|Disease||Category||Pathogenesis / Heredity||Pathology, Cardinal Symptoms|
|Cystic Fibrosis||Autosomal Recessive. CFTR gene defect on Chrom 7 ——> No Cl– transport and failure to hydrate mucous secretions (no NaCl transport) ——> excessively viscous mucoid exocrine secretions||Meconium ileus (caused by thick, mucoid meconium), respiratory bronchiectasis,Pseudomonas pneumonia, pancreatic insufficiency, hypertonic (high Cl–concentration) sweat.|
|Fanconi Anemia||Autosomal Recessive congenital pancytopenia.||Normocytic anemia with neutropenia.
Short stature, microcephaly, hypogenitalism, strabismus, anomalies of the thumbs, radii, and kidneys, mental retardation, and microphthalmia.
|Hartnup’s Disease||Autosomal Recessive. Defect in GI uptake of neutral amino acids ——> malabsorption of tryptophan(niacin precursor) ——> niacin deficiency among other things.||Pellagra-like syndrome (diarrhea, dementia, dermatitis), light-sensitive skin rash, temporary cerebellar ataxia.|
|Kartagener’s Syndrome||Autosomal Recessive. Defect in dynein arms ——> lost motility of cilia||Recurrent sinopulmonary infections (due to impaired ciliary tract). Situs inversus, due to impaired ciliary motion during embryogenesis: lateral transposition of lungs, abdominal and thoracic viscera are on opposite sides of the body as normal. Possible dextrocardia, male sterility.|
|Pyruvate Dehydrogenase Deficiency||Autosomal Recessive. Pyruvate Dehydrogenase deficiency ——> buildup of lactate and pyruvate ——> lactic acidosis.||Neurologic defects.
Treatment: Increase intake ofketogenic nutrients (leucine, lysine) ——> increase formation of Acetyl-CoA from other sources.
|Xeroderma Pigmentosum||Autosomal Recessive. Defect in DNA repair, inability to repair thymine dimers resulting from UV-lightexposure ——> excessive skin damage and skin cancer.||Dry skin, melanomas, pre-malignant lesions, other cancers. Ophthalmic and neurologic abnormalities.|
|Familial Hypercholesterolemia||Autosomal Dominant Disorders||Autosomal Dominant. LDL-Receptor defect.||Heterozygous: accelerated atherosclerosis. Homozygous: accelerated atherosclerosis, MI by age 35, xanthomas.|
|Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Syndrome)||Autosomal Dominant Disorders||Autosomal Dominant.||Telangiectasias of skin and mucous membranes.|
|Hereditary Spherocytosis||Autosomal Dominant Disorders||Autosomal Dominant. Band-3 deficiency in RBC membrane ——> spherical shape to cells. Other RBC structural enzyme deficiencies can cause it, too.||Sequestration of spherocytes in spleen ——> hemolytic anemia.|
|Huntington’s Disease||Autosomal Dominant Disorders||Autosomal Dominant, 100% penetrance.
Genetic defect on Chrom 4 ——> atrophy of caudate nuclei, putamen, frontal cortex.
|Progressive dementia with onset in adulthood, choreiform movements, athetosis.|
|Marfan’s Syndrome||Autosomal Dominant Disorders||Autosomal Dominant. Fibrillin deficiency ——> faulty scaffolding in connective tissue (elastin has no anchor).||Arachnodactyly, dissecting aortic aneurysms, ectopia lentis (subluxation of lens), mitral valve prolapse.|
|Neurofibromatosis (Von Recklinghausen Disease)||Autosomal Dominant Disorders||Autosomal Dominant. NF1 gene defect (no GTPase protein) ——> dysregulation of Ras tumor-suppressor protein.||Multiple neurofibromas (Café au Lait spots) which may become malignant,Lisch nodules (pigmented hamartomas of the iris).
Increased risk for tumors: pheochromocytoma, Wilms tumor, Rhabdomyosarcoma, leukemias.
|Tuberous Sclerosis||Autosomal Dominant Disorders||Autosomal Dominant.||Tubers (glial nodules), seizures, mental retardation. Associated with adenoma sebaceum (facial lesion), myocardial rhabdomyomas,renal angiomyolipomas.|
|Von Hippel-Lindau Syndrome||Autosomal Dominant Disorders||Autosomal Dominant, short arm of chromosome 3. Same genetic region is associated with incidence ofrenal cell carcinoma.||(1) Hemangioblastomas of cerebellum, medulla, or retina, (2) adenomas, (3) cysts in visceral organs. High risk for renal cell carcinoma.|
|Congenital Fructose Intolerance||Carbohydrate Metabolism Defect||Autosomal Recessive. Aldolase B deficiency ——> buildup of Fructose-1-Phosphate in tissues ——> inhibit glycogenolysis and gluconeogenesis.||Severe hypoglycemia. Treatment: Remove fructose from diet.|
|Galactosemia||Carbohydrate Metabolism Defect||Autosomal Recessive. Inability to convert galactose to glucose ——> accumulation of galactose in many tissues.
(1) Classic form: Galactose-1-phosphate Uridyltransferase deficiency.
(2) Rarer form: Galactokinase deficiency.
|Failure to thrive, infantile cataracts, mental retardation. Progressive hepatic failure, cirrhosis, death.
Galactokinase-deficiency: infantile cataracts are prominent.
Treatment: in either case,remove galactose from diet.
|Angelman Syndrome||Chromosomal||Deletion of part of short arm of chromosome 15, maternal copy. An example of genomic imprinting.||Mental retardation, ataxic gait, seizures.Inappropriate laughter.|
|Cri du Chat Syndrome||Chromosomal||5p-, deletion of the long arm of chromosome 5.||“Cry of the cat.” Severe mental retardation, microcephaly, cat-like cry. Low birth-weight, round-face, hypertelorism (wide-set eyes), low-set ears, epicanthal folds.|
|Chromosomal||Trisomy 21, with risk increasing with maternal age. Familial form (no age-associated risk) is translocationt(21,x) in a minority of cases.||Most common cause of mental retardation. Will see epicanthal folds, simian crease, brushfield spots in eyes. Associated syndromes: congenital heart disease, leukemia,premature Alzheimer’s disease (same morphological changes).|
|Chromosomal||Trisomy 18||Mental retardation, micrognathia, rocker-bottom feet, congenital heart disease, flexion deformities of fingers. Death by 1 year old.|
|Chromosomal||Trisomy 13||Mental retardation, microphthalmia, cleft lip and palate, polydactyly, rocker-bottom feet, congenital heart disease. Similar to and more severe than Edward’s Syndrome. Death by 1 year old.|
|Prader-Willi Syndrome||Chromosomal||Deletion of part of short arm of chromosome 15, paternal copy. An example of genomic imprinting.||Mental retardation, short stature, hypotonia, obesity and huge appetite after infancy. Small hands and feet, hypogonadism.|
|Progressively longer tandem repeats on the long arm of the X-chromosome. The longer the number of repeats, the worse the syndrome. Tandem repeats tend to accumulate through generations.||Second most common cause of mental retardation next to Down Syndrome. Macro-orchidism (enlarged testes) in males.|
|Klinefelter’s Syndrome (XXY)||Chromosomal
|Non-disjunction of the sex chromosome during Anaphase I of meiosis ——> Trisomy (47,XXY)||Hypogonadism, tall stature, gynecomastia. Mild mental retardation. Usually not diagnosed until after puberty. One Barr body seen on buccal smear.|
|Turner’s Syndrome (XO)||Chromosomal
|Non-disjunction of the sex chromosome during Anaphase I of meiosis ——> Monosomy (45,X)||Streak gonads, primary amenorrhea, webbed neck, short stature, coarctation of Aorta, infantile genitalia. No mental retardation. No Barr bodies visible on buccal smear.|
|Trisomy (47,XXX) and other multiple X-chromosome abnormalities.||Usually phenotypically normal. May see menstrual abnormalities or mild mental retardation in some cases.|
|Ehlers-Danlos Syndrome||Connective Tissue disease||Various defects in collagen synthesis.
||Laxity of joints, hyperextensibility of skin, poor wound healing, aneurysms.
|Osteogenesis Imperfecta||Connective tissue disease||Defects in Collagen Type I formation.||Multiple fractures after birth,blue sclerae, thin skin, progressive deafness in some types (due to abnormal middle ear ossicles).
Type-I is most common;Type-II is most severe; Type-IV is mildest form.
(Glycogen Storage Disease Type III)
|Glycogen Storage Disease||Autosomal Recessive. Debranching enzyme deficiency (can only break down linear chains of glycogen, not at branch points) ——> accumulate glycogen in liver, heart, skeletal muscle.||Stunted growth, hepatomegaly, hypoglycemia.|
(Glycogen Storage Disease Type V)
|Glycogen Storage Disease||Autosomal Recessive. muscle phosphorylase deficiency (cannot utilize glycogen in skeletal muscle) ——> accumulation of glycogen in skeletal muscle.||Muscle cramps, muscle weakness, easy fatigability. Myoglobinuria with strenuous exercise.|
(Glycogen Storage Disease Type II)
|Glycogen Storage Disease||Autosomal Recessive. alpha-1,4-Glucosidase deficiency (cannot break down glycogen) ——> accumulate glycogen in liver, heart, skeletal muscle.||Cardiomegaly, hepatomegaly, and systemic findings, leading to early death.|
|Von Gierke’s Disease
(Glycogen Storage Disease Type I)
|Glycogen Storage Disease||Autosomal Recessive. Glucose-6-Phosphatase deficiency (cannot break down glycogen) ——> accumulate glycogen in liver and kidney.||Severe fastinghypoglycemia, hepatomegaly from lots of glycogen in liver.|
|Hemophilia A (Factor VIII Deficiency)||Hemophilia||X-Linked Recessive. Factor VIII deficiency||Hemorrhage, hematuria, hemarthroses. Prolonged PTT.|
|Hemophilia B (Factor IX Deficiency)||Hemophilia||X-Linked Recessive. Factor IX deficiency.||Milder than Hemophilia A. Hemorrhage, hematuria, hemarthroses. Prolonged PTT.|
|Von Willebrand Disease||Hemophilia||Autosomal dominant and recessive varieties. Von Willebrand Factor deficiency ——> defect in initial formation of platelet plugs, and shorter half-life of Factor VIII in blood.||Hemorrhage, similar to hemophilia.
Type-I: Most mild. Type-II: Intermediate. Type-III: most severe, with recessive inheritance (complete absence).
|Autosomal Recessive. Unknown. Numerous chromosomal breaks and elevated AFP is found. Symptomatic by age 2 years.||Cerebellar ataxia, telangiectasia (enlarged capillaries of face and skin),B and T-Cell deficiencies, IgA deficiency.|
|Chédiak-Higashi Syndrome||Immune deficiency
|Defect in polymerization of microtubules in neutrophils ——> failure in neutrophil migration and phagocytosis. Also results in failure in lysosomal function in neutrophils.||Recurrent pyogenic infections, Staphylococcus, Streptococcus.|
|Chronic Granulomatous Disease||Immune deficiency
|X-Linked (usually) NADPH Oxidase deficiency ——> no formation of peroxides and superoxides ——> no oxidative burst in phagocytes.||Failure of phagocytes leads to susceptibility to infections, especially Staph Aureusand Aspergillus spp. B and T cells usually remain normal.|
|Chronic Mucocutaneous Candidiasis||Immune deficiency
|T-Cell deficiency specific to Candida.||Selective recurrent Candidainfections. Treat with anti-fungal drugs.|
|Job’s Syndrome||Immune deficiency
|A failure to produce gamma-Interferon by T-Helper cells, leading to an increase in TH2 cells (no negative feedback) ——> excessively high levels of IgE.||High histamine levels, eosinophilia. Recurrent cold(non-inflammatory) Staphylococcal abscesses(resulting from high histamine), eczema.|
|Selective IgA Deficiency||Immune deficiency
|IgA deficiency may be due to a failure of heavy-chain gene switching.||The most common congenital immune deficiency. There also exists selective IgM and IgG deficiencies, but they are less common.|
|Severe Combined Immunodeficiency (SCID)||Immune deficiency
|Autosomal Recessive. Adenosine Deaminase deficiency ——> accumulation of dATP ——> inhibit ribonucleotide reductase ——> decrease in DNA precursors||Severe deficiency in both humoral and cellular immunity, due to impaired DNA synthesis. Bone marrow transplant may be helpful in treatment.|
|Thymic Aplasia (DiGeorge Syndrome)||Immune deficiency
|Failure of development of the 3rd and 4th Pharyngeal Pouches ——> agenesis of the thymus and parathyroid glands.||T-Cell deficiency from no thymus. Hypocalcemic tetany from primary parathyroid deficiency.|
|Wiskott-Aldrich Syndrome||Immune deficiency
|Inability to mount initial IgM response to the capsular polysaccharides of pyogenic bacteria.||In infancy, recurrent pyogenic infections, eczema, thrombocytopenia, excessive bleeding. IgG levels remain normal.|
|X-Linked Agammaglobulinemia (Bruton’s Disease)||Immune deficiency
|X-Linked. Mutation in gene coding for tyrosine kinase causes failure of Pre-B cells to differentiate into B-Cells.||Recurrent pyogenic infections after 6 months (when maternal antibodies wear off). Can treat with polyspecific gamma globulin preparations.|
|Fabry’s Disease||Lysosomal Storage Disease||X-Linked Recessive. alpha-Galactosidase A deficiency ——> buildup of ceramide trihexoside in body tissues.||Angiokeratomas (skin lesions) over lower trunk, fever, severe burning pain in extremities, cardiovascular and cerebrovascular involvement.|
|Gaucher’s Disease||Lysosomal Storage Disease||Autosomal Recessive. Glucocerebrosidase deficiency ——> accumulation of glucocerebrosides (gangliosides, sphingolipids) in lysosomes throughout the body.||
|Niemann-Pick Lipidosis||Lysosomal Storage Disease||Autosomal Recessive. Sphingomyelinase deficiency ——> accumulation of sphingomyelin in phagocytes.||Sphingomyelin-containingfoamy histiocytes in reticuloendo-thelial system and spleen. Hepatosplenomegaly, anemia, fever, sometimes CNS deterioration. Death by age 3.|
|Hunter’s Syndrome||Lysosomal Storage Disease||X-Linked Recessive. L-iduronosulfate sulfatase deficiency ——> buildup ofmucopolysaccharides (heparan sulfate and dermatan sulfate)||Similar to but less severe than Hurler Syndrome. Hepatosplenomegaly, micrognathia, retinal degeneration, joint stiffness, mild retardation, cardiac lesions.|
|Hurler’s Syndrome||Lysosomal Storage Disease||Autosomal Recessive. alpha-L-iduronidase deficiency ——> accumulation of mucopolysaccharides(heparan sulfate, dermatan sulfate) in heart, brain, liver, other organs.||Gargoyle-like facies, progressive mental deterioration, stubby fingers, death by age 10. Similar to Hunter’s Syndrome.|
|Tay-Sachs Disease||Lysosomal Storage Disease||Autosomal Recessive. Hexosaminidase A deficiency ——> accumulation of GM2 ganglioside in neurons.||CNS degeneration, retardation, cherry red-spot of macula, blindness (amaurosis). Death before age 4.|
|Albinism||Nitrogen Metabolism Defect||Autosomal Recessive. Tyrosinase deficiency ——> inability to synthesize melanin from tyrosine. Can result from a lack of migration of neural crest cells.||Depigmentation, pink eyes, increased risk of skin cancer.|
|Alkaptonuria||Nitrogen Metabolism Defect||Autosomal Recessive. Homogentisic Oxidase deficiency (inability to metabolize Phe and Tyr) ——> buildup and urinary excretion of homogentisic acid.||Urine turns dark and black on standing, ochronosis(dark pigmentation of fibrous and cartilage tissues), ochronotic arthritis, cardiac valve involvement. Disease is generally benign.|
|Homocystinuria||Nitrogen Metabolism Defect||Autosomal Recessive. Cystathionine synthase defect (either deficiency, or lost affinity for pyridoxine, Vit. B6) ——> buildup of homocystine and deficiency of cysteine.||Mental retardation, ectopia lentis, sparse blond hair, genu valgum, failure to thrive, thromboembolic episodes, fatty changes of liver.
Treatment: Cysteine supplementation, give excess pyridoxine to compensate for lost pyridoxine affinity.
|Lesch-Nyhan Syndrome||Nitrogen Metabolism Defect||X-Linked Recessive. Hypoxanthine-Guanine Phosphoribosyltransferase (HGPRT) deficiency ——> no salvage pathway for purine re-synthesis ——> buildup of purine metabolites||Hyperuricemia (gout), mental retardation, self-mutilation (autistic behavior), choreoathetosis, spasticity.|
|Maple Syrup Urine Disease||Nitrogen Metabolism Defect||Autosomal Recessive. Deficiency of branched chain keto-acid decarboxylase ——> no degradation of branched-chain amino acids ——> buildup of isoleucine, valine, leucine.||Severe CNS defects, mental retardation, death. Person smells like maple syrup or burnt sugar. Treatment:remove the amino acids from diet.|
|Phenylketonuria (PKU)||Nitrogen Metabolism Defect||Autosomal Recessive. Phenylalanine hydroxylase deficiency (cannot break down Phe nor make Tyr) ——> buildup of phenylalanine, phenyl ketones (phenylacetate, phenyl lactate, phenylpyruvate) in body tissues and CNS.||Symptoms result from accumulation of phenylalanine itself. Mental deterioration, hypopigmentation (blond hair and blue eyes), mousy body odor (from phenylacetic acid in urine and sweat).
Treatment: remove phenylalanine from diet.
|Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency||RBC Disease||X-Linked Recessive. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency ——> no hexose monophosphate shunt ——> deficiency in NADPH ——> inability to maintain glutathione in reduced form, in RBC’s||Susceptibility to oxidative damage to RBC’s, leading tohemolytic anemia. Can be elicited by drugs (primaquine, sulfonamides, aspirin), fava beans (favism). More prevalent in blacks.|
|Glycolytic enzyme deficiencies||RBC Disease||Autosomal Recessive. Defect in hexokinase, glucose-phosphate isomerase, aldolase, triose-phosphate isomerase, phosphate-glycerate kinase, or enolase. Any enzyme in glycolysis pathway.||Hemolytic anemia results from any defect in the glycolysis pathway, as RBC’s depend on glycolysis for energy.|
|Autosomal Recessive Polycystic Kidney Disease (ARPKD)||Renal||Autosomal Recessive.||Numerous, diffuse bilateral cysts formed in the collecting ducts. Associated with hepatic fibrosis.|
|Bartter’s Syndrome||Renal||Juxtaglomerular Cell Hyperplasia, leading to primary hyper-reninemia.||Elevated renin and aldosterone, hypokalemic alkalosis. No hypertension.|
|Fanconi’s Syndrome Type I
|Renal||Autosomal Recessive. Deficient resorption in proximal tubules.||(1) Cystine deposition throughout body, cystinuria. (2) Defective tubular resorption leads to amino-aciduria, polyuria, glycosuria, chronic acidosis;Hypophosphatemia andVitamin-D-resistant Rickets.|
|Fanconi’s Syndrome II
|Renal||Autosomal Recessive. Defective resorption in proximal tubules.||Similar to Fanconi Syndrome Type I, but without the cystinosis. Adult onset osteomalacia, amino-aciduria, polyuria, glycosuria.|
|Autosomal Dominant Polycystic Kidney Disease (ADPKD)||Renal
Autosomal Dominant Disorders
|Autosomal Dominant.||Numerous, disparate, heterogenous renal cysts occurring bilaterally. Onset in adult life. Associated with liver cysts.|