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Clinical correlates Flashcards

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USMLE® Step 1 flashcards
0
Q

Systemic carnitin edeficiency

A

. Presents at an earlyage • Characterized by hypoglycemia due to impaired gluconeogenesis (remember, acetyl CoA is an activator of pyruvate carboxylase) • Also, ketogenesis is decreased if liver carnitine is deficient

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1
Q

Biochemical consequences of MCAD deficiency

A

Decreased β- oxidation: • Decreased β oxidation of medium chain fatty acids• C8-C10 acyl carnitines in blood• Increased flux through ω-oxidation (Dicarboxylic acids in urine) Hypoglycemia: • Decreased utilization of fatty acids by peripheral tissues• Increased reliance on glucose as an energy source• Decreased ATP and acetyl CoA to activategluconeogenesis Hypoketonemia: • Decreased β-oxidation in liver• Decreased substrate for ketogenesis (acetyl CoA)

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2
Q

Myopathic carnitine deficiency Characteristics

A

Characterized by muscle weakness and cardiomyopathy (presents at a later age) • Presence of CK-MM and myoglobin in urine indicates skeletal muscle damage

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3
Q

CPT-I and CPT-II deficiency

A

• CPT-I deficiency is characterized by a hypoglycemia and predominantly affects the liver isoform (systemic form) – Serum carnitine levels are usually elevated • CPT-II deficiency is 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

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4
Q

Zellweger syndrome

A

Defective peroxisomal oxidation of long chain fatty acids • Levels of C-26 fatty acids in circulation are increased. • Neurological manifestations (delayed development) and extensive demyelination are seen • Hepatomegaly and hepatocellular failure • Usually fatal in infancy

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5
Q

Refsum disease

A

• A disorder characterized by deficiency of the peroxisomal phytanyl CoA alpha-hydroxylase (defect in alpha-oxidation of phytanic acid dietary branched chain fatty acid, found in dairy)• In this disorder, phytanate accumulates in tissues, especially the neurologic tissues • Characterized by visual defects, ataxia and polyneuropathy and skeletal manifestations• Management includes dietary restriction of branched chain fatty acids

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6
Q

SLOS (Smith-Lemli-Opitz Syndrome)

A
  • Genetic defect of cholesterol synthesis (autosomal recessive)
  • Cause: 7-dehydrocholesterol Reductase, needed for the correct double bond formation in ring B, is partially deficient.
  • Relatively common, leads to microencephaly and other embryonic malformations.
  • Surviving children have an IQ 20-40
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7
Q

Cushing’s syndrome: Characteristic, Cause, Symptoms

A

● High cortisol concentration and low ACTH concentration in plasma (high cortisol in urine) ● This is due to a hyperfunction of the adrenal cortex, usually due to an adrenocortical tumor ● Glucocorticoid excess leads to protein loss and to characteristic fat distribution Characteristic fat distribution in the: -Face -Neck -Truncus -Hirsutism -Early pubic hair development

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8
Q

Addison’s disease:Primary adrenal cortical insufficiency

A

● 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

Symptoms: Failure to thrive Muscle weakness, Fatigue, Weight loss Hyperpigmentation Salt craving Hyponatremia Hyperkalemia Hypovolemia Hypotension Abdominal pain Vomiting, Constipation

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9
Q

Hypoalphalipoproteinemiashows

very low serum HDL cholesterol below 35 mg/dl

A

Shows very low serum HDL cholesterol below 35 mg/dl.

If it is acquired, it is related to _obesity, smoking, some medical drug_s and also to cholesterol reducing drugs.

Normal levels of HDL are in the range of 40-70 mg/dL. Lower levels can be a risk factor for coronary heart disease.

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10
Q

Tangier disease (Hereditary Disease): Cause & Symptoms

A

Cause: 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 the lipid poor apo A-1 & HDL.

Symptoms: Childhood to coronary disease, corneal opacities and orange tonsils, also enlargement of liver and spleen.

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11
Q

Abetalipoproteinemia: Cause, Characteristics, Symptoms

A

Cause: 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.MTP (or MTTP) is essential for the assembly of chylomicrons and VLDL.

Characteristic: very low amounts of serum VLDL, LDL and chylomicrons.

Symptoms: fat malabsorption and TAG accumulation in liver and intestine, retinitis pigmentosa and peripheral neuropathy.

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12
Q

3-B Hydroxysteroid DH deficiency

A
  • No mineralcorticoid, glucorcorticoid, active androgens or estrogens - Marked excretion of salt in urine - Female like genitalia
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13
Q

17-alpha hydroxylase Deficiency

A
  • No sex hormones, no cortisol - Overproduction of mineralcorticoids–> sodium & fluid retention–> hypertension - Female like genitalia
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14
Q

21 Hydroxylase Deficiency

A
  • Most common CAH
  • Partial and complete deficiencies are known. Absent glucocorticoid & mineralcorticoid (Classic form). Or deficient glucocorticoid & mineralcorticoid (non-classic form)
  • Overproduction of androgens–> masculinization of ext genitalia in females and early virilization in males
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15
Q

11B Hydroxylase deficiency

A
  • low aldosterone, cortisol, corticosterone in serum - increased production of deoxycorticosterone cause fluid retention. It also inhibits renin/angiotensin system–> low renin hypertension - Masculinization ext genitalia in females & early virilization males
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16
Q

Cholesterol Type I

A

Hyperchylomicronemia

• High levels of chylomicrons in blood after a fast of 12-14 hrs. Cause: Genetic deficiency of LPL(Type Ia) or of apo C-II (Type Ib) or presence of a LPL inhibitor protein (Type Ic)

Symptoms:

  • Childhood onset, often abdominal colic
  • Eruptive XANTHOMAS 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.
  • Patients can encounter lipemia retinalis, hepatosplenomegaly, irritability and recurrent epigastric pain with increased risk of pancreatitis
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17
Q

Cholesterol Type IIa: Characteristic, Cause, Symptoms

A

Familial Hypercholesterolemia

• High levels of LDL with normal VLDL

Cause: Defective LDL-receptor (autosomal dominant) Symptoms:

• The heterozygous form occurs in 1:500. Adult onset, risk of coronary heart disease. The homozygous form occurs in 1:1million. Childhood onset, risk of MI and death in childhood.

Symptoms: xanthoma over tendon and xanthelasmas

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18
Q

Type IIb Characteristic, Causes

A

Characteristic: Familial combined hyperlipidemiaonset in puberty, prevalence 1:100(1:10 in patients with cardiovascular disease)

Characteristics: high serum LDL and high VLDL

Causes very complex:overproduction of apo B-100?or overproduction of VLDL?or defective clearance of LDL?It most likely involves several genes

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19
Q

Cholesterol Type III Characteristic, Cause, Symptom

A

Dysbetalipoproteinemia (rare)

Characteristic:  High remnants: IDL and chylomicron remnants due to apo E deficiency (homozygous for less functional apo E-2), [b-VLDL]

Cause: Apo E deficiency

Symptoms:  Type III is characterized by palmar xanthomas and tubereruptive xanthomas over the elbows and knees.

Adult onset with accelerated atherosclerosis

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20
Q

Type IV (common about 1:100) Characteristic, Cause, Symptom

A

Hyperlipidemia

Characteristic:Hyperprebetalipoproteinemia, High serum VLDL

Cause: LPL deficiency or overproduction of VLDL High serum TAG can lead to pancreatitis

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21
Q

Cholesterol Hyperlipidemia Type V

A

Hypertriacylglycerolemia

High serum VLDL and high chylomicrons

Patients serum: creamy layer of top and turbid infranatant

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22
Q

Tay-Sachs: Enz, Accumulating substrate, Symptoms

A

Enz: B-Hexosaminidase Accumulating substrate: Ganglioside (GM2) Symptoms: Neurodegeneration at 3-6 months, blindness, development milestone delay, cherry spot macula, onion shell in lysosomes, fatal by 2-6 years

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23
Q

Gaucher disease: Enz, Accumulating substrate, symptoms

A

Enzyme: B-Glucosidase Accumulating substrate: Glucosyl ceramide (glucocerebroside) Symptoms: Macrophages filled with glucocerebroside, Hepatosplenomegaly, osteoporosis of long bones.

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24
Q

Fabry disease: Enz, Accumulating substrate, symptoms

A

Enz: Galactosidase Accumulating substrate: Globoside (aka ceramide trihexoside) Symptoms: Perioheral neuropathy, Globoside accumulates in bv of nerves, heart, kidney & skin. Children susceptible to kidney damage, heart attack & stroke. Angiokeratoma

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25
Q

Niemann-Pick disease: Enz, Accumulating substrate, Symptpms

A
  • Enz: Sphingomyelinase
  • Accumulating substrate: Sphingomyelin
  • Symptoms: Type A: death 2-3 years, Cherry red spot in macula Type B: Hepatosplenomegaly, foamy cells
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26
Q

Metachromatic leukodystrophy: Enz, Accumulating substrate, symptoms

A

Enz: Aryl Sulfatase Accumulating substrate: Sulfatide Symptoms: Progressive paralysis, Demyelination

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27
Q

I cell disease: Cause, Characteristic, Symptoms

A

Cause: Defect in trafficking enzymes to lysosomes. Golgi fails to add mannose-6-P marker to enzymes. These Enz secreted in blood. Characteristic: Accumulatikn glycoaminoglycans and sphingolipids in lysosomes. Intracytoplasmic inclusion in fibroblast called Inclusion cells (I-cells) Symptoms: similar to Hurler but more severe and earlier onset. Propotic eyes, full & prominent mouth caused by gingival hypertrophy, umbilical hernia.

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28
Q

Pomp disease: Enz, accumulating substrate, symptoms

A

Enz: Lysosomal acid Maltese (1–> 4 Glucosidase) Acc: Glycogen in heart, muscle, liver & kidney Symptoms: Cardiac failure, myopathy, Hepatocellular failure.

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29
Q

Acute Intermittent Porphyria Enzyme deficient, Accumulating substrate, Symptoms, Treatment, Comment

A

Deficient Enzymes: Hydroxymethylbilane synthase (porphobilinogen deaminase) Genetic defect autosomal dominant trait

Accumulating substrate: ALA (can act like GABA) and Porphobilinogen

Symptoms: dark color urine due to formation of Porphobilinogen, very severe abdominal pain, abdominal colic, highly agitated state, tachycardia, respiratory problems, nausea, confusion, mental disturbance, **weakness of lower extremities. **

Patients are not photosensitive, as HMB cannot be formed, however, ALA and porphobilinogen accumulate and at very high levels can act as neurotransmitters.ALA has a similar structure to GABA

Treatment: pain medication, intravenous glucose and saline infusion. [_hypoglycemia induces ALAS1 synthesis]_In severe cases, intravenous hemin administration may be needed (Hemin is ferric protoporphyri )

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30
Q

Congenital Erythpoeitic Porphyris Deficient Enz, Accumulating substrate, Symptoms, Treatment

A

Deficient Enz: Deficiency of uroporphyrinogen III synthase (formed by alternative splicing)

Genetic defect autosomal recessive trait

Accumulating substrate: Uroporphyrin 1 and Coproporphyrin 1

Symptoms: extremely painful photosensitivity, severe damage to skin beginning in childhood, blisters, poor wound healing, ulcers, infections, hypertrichosis, ** can include reddish-brown teeth**, “werewolf” features, hairy front and arms

Treatment: bone marrow transplantation

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31
Q

Porphyria cutaneous Tarda

Deficient Enz, Substrate accumulation, symptoms, treatment

A

Deficient Enzyme: Deficiency of uroporphyrinogen III decarboxylase. Type I (sporadic, 80%) Type II (familial, autosomal dominant trait, 20%)

It’s the most common porphyria and often due to a chronic disease of the liver. Liver damage can lead to acquired PCT. (hepatitis, ethanol abuse)

Accumulating substrate: Uroporphyrin 3

Symptoms: Urine is red Cutaneous lesions and accumulation of the red uroporphyrin III in skin and also in the liver.

Erosions and bullous lesions in sun-exposed areas of the patients are produced by minor trauma because of increased skin fragility.These lesions heal with scarring, pigment changes, and formation of small white papules

Treatment: avoidance of sunlight, iron, & alcohol

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32
Q

Wilson’s disease

A

. Characteristic: Low ceruloplasmin levels are found in Wilson’s disease • Cause: deficiency of a COPPER-TRANSPORTING ATPase which is needed to link copper to ceruloplasmin and is also needed to release copper into BILE. • Apoceruloplasmin is released from the liver into serum and as it is without copper, it is degraded in serum. • Symptoms: Damage due to copper accumulation in liver, brain, eyes, “Kayser-Fleischer rings” and kidney.

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33
Q

Phenylketonuria 1 (Classic PKU) Deficient Enz, Accumulating substrate, Symptoms, Treatment. Comments

A
  • Phenylalanine Hydroxylase (PAH) - Phenylalanine, Phenylpyruvate, Phenylacetate, phenylactate - Delay in milestones and low IQ, seizures, MOUSEY ODOR URINE, decreased pigmentation of skin and hair. - Dietary restriction of Phenylalanine (low protein diet), avoid eggs, meat…; avoid Aspartame & Use Sapropterin (synthetic BH4) if Enz has low affinity for BH4,Tyrosine now essential aa Comments: Autosomal recessive. Guthrie test, mass spec & fluorimetric assay. Melanin is inhibited by high Phe conc (inhibits tyrosinase)
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34
Q

Maternal PKU: Deficient Enz, Accumulating substrate, Symptoms,Treatment, Comments

A
  • Phenylalanine Hydroxylase (of mother) - Phenylalanine, phenylpyruvate - Microencephaly, mental retardation, congenital heart defects of foetus/newborn. - Mother must maintain low level of Phe before conception & during pregnancy. Comments: Elevated Phe has teratogenic properties. Maternal PKU syndrome occurs even though the fetus is NOT deficient in PHA (fetus heterozygous)
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35
Q

PKU 2 & 3

A

-Deficiency of dihydrobiopterin reductase (II) or dihydrobiopterin synthesis (III) leading to a lack of the essential coenzyme tetrahydrobiopterin (BH4) - phenylalanine, Phenylpyruvate - Much more severe CNS symptoms – worse than Type I; decreased neurotransmitter synthesis (serotonin, dopamine, catecholamines) [also dependent on BH4] - Treatment includes low phe diet and providing dietary supplements of biopterin and precursors of the neurotransmitters

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36
Q

Alkaptonuria Deficient Enz, Accumulating substrate, Symptoms, Treatment

A
  • Homogentisic acid oxidase is deficient -Homogentisate - Discoloration of cartilage and connective tissue (Ochronosis) Due to excess of homogentisic acid (Homogentisic aciduria), Darkening of urine on standing & may cause severe arthritis. -Dietary restriction of phe & tyr may reduce deposition of homogentisic acid
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37
Q

Tyrosinosis (Tyrosinemia type I & II) Deficient Enz, Accumulating substrate, Symptoms, Treatment

A

Type I - deficiency of Fumaryl acetoacetate hydrolase [catalyses laststep in tyrosine degradation]

Symptoms for Type 1: Manifestations are severe and usually fatal. Accumulation of fumarylacetoacetate causes liver and kidney damage. Death due to liver failure within first year -

Type II - deficiency of Tyrosine aminotransferase [catalyses conversion of tyrosine to p-hydroxyphenylalanine]

Symptoms Type 2: Leads to lesions in the eye and skin. Manifestation of neurological problems.

  • Patients may respond to low phenylalanine and tyrosine diets.
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38
Q

Maple Syrup Urine disease (MSUD) Deficient Enz, Accumulating substrate, Symptoms, Treatment, Comments

A
  • Deficiency in Branched-chain a-ketoacid dehydrogenase - Accumulation of BCAA and associated a- ketoacids. - Ketosis and the characteristic odour of maple syrup in the urine - the first symptoms develop. Symptoms develop in neonates aged 4-7 days • Presents with poor feeding, vomiting, poor weight gain and increasing lethargy. •Neurological signs develop rapidly •Coma and death of the child in early infancy. - Treatment is by dietary restriction of branched chain amino acids Supplementation of dietary thiamine (coenzyme) may be useful in patients that have an enzyme with low coenzyme affinity - Comments: Problems of treatment: – Very difficult to treat – BCAA are very abundant in most protein sources – The 3 BCAA are all essential – Catabolic states mobilize tissue protein which then releases amino acids to metabolism
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39
Q

Methylmalonic aciduria Deficient Enz, accumulating substrate, Symptoms, Treatment, Comments

A
  • Methylmalonyl-CoA mutase – Accumulation of methylmalonyl-CoA. Then qConverted to methylmalonic acid (accumulation). Causes metabolic acidosis and methylmalonic acidaemia/methylmalonic aciduria. - Methylmalonyl-CoA is also sometimes used instead of malonyl-CoA for fatty acid synthesis. Leads to branched fatty acids into membranes - results in neurological problems: seizures, encephalopathy - On diagnosis, children are usually placed on a gastrostomy tube for feeding at regular intervals • They are given special diets low in branched chain amino acids on diagnosis • Milder form of the disease due to reduced affinity for coenzymes • Vitamin B12 (cobalamin) supplementation.
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40
Q

Homocystinuria Deficient Enz, Accumulating substrate, Symptoms, Treatment

A
  • cystathionine β-synthase
  • Acc: High plasma & urinary levels of homocysteine
  • Symptoms:+ dislocation of lens (ectopia lentis), skeletal abnormalities,** osteoporesis**, premature arterial disease.
  • Treatment of homocysturia is usually by dietary supplementation.

Some patients respond to oral vitamin B6 (pyridoxine) [this is a precursor of pyridoxal phosphate (PLP) a coenzyme required by cystathionine β-synthase]. Milder form due to low coenzyme affinity. Dietary restriction of methionine. Supplementation with folic acid and vitamin B12.

41
Q

Link between homocysteine and atherosclerosis

A

Further links between homocysteine and athersclerosis are: - Homocysteine’s ability to generate superoxide and hydrogen peroxide. - Formation the reactive product of homocysteine, homocysteine thiolactone - Homothiolactone promotes lipoprotein precipitation and platelets aggregation = formation atherosclerotic plaques - Increased homocysteine inhibits ApoA-I synthesis.

42
Q

Cystinuria Defiecient Enz, accumulating substrate, Symptoms

A
  • Cystine Transporter (C.O.A.L) - Cystine in urine - Tubular Reabsorption of Cysteine is decreased (also for ornithine, Arginine, lysine), cystine stones in children
43
Q

CSPI Deficiency (Type 1 Hyperammonemia) Deficient Enz, Acc substrate, Symptoms

A
  • CPS1
  • Symptoms: Ammonia intoxication includes tremors, SLURRING of speech, somnolence, vomiting, CEREBRAL OEDEMA, and BLURRING VISION

• Highly toxic for the brain, because: 1. Glutamate dehydrogenase and glutamine synthetase deplete the brain of the neurotransmitters (glutamate and GABA)

  1. High glutamine levels in brain cells leads to cerebral oedema.

Treatment: L-arginine supplementation. Rationale: Arginine stimulates the formation of N-acetylglutamate High levels of NAG might stimulate deficient CPS Benzoic acid – combines with glycine. Requires activation to CoA derivative. Product is Hippuric acid= Excretion of 1 atom of nitrogen

Or - Phenylbutyrate (prodrug) – combines with glutamine Product is Phenylacetylglutamine. Excretion of 2 atom of nitrogen

  • Dialysis: acute emergency situation- Low protein / high carbohydrate diet to minimize N intake- Prescribe α-keto acids (expensive) - prevention of stresses that induce a catabolic state- Long term: Liver transplantation
44
Q

OTC Deficiency (Type II Hyperammonaemia)

A
  • Mitochondrial ornithine transcarbamoylase(most common & more severe in males) - Elevated serum & *urine*of OROTIC ACIDURiA – (orotic aciduriasbecause elevated carbamoyl phosphate drives pyrimidine biosynthesis : oritic acid) Symptoms: +Hyperammonaemia +Decreased BUN (blood urea nitrogen) + High blood GLUTAMINE levels + Orotic aciduria + CEREBRAL OEDEMA, lethargy, convulsions, coma, that can lead to death -Treatments: Dialysis, benzoin acid, Phenylbutyrate, low prot/high carb diet, liver transplant & prevention of stresses that induce a catabolic state
45
Q

Argininosuccinate Synthetase Deficiency (Classic Citrullina

A
  • Diagnosis: hyperammonemia, with very high levels of serum citrulline, and citrulline in the urine
  • Treatment may include arginine administration:

– Enhances urinary citrulline excretion

– Sometimes allows the urea cycle to progress due to high levels of substrate• Also other treatments listed previously

46
Q

Argininosuccinic aciduria) Deficient Enz, Acc substrate, symptoms, treatment

A
  • Argininosuccinate Lyase Deficiency
  • Ariginosuccinate in plasma, cerebral spinal fluid & urine. Blood ammonia, blood glutamine level & serum citrulline.
  • Hyperammonemia, decreased urea cycle, lethargy, feeding difficulties, seizures and mental retardation
  • Treatment: Arginine administration, Dialysis, benzoinc acid, Phenylbutyrate, low prot/high carb diet, liver transplant & prevention of stresses that induce a catabolic state
47
Q

Hyperargininaemia

Def Enz, Acc substrate, Symptoms, Tratment

A
  • Arginase Deficiency
  • Acc substrate: Blood ammonia (not as high as other UCD), high Arginine levels & blood glutamine levels
  • Symtoms: Hyperamonnemia, decreased urea formation, lethargy, irritability, feeding difficulties, SEIZURES, mental retardation.
  • Treatment: Diet excluding Argininine, Dialysis, benzoin acid, Phenylbutyrate, low prot/high carb diet, liver transplant & prevention of stresses that induce a catabolic state
48
Q

Acquired Hyperammonemia

A
  • Liver disease
  • Accumulation: blood ammonomia
  • Symotoms: Apatheric, confused, disoriented, drowsy, slurred, speech, flapping tremor.
  • Treatment: Low prot diet, lactulose (cause production of lactic acid in colon from bacterial flora –> acidic conditions favour NH4+ and promotes NH3 to enter lumen from tissue) , neomycin (Redcution in bacterial ureases in gut), other treatment related to UCD
49
Q

Pernicious Anemia

A
  • Unable to absorb Vit B12 because no production of intrinsic factor. The parietal cell, which produce the IF, are being attacked by the immune system. - Consequences: Accumulation of abnormal fatty acids–> neurological CNS, can produce megaloblastic anemia. - Treatment: Lifetime intramuscular injection of cyanocobalamin Anemia reversible but CNSq effects are not.
50
Q

Parkinson’s Disease Cause, Symptoms

A

Cause: Loss of Dopamine producing cells in the basal ganglia

Symptoms: Movement disorders, SPASTICITY, TREMORS, loss of memory, mood disturbances, postural instability

Treatment: Administer L-DOPA & dopa decarboxylase inhibitor (Carbidopa). L-DOPA can cross the blood brain barrier can be converter to dopamine in brain because it contains it’s own decarboxylase.

51
Q

Pheochromocytoma Cause, Accumulating substrate, symptoms

A

Cause: Adrenal Tumour Synthesis Acc: High urinary vinillyl mandelic acid (VMA) and catecholamine. Substrate: Headache, sweating, tachycardia, hypertension (must use 24hr urinary measurement episodic symptoms)

52
Q

Carcinoid Syndrome Cause, Acc substrate, Symptoms

A

Cause: Tumor of serotonin producing cells in GIT (APUD cells) Acc: 5-hydroxyindole acetic acid (5-HIAA) in urine Symptoms: CUTANEOUS FLUSHING, sometimes accompanied by sweating, GI hypermobility causing diarrhea, bronchopasm

53
Q

Albinism Cause, Symptoms

A

Cause: deficient tyrosinase Symptoms: Lower visual acuity and phoptophobia, lighn skin color & hair

54
Q

Kernicterus Cause, Acc, Symptoms

A

Cause: Unconjugated bilirubin crosses blood brain barrier Acc: Serum Unconjugated bilirubin Symptoms: Lethargy, altered muscle tone, HIGH PITCHED CRY, choreoathetosis, spasticity, lethargy, altered muscle tone, ataxia, mental retardation Comments: Hypoalbuminemia, low pH(weakens albumin-bilirubin bond), drugs )0(salicylates sulfonamides) that compete with bilirubin for albumin binding cause increase Unconjugated bilirubin and increase rick of Kernicterus.

55
Q

Crigler-Najjar syndrome I

Cause, Accumulates, symptoms, Treatment, comments

A
  • Cause: Almost complete deficiency of the enzyme microsomal bilirubin glucuronyl transferase
  • Acc: Serum Unconjugated bilirubin
  • Symptoms: kernicterus and mental retardation -

Treatment: Daily phototherapy, exchange transfusion and prevention of kernicterus

Comments: Inherited Unconjugated hyperbilirubinemia. Most severe. Usually fatal by 2 years of life (if not treated). Death usually due to complications of kernicterus

56
Q

Crigler-Najjar syndrome II (Arias syndrome) Cause, Acc, Symptoms, Treatemnt, Comments

A
  • Cause: lower activity of bilirubin glucuronyl transferase (10-20% of normal)
  • Acc: Serum Unconjugated bilirubin
  • Symptoms: Kernicterus and mental retardation
  • Treatment: Children respond to PHENOBARBITAL (induces the enzyme).Regular phototherapy is used in patients with persisting high bilirubin levels

Comments: Inherited, less severe than 1

57
Q

Gilbert’s syndrome

Cause, ass, symptoms, treatment, comment

A
  • Cause: UDP-glucuronyl transferase activity is about 50% of normal
  • Acc serum Unconjugated bilirubin
  • symptoms: Characterized by a mild increase in unconjugated bilirubin. Characterized by occurrence of mild jaundice (2-5 mg/dL) usually following an infection or stress or starvation Comment: 3-7% population, least severe
58
Q

Dubin-Johnson syndrome

Cause, Acc, symptom, treatment

A
  • Cause: Inherited deficiency of the ABC transporter that transports conjugated bilirubin from the hepatocyte into the biliary canaliculus
  • Acc: conjugated (direct) bilirubin
  • symptoms: asymptomatic except for mild intermittent jaundice , “black liver”. Typically presents in young adults
59
Q

Hypoalbuminemia Cause

A

Decrease synthesis, increased loss of albumin

60
Q

Bernard-Soulier syndrome Cause, symptoms

A
  • Glycoproteins 1b(Gp1b)
  • Gp1b cannot bind to vWB factor —> increased bleeding time
61
Q

Thrombasthenia of Glanzman and Naegeli Defective Enz, Symptoms

A
  • GpIIb/GpIIa
  • No fibrinogen bridging of platelets to other platelets can occur, and bleeding time is significantly prolonged
62
Q

Thrombocytopenia

A
  • Low platelet count
  • increased bleeding time
63
Q

Hemophilia A

Cause, Symptoms, Comments

A
  • Factor VIII defect –> Defect in the intrinsic coagulation pathway—> increased clotting time & increased APTT.
  • Symptoms: Massive hemorrhage after trauma and surgical, spontaneous hemorrhages, particularly **joints-hemarthrosis **(bleeding into joints)
  • X-linked
64
Q

Hemophilia B Cause, symptoms

A

Cause: Factor IX defect

Symptoms: Defect in the intrinsic pathway—> increased clotting time and increased APTT. Massive hemorrhages

65
Q

Von Willebrand disease

A
  • Defect in formation of platelet plug
  • Defect in coagulation because instability of factor VIII
  • lab findings: Bleeding time & APTT prolonged. Platelet count normal and PT(INR) normal. vWF levers are low.
  • Symptoms: Increased mucosal bleeding, Epistaxis, Oncreased post-operative bleeding.
66
Q

Megaloblastic Anemia Deficiency

A
  • Folate Deficiency and/or Vit B12 deficiency
  • Megaloblastic cells(large abnormal immature erythrocytes) - Must be treated with both Vit B12 and Folate
67
Q

Vit B12 Deficiency

Cause, Acc substrate, Symptoms, Treatment

A
  • Cause: Vit B12 deficiency commonly cause by improper absorption due to lack of intrinsic factor (IF,pernicious anemia)
  • Acc: Abnormal fatty acids, homocysteine in plasma and urine, methylmalonyl CoA
  • Symptoms: Magaloblastic anemia Neurological defects (myelin degeneration in both motor and sensory pathways due to Methymalonyl CoA accumulation)
  • Treatment: Lifetime intramuscular injections of cyanocobalamin
  • Other causes of Vit B12 deficiency: pure vegan diet, chronic pancreatitis, terminal ileal disease(Chron’s disease)
68
Q

Histidinemia Deficient, Acc, comments

A
  • Deficient: Folate deficiency
  • Acc: FIGlu
  • Symptoms: FIGlu(N-formiminoglutamate) excretion test used for diagnosing deficiency of Folic acid.
69
Q

Leach-Nyhan Syndrome Deficiency, Acc, symptoms

A
  • Deficiency of Hypoxanthine-guanine Phosphoribosylthransferase(HGPRT)
  • Acc: Uric acid in urine
  • Symptoms: Orange crystals found in babies diaper, self-mutilation and gout
  • Results in inability to salvage purines Hypoxanthine and guanine, causes increased PRPP levels and increase in de novo synthesis
70
Q

Adnosine Deaminase Deficiency Deficient, Acc, symtomps, comments

A
  • ADA deficiency
  • Acc: Adenosine
  • Symptoms: Causes severe combined immunodeficiency (SCIDS), DNA is not synthesized in T cells and B cells -

Comments: Accumulation of dATP causes inhibition of Ribonucleotide Reductase

71
Q

Purine Nucleoside Phosphorylase (PNP) deficiency Deficiency, Acc, symptoms

A
  • PNP deficiency
  • Purine nucleoside and nucleotides
  • Causes impairment of T-cell function, Decreased Uric acid
72
Q

Gout

Deficiency, Accumulation, Symptoms, Treament

A
  • Primary: genetic
  • Secondary: Leukemia, Polycythemia, HGPRT deficiency, treatment of cancer with antimetabolites, coronal renal insufficiency
  • Acc: Uric acid in urine & blood
  • Symptoms: Presence of mono sodium urate crystals - Treatment: Allupurinol
73
Q

Acquired Hypertriacylglycerolemias often associated with:

A
  • Hypertension
  • Untreated Diabetes mellitus
  • alcohol abuse
  • Usage of oral contraceptives
  • Hyperuricemia
74
Q

Acquired Hypercholesterolemias

A
  • Hypothyroidism
  • Nephrotic syndrome
  • Obstructive liver diseases
  • Treatment with specific medical drugs
75
Q

Wernicke- Korsakoff Syndrome

Cause, Symptoms, Treatment

A

Cause: Thiamine (vitamin B1) deficiency

Symptoms: Mental confusion, ataxia, ophthalmoplegia, confabulation

Treatment: Thiamine supplement

Comment: Most common in chronic alcoholics, diagnosis- increase in erythrocyte transketolase activity on addition of TPP, Polished rice, white sugar, white flour is low in thiamine

Chronic Stage: referred as Korsakoff’s psychosis, retrograde and/or anterograde amnesia, sometimes irreversible

76
Q

Beri Beri

Cause, Symptoms, Treaments

A
  • Cause:Thiamine (vitamin B1) deficiency
  • Symptoms:
    • Polyneuropathy (disruption of motor, sensory and reflex arcs; could progress to paralysis (dry beri beri),
    • Cardiovascular symptoms-cardic failure (wet beri beri
  • Treatments: Thiamine suppement
  • Comments: Diagnosis: increase in erythrocyte transketolase activity on addition of TPP, Polished rice, white sugar, white flour is low in thiamine
77
Q

Vitamin A Deficiency

Deficiency, Symptoms, Clinical Uses, Toxicity

A

Deficiency: Dietary defieciency (common cause), or malabsorption of fats

Symptoms: Night blindness (earliest symptom, inability to see dim light), Xerophthalmia (dryness of the conjuctiva and cornea, Bitot’s spots (Increased keratinization), Keratomalacia (corneal erosion and ulceration), increased risk of pulmonary infections, weakned innate immunity (once you hit Keratomalcia it is irreversible)

Clinical uses: retinoic acid is used in the treatment of acne (topical treatment), all-trans retinoic acid is used in the treatment of acute promyelocytic leukemia

Toxicity: Hypervitaminosis A- raised intracranial pressure-headaches-may mimic brain tumors, dry and prurtic skin, enlarged liver, should be avoided during pregnancy (teratogenic)

Sources: Liver, Kidney, egg yolk (provitamin form: B-carotene)

78
Q

Vitamin D & Deficiency

Types, Sources, & Function

Cause, Symptoms, Toxicity

A
  • Types: Ergocalciferol(D2): in plants & Cholecalciferol(D3): in animals. Precursor for D3 is 7-dehydrocholesterol
  • Functions:
  • Intestine: stimulate absorption of Ca2+ & PO4 by increased synthesis of specific calcium binding protein
  • Bone: mobilizes Ca & PO4
  • Kidneys: inhibit Ca2+ excretion by stimulating parathyroid dependent calcium reabsorption –>Increases plasma calcium

​Deficiency:

  • Cause: Decreased intake/fat malabsorption, inadequate exposure to sunlight, chronic renal disease, chronic liver disease
  • Acc: Parathyroid hormone, demineralization of bone
  • Symptoms: Rickets in children & Osteomalacia in Adults

Hypervitaminosis D: Hypercalcemia, lg term–> calcification in soft tissues like kidney

79
Q

Rickets

Deficiency, Acc, Symptoms

A
  • VItamins Vitamin D deficiency in kids
  • Accumulation: Parathyroid hormone, demineralization of bone
  • Symptoms: Characteristic bow-leg deformity, overgrowth at costochondrial junction, rachitic rosary, pigeon chest deformity, frontal bossing
  • There are ↓ levels of Ca2+& PO4in ECF
80
Q

Osteomalacia

Deficiency, Accm Symtoms, Comments

A
  • Vitamins Vitamin D deficiency in adults
  • Acc: Parathyroid hormone, demineralization of bone
  • Symptoms: Bones are de-mineralized and are susceptible to fracture
  • Comments: Can be secondary to dietary deficiency, renal disease or liver disease. There are ↓ levels of Ca2+& PO4in ECF
81
Q

Vitamin E

Role, Deficiency: Cause, Symptoms

A

Role: Anti-oxidant, prevents peroxidation of lipids & scavenges free radicals

Deficiency:

Cause: Fat malabsorption

Symptoms: Hemolytic anemia, reduced deep tendon reflexes and Gait problems due to axonal degeneration

Comments Alpha tocopherol is the most active form

82
Q

Why is aldosterone synthesis increased in patients with CYP 17 deficiency?

A

CYP 17 is needed for cortisol synthesis and deficiency results in CAH.CYP 17 is not needed for aldosterone synthesis.

The uncontrolled stimulation of the adrenal cortex by ACTH due to lack of cortisol leads to more aldosterone synthesis than usual.

83
Q

Hartbup’s Disease

Cause, Symptoms, Treatment

A
  • Cause: Inherited defect in the transport of neutral amino acids like tryptophan + Decreased dietary absorption of tryptophan and oncreased excretion of tryptophan

—> NAD+ deficiency (Tryptophan precursor of NAD+)

  • Symptoms: **Pellagra, Dementia, Diarrhea, Dermatitis, Death **
  • Treatment: Niacin supplementation

Ingested niacin may not be sufficient.

84
Q

What is Lymphotcytopenia?

A

Tcell and Bcell depletion

(cytopenia: reduction in blood cells)

85
Q

Multiple Sclerosis

Cause, Symptoms

A
  • Cause: Progressive destruction of CNS myelin–> formation of sclerotic plaques caused by autoimmune reaction.

Episodal periods of destruction

  • Symptoms: Weakness, Lack of coordination, Loss of vision & fatal.
86
Q

Vitamin K

Role, Types, Deficiency in neonates & adults: Cause, Symptoms & Treatment for each

A
  • Coenzyme of y-carboxylase for the synthesis of the mature clotting factors (II,VII,IX,X, Protein C & S)
  • Types: Phylloquinone(plants), Menaquinone (bacteria in intestine)

Deficiency:

  • Neonates:
  • Cause: Sterile intestine - no synthesis of Vit K
    • Hemorrhagic disease of newborn
      • Bleeding in the skin, umbilicus, viscera
      • Intracranial bleeding
    • Treatment: Intramuscular injection of Vit K
  • Adults:
    • Cause: fat malabsorption, antibiotics
      • Hematuria
      • Melena (black tarry stools)
      • Ecchymoses (bruises)
      • Bleeding from gums
  • Warfarin inhibits liver epoxide reductase–> prevent regenration of resuced Vit K
87
Q

Vit C

Function, Deficiency

A
  • Function:
    • Required for maintenance of normal connective tissue (collagen synthesis) and wound healing (reqd for cross-linking of CLG - acts as a coenxyme for hydroxylation of proline and lysine)
    • Requied for absortion of Iron: reduces iron to ferrous state in stomach
    • Anti-oxidant: regenrates anti-oxidant form of Vit E
  • Deficiency: Scurvy:
    • Perifollicular hemorrhages
    • Bleeding from gums
    • Loose teeth
    • Bleeding into joints
88
Q

Vit B1 (Thiamine)

Coenzyme form, Sources

A
  • Coenzyme: TPP (Thiamine pyrophosphate)
  • Sources: widely available BUT not in polished rice, white flou, & white sugar
  • Deficieceny: Beri-Beri & Wernicke-Korsakoff
89
Q

Vit B2 (Riboflavin) (b in the word which is 2nd letter of alphabet)

Coenzyme forms, Deficiency

A
  • Coenzyme:
    • Flavin mononucleotide (FMN)
    • Flavin dinucleotide (FAD)
  • Deficiency:
    • Cause: nutritional
    • Symptoms:
      • Cheilosis: pallor, cracks at angles of mouth
      • Glossitis
      • Facial dermatitis
90
Q

Vit B3 (Niacin)

  • Coenzyme forms, Therapeutic , Deficiency
A
  • Coenzyme: NAD+, NADP+
  • Therapeutic uses: Niacin inhibits lipolysis in the adipose tissue and greatly reduces production of free fatty acids: treatment of type IIb hyperliproteinemia
  • Deficiency
    • Cause: Corn based diet, Hartnup disease (Tryp not absorbed by renal tubules), Carcinoid syndrome (exessive formation of Serotonin & 5-HIAA)
    • Symptom: Pellagra (neck-lace like skin damage) characterized by:
      • Dermatitis
      • Diarrhea
      • Dementia

Tryptophan

91
Q

Pyridoxine Deficiency

Drug, Symptoms

A
  • Drug: Isoniazid
    • Inactivates pyridoxine
    • Pyridoxine supplements given as part of anti TB regimes
  • _​_Symptoms:
    • Microcytic anemia (reduced heme synthesis as result of ALA synthase activity)
    • Peripheral neuropathy
    • Increased risk of Cardiovascular disease (high levels of plasma homocysteine)
    • Seizure
92
Q

Copper Deficiency

Symptoms

A
  • Symptoms:
    • Microcytic anemia: ceruloplasmin (ferroxidase) is required for iron metabolism
    • Degradation of vascular tissue: decreased lysyl oxidase activity
    • Defects in hair
93
Q

Menkes syndrome

Cause, Symptoms

A
  • Cause: Inherited defect in absorption of copper from the GI tract
  • X-linked
  • Symptoms:
    • Hair is twisty, graiyish and “kinky”
    • Aneurysms
    • Cerebral dysfunction
94
Q

Iron

Type (absorbed and trasnport), storage forms, deficiency

A
  • Type:
    • Absorbed as Ferrous
    • Transported by ferritin as ferric
  • Storage forms:
    • Ferritin (usually measured)
    • Hemosiderin
  • Deficiency:
    • hypochromic mycrocytic
    • Fatigue and pallor
    • Brittle nails
    • Pica (appetite for soil)
95
Q

Hereditary Hmeochromatosis

Cause, Damages tissues by, Symptoms

A
  • Genetic defect causing excessive absorption of Iron. bacause defect in HFE gene.This gene, located on the basolateral surface of intestinal crypt cell, senses the sytemic iron balance. Defect leads to loss of sensation
  • Accumulation in Liver & Pancreas
  • Damages tissues by:
    • Lipid peroxidation
    • DNA damage
  • Symptoms:
    • Common: males, age 40
    • Cirrhosis, hepatocellular carcinoma
    • Diabetes
    • Disfunctional heart
    • Acute synovitis
    • Brownish skin pigmentation (bronze color of skin)
    • High serum ferritin level
96
Q

Marasmus

Cause, Symptoms, Comments

A
  • Cause:Chronic dietary restriction of carbohydrates, lipids, protein and other nutrients
  • Symptoms:Extensive tissue and muscle wasting (emaciation). Dry skin, loose skin folds hanging over buttocks. Drastic loss of body fat like on buttocks and thighs
  • Comments: Children look severely starved and show less than 80% of standard weight. Associated in adults with diseases like anorexia nervosa, GI cancer, chronic illness. (also old age)
97
Q

Cachexia

A
  • A wasting disorder characterized by loss of appetite and muscel atrophy that cannot be reversed bu conventional suport
  • Cancer, AIDS, chronic pulmonary and rrenal disease can lead to cachexia
98
Q

Anorexia nervosa

A

Patients refuse to maintain normal body weight as they feel fat even when undernourished

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

99
Q

Kwashiorkor

Cause, Symptom, Diet

A
  • Deficiency of dietary protein and dietary essential amino acids. Diet can be otherwise adequate in calories
  • Symptoms:
    • Muscle wasting due to lack of essential amino acids, stunted growth
    • Decreased concentration of blood albumin < 2.8 g/dL
    • Edema found in the abdomen and legs
  • Comments:
    • Diets of wheat gruel
    • PATs could look well nourished or obese when dressed
    • Children often after weaning off, about one year old and when the diet consits predominantly of carbohydrates

Medical Biochemistry (8 decks)

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