Diseases For Final

Front 1

I-cell disease

Back 1

- defect in trafficking enzymes to the lysosomes
- enzymes (without the mannose-6-P marker) are secreted into the blood stream
- high concentration of lysosomal enzymes in the blood
- accumulation of glycosaminoglycans and sphingolipids in the lysosomes

Hint 1

intracytoplasmic inclusions in the fibroblasts called "I cells" or "inclusion cells"

Front 2

Hurler syndrome

Back 2

• Enzyme deficient: Iduronidase
• Substrates accumulating: Dermatan sulfate and heparan sulfate
• Enzyme replacement therapy with iduronidase has been successful in many patients

Hint 2

Coarse facial features, short stature, developmental delay, hepatosplenomegaly, restricted joint mobility

Front 3

Hunter syndrome

Back 3

• X-linked recessive (affects males predominantly)
• Enzyme deficient: Iduronate sulfatase
• Substrates accumulating: Dermatan sulfate and heparan sulfate
• Coarse facial features, hepatosplenomegaly, mild to moderate mental retardation, but NO corneal clouding

Front 4

Tay-Sachs disease

Back 4

• Deficient enzyme:β-
Hexosaminidase A
• Accumulating substrate: Ganglioside (GM2). Also known as gangliosidosis
• Progressive neurodegeneration after the age of 3-6 months, blindness
• Developmental milestone delay

• Carriers (heterozygotes) have one copy of the mutant gene and 50% hexosaminidase activity
- cherry red spot on macula
- onion-shell inclusions in lysosomes

Hint 4

Onion-shell inclusions in lysosomes

Cherry-red spot on macula

Front 5

Gaucher disease

Back 5

• Deficient enzyme: β-Glucosidase
• Accumulating substrate: Glucosyl
ceramide (aka glucocerebroside)
• Adult form (most common) shows no neurological damage but marked hepatosplenomegaly and osteoporosis of long bones
- crumpled tissue paper appearance of cytoplasm

Hint 5

"crumpled tissue paper" appearance of cytoplasm

Front 6

Fabry disease

Back 6

• X-linked recessive disorder (Males commonly affected)
• Deficientenzyme: alpha - Galactosidase
• Accumulatingsubstrate: Globoside (aka ceramide trihexoside)
- Manifested as skin rash ‘bathing-trunk distribution’

Hint 6

Manifested as skin rash ‘bathing-trunk distribution’

Front 7

Niemann-Pick disease

Back 7

• Deficient enzyme:
Sphingomyelinase
• Accumulating substrate: Sphingomyelin (sphingophospholipid)
• Type A is a severe infantile form – fatal by 2-3 years
• Type B appears later in childhood, presents with hepatosplenomegaly
• Cherry-red spot in macula on retinal examination

Hint 7

Deficiency of sphingomyelinase causes lipid droplet accumulation- ‘Foamy cell appearance’

Front 8

Metachromatic leukodystrophy

Back 8

• Deficient enzyme: Aryl Sulfatase A
• Accumulating substrate: Sulfatide
• Progressive paralysis and demyelination

Front 9

Pompe disease

Back 9

• A small amount of cellular glycogen is degraded
by the lysosomal acid maltase (1→4 glucosidase)
• Generalized accumulation of glycogen in heart, muscle, kidney and liver as vacuoles in the lysosomes (glycogen storage disorder type II)

Hint 9

Lysosomal (acid) glucosidase deficiency

Front 10

MCAD deficiency

Back 10

- decreased ability to oxidize fatty acids
- severe hypoglycemia in response to fasting due to inability of Beta-oxidation and switch to only glucose as energy source
- medium chain acyl carnitines are excreted in urine
- dicarboxylic acids are found in urine due to omega-oxidation
- decreased substrate for ketogenesis (acetyl CoA) which can lead to hypoketonemia
- less acetyl CoA for gluconeogenesis

Hint 10

– Management of hypoglycemia by using IV glucose

Front 11

Primary Carnitine deficiency

Back 11

– Transport of long chain fatty acids into the mitochondria is impaired, and Beta-oxidation is decreased
– Is characterized by hypoglycemia due to impaired gluconeogenesis
– Also, ketogenesis is decreased if liver carnitine is deficient (systemic carnitine deficiency) – presents at an early age
– Myopathic carnitine deficiency is characterized by muscle weakness and cardiomyopathy (presents at a later age)

Hint 11

management:
– Cease muscle activity and give glucose
– Carnitine supplementation

Front 12

CPT-I deficiency

Back 12

characterized by a hypoglycemia and predominantly affects the liver isoform (systemic form)

– Serum carnitine levels are usually elevated

Front 13

CPT-II deficiency

Back 13

characterized by cardiomyopathy and muscle weakness (myopathic form). Lipid deposits (triglycerides) are found in skeletal muscle. Prolonged exercise results in myoglobinuria and elevated CK-MM levels in serum

Front 14

Jamaican vomiting sickness

Back 14

- caused when ingestion of unripe ackee fruit results in hypoglycemia and vomiting
- unripe ackee fruit contains 'hypoglycin A' that is an inhibitor of MCAD

Front 15

Zellweger Syndrome

Back 15

- defective peroxisomal biogenesis mainly affecting the liver and brain
- increased levels of C-26 in circulation

Front 16

Refsum disease

Back 16

- deficiency of peroxisomal phytanyl CoA alpha-hydroxylase (defect in alpha-oxidation)
- phytanate accumulates in neurologic tissues

Front 17

SLOS (Smith-Lemli-Opitz Syndrome)

Back 17

- genetic defect of cholesterol synthesis
- relatively common leads to microencephaly and other embryonic malformations
- deficiency in 7-dehydrocholesterol-7- reductase

Front 18

Cholelithiasis

Back 18

- bile salt deficiency
- causes cholesterol to precipitate in the gall bladder
- black pigment gallstones

Front 19

3-beta-hydroxysteroid dehygrogenase deficiency

Back 19

- virtually no glucocorticoids, mineralocorticoids, active androgens, or estrogens
- this enzyme catalyzes reaction of pregenolone to progesterone

Front 20

17-alpha-hydroxylase deficiency

Back 20

- virtually no sex hormones or cortisol are produced
- this enzyme catalyzes progesterone to cortisol and sex hormone precursor

Front 21

21-alpha-hydroxylase deficiency

Back 21

- mineralocorticoids and glucocorticoids are virtually absent (classic form) or deficient (non-classic form)
- overproduction of androgens leads to masculinization of external genitalia in females and early virilization in males

Front 22

11-beta-hydroxylase deficiency

Back 22

- decrease in serum cortisol, aldosterone, and corticosterone
- masculinization and virilization in males

Front 23

Cushing's syndrome: hypercortisolism

Back 23

● This is due to a hyperfunction of the adrenal cortex, usually due to an adrenocortical tumor
● High cortisol concentration and low ACTH concentration in plasma (high cortisol in urine)
● Glucocorticoid excess leads to protein loss and to characteristic fat distribution

Front 24

Addison's disease

Back 24

- primary adrenal cortical insufficiency
● Adrenal cortex atrophy due to disease
● Mostly by autoimmune destruction
● Aldosterone and cortisol levels are low, and ACTH is high, which does not lead to hyperplasia due to cortex atrophy

Front 25

Hyperlipidemia Type I

Back 25

- rare
- Hyperchylomicronemia after fasting
– genetic lipoprotein lipase deficiency (Type Ia) or deficiency of apo C-II (Type Ib) or
LPL inhibitor protein (Type Ic)
• Eruptive xanthomas which usually occur in clusters on the skin of the trunk, buttock or extremities.
• The patient’s blood shows in a vial lipemic plasma which is characterized by a creamy layer on top with clear infranatant.

Front 26

Hyperlipidemia Type IIa

Back 26

- common
- Familial hypercholesterolemia (FH)
- high serum LDL (VLDL normal)
- LDL-receptor deficiency
- heterozygous
- adult onset, common
- homozygous
- childhood onset, rare
- characteristic: xanthoma over tendon and xanthelasmas
• Adult onset with accelerated atherosclerosis

Front 27

Hyperlipidemia Type IIb

Back 27

- very common
- onset in puberty, prevalence 1:10
- high serum LDL and high VLDL
- very complex
- most likely involves several genes

Front 28

Hyperlipidemia Type III

Back 28

- rare
- Familial dysbetalipoproteinemia or
broad beta disease
– high IDL
– high chylomicron remnants
– high VLDL and high b-VLDL (VLDL with higher cholesterol than normal VLDL)
• Type III is characterized by palmar xanthomas and tubereruptive xanthomas over the elbows and knees
• Adult onset with accelerated atherosclerosis
- hypercholesterolemia
- patients are homozygotic for api E-2 which leads to less uptake of lipoprotein remnants into the liver

Front 29

Hyperlipidemia Type IV

Back 29

- common
- Hyperprebetalipoproteinemia
- High serum VLDL which may result from
LPL deficiency or overproduction of VLDL
- High serum TAG can lead to pancreatitis

Front 30

Hyperlipidemia Type V

Back 30

- Mixed Hypertriacylglycerolemia
- high VLDL
- high chylomicrons
- The patients serum in a vial is characterized by a creamy layer on top with turbid infranatant

Front 31

Hypoalphalipoproteinemia (Tangier disease)

Back 31

- show serum HDL-C below 35 mg/dL
- If it is acquired, it is related to obesity, smoking, some medical drugs and also to cholesterol reducing drugs.
- Tangier disease is a genetic disease that leads to very low serum HDL in childhood.
- Tangier disease is related to a defective cholesterol ABC transporter in the plasma membrane. This leads to less substrate for LCAT and to early degradation of lipid poor apo A-1 in serum and to very low HDL.
- childhood coronary disease
- enlargement of liver and spleen

Front 32

Abetalipoproteinemia

Back 32

This disease is characterized by very low amounts of serum VLDL, LDL and chylomicrons. The name refers to nearly absent LDL in blood.
This hypolipidemia is due to a defect in the microsomal TAG transfer protein (MTP) which normally interacts with apo B and is needed for the formation of VLDL or CM.
The clinical features include fat malabsorption and TAG accumulation in liver and intestine, retinitis pigmentosa and peripheral neuropathy

Front 33

cystinuria

Back 33

• Tubular reabsorption of Cystine is decreased (along with dibasic aa ornithine, arginine, lysine) due to an inherited deficiency of the cystine transporter (COAL)
• Cystine is excreted in urine
• Cystine tends to precipitate in the renal tubules (cystine stones) in the renal tract
• One of the causes of renal stones in children

Front 34

Hartnup's disease

Back 34

• Inherited defect in the transport of the neutral amino acids like tryptophan
• Decreased dietary absorption of tryptophan and increased excretion of tryptophan
– Most patients are normal
• Manifestations of tryptophan deficiency
– May lead to NAD+ deficiency (pellagra)
- tryptophan can be used to produce NAD+
– A few of the patients
– Low protein diet, those lacking niacin supplementation
• The explanation for pellagra is that niacin is not synthesized from tryptophan in sufficient amounts in these patients
– The 4 D‟s
- diarrhea, dermatitis, dementia and death

Front 35

Phenylketonuria (PKU)

Back 35

symtoms if untreated
- Mental retardation, Seizures, Spasticity
Autistic behaviors, Hypopigmentation, Skin rashes
- autosomal recessive disorder
- responds well to dietary restriction of phenylalanine
- deficiency of phenylalanine hydroxylase
- phenyl alanine is converted to phenylpyruvic acid instead which leads to mousy smelling urine
- tyrosine also becomes an essential amino acid
- decreased pigmentation due to the increased phenylalanine inhibiting the use of tyrosine in the production of melanin
- whether in the first week of life or post infant, cessation of a Phe free diet results in decreased IQ
- treatment of PKU is avoidance of Phe and/or sapropterin

Front 36

Maternal PKU syndrome

Back 36

Note: Maternal PKU syndrome occurs even though the fetus is NOT deficient in phenylalanine hydroxylase (Typically the fetus is heterozygous)
- • Women with PKU must maintain low Phe levels before conception and during pregnancy.
– Strict adherence must be maintained prior to conception and throughout pregnancy
• High maternal blood Phe leads to fetal defects: – microcephaly
– mental retardation
– congenital heart defects

Front 37

PKU II

Back 37

- malignant PKU
• Deficiency of dihydrobiopterin synthesis or dihydrobiopterin reductase (BH2/BH4)
• Much more severe CNS symptoms
– Decreased neurotransmitter synthesis (serotonin, dopamine, catecholamines)
• Treatment includes dietary Phe restriction and providing dietary biopterin and precursors of the neurotransmitters
– Difficult because of Blood Brain Barrier • Worse prognosis then PKU I

Front 38

Alkaptonuria

Back 38

- deficiency in homogentisic acid oxidase
- homogentisic acid accumulates and leads to deposits of ochronotic pigment in cartilage tissues
- leads to degenerative arthritis
- bluish-black discoloration of the sclera and auriculum
- darkened urine
- dietary restriction of Phe and tyrosine

Front 39

Tyrosinosis (Tyrosinemia Type I)

Back 39

• Build up of fumaryl acetoacetate causes kidney and liver damage
• Inborn error of phenylalanine-tyrosine catabolism
• Deficiency of fumaryl acetoacetate hydrolase
• Manifestations are severe and usually fatal – Liver failure
– Renal failure
– Cabbage like odor of the urine
• Dietary restriction of Phe & Tyr may be tried – Difficult to accomplish
– Two essential amino acids must be avoided
– Tyrosine is required for NT synthesis

Front 40

Maple Syrup Urine disease (MSUD)

Back 40

- inability to break down branched chain amino acids (valine, leucine, isoleucine)
- alpha-keto acid dehydrogenase needs TPP (vitamin B1) and there could be a problem with either of these two to cause the disease
- buildup of the branched chain amino acids leads to the neurologic manifestations
• Relatively rare inborn error of metabolism
• Symptoms develop in neonates aged 4-7 days
• Can be detected early in life by neonatal screening
• Presents with poor feeding, vomiting, poor weight gain and increasing lethargy.
• Neurological signs (e.g. alternating muscular hypotonia and hypertonia, seizures, encephalopathy) develop rapidly.
• Ketosis and the characteristic odor of maple syrup in the urine are usually present when the first symptoms develop.
• Coma and death of the child in early infancy if not recognized and treated
-

Front 41

Methylmalonyl CoA mutase deficiency

Back 41

• Results in elevated levels of methylmalonic acid in circulation
• Causes metabolic acidosis due to the accumulation of methylmalonic acid
• Associated with neurological manifestations: seizures, encephalopathy
• In some children a milder form of the disease may manifest
• In some children, there is improvement with vitamin B12 (cobalamin) supplementation
– This form of the deficiency is due to a mutation that causes the methylmalonyl CoA mutase enzyme to have a reduced affinity for the B12 coenzyme

Front 42

Homocystinuria

Back 42

• A group of disorders in which there is a defect in homocysteine metabolism
• Characterized by high plasma & urinary levels of homocysteine
• Deficiency of cystathionine β-synthase
(transulfuration pathway)
• Homocysteine binds to connective tissue and disrupts its structure
• Characterizedbydislocationoflens (ectopia lentis), Skeletal abnomalities, Mental retardation, premature arterial disease
• Some patients respond to oral vitamin B6

Front 43

Hyperammonemia Type I

Back 43

- Disorder of the urea cycle
- CPS I deficiency
- Hyperammonemia, Neurological manifestations

– Sometimes responds to Arginine intervention – Rationale: Arg stimulates the formation of N-
acetylglutamate
– High levels of NAG might stimulate deficient CPSI

Front 44

Hyperammonemia Type II

Back 44

- Disorder of the urea cycle
- OTC (ornithine transcarbamoylase) deficiency
- X-linked
- Most common
- Hyperammonemia,
Increased orotic acid excretion in urine

Front 45

Citrullinemia

Back 45

- Disorder of the urea cycle
- Argininosuccinate synthetase deficiency
- Hyperammonemia, Increased citrulline levels

Front 46

Argininosuccinic aciduria

Back 46

- Disorder of the urea cycle
- ASL (Argininosuccinate lyase) deficiency
- Hyperammonemia Increased arginino succinate levels

Front 47

Argininemia

Back 47

- Disorder of the urea cycle
- Arginase deficiency
- Increased arginine levels

Front 48

Parkinson's disease

Back 48

• Neurodegenerative disorder
• Loss of dopamine producing cells in the basal ganglia
• Characterized by movement disorders: spasticity, tremors, loss of memory, mood disturbances, postural instability
• Symptoms are improved by administration of L-DOPA.
• L-Dopa is converted to Dopamine in the brain, that improves the symptoms
•Peripheral dopamine formation must be inhibited by administration of a Dopa decarboxylase inhibitor along with the L-Dopa

Front 49

Pheochromocytoma

Back 49

• Episodic symptoms
• Characterized by overproduction of catecholamines
– Adrenal medulla tumor
• Predominant Symptoms include:
– Headache, Sweating, Tachycardia are
• Patientshavehypertension
• Must use 24 hour urinary measurement – During a symptom episode

Front 50

Carcinoid syndrome

Back 50

• Tumor of serotonin producing cells in GIT (APUD cells)
•Cutaneous flushing, sometimes accompanied by sweating
•Gastrointestinal hypermotility causing diarrhea
•Bronchospasm
- increased 5-HIAA excretion in urine (degradation product of serotonin)

Front 51

Albinism

Back 51

• Is a group of disorders in which there is partial or complete deficiency of melanin in the skin, hair and eyes
• The severe form of albinism affects the eyes: – Oculocutaneousalbinism
• Deficiency of the TYROSINASE enzyme – Deficient conversion of Tyrosine to MELANIN
• Results in lower visual acuity and photophobia
• Subjects with albinism have light colored skin and hair
• Increased risk of skin damage on exposure to sunlight and increased risk of skin cancer

Front 52

Lesch-Nyhan Syndrome

Back 52

The X-linked genetic disorder Lesch-Nyhan Syndrome results from a deficiency of HGPRT.
• results in an inability to salvage purines hypoxanthine and guanine
• The end product of degradation of hypoxanthine and guanine is uric acid.
• Therefore, children with Lesch-Nyhan Syndrome have excess uric acid in urine.
• Orange crystals are often found in the baby’s diaper.
• Lesch-Nyhan Syndrome causes severe mental retardation, self-mutilation, and involuntary movements, gout.
• Lesch-Nyhan Syndrome causes increased PRPP levels and an increase in de novo purine synthesis.

Front 53

ADA Deficiency - SCIDS

Back 53

• Guanosine and inosine are better substrates for purine nucleoside phosphorylase than is adenosine.
• Adenosine deaminase (ADA) deficiency causes SCIDS.
• DNA is not synthesized in T-cells and B-cells because of an accumulation of dATP.
• This was the first disease approved for human gene therapy trials.
- dATP is an inhibitor of ribonucleotide reductase, and therefore DNA synthesis
- lymphocytopenia - T-cell and B-cell depletion

Front 54

PNP deficiency

Back 54

• Purine nucleoside phosphorylase (PNP) deficiency causes impairment of T-cell function.
• PNP deficiency is characterized by decreased uric acid production and increased purine nucleosides and nucleotides.

Front 55

Gout

Back 55

Gout is characterized by hyperuricemia; acute arthritic joint inflammation caused by deposition of uric acid crystals.
Primary gout is genetic and affects mainly males over 30 years old.
Secondary gout is brought on by a number of disorders including leukemia (excess white cells in the blood), polycythemia (increase in RBC mass), HGPRT deficiency, treatment of cancer with antimetabolites, or chronic renal insufficiency.
Gout affects men and women of any age.

Front 56

Orotic Aciduria

Back 56

• orotate phosphoribosyltransferase deficiency
- OMP decarboxylase deficiency
• Causes abnormal growth, megaloblastic anemia, and the excretion of large amounts of orotic acid in the urine.
• The rare genetic form is present in patients who inherit a lack of the two enzymes.
• An acquired form of the disease may appear in patients being treated for cancer with a pyrimidine analog.
• The genetic form is treated with dietary uridine in spite of the poor use of dietary nucleosides.
• Apparently enough uridine is absorbed to satisfy the patient’s requirements for pyrimidine nucleotides.

Front 57

Acute Intermittent Porphyria

Back 57

- accumulation of ALA and porphobilinogen in blood and urine
- deficiency of HMB synthase (porphobilinogen deaminase)
- change of normal urine color to dark purple color after 24 hrs exposure to light and air
- very severe abdominal pain, abdominal colic
- highly agitated state, tachycardia, respiratory problems, nausea
- confusion, mental disturbance
- weakness of lower extremities
- NOT PHOTOSENSITIVE
- occurs in patients who are treated with specific drugs which stimulate cytochrome P450, triggered by infections, ethanol abuse or abnormal estrogen metabolism
- barbiturates make the problem worse

Front 58

Congenital Erythropoietic Porphyria

Back 58

- build up of uroporphyrin I and coproporphyrin I in tissues and blood and urine (red)
- deficiency of uroporphyrinogen III synthase
- genetic defect autosomal recessive trait
- extremely painful photosensitivity
- severe damage to the skin beginning in childhood and poor wound healing
- treatment - bone marrow transplant\

Front 59

Porphyria Cutanea Tarda

Back 59

- uroporphyrin III in tissues and blood and urine
- deficiency of uroporphyrinogen III decarboxylase
- Type 1 (sporadic 80%)
- Type 2 (familial, autosomal dominant trait 20%)
- accumulation of urophorphyrin in skin and liver which leads to cutaneous lesions
- photosensitive
- erosions and bullous lesions when sun-exposed which heal by scaring
- most common porphyria and a chronic disease of the liver
- the urine is red upon release
- treatment is avoidance of sun-light, alcohol and iron

Front 60

Pre-hepatic jaundice

Back 60

- increased breakdown of RBCs --> increased formation of bilirubin --> increased unconjugated bilirubin in circulation --> increased uptake and conjugation of bilirubin by liver --> increased excretion of conjugated bilirubin into bile and intestine --> increased formation of urobilinogen in intestine --> increased excretion of urobilin in urine and stercobilin in feces
- acholuric jaundice - no bilirubin in urine

Front 61

Hepatocellular jaundice

Back 61

- increased unconjugated and conjugated bilirubin in serum
- decreased uptake and conjugation of bilirubin by liver and decreased secretion of conjugated bilirubin
- loss of bilirubin in urine
- decreased excretion of urobilin in urine
- decreased excretion of stercobilin in feces
- additional lab findings are elevated levels of ALT and AST

Front 62

Posthepatic (obstructive jaundice)

Back 62

• Serum conjugated bilirubin is elevated as the excretion of conjugated bilirubin into biliary canaliculus is reduced due to the biliary obstruction. Conjugated bilirubin regurgitates into plasma (as it cannot be excreted into bile)
• Urobilinogen in urine is absent/ low (depending on the extent of obstruction)
• Additional lab findings are elevated levels of ALP

Front 63

Jaundice in newborns

Back 63

• Newborn infants have low activity of hepatic UDP-glucuronyl transferase
- increase in unconjugated bilirubin
- Unconjugated bilirubin crosses the blood brain barrier and deposits in the basal ganglia of brain, resulting in ‘kernicterus’, as it is lipid soluble
- results in (choreoathetosis, spasticity, muscular rigidity, ataxia, mental retardation)

Front 64

Phototherapy in neonatal jaundice

Back 64

- light converts bilirubin to more polar, water soluble isomers, that can be excreted in bile without conjugation

Front 65

Crigler-Najjar syndrome I

Back 65

- inherited hyperbilirubinemia
• Crigler-Najjar syndrome I is the most severe and is associated with an almost complete deficiency of the enzyme UDP-glucuronyltransferase
• Management of Crigler-Najjar syndrome type I is daily phototherapy, exchange transfusion and prevention of kernicterus
- phenobarbital does not help

Front 66

Crigler-Najjar syndrome II

Back 66

- aka arias syndrome
– Characterized by lower activity of bilirubin glucuronyl transferase (10-20% of normal)
– Characterized by jaundice, but less severe than type I (serum bilirubin levels usually 6-22mg/dL)
– Children respond to phenobarbital (induces the enzyme)
– Regular phototherapy is used in patients with persisting high bilirubin levels

Front 67

Gilbert’s syndrome

Back 67

– Present in 3-7% of population
– Characterized by occurrence of mild jaundice (2-5 mg/dL) usually following an infection or stress or starvation
– UDP-glucuronyl transferase activity is about 50% of normal
– Characterized by a mild increase in unconjugated bilirubin

Front 68

Dubin-Johnson syndrome

Back 68

– Inherited deficiency of the ABC transporter that transports conjugated bilirubin from the hepatocyte into the biliary canaliculus
– Characterized by elevated levels of conjugated (direct) bilirubin in circulation

Front 69

Hemophilia A

Back 69

• Inherited coagulation disorder – defect in the intrinsic coagulation pathway (Increased clotting time and increased APTT)
• Inherited in an X-linked recessive manner
• Patients with hemophilia A and B have similar manifestations
- DEFICIENT IN COAGULATION FACTOR VIII
Bleeding time - normal (Platelet plug formation is normal)
Platelet count - normal
Clotting time - increased (defect in the intrinsic pathway) Prothrombin time (INR) – Normal (extrinsic and
common coagulation pathway are normal)
APTT (Intrinsic pathway) - Increased (Defect in intrinsic pathway)

Front 70

Hemophilia B

Back 70

• Inherited coagulation disorder – defect in the intrinsic coagulation pathway (Increased clotting time and increased APTT)
• Inherited in an X-linked recessive manner
• Patients with hemophilia A and B have similar manifestations
- DEFICIENT IN COAGULATION FACTOR IX
Bleeding time - normal (Platelet plug formation is normal)
Platelet count - normal
Clotting time - increased (defect in the intrinsic pathway) Prothrombin time (INR) – Normal (extrinsic and
common coagulation pathway are normal)
APTT (Intrinsic pathway) - Increased (Defect in intrinsic pathway)

Front 71

Von Willebrand Disease

Back 71

• Most common inherited bleeding disorder
• Defect either qualitative or quantitative
• Inheritance can be either dominant or recessive
• Instability of Factor VIII (may result in increased APTT)
Bleeding time – Prolonged (indicates a
defect in platelet plug formation)
Platelet count – Normal
APTT – Prolonged (Factor VIII levels may be low normal)
PT (INR) – Normal (Extrinsic pathway is normal)
vWF levels - LOW

Front 72

Thrombocytopenia

Back 72

low platelet count

Front 73

Bernard-Soulier syndrome

Back 73

- Glycoprotein Ib defect (GpIb)
- qualitative defect
- normal platelet count
- increase in bleeding time

Front 74

Thrombasthenia of Glanzman and Naegeli

Back 74

- Glycoprotein IIb/IIIa defect (GpIIb/IIIa)
- qualitative defect
- normal platelet count
- increase in bleeding time

Front 75

Kernicterus

Back 75

- increased unconjugated bilirubin
- unconjugated bilirubin crosses blood-brain barrier and deposits in the brain basal ganglia causing neurological problems
- usually occurs in children
- sulfonamides and salicylates exacerbate the problem by displacing bilirubin from albumin

Front 76

Deficiency of Vitamin A

Back 76

• Dietary deficiency is the commonest cause – fat free diets
• Malabsorption of fats can also lead to deficiency
Signs and symptoms
 Night blindness – earliest symptom; inability to see in dim light
 Xerophthalmia – dryness of the conjunctiva and cornea.
 Bitot’s spots
 Keratomalacia – corneal erosion and ulceration
 Increased risk of pulmonary infections
 Immune deficiency – weakened innate immunity

Front 77

Vitamin A toxicity

Back 77

• Hypervitaminosis A – raised intracranial pressure – headaches – may mimic brain tumors
• Dry and pruritic skin
• Enlargedliver
• Pregnancy – spontaneous abortions and congenital malformations in the fetus.
Vitamin A supplements (greater than the daily requirement) should be avoided in pregnancy

Front 78

Rickets

Back 78

Rickets:
 Vitamin D deficiency in children
 Decreased calcium absorption from the diet → ↑Parathyroid hormone release → ↑demineralization of bone **
 Demineralization of bone – soft pliable bones
 Characteristic bow-leg deformity
 Overgrowth at costochondral junction – rachitic rosary
 Pigeon chest deformity
 Frontal bossing

Front 79

Osteomalacia

Back 79

Osteomalacia: Vitamin D deficiency in an adult
Bones are de-mineralized and are susceptible to fracture
Osteomalacia can be secondary to dietary deficiency, renal disease or liver disease

Front 80

Wilson's disease

Back 80

- deficiency in Ceruloplasmin
- ceruloplasmin creates ferrous iron (Fe+2 to Fe+3)
- accumulation of toxic levels of copper in vital organs including liver, brain and eye
- defect is found in the copper transporting ATPase in the liver
- the is protein is needed to attach copper to ceruloplasmin and also to excrete copper into the bile (reason for the accumulation of copper)
- the accumulation of copper can lead to hemolysis, Kayser Fleischer rings ( deposition of copper in the cornea), and neurological damage

Front 81

Beriberi

Back 81

- thiamine deficiency
• Common when polished rice is the major diet component
• Affects highly aerobic tissues (Brain and cardiac muscle)
• Polyneuropathy – disruption of motor, sensory and reflex arcs; could progress to paralysis (dry beri beri)
• Cardiovascular symptoms – cardiac failure (wet beri beri)

Front 82

Wernicke - Korsakoff syndrome

Back 82

- thiamine deficiency
• Associated with chronic alcoholism
• Ophthalmoplegia and nystagmus (to and fro movement of eyeballs)
• Ataxia, confusion, disorientation and loss of memory
• Confabulation
Diagnosis – increase in erythrocyte transketolase activity on addition of TPP

Front 83

Riboflavin deficiency

Back 83

• Nutritional
Signs and symptoms
• Cheilosis – areas of pallor, cracks and fissures at the angles of the mouth
• Glossitis – inflammation and atrophy of the tongue
• Facial dermatitis

Front 84

Pellagra

Back 84

- niacin deficiency
• Dermatitis
– Exposed areas of body
– Redness, thickening and roughening of skin
• Diarrhea • Dementia
– Degeneration of neurons in the brain and the spinal tracts.
• Death
- corn based diets can cause pellagra ( corn is deficient in niacin and tryptophan)

Front 85

multiple carboxylase deficiency

Back 85

- Inherited deficiency of incorporation of biotin in these enzymes results in manifestations of biotin deficiency
• Biotin supplementation improves symptoms in many children with multiple carboxylase deficiency***

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Folic acid deficiency

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• Dietary inadequacy – lack of green leafy vegetables
• Impaired absorption
• Increased requirement as in pregnancy
• Folate antagonists – methotrexate (inhibitor of dihydrofolate reductase)
• Folate trapping due to cobalamin deficiency

Megaloblastic anemia:
• Macrocytes in peripheral blood smears
• Megaloblasts in bone marrow

Diminished synthesis of purines and pyrimidines --> inability of cells to synthesize DNA --> delayed mitosis; larger cells

*****Treatment:
Megaloblastic anemia should never be treated with folic acid alone. Ideal treatment is a combination of folic acid and cobalamin till the definite cause is established

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Menke's syndrome

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• Inherited defect in absorption of copper from the GI tract.
• Lowlevelsofcopperinplasma and most tissues
• GeneticX-linkeddisease,rare
• Hair is twisty, grayish and
“kinky”
• Copper deficiency can lead to aneurysms and cerebral dysfunction
- degradation of vascular tissue - due to decreased lysyl oxidase activity

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Hereditary Hemochromatosis

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• Autosomalrecessivedisorder
• One of the commonest genetic disorders
• Genetic defect causing excessive absorption of iron
• Excessive accumulation of iron in the parenchymal organs, most importantly liver and pancreas
- HFE gene on the basolateral surface of intestinal crypt cell senses the systemic iron balance
- defect in gene - loss of sensing mechanisms - increased absorption
Excess iron damages tissues by:
• Lipid peroxidation through free radicals • DNA damage
Clinical Features:
• More common in males; presenting age 40
• Liverdamage–cirrhosis;hepatocellularcarcinoma
• Diabetes – destruction of pancreas
• Cardiacdysfunction
• Acutesynovitis
• Brownish skin pigmentation (Bronze color of skin)

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Marasmus

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- protein-calorie malnutrition, energy deficiency is predominant

- associated with adults with diseases like anorexia nervosa, GI cancer, chronic illness and old age

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Kwashiorkor

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- protein malnutrition is predominant, despite of adequate intake of carbohydrates

• Deficiency of dietary protein, diet can be otherwise adequate in calories
• Muscle wasting due to lack of essential amino acids, stunted growth
• Decreased concentration of albumin < 2.8 g/dL • Edema found in the abdomen and legs

• Patients could look well nourished or obese
• Decreased ability to produce digestive enzymes and new intestinal epithelial cells
• Also found as result of other diseases, like partial obstruction of the upper GI tract
• Children often after weaning off, about one year

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Marasmic Kwashiorkor

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- most severe form of PEM (protein energy malnutrition)

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Anorexia nervosa

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• Patients refuse to maintain normal body weight as they feel fat even when undernourished
• Patients say “no” to the normal food demands of their body
• Even when dangerously underweight, the fear of gaining weight prevents food uptake
• This disease is often related to low self-esteem

• Brain and nerves: bad memory, fatigue
• Heart: low blood pressure, palpitations
• Blood: anemia
• Muscles: weak, joints: swollen
• Kidneys: kidney stones, kidney failure
• Body fluids: low minerals like potassium, magnesium and sodium
• Intestine:constipation
• Hormones: loss of menstrual cycle

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Multiple myeloma

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- tumor of plasma cells
- results in a large increase in one type of immunoglobin (gamma-globin)