate (OAA) into phosphoenolpyruvate (PEP) to produce glucose

Rate-limiting enzyme of gluconeogenesis

Enzyme that converts glucose-6-phosphate (G6P) into glucose

Glycogen storage disease type I caused by a deficiency in glucose-6-phosphatase

Enzyme that converts propionyl CoA to methylmalonyl CoA with biotin.

Enzyme that converts methylmalonyl CoA to succinyl-CoA, requiring vitamin B12.

Leads to accumulation of methylmalonyl CoA causing neurological issues.

Glycogen storage disease characterized by reduced alpha 1,6 glucosidase (debranching enzyme).

Glycogen storage disease where a lysosomal debranching enzyme (alpha 1,4 glucosidase) is deficient.

Glycogen storage disease involving a deficiency in muscle glycogen phosphorylase.

Impaired absorption of neutral amino acids, mainly tryptophan.

Impaired reabsorption of various substances, including amino acids, glucose, bicarbonate, and phosphate in the proximal tubules.

Alternative pathway for glucose metabolism creating NADPH, crucial for cellular redox reactions.

Leads to decreased NADPH production, increasing susceptibility to hemolysis.

Genetic disorder causing buildup of homocysteine due to cystathionine synthase deficiency.

Nutritional disorder caused by protein deficiency leading to hypoalbuminemia and edema.

Congenital hypothyroidism, resulting in mental retardation, stunted growth, and other symptoms.

Inability to digest lactose, leading to lactose intolerance symptoms.

Used to treat hyperammonemia by promoting ammonia excretion.

Inherited disorder affecting branched-chain amino acid metabolism, causing specific odor in urine.

Genetic disorder affecting connective tissue, causing specific physical characteristics and risks.

X-linked recessive disorder affecting copper absorption and utilization.

Leads to tryptophan depletion, reducing niacin synthesis.

A disease caused by niacin deficiency, characterized by dementia, dermatitis, and diarrhea.

Lifestyle changes are the initial approach; niacin is the most effective treatment after lifestyle changes.

Essential for coenzyme A (CoA) reactions; deficiency leads to adrenal insufficiency and burning feet syndrome.

INH use depletes B6; leading to seizures and neuropathy.

B6 deficiency due to INH reduces GABA, which contributes to seizures.

B6 is a cofactor, essential in treating homocysteinuria.

Essential for heme synthesis; deficiency results in sideroblastic anemia.

Vitamin B6 is necessary for various decarboxylase reactions.

Vitamin B6 is required for niacin synthesis.

B6 is important for hepatic transaminase reactions.

Essential for decarboxylase reactions (pyruvate—>oxaloacetate, acetyl-CoA—>malonyl-CoA, propionyl-CoA—>methylmalonyl-CoA).

Consumption of raw egg whites due to avidin binding to biotin.

Converted to tetrahydrofolate (THF) in the body.

Dark green leafy vegetables are a good source of folate (B9).

Folate deficiency can cause an elevated mean corpuscular volume (MCV) in blood tests.

Deficiencies in B9 (folate) and B12 can cause megaloblastic anemia and hypersegmented neutrophils.

Maternal folate deficiency can lead to neural tube defects in the developing fetus.

Antiepileptic drugs can impair folate absorption, leading to deficiency.

B12 converts homocysteine to methionine and methylmalonyl-CoA to succinyl-CoA.

Elevated serum methylmalonyl-CoA levels suggest B12 deficiency.

A positive nitroprusside cyanide test, causing urine to turn purple, blue, or magenta.