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• Ornithine transcarbamylase deficiency - most common urea cycle disorder - X-linked recessive (vs other urea cycle enzyme deficiencies!) - often present in the first few days of life - ↑ orotic acid in blood and urine- ↓ BUN (blood urea nitrogen)- symptoms of hyperammonemia- no megaloblastic anemia (vs orotic aciduria)
• Cystinuria - autosomal recessive - defect of renal PCT and intestinal amino acid transporter that prevents reabsorption of Cystein, Ornithine, Lysine, and Arginine (COLA) - excess cystein in the urine can lead to recurrent precipitation of cystine stones Treatment:- urinary alkalinization (eg potassium citrate, acetazolamide)- chelating agents (eg penicillamine) - urinary cyanide-nitroprusside test is diagnostic
• Neurofibromatosis - autosomal dominant Neurofibromatosis type 1 = Recklinghausen disease- Mutation of the tumor suppressor gene NF1 located on chromosome 17- café-au-lait spots- peripheral neurofibromas- Lisch nodules (asymptomatic hamartomas of the iris)- freckling in the axilla, neck, groin and submammary regions- early age of onset- increased risk of meningeomas and pheochromocytoma Neurofibromatosis type 2 = bilateral acoustic neurofibromatosis- Mutation of the tumor suppressor gene NF2 on chromosome 22- vestibular schwannomas- tinnitus, vertigo → deafness- late age of onset- increased risk of meningeoma and ependymomas
• Hurler Syndrome - most severe mucopolysaccharidosis  - deficient iduronidase --> accumulation of heparan and dermatan slfate - coarse facies- enlarged skull- corneal clouding- hepatosplenomegaly- thickened skin- hernias- contractures- mental delay
• Hunter Syndrome - Mucopolysaccharidosis II - X-linked - progressive - symptoms between ages 2 and 4 years - abdominal hernias- atypical retinitis pigmentosa
• Duchenne muscular dystrophy - X-linked disorder typically due to frameshift or nonsense mutations → truncated or absent dystrophin protein → progressive myofiber damage. - Weakness begins in pelvic girdle muscle and progresses superiorly.- Pseudohypertrophy of the calf muscles due to fibrofatty replacement of muscle- Waddling gait- Onset before 5 years of age- Dilated cardiomyopathy is common cause of death- Gower sign – patient uses upper extremities to help stand up. - ↑ CK and aldolase; genetic testing confirms diagnosis. - Dystrophin gene (DMD) is the largest protein-coding human gene → ↑ chance of spontaneous mutation. Dystrophin helps anchor muscle fibers, primarily in skeletal and cardiac muscle. It connect the intracelular cytoskeleton (actin) to the transmembrane proteins α- and β-dystroglycan, which are connected to the extracellular matrix (ECM). Loss of dystrophin → myonecrosis.
• Achondroplasia - autosomal dominat- gain-of-function in fibroblast growth receptor 3 (FGR3) - short limb dwarfism (most common form) - proliferation of cartilage is greatly retarded in the metaphyses of long bones
• Hardy-Weinberg population genetics If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of seperate alleles, then p2 + 2pq + q2 = 1 and p + q = 1, which implies that: p2 = frequency of homozygosity for allele pq2 = frequency of homozygosity for allele q2pq = frequency of heterozygosity  The frequency of an X-linked recessive disease in males = q and in females q2 Hardy-Weinber assumptions include:- No mutation occurring at the locus- Natural seleciton is not occuring- Completely random mating- No net migration
• Cystic fibrosis Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.Most common lethal genetic disease in Caucasian population. - CFTR encodes an ATP-gated Cl- channel that secretes Cl- in lungs and GI tract, and reabsorbs Cl- in sweat glands.- Most common mutation → misfolded protein → retained in RER and not transported to cell membrane → ↓ Cl- and H2O secretion; ↑ intracellular Cl- results in compensatory ↑ Na+ reabsorption via epithelial Na+ channels → ↑ H2O reabsorption → abnormally thick mucous. ↑ Na+ reabsorption also causes more negative transepithelial potential difference. - ↑ Cl- concentration (>60 mEq/L) in sweat is diagnostic- Can present with contraction alkalosis and hypocalemia (ECF effects analogous to a patient taking a loop diuretic) because of ECF H2O/Na+ losses and concomitant renal K+/H+ wasting.- ↑ immunoreactive trypsinogen (newborn screening). - Recurrent pulmonary infection (eg, S aureus [early infancy], P aeruginosa [adolescence]), chronic bronchitis and bronchiectasis → reticulonodular pattern on CXR, opacification of sinuses.- Pancreatic insufficiency, malabsorption with steatorrhea, fat-soluble vitamin deficiencies (ADEK), biliary cirrhosis, liver disease. Meconium ileus in newborns.- Infertility in men (absence of vas deferens, spermatogenesis may be unaffected) and subfertility in women (amenorrhea, abnormally thick cervical mucus).- Nasal polyps, clubbing of nails Treatment: Chest physiotherapy, albuterol, aerosolized dornase alfa (DNase), and hypertonic saline facilitate mucus clearance. Azithromycin used as anti-inflammatory agent. Ibuprofen slows disease progression.- In patients with Phe508 deletion: combination of lumacaftor (corrects misfolded proteins and improves their transport to cell surface) and ivacaftor (opens Cl- channels → improve chloride transport).
• Edwards syndrome (trisomy 18) - severe intellectual disability- rocker-bottom feet- micrognathia (small jaw)- low-set ears- clenched hands with overlapping fingers- prominent occiput- congenital heart disease - 2nd most common autosomal trisomy resulting in live birth - ↓ AFP, ↓ β-hCG, ↓ estriol, ↓ inhibin A
• Down syndrome (trisomy 21) - intellectual disability- flat facies- prominent epicanthal folds- single palmar crease- gap between 1st 2 toes- duodenal atresia- Hirschsprung disease- congenital heart disease (eg, atrioventricular septal defect)- Brushfield spots - early-onset Alzheimer disease- ↑ risk of ALL and AML - 95% due to meiotic nondisjunction- 4% of cases due to unbalanced Robertsonian translocation (chromosomes 14 and 21)- Only 1% of cases due to postfertilization mitotic error - Incidence 1:700 - First trimester ultrasound: ↑ nuchal translucency and hypoplastic nasal bone- ↑ β-hCG, ↑ inhibin A- ↓ AFP, PAPP-A, estriol
• Cri-du-chat syndrome Congenital microdeletion of short arm of chromosome 5 (46, XX or XY, 5p-). - Microcephaly- Moderate to severe intellectual disability- High-pitched crying/meowing- Epicanthal folds- Cardiac abnormalities (VSD)
• Williams syndrome Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene). Findings:- Distinctive "elfin" facies- Intellectual disability- Hypercalcemia (↑ sensitivity to vitamin D)- Well-developed verbal skills- Extreme friendliness with strangers- Cardiovascular problems (eg, supravalvular aortic stenosis, renal artery stenosis)
• Familial adenomatous polyposis - Autosomal dominant disease - Colon becomes covered with adenomatous polyps after puberty - Progresses to colon cancer unless colon is resected - mutation on APC gene
• Hereditary hemorrhagic telangiectasia Autosomal dominant disorder; also known as Osler-Weber-Rendu syndrome - inherited disorder of blood vessels - branching skin lesions (telangiectasias)- recurrent epistaxis- skin discolorations- arteriovenous malformations (AVMs)- GI bleeding- hematuria
• Hereditary spherocytosis Autosomal dominant disorder - Spheroid erythrocytes due to spectrin or ankyrin defect - hemolytic anemia-  ↑ MCHC-  ↑ RDW Treatment: splenectomy
• Li-Fraumeni syndrome Abnormalities in TP53 --> multiple malignancies at an early age - Also known as SBLA cancer syndrome (sarcoma, breast, leukemia, adrenal gland)
• Multiple endocrine neoplasias (MEN) Several distinct syndromes (1, 2A, 2B) characterized by familial tumors of endocrine glands, including those of the pancreas, parathyroid, thyroid, and adrenal medulla. MEN 1 is associated with MEN1 gene.--> 3 P's: Parathyroid, Pancreas, Pituitary glandMEN 2A and 2B are associated with RET gene.--> MEN 2A: Medullary thyroid carcinoma, pheochromocytoma, hyperparathyroidism (20-30%)--> MEN 2B: Medullary thyroid carcinoma, pheochromocytoma, neurinomas, marfanoid habitus
• Tuberous sclerosis Autosomal dominant disorder Neurocutaneous disorder with multi-organ system involvement - characterized by numerous benign hamartomas- adenoma sebaceum- white spots- Koenen-tumor (under nails)
• Genetic disorder by chromosome: 3 - von Hippel-Lindau - Renal cell carcinoma
• Genetic disorder by chromosome: 4 - ADPKD (PKD2) - Achondroplasia - Huntington disease
• Genetic disorder by chromosome: 5 - Cri-du-chat syndrome - Familial adenomatous polyposis
• Genetic disorder by chromosome: 6 - Hemochromatosis (HFE gene)
• Genetic disorder by chromosome: 7 - Williams disease - Cystic fibrosis
• Genetic disorder by chromosome: 9 - Friedreich ataxia - Tuberous sclerosis (TSC1)
• Genetic disorder by chromosome: 11 - Wilms tumor - β-globulin gene defects (e.g. sickle cell anemia, β-thalassemia) - MEN1
• Genetic disorder by chromosome: 13 - Patau syndrome - Wilson disease - Retinoblastoma (RB1) - BRCA2
• Genetic disorder by chromosome: 15 - Praderman-Willi syndrome - Angelman syndrome - Marfan syndrome
• Genetic disorder by chromosome: 16 - ADPKD (PKD1) - α-thalassemia
• Genetic disorder by chromosome: 17 - Neurofibromatosis type 1 - BRCA1 - p53
• Genetic disorder by chromosome: 22 - Neurofibromatosis type 2 - DiGeorge syndrome (22q11)
• Becker muscular dystrophy X-linked disorder typically due to non-frameshift deletions in dystrophin gene (partially functional instead of truncated). - Less severe than Duchenne. - Onset in adolescence or early adulthood. - Deletions can cause both Duchenne and Becker dystrophies. - 2/3 of cases have large deletions spanning one or more exons.
• Myotonic dystrophy type 1 - Autosomal dominant - CTG trinucleotide repeat expansion in the DMPK gene → abnormal expression of myotonin protein kinase → myotonia, muscle wasting, cataracts, testicular atrophy, frontal balding, arrhythmia. - CTG for Cataracts, Toupee (early balding in men), Gonadal atrophy 
• Rett syndrome - Sporadic disorder seen almost exclusively in girls (affected males die in utero or shortly after birth). - Most cases are caused by de novo mutation of MECP2 on X chromosome. Symptoms usually appear between ages 1-4. - Regression (Retturn) in motor, verbal, and cognitive abilities- Ataxia- Seizures- Growth failure- Stereotyped hand-wringing
• Trinucleotide repeat expansion diseases Huntington disease: (CAG)n- Caudate has ↓ ACh and GABA Myotonic dystrophy: (CTG)n- Cataracts, Toupee, Gonadal atrophy Fragile X syndrome: (CGG)n- Chin (protruding), Giant Gonads Friedreich ataxia: (GAA)n- Ataxic GAAit
• 22q11 deletion syndromes Microdeletion at chromosome 22q11 → variable presentations including cleft palate, abnormal facies, thymic aplasia → T-cell deficiency, cardiac defects, and hypocalcemia 2˚ to parathyroid aplasia. (CATCH-22) - Due to aberrant development of 3rd and 4th branchial (pharyngeal) pouches. - DiGeorge syndrome – thymic, parathyroid, and cardiac defects - Velocardiofacial syndrome – palate, facial, and cardiac defects
• Variable expressivity Patients with the same genotype have varying phenotypes. Example: 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity.
• Incomplete penetrance Not all individuals with a mutant genotype show the mutant phenotype. % penetrance x probability of inheriting genotype = risk of expressing phenotype. Example: BRCA1 gene mutations do not always result in breast or ovarian cancer.
• Codominance Both alleles contribute to the phenotype of the heterozygote. Example: Blood groups A, B, AB; α1-antitrypsin deficiency; HLA groups.
• Pleiotropy One gene contributes to multiple phenotypic effects. Example: Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor.
• Loss of heterozygosity If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops. Example: Retinoblastoma and the "two-hit hypothesis," Lynch syndrome (HNPCC), Li-Fraumeni syndrome.
• Dominant negative mutation Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning. Example: Mutation of a transcription factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding.
• Mosaicism Presence of genetically distinct cell lines in the same individual.  Somatic mosaicism – mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs. Gonadal mosaicism – mutation only in egg or sperm cells. If parents and relatives do not have the disease, suspect gonadal (or germline mosaicism) McCune-Albright syndrome – due to mutation affecting G-protein signaling. Presents with unilateral café-au-lait spots with ragged edges, polyostotic fibrous dysplasia (bone is replaced by collagen and fibroblasts), and at least one endocrinopathy (eg, precocious puberty). Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism.
• Locus heterogeneity Mutations at different loci can produce a similar phenotype. Example: Albinism
• Allelic heterogeneity Different mutations in the same locus can produce the same phenotype. Example: β-thalassemia
• Heteroplasmy Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease. Example: mtDNA passed from mother to all children.
• Linkage disequilibrium Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.
• Uniparental disomy Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent. Heterodisomy (heterogenous) indicates a meiosis I error.Isodisomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair. Uniparental is euploid (correct number of chromosomes). Most occurences of uniparental disomy (UPD) → normal phenotype. Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier. Examples: Prader-Willi and Angelman syndromes.
• Mitochondrial diseases Mitochrondrial DNA codes for mitochondrial oxidative phosphorylation enzxmes.- Inheritance is only from mother to child Leber hereditary optic neuropathy- Loss of retinal cells, which leads to central vision loss Myoclonic epilepsy with ragged red fibers (MERRF)- Epilepsy, ataxia, peripheral neuropathy- Deterioration in cognitive ability- Sensorineural hearing loss and ocular dysfunction- Short stature- Cardiomyopathy- Muscle biopsy: ragged red fibers on Gomori trichrome staining due to the accumulation of mitochondria Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS)
• Robertsonian translocation Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.One of the most common types of translocation. Occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost. - Balanced translocations normally do not cause any abnormal phenotype.- Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal inbalance (eg, Down syndrome, Patau syndrome).

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