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122 Cards in this Set

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Adenosine deaminase deficiency
Excess ATP and dATP imbalances the nucleotide pool via feedback inhibition of ribonucleotide reductase which prevents DNA syntehsis and thus decreases lymphocyte count.
What does adenosine deaminase deficiency cause?
It is one of the major causes of SCID=severe combined immunodeficiency disease.

Think bubble boy. SCID happens to kids and is the first disease to be treated by experimental human gene therapy.
What are two purine salvage deficiencies?
Adenosine deaminase deficiency

Lesch-Nyhan syndrome
What are the findings in Lesch-Nyhan syndrome?
retardation, self-mutilation, aggression, hyperuricemia, gout, choreoathetosis
What is the issue in Lesch-Nyhan syndrome?
defective purine salvage owing to absence of HGPRT which converts hypoxanthine to IMP and guanine to GMP.

This results in excess uric acid production.

He's Got Purine Recovery Trouble.
What is the inheritance pattern of Lesch-Nyhan syndrome?
X-linked recessive
Ehlers-Danlos syndrome
Faulty collagen synthesis causing
1) hyperextensible skin
2) tendency to bleed ( so easy bruising)
3) Hypermobile joints
What can Ehlers-Danlos syndrome be associated with?
joint dislocation, berry aneurysms, organ rupture.
Ehlers-Danlos syndrome- what is most frequently involved?
Type III collagen is most frequently affected.
Osteogenesis imperfecta
genetic bone disorder aka brittle bone disease caused by a variety of gene defects.

Most common form is autosomal dominant with abnormal type I collagen causing multiple fractures with minimal trauma, blue sclerae due to the translucency of the CT over the choroid, hearing loss, dental imperfections due to lack of dentin.

Type II is fatal in utero or neonate period
Alport's syndrome
Due to a variety of gene defects resulting in abnormal type IV collagen. Most common form is X-linked recessive. Characterized by progressive hereditary nephritis and deafness. May be associated with ocular disturbances.

Remember that Type IV collagen is an important structural component of the basement membrane of the kidney, ears, and eyes.

BM has basketweave appearance on EM.
Marfan's syndrome
caused by a defect in fibrillin. It affects skeleton, heart, and eyes.

Clinical findings: tall w/ long extremities, pectus excavatum, hyperextensive joints, and long,tapering fingers and toes, cystic medial necrosis of aorta, aortic incompetence and dissecting aortic aneurysms, flooppy mitral valve, subluxation of lenses.
Emphysema cause (genetic cause)
can be caused by alpha1-antitrypsin deficiency, resulting in excess elastase activity.
Hypophosphatemic rickets
formerly known as vitamin D-resistant rickets. Inherited disorder resulting in increased phosphate wasting at proximal tubule. Results in rickets-like presentation.
Fragile X Syndrome
X-lined defect affecting the methylation and expression of the FMR1 gene. Assocaited with chromosomal breakage. The 2nd most common cause of genetic mental retardation (after Down syndrome).

Findings: macro-orchidism, long face with a large jaw, large everted ears, autism, mitral valve prolapse.
What are important X-linked recessive disorders?
Be Wise, Fool's GOLD Heeds Silly Hope.
Bruton's agammaglobulinemia, Wiskott-Aldrich syndrome, Fabry's disease, G6PD deficiency, Ocular albinism, Lesch-Nyhan syndrome, Duchenne's (and becker's) mucular dystrophy, Hunter's Syndrome, Hemophilia A and B.

Female carriers are rarely affected due to random inactivation of an X chromosome in each cells.
What are important autosomal recessive diseases?
albinism, ARPKD, cystic fibrosis, glycogen storage diseases, hemochromatosis, mucopolysaccharidoses, phenylketonuria, sickle cell anemias, sphingolipidoses, thalassemias.
What are the 4 trinucleotide repeat disorders?
Huntington's disease (CAG)
MyoTonic (CTG)
FraGile X syndrome (CGG)
Friedreich's ataxia (GAA)
Patau's syndrome
trisomy 13
Findings: severe mental retardation, rocker bottom feet, microphthalmia, microcephaly, cleft lip / palate, holoprosencephaly, polydactyly, congenital heart disease,. Death usually occurs within 1 year of birth.

(think Puberty=13, Patau's trisomy 13)
Edward's Syndrome
Trisomy 18
Findings: severe mental retardation, rocker-bottom feet, micrognathia (small jaw), low-set ears, clenched hands, prominent occiput, congenital heart disease. Death usually occurs within 1 year of birth.
Most common trisomy resulting in live birth after Down syndrome.
Think E-lection age = 18 E-dward's syndrome =18
Down Syndrome
trisomy 21
Findings: mental retardation, flat facies, prominent epicanthal folds, simian crease, gap between 1st 2 toes, duodenal atresia, congenital heart disease (most commonly septum primum-type ASD). Associated with increased risk of ALL and Alzheimer's disease.
Causes of Down Syndrome
95% of cases due to meiotic nondisjunction of homologous chromosomes (associated with advanced maternal age; from 1:1500 in women <20 to 1:25 in women > 45)

4% of cases due to robertsonian translocation.

1% of cases due to Down mosaicism (no maternal association)
Results of pregnancy quad screen when mom is pregnant with a fetus with Down Syndrome
decreased AFP

increased beta-hCG

decreased estriol

increased inhibin A
Cri-du-chat Syndrome
Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p-)

Findings: microcephaly, moderate to severe mental retardation, high-pitched crying/mewing, epicanthal folds, cardiac abnormalities

Cri-du chat = cry of the cat
Williams syndrome
Congenital microdeletion of long arm of chromosome 7 (deleted region includes elastin gene)

Findings: distinctive "elfin" facies, mental retardation, hypercalcemia (increased sensitivity to Vit D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.
22q11 deletion syndromes
CATCH-22
Variable presentaiton, including cleft palate, abnormal facies, thymic aplasia (T cell deficiency), cardiac defects, hypocalcemia 2ndary to parathyroid aplasia, due to microdeletion at chromosome 22q11.

Due to aberrant development of 3rd and 4th branchial pouches.
What are 2 examples of 22q11 deletion syndromes?
DiGeorge syndrome: thymic, parathyroid, and cardiac defects

Velocardiofacial syndrome: palate, facial, and cardiac defects
Marasmus
energy malnutrition resulting in tissue and muscle wasting, loss of subcutaneous fat, and variable edema
Kwashiorkor
-protein malnutrition resulting in skin lesions, edema, liver malfunction (fatty change due to decreased apolipoprotein synthesis). Clinical pictures is small child with swollen belly.

Kwashiorkor results from a protein-deficient MEAL: Malnutrition, Edema, Anemia, Liver (fatty)
Glycolytic enzyme deficiency
Associated with hemolytic anemia. Inability to maintain activity of Na+-K+ ATPase leads to RBC swelling and lysis.

RBCs metabolize glucose anaerobically (no mitochondria) and thus depend solely on glycolysis.

Due to deficiencies in pyruvate kinase (95%), phosphoglucose isomerase (4%), and other glycolytic enzymes
Pyruvate dehydrogenase deficiency
Causes backup of substrate (pyruvate and alanine), resulting in lactic acidosis. Can be congenital or acquired (asin alcoholics due to B1 deficiency).

Findings: neurologic defects.

Tx: increased intake of ketogenic nutrients (high fat content or increased lysine and leucine which are the only purely ketogenic amino acids).
Glucose-6-phosphate dehydrogenase deficiency
X-linked recessive disorder, most common human enzyme deficiency. More prevalent amont blacks and increases malarial resistance. NADPH is necessary to keep glutathione reduced, which in turn detoxifies free radicals and peroxides. Decreased NADPH in RBCs leads to hemolytic anemia due to poor RBC defense against oxidizing agents.
Fructose intolerance
Hereditary deficiency of aldolase B. Autosomal recessive. Fructose-1-phosphate accumulates, causing a decrease in available phosphate, which results in inhibition of glycogenolysis and gluconeogenesis.

Sx: hypoglycemia, jaundice, cirrhosis, vomiting

Tx: decreased intake of both fructose and sucrose (glucose and fructose)
Essential fructosuria
Involes a defect in fructokinase. Autosomal recessive. A benign, asymptomatic condition, since fructose does not enter cells.

Sx: fructose appears in blood and urine.

Tx: milder symptoms than analogous disorders of galactose metabolism.
Classic galactosemia
Absence of galactose-1-phosphate uridyltransferase. Autosomal Recessive. Damage is caused by accumulation of toxic substances (including galactitol, which accumulates in the lens of the eye).

Sx: failure to thrive, jaundice, hepatomegaly, infantile cataracts, mental retardation.

Tx: excluse galactose and lactose (galactose + glucose) from diet
Galactokinase deficiency
Hereditary deficiency of galactokinase. Galactitol accumulates if galactose is present in diet. Relatively mild condition. Autosomal recessive.

Sx: galactose appears in blood and urine, infantile cataracts. May initially present as failure to track objects or to develop a social smile.
What might be seen on a blood smear of someone with G6PD deficiency?
Heinz bodies--oxidized hemoglobin precipitated within RBCs

Bite cells--result from the phagocytic removal of Heinz bodies of macrophages
What are some things that can precipitate hemolysis in someone with G6PD deficiency?
Oxidizing agents like fava beans, sulfonamides, primaquine, antituberculosis drugs.

Infection because free radicals are generated via inflammatory response can diffuse into RBCs and cause oxidative damage.
Lactase deficiency
age dependent and / or hereditary lactose intolerance (African Americans, Asians) due to loss of brush-border enzyme. May also follow gastroenteritis.

Sx: bloating, cramps, osmotic diarrhea

Tx: avoid dairy products or add lactase pills to the diet.
Hyperammonemia
can be acquired (from liver disease) or hereditary. Results in excess NH4+ which depletes alpha-ketoglutarate, leading to inhibition of TCA cycle.
Symptoms of ammonia intoxication
tremor, slurring of speech, somnolence, vomiting, cerebral edema, blurring of vision
Treatment of hyperammonemia
limit protein in diet. Benzoate or phenylbutyrate (both of which bind AA and lead to excretion) may be given to decrease ammonia levels.
Prader-Willi syndrome
Due to deletion of normally active paternal allele on chromosome 15

Mental retardation, hyperphagia, obesity, hypogonadism, hypotonia
AngelMan's syndrome
deletion of normally active maternal allele on chromosome 15.

mental retardation, seizures, ataxia, inappropriate laughter

aka "happy puppet"
Onithine transcarbamoylase (OTC) deficiency
most common urea cycle disorder. x-linked recessive. (other urea enzyme deficiencies are autosomal recessive).

This deficiency interferes with the body's ability to eliminate ammonia.

Often evident in the first few days of life, but may present with late onset. Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway).

Findings: orotic acid in blood and urine, decreased BUN, sx of hyperammonemia.
What causes phenylketonuria?
decrease in phenylalanine hydroxylase or decreased tetrahydrobiopterin cofactor. Tyrosine becomes essential. Increased phenylalanine leads to excess phenylketones in urine.
Findings in phenylketonuria
mental retardation, growth retardation, seizures, fair skin, eczema, musty body odor

It is autosomal recessive.
Treatment for phenylketonuria
decreased phenylalanine (contained in aspartame such as nutrasweet) and increase in tyrosine in diet
Maternal PKU
lack of proper dietary therapy during pregnancy.

Findings in infant: microcephaly, mental retardation, growth retardation, congenital heart defects.
Alkaptonuria
aka ochronosis

Congenital deficiency of homogentisic acid oxidase in the degradative pathway of tyrosine

autosomal recessive, benign disease.

Findings include dark CT, pigmented sclera, urine turns black on standing. May have debilitating arthralgias.
albinism causes
Congenital deficiency of either of the falling: tyrosinase- autosomal recessive OR defective tyrosine transporters (decreased amts of tyrosine and thus melanin).

Can result from a lack of migration of neural crest cells.
inheritance and consequences in albinism
Inheritance: variable due to locus heterogeneity vs ocular albinism which is X-linked recessive.

Consequences: lack of melanin results in an increased risk of skin cancer.
Findings in homocystinuria
Very much increase in homocysteine in urine, mental retardation, osteoporosis, tall stature, kyphosis, lens subluxation (downward and inward), and atherosclerosis (stroke and MI).
What are the 3 forms homocystinuria?
ALL are autosomal recessive.

1) cystathionine synthase deficiency (tx: decreased Met and increased Cyst, and increased B12 and folate in diet)

2) decreased affinity of cystathionine synthase for pyridoxal phosphate (tx: increased vitamin B6 in diet)

3) homocysteine methyltransferase deficiency.
What is common between the 3 forms of homocystinuria?
All forms result in excess homocysteine and cysteine becomes an essential amino acid.
What is cystinuria?
Hereditary defect of renal tubular amino acid transporter for cysteine, ornithine, lysine, and arginine in the PCT of the kidneys.

Autosomal recessive. Fairly common (1:7000)
What are the clinical effects of cystinuria and treatment?
Excess cystine in the urine can lead to the precipitation of cystine kidney stones (cystine staghorn calculi).

Tx: acetazolamide to alkalinize the urine.
Maple syrup urine disease
blocked degradation of branched amino acids (Ile, Leu, Val) due to decrease in alphaketoacid dehydrogenase. Causes increase in alpha-ketoacids in the blood, especially Leu.

Causes severe CNS defects, mental retardation, and death. Urine smells like maple syrup.
Hartnup Disease
an autosomal-recessive disorder characterized by defective neutral amino acid transporter on renal and intestinal epithelial cells.

Causes tryptophan excretion in urine and absorption from the gut. LEADS TO PELLAGRA.
Pellagra:
The 3 D's: diarrhea, dermatitis, dementia.

can be caused by Vit B3 deficiency, Hartnup disease, malignant carcinoid syndrome, and INH (isoniazid).
Von Gierke's disease
type I glycogen storage disease

deficient in glucose-6-phosphatase

Findings: severe fasting hypoglycemia, very increased glycogen in the liver, increased blood lactate, hepatomegaly.
Pompe's disease
Type II glycogen storage disease

Deficient in lysosomal alpha-1,4-glucosidase (acid maltase)

Findings: cardiomegaly and systemic findings leading to early death.

Pompe's trashes the PUMP (heart, liver, muscle)
Cori's disease
Type III glycogen storage disease

Deficient in debranching enzyme (alpha-1,6-glucosidase)

Findings: milder form of type I with normal blood lactate levels.

Gluconeogenesis is intact.
McArdle's disease
type V glycogen storage disease

Deficient in skeletal muscle glycogen phosphorylase

Findings: increased glycogen in muscle, but can not break it down, leading to painful muscle cramps, myoglobulinuria with strenuous exercise.

McArdle's=Muscle
What are the sphingolipidoses? (lysosomal storage diseases that result in the build up of sphingolipids)
Fabry's disease, Gaucher's disease, Niemann-Pick disease, Tay-Sachs disease, Krabbe's disease, Metachromatic leukodystrophy
What are the mucopolysaccharidoses? (lysosomal storage diseases that result in the build up of mucopolysaccharides)
Hurler's syndrome

Hunter's syndrome
Enzyme deficient in Fabry's disease
alpha-galactosidase A
Enzyme deficient in Gaucher's disease
beta-glucocerebrosidase
Enzyme deficient in Niemann-Pick Disease
sphingomyelinase
Enzyme deficient in Tay-Sachs Disease
Hexosaminidase A
Enzyme deficient in Krabbe's disease
Galactocerebrosidase
Enzyme deficient in Metachromatic leukodystrophy
Arylsulfatase A
Enzyme deficient in Hurler's syndrome
alpha-L-iduronidase
Enzyme deficient in Hunter's Syndrome
Iduronate Sulfatase
Inheritance and findings in Fabry's disease
X-linked recessive

Findings: peripheral neuropathy of hands/feet, angiokeratomas, cardiovascular/renal disease
Inheritance and findings in Gaucher's disease
Autosomal recessive

Findings: hepatosplenomegaly, aseptic necrosis of femur, bone crises, Gaucher's cells (macrophages that look like crumpled tissue paper)
Inheritance and findings in Niemann-Pick disease
Autosomal Recessive

Findings: progressive neurodegeneration, hepatosplenomegaly, cherry-red spot on macula, foam cells
Inheritance and findings in Tay-Sachs disease
Autosomal recessive

Findings: progressive neurodegeneration, developmental delay, cherry-red spot on macula, lysosomes with onion skin, no hepatosplenomegaly (vs Niemann-Pick)
Inheritance and findings in Krabbe's disease
Autosomal Recessive

Findings: Peripheral neuropathy, developmental delay, optic atrophy, globoid cells
Inheritance and findings in Metachromatic Leukodystrophy
Autosomal recessive

Findings: central and peripheral demyelination with ataxia, dementia.
Inheritance and findings in Hurler's Syndrome
Autosomal Recessive

Findings: developmental delay, gargoylism, airway obstruciton, corneal clouding, hepatosplenomegaly
Inheritance and findings in Hunter's Syndrome
X-linked recessive

findings: mild Hurler's plus aggressive behavior, no corneal clouding
Accumulated substrate in Fabry's disease
ceramide trihexoside
Accumulated substrate in Gaucher's disease
glucocerebroside
Accumulated substrate in Niemann-Pick disease
sphingomyelin
Accumulated substrate in Tay-Sachs disease
GM2 ganglioside
Accumulated substrate in Krabbe's disease
Galactocerebroside
Accumulated substrate in Metachromatic leukodystrophy
cerebroside sulfate
Accumulated substrate in Hurler's syndrome
heparan sulfate, dermatan sulfate
Accumulated substrate in Hunter's syndrome
heparan sulfate, dermatan sulfate
carnitine deficiency
inability to transport LCFAs into the mitochondria resulting in toxic accumulation.

Causes weakness, hypotonia, and hypoketotic hypoglycemia
acyl-CoA dehydrogenase deficiency
Increased dicarboxylic acids, decreased glucose and ketones
Type I dyslipidemia- what is it? what is increased?
Hyperchylomicronemia

Chylomicrons are increased.

On blood test you will find elevated levels of triglycerides and cholesterol
Type I dislipidemia pathophysiology
Lipoprotein lipase deficiency OR altered apolipoprotein C-II.

Causes pancreatitis, hepatosplenomegaly and eruptive/ pruritic xanthomas (no increased risk for atherosclerosis).
Type IIa dyslipidemia- what is it? what is increased?
Familial hypercholesterolemia

LDL is increased

In the blood cholesterol will be increased
Type IIa dyslipidemia pathophysiology
Autosomal dominant absent or decreased LDL receptors.

Causes accelerated atherosclerosis, tendon (Achilles) xanthomas, and corneal arcus.
Type IV dyslipidemia- what is it? what is increased?
Hypertriglyceridemia

Increased VLDL

Will find elevated blood levels of triglycerides
Type IV dyslipidemia pathophysiology
hepatic overproduction of VLDL.

Causes pancreatitis.
Abetalipoproteinemia
Hereditary inability to synthesize lipoproteins due to deficiencies in apoB-100 and apoB-48.
Inheritance of abetalipoproteinemia
autosomal recessive
Clinical findings in abetalipoproteinemia / onset
Findings: failure to thrive, steatorrhea, acanthocytosis, ataxia, night blindness

Symptoms appear in the first few months of life.

Intestinal biopsy shows accumulation within enterocytes due to inability to export absorbed lipid as chylomicrons.
Achondroplasia
cell signaling defect of fibroblast grwoth factor receptor 3. results in dwarfism, short limbs, but head and trunk are normal size. associated with advanced paternal age.
von Hippel-Lindau disease
autosomal dominant

Findings: hemangioblastomas of retina / cerebellum / medulla; about half of affected individuals develop multiple bilateral renal cell carcinomas and other tumors.

associated with deletion of VHL gene (which is a tumor suppressor) on chromosome 3 (3p)

Results in constitutive expression of HIF (transcription factor) and activation of angiogenic growth factors. Von Hippel-Lindau=3 words for chromosome 3
What are the autosomal dominant disorders?
achondroplasia, ADPKD, FAP, Familial hypercholesterolemia (type IIA), Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), Hereditary spherocytosis, Huntington's Disease, Marfan's syndrome, MENs, Neurofibromatosis type 1 (von recklinghausen's disease), Neurofibromatosis type 2, Tuberous sclerosis, von HIppel-Lindau disease
Chediak-Higashi syndrome
microtubule polymerization defect resulting in decreased phagocytosis.

Results in recurrent pyogenic infections, partial albinism, and peripheral neuropathy
Kartagener's syndrome
immotile cilia due to a dynein arm defect.

Results in male and female infertility (sperm immotile), bronchiectasis and recurrent sinusitis (bacteria and particles are not pushed out).

associated with situs inversus (organs are switched from left to right or right to left)
Hereditary sideroblastic anemia. Defect and inheritance pattern
X-linked

delta-aminolevulinic acid synthase gene is defective which interrupts heme synthesis.
Lead Poisoning affected Enzyme
Ferrochelatase and ALA dehydratase
What is the accumulated substrate in lead poisoning?
protoporphyrin (blood)
Presenting symptoms in Lead Poisoning
Microcytic anemia, GI, and kidney disease.

Children-exposure to lead paint and then mental deterioration.

Adults--environmental exposure (battery/ammunition/ radiator factory) with following symptoms of headache, memory loss, demyelination.
Acute intermittent porphyria affected enzyme
porphobilinogen deaminase (aka uroporphyrinogen-I-synthase)
Acute intermittent porphyria accumulated substrate
porphobilinogen, delta-ALA, uroporphyrin (urine)
Acute intermittent porphyria presenting symptoms
Symptoms= 5 Ps
Painful abdomen
Pink urine
Polyneuropathy
Psychological disturbances
Precipitated by drugs

Tx: glucose and heme, which inhibit ALA synthase.
Porphyria cutanea tarda affected enzyme
Uroporphyrinogen decarboxylase
Porphyria cutanea tarda accumulated substrate
uroporphyrin (tea-colored urine)
Porphyria cutanea tarda presenting symptoms
Blistering cutaneous photosensitivity. Most common porphyria.
What enzyme deficiency causes Sideroblastic anemia (X-linked)?
delta-aminolevulinic acid synthase -- rate limiting step

Glycine + succinyl-CoA converted delta-aminolevulinic acid
What enzyme deficiency causes Lead poisoning?
delta-aminolevulinic acid dehydratase

delta-aminolevulinic acid converted to porphobilinogen
What 2 metabolic pathways is carbamoyl phosphate involved in?
de novo pyrimidine synthesis and the urea cycle
ornithine transcarbamoylase deficiency (urea cycle)
leads to accumulation of carbamoyl phosphate which is then converted to orotic acid.

Will have increased orotic acid with hyperammonemia
orotic aciduria- cause, findings, tx
Cause: inability to convert orotic acid to UMP (de novo pyrimidine synthesis pahtwya) due to defect in either orotic acid phosphoribosyltransferase or orotidine 5'-phosphate decarboxylase. AUTOSOMAL RECESSIVE

Findings: increased orotic acid in urine, megaloblastic anemia (does not improve with admin of Vit B12 or folic acid), failure to thrive. No hyperammonemia... compare OTC deficiency
I-cell disease
inclusion cell disease--inherited lysosomal storage disorder.

Failure of addition of mannose-6-phosphate to lysosome proteins (enzymes are secreted outside the cell instead of being targeted to the lysosome).

Results in coarse facial features, clouded corneas, restricted joint movement and high plasma levels of lysosomal enzymes.

Often fatal in childhood.