How to approach USMLE questions ? ( Lesch–Nyhan syndrome )

Signs and Symptoms Associated with Down Syndrome

Down syndrome is the most common autosomal trisomy identified in liveborn infants. As many as 95% of Down syndrome cases arise due to chromosomal nondisjunction during maternal meiosis (47 XX, +21) an abnormality that positively correlates with increasing maternal age. Two of the more prominent and consistent lectures of Down syndrome are mental retardation and facial dysmorphism. Almost every organ and system, however, is affected

Signs and Symptoms Associated with Down Syndrome

Trisomy 21 (Down syndrome) is characterized by mental retardation, facial dysmorphism, single palmar crease, endocardial cushion defects, and duodenal atresia. Affected individuals have an increased risk of AML-M7 and ALL in childhood and early Alzheimer disease in adulthood. 

Homocystinuria

Homocystinuria is caused by cystathionine synthetase deficiency. Affected individuals manifest with skeletal abnormalities resembling those of Marfan syndrome. In addition, they are also at high risk of developing thromboembolism. About 50% of affected patients respond to high doses of vitamin B6 (pyridoxine).

Homocystinuria is the most common inborn error of methionine metabolism and is caused by cystathionine synthetase deficiency. Thromboembolic episodes involving both large and small vessels, especially those of the brain, are classically associated with this condition and may occur at any age. Other clinical manifestations resemble those of Marfan syndrome. These include ectopia lentis, elongated limbs, arachnodactyly, and scoliosis.

Glycogen storage diseases

Polycistronic mRNA (Bacterial lac operon)

Bacterial mRNA can be polycistronic, meaning that one mRNA codes for several proteins. An example of polycistronic mRNA is the bacterial lac operon, which codes for the proteins necessary for lactose metabolism by E. coil; the transcription and translation of these bacterial proteins is regulated by a single promoter, operator, and set of regulatory elements. 

Multiple origins of replication (DNA replication)

The process of DNA replication is similar in eukaryotes and prokaryotes. The key steps involved in DNA replication are:
1. Unwinding of double stranded DNA (dsDNA) by helicase to produce single stranded DNA (ssDNA)
2. Formation of a replication fork
3. Formation of an RNA primer by the action of the enzyme primase
4. Synthesis and concurrent proofreading of daughter DNA strands by DNA polymerases
5. Ligation of Okazaki fragments on lagging strands by ligase and removal and replacement of RNA primers with DNA by DNA polymerase I
6. Reconstitution of chromatin and ligation of daughter strands.

In E. coil, a prokaryote, the three major types of DNA polymerase are DNA polymerase I, II and III. In eukaryotes there are five major DNA polymerases: alpha, beta, gamma, delta and epsilon. Though the eukaryotic genome is much larger and more complex than the prokaryotic genome, interestingly the size of the eukaryotic genome is not the source of its complexity. Its complexity results from the presence of a large number of non-coding DNA regions between coding regions. Within genes there are introns (Non-coding regions - Think “IN” between) separating exons (Coding regions - Think “EX” pressed). Prokaryotes rarely have introns within their genes.
In contrast to prokaryotes which typically have a single origin of replication eukaryotes have multiple origins of replication? With multiple origins of replication, the genome can be copied much more quickly because multiple regions are being replicated at once. 

Bilirubin metabolism

Case studies electrolyte and acid-base disorder

Case 1

Mr. Frank is a 60 year-old with pneumonia. He is admitted with dyspnea, fever, and chills. His blood gas is below:
pH 7.28
CO2 56
PO2 70
HCO3 25
SaO2 89%
What is your interpretation?

• Uncompensated respiratory acidosis

Case 2

Ms. Strauss is a 24 year-old college student. She has a history of Crohn's disease and is complaining of a four day history of bloody-watery diarrhea. A blood gas is obtained to assess her acid/base balance:
pH 7.28
CO2 43
pO2 88
HCO3 20
SaO2 96%
What is your interpretation?

• Uncompensated metabolic alkalosis

Case 3

Mr. Karl is a 80 year-old nursing home resident admitted with urosepsis. Over the last two hours he has developed shortness of breath and is becoming confused. His ABG shows the following results:
pH 7.02
CO2 55
pO2 77
HCO3 14
SaO2 89%
What is your interpretation?

• Combined respiratory and metabolic acidosis

Case 4

Mrs. Lauder is a thin, elderly-looking 61 year-old COPD patient. She has an ABG done as part of her routine care in the pulmonary clinic. The results are as follows:
pH 7.37
CO2 63
pO2 58
HCO3 35
SaO2 89%
What is your interpretation?

• Fully compensated respiratory acidosis

Case 5

Ms. Steele is a 17 year-old with intractable vomiting. She has some electrolyte abnormalities, so a blood gas is obtained to assess her acid/base balance.
pH 7.50
CO2 36
pO2 92
HCO3 27
SaO2 97%
What is your interpretation?

• Hypochloremic metabolic alkalosis (anion gap)

Case 6

Mr. Longo is a 18 year-old comatose, quadriplegic patient who has the following ABG done as part of a medical workup:
pH 7.48
CO2 22
pO2 96
HCO3 16
SaO2 98%
What is your interpretation?

• Respiratory alkalosis with metabolic acidosis

Case 7

Mr. Casper is a 55 year-old with GERD. He takes about 15 TUMS antacid tablets a day. An ABG is obtained to assess his acid/base balance:
pH 7.46
CO2 42
pO2 86
HCO3 29
SaO2 97%
What is your interpretation?

• Uncompensated Metabolic alkalosis 

Case 8

Mrs. Dobins is found pulseless and not breathing this morning. After a couple minutes of CPR she responds with a pulse and starts breathing on her own. A blood gas is obtained:
pH 6.89
CO2 70
pO2 42
HCO3 13
SaO2 50%
What is your interpretation?

• Combined respiratory acidosis with metabolic acidosis

Case 9

After resuscitating Mrs. Dobins, you find Mr. Simmons to be in respiratory distress. He has a history of Type-I diabetes mellitus and is now febrile. His ABG shows:
pH 7.00
CO2 59
pO2 86
HCO3 14
SaO2 91%
What is your interpretation?

• Combined respiratory acidosis with metabolic acidosis

Case 10

Ms. Berth was admitted for a drug overdose. She is being mechanically ventilated and a blood gas is obtained to assess her for weaning. The results are as follows:
pH 7.54
CO2 19
pO2 100
HCO3 16
SaO2 98%
What is your interpretation?

• Respiratory alkalosis with metabolic acidosis

Case 11

Mrs. Puffer is a 35-year-old single mother, just getting off the night shift. She reports to the ED in the early morning with shortness of breath. She has cyanosis of the lips. She has had a productive cough for 2 weeks. Her temperature is 102.2, blood pressure 110/76, heart rate 108, respirations 32, rapid and shallow. Breath sounds are diminished in both bases, with coarse rhonchi in the upper lobes. Chest X-ray indicates bilateral pneumonia.
ABG results are:
pH= 7.44
PaCO2= 28
HCO3= 24
PaO2= 54

• Compensated respiratory alkalosis

Case 12

Mr. Worried is a 52-year-old widower. He is retired and living alone. He enters the ED complaining of shortness of breath and tingling in fingers. His breathing is shallow and rapid. He denies diabetes; blood sugar is normal. There are no EKG changes. He has no significant respiratory or cardiac history. He takes several antianxiety medications. He says he has had anxiety attacks before. While being worked up for chest pain an ABG is done:
ABG results are:
pH= 7.48
PaCO2= 28
HCO3= 22
PaO2= 85

• Uncompensated respiratory alkalosis

Case 13

Mr. Sweet, a 24-year-old DKA (diabetic ketoacidosis) patient from the ED. The medical diagnosis tells you to expect acidosis. In report you learn that his blood glucose on arrival was 780. He has been started on an insulin drip and has received one amp of bicarb. You will be doing finger stick blood sugars every hour.
ABG results are:
pH= 7.33
PaCO2= 25
HCO3=12
PaO2= 89

• Metabolic acidosis with respiratory alkalosis

Case 14

A 24 year-old woman is found down in Pioneer Square by some bystanders. The medics are called and, upon arrival, find her with an oxygen saturation of 88% on room air and pinpoint pupils on exam. She is brought into the Harborview ER where a room air arterial blood gas is performed and reveals: pH 7.25, PCO2 60, PO2 65, HCO3 -  26. On his chemistry panel, her sodium is 137, chloride 100, bicarbonate 26.

• Acute Uncompensated respiratory acidosis 

Case 15

A 60 year-old man with amyotrophic lateral sclerosis is brought into clinic by his family who are concerned that he is more somnolent than normal. On further history, they report that he has been having problems with morning headaches and does not feel very refreshed when he wakes up. An arterial blood gas is performed and reveals:  pH 7.37, PCO2 57, PO2 70, HCO3- 32.

•  Chronic Compensated respiratory acidosis

Case 16

A 65 year-old man is brought into the VA hospital with complaints of severe nausea and weakness. He has had problems with peptic ulcer disease in the past and has been having similar pain for the past two weeks. Rather than see a physician about this, he opted to deal with the problem on his own and, over the past week, has been drinking significant quantities of milk and consuming large quantities of TUMS (calcium carbonate).  On his initial laboratory studies, he is found to have a calcium level of 11.5 mg/dL, a creatinine of 1.4 and bicarbonate of 35. The resident working in the ER decides to draw a room air blood gas that reveals: pH 7.45, PCO2 49, PO2 68, HCO3- 34. On his chemistry panel, the sodium is 139, chloride 95, HCO3- 34.

• Compensated metabolic alkalosis

Case 17

A 45 year-old woman with a history of inhalant abuse presents to the emergency room complaining of dyspnea. She has an SpO2 of 99% on room air and is obviously tachypneic on exam with what appears to be Kussmaul’s respirations. A room air arterial blood gas is performed and reveals: pH 6.95, PCO2 9, PO2 128, HCO3- 2. A chemistry panel revealed sodium of 130, chloride 98, HCO3- 2.

• Increased Anion gap metabolic acidosis with respiratory alkalosis

Case 18

A 68 year-old man with a history of very severe COPD (FEV1 ~ 1.0L,  < 25% predicted) and chronic carbon dioxide retention (Baseline PCO2 58) presents to the emergency room complaining of worsening dyspnea and an increase in the frequency and purulence of his sputum production over the past 2 days. His oxygen saturation is 78% on room air. Before he is place on supplemental oxygen, a room air arterial blood gas is drawn and reveals: pH 7.25, PCO2 68, PO2 48, HCO3-  31.

• Respiratory acidosis with metabolic compensation

Case 19

A 47 year-old man with a history of heavy alcohol use presents with a two-day history of severe abdominal pain, nausea and vomiting. On exam, his blood pressure is 90/50 and he is markedly tender in his epigastrum. His initial laboratory studies reveal sodium of 132, chloride 92, HCO3- 16, creatinine 1.5, amylase 400 and lipase 250. A room air arterial blood gas is drawn and reveals pH 7.28, PCO2 34, PO2 88, HCO3- 16.

• Increased anion gap metabolic acidosis with respiratory compensation

Case 20

A climber is coming down from the summit of Mt. Everest. At an altitude of 8,400 m (PB ~ 272 mmHg), he has a blood gas drawn while breathing ambient air as part of a research project. The blood gas reveals pH 7.55, PCO2 12, PO2 30 and HCO3- 10.5.

• Respiratory alkalosis with metabolic compensation

Case 21

A 57 year-old woman presents with 2 days of fevers, dyspnea and a cough productive of rust-colored sputum. Her room air oxygen saturation in the emergency room is found to be 85% and the intern decides to obtain a room air arterial blood gas while they are waiting for the chest x-ray to be done. The blood gas reveals: pH 7.54, PCO2 25, PO2 65, HCO3- 22

• Acute uncompensated respiratory alkalosis

DISEASES WITH THEIR ENZYME DEFICIENCIES

Criggler-Najjar - UDP-glucuronyl transferase
Von-Gierke’s - Glucose -6- phosphatase
Pompe’s - Acid maltase( Acid α glucosidase)
Mc Ardle’s - Muscle glycogen phosphorylase
Tarui’s disease - Muscle phosphorylase
Niemann-Pick’s - Sphingomyelinase
Farber’s - Ceramidase
Gaucher’s - β-glucosidase
Krabbe’s - β-galactosidase
Tay-Sach’s - Hexosaminidase-A
Phenylketonuria - Phenylalanine hydroxylase
Alkaptonuria - Homogentisate oxidase
Albinism - Tyrosinase
Fabry’s - α-galactosidase
Lesch-Nyhan syndrome - HGPRT
Sandhoff - Hexosaminidase-β
Xeroderma pigmentosum - DNA exinuclease
Sudden infant death syndrome - Medium chain acyl CoA dehydrogenase
Maple syrup urine - Branched chain α-ketoacid dehydrogenase
Acute Intermittent Porphyria- Uroporphyrinogen-1 synthase
Maple syrup urine disease - Alpha ketoacid decarboxylase
Hereditary fructose intolerance Aldolase b
Fructosuria - Fructokinase b
Galctosemia - Galactose-1-phosphate uridyl transferase

Important presentation about Thalassemia (Microcytic Anemia)

• Definition: hereditary underproduction of either the alpha or beta globin chains of the hemoglobin A  resulting in a  microcytic anemia.
• Beta thalassemias are due to mutations in the HBB gene on chromosome 11.
• The α thalassemias involve the genes HBA1 and HBA2 on chromosome 16.

Beta- Thalassemia

• The β-globin mutations associated with β-thalassemia fall into two categories: 
• (1) β0, in which no β-globin chains are produced; and 
• (2) β+, in which there is reduced (but detectable) β-globin synthesis
• Individuals inheriting one abnormal allele have thalassemia minor or thalassemia trait, which is asymptomatic or mildly symptomatic. 
• Most individuals inheriting any two β0 and β+ alleles have β-thalassemia major; 
• occasionally, individuals inheriting two β+ alleles have a milder disease termed β-thalassemia intermedia.

Alpha-Thalassemias

• alpha- thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns.The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal . The severity of the alpha- thalassemias is correlated with the number of affected alpha-globin genes.  
•  alpha0 thalassaemias, where there is lots of gama4 but no alpha-globins at all (referred to as Hb Barts), often result in still birth.

• The most severe form of alpha thalassemia major causes stillbirth.
• Other symptoms can include:
• Bone deformities in the face
• Fatigue
• Growth failure
• Shortness of breath
• splenomegaly

Diagnostic features of beta-thalassaemia

Dx

• A physical exam may reveal a swollen (enlarged) spleen.
• Blood test:
• Red blood cells will appear small and abnormally shaped when looked at under a microscope.
• A complete blood count (CBC) reveals anemia.
• A test called hemoglobin electrophoresis shows the presence of an abnormal form of hemoglobin

Rx

• Treatment for thalassemia major often involves regular blood transfusions and folate supplements.
• If you receive blood transfusions, you should not take iron supplements. Doing so can cause a high amount of iron to build up in the body, which can be harmful.
• Persons who receive significant numbers of blood transfusions need a treatment called chelation therapy to remove excess iron from the body.
• Bone marrow transplant may help treat the disease in some patients, especially children.
• Hydrops fetalis: none available 
• Haemoglobin H: no specific therapy required; avoid iron therapy; folic acid if necessary 

TREATMENT OF BETA-THALASSAEMIA MAJOR

Sphingolipidoses (lipid storage diseases)

These are a group of inherited diseases that are often manifested in childhood due to deficiency of sphingolipid degrading enzymes (in lysosomes) .

all are autosomal recessive disorders except Fabry disease (X-linked)

Common features:

(1) Complex lipids containing ceramide accumulate in cells, particularly neurons, causing neurodegeneration and shortening the life span.

(2) The rate of synthesis of the stored lipid is normal.

(3) The enzymatic defect is in the lysosomal degradation pathway of sphingolipids.

Glucose Intolerance and Blood Glucose Level.

Glucose Intolerance:

Carbohydrates Metabolism:

Blood Glucose Level:

In the body, glucose has a normal concentration of 70-90 mg/dL.

In a glucose tolerance test, blood glucose is measured for several hours after ingesting glucose.

Glycolysis:

Protein synthesis

is the process in which cells build proteins. The term is sometimes used to refer only to protein translation but more often it refers to a multi-step process, beginning with amino acid synthesis and transcription of nuclear DNA into messenger RNA which is then used as input to translation.

The cistron DNA is transcribed into a variety of RNA intermediates. The last version is used as a template in synthesis of a polypeptide chain. Proteins can often be synthesized directly from genes by translating mRNA. When a protein is harmful and needs to be available on short notice or in large quantities, a protein precursor is produced. A proprotein is an inactive protein containing one or more inhibitory peptides that can be activated when the inhibitory sequence is removed by proteolysis during posttranslational modification. A preprotein is a form that contains a signal sequence (an N-terminal signal peptide) that specifies its insertion into or through membranes; i.e., targets them for secretion. The signal peptide is cleaved off in the endoplasmic reticulum.. Preproproteins have both sequences (inhibitory and signal) still present.

For synthesis of protein, a succession of tRNA molecules charged with appropriate amino acids have to be brought together with an mRNA molecule and matched up by base-pairing through their anti-codons with each of its successive codons. The amino acids then have to be linked together to extend the growing protein chain, and the tRNAs, relieved of their burdens, have to be released. This whole complex of processes is carried out by a giant multimolecular machine, the ribosome, formed of two main chains of RNA, called ribosomal RNA (rRNA), and more than 50 different proteins. This molecular juggernaut latches onto the end of an mRNA molecule and then trundles along it, capturing loaded tRNA molecules and stitching together the amino acids they carry to form a new protein chain.

Protein biosynthesis, although very similar, is different for prokaryotes and eukaryotes.

Amino acids
Amino acids are the monomers which are polymerized to produce proteins. Amino acid synthesis is the set of biochemical processes (metabolic pathways) which build the amino acids from carbon sources like glucose.

Many organisms have the ability to synthesize only a subset of the amino acids they need. Adult humans, for example, need to obtain 8 of the 20 amino acids from their food.





Transcription

Simple diagram of transcription elongationIn transcription an mRNA chain is generated, with one strand of the DNA double helix in the genome as template. This strand is called the template strand. Transcription can be divided into 3 stages: Initiation, Elongation and Termination, each regulated by a large number of proteins such as transcription factors and coactivators that ensure the correct gene is transcribed.

The DNA strand is read in the 3' to 5' direction and the mRNA is transcribed in the 5' to 3' direction by the RNA polymerase.

Transcription occurs in the cell nucleus, where the DNA is held. The DNA structure is two helixes made up of sugar and phosphate held together by the bases. The sugar and the phosphate are joined together by covalent bond. The DNA is "unzipped" by the enzyme helicase, leaving the single nucleotide chain open to be copied. RNA polymerase reads the DNA strand from 3 prime (3') end to the 5 prime (5') end, while it synthsizes a single strand of messenger RNA in the 5' to 3' direction. The general RNA structure is very similar to the DNA structure, but in RNA the nucleotide uracil takes the place that thymine occupies in DNA. The single strand of mRNA leaves the nucleus through nuclear pores, and migrates into the cytoplasm.

The first product of transcription differs in prokaryotic cells from that of eukaryotic cells, as in prokaryotic cells the product is mRNA, which needs no post-transcriptional modification, while in eukaryotic cells, the first product is called primary transcript, that needs post-transcriptional modification (capping with 7 methyl guanosine, tailing with a poly A tail) to give hnRNA (heterophil nuclear RNA). hnRNA then undergoes splicing of introns (non coding parts of the gene) via spliceosomes to produce the final mRNA.


Translation

The synthesis of proteins is known as translation. Translation occurs in the cytoplasm where the ribosomes are located. Ribosomes are made of a small and large subunit which surrounds the mRNA. In translation, messenger RNA (mRNA) is decoded to produce a specific polypeptide according to the rules specified by the trinucleotide genetic code. This uses an mRNA sequence as a template to guide the synthesis of a chain of amino acids that form a protein. Translation proceeds in four phases: activation, initiation, elongation and termination (all describing the growth of the amino acid chain, or polypeptide that is the product of translation).

In activation, the correct amino acid (AA) is joined to the correct transfer RNA (tRNA). While this is not technically a step in translation, it is required for translation to proceed. The AA is joined by its carboxyl group to the 3' OH of the tRNA by an ester bond. When the tRNA has an amino acid linked to it, it is termed "charged". Initiation involves the small subunit of the ribosome binding to 5' end of mRNA with the help of initiation factors (IF), other proteins that assist the process. Elongation occurs when the next aminoacyl-tRNA (charged tRNA) in line binds to the ribosome along with GTP and an elongation factor. Termination of the polypeptide happens when the A site of the ribosome faces a stop codon (UAA, UAG, or UGA). When this happens, no tRNA can recognize it, but releasing factor can recognize nonsense codons and causes the release of the polypeptide chain. The capacity of disabling or inhibiting translation in protein biosynthesis is used by antibiotics such as: anisomycin, cycloheximide, chloramphenicol, tetracycline, streptomycin, erythromycin, puromycin etc.

Translation the process of converting the mRNA codon sequences into an amino acid polypeptide chain.

1.Initiation - A ribosome attaches to the mRNA and starts to code at the FMet codon (usually AUG, sometimes GUG or UUG).
2.Elongation - tRNA brings the corresponding amino acid (which has an anticodon that identifies the amino acid as the corresponding molecule to a codon) to each codon as the ribosome moves down the mRNA strand.
3.Termination - Reading of the final mRNA codon (aka the STOP codon), which ends the synthesis of the peptide chain and releases it.

Events following protein translation

The events following biosynthesis include post-translational modification and protein folding. During and after synthesis, polypeptide chains often fold to assume, so called, native secondary and tertiary structures. This is known as protein folding.

Many proteins undergo post-translational modification. This may include the formation of disulfide bridges or attachment of any of a number of biochemical functional groups, such as acetate, phosphate, various lipids and carbohydrates. Enzymes may also remove one or more amino acids from the leading (amino) end of the polypeptide chain, leaving a protein consisting of two polypeptide chains connected by disulfide bonds.

Abnormal Digestion of food in the Small intestine--Pancreatic Failure

A serious cause of abnormal digestion is failure of the pancreas to secretes pancreatic juice into the small intestine.Lack of pancreatic secretion frequently occurs

(1)in pancreatitis

(2)when the pancreatic duct is blocked by a gallstone at the papilla of Vater

(3)after the head of pancreas has been removed because of malignancy.

Loss of pancreatic juice means loss of trypsin,chymotrypsin, carboxypolypeptidase, pancreatic amylase, pancreatic lipase, and still a few other digestive enzymes.Without these enzymes,as much as 60% of the fat entering the small intestine may be unabsorbed, as well as one third to one half of the proteins and carbohydrates.As a result, large portions of the ingested food cannot be used for nutrition, and copious fatty feces are excreted.

Pancreatitis

means inflammation of the pancreas, and this can occur in the form of either acute pancreatitis or chronic pancreatitis.

The most common cause of pancreatitis is drinking excess alcohol, and the second most common cause is blockage of the papilla of Vater by a gallstone; the two together account for more than 90% of all cases.When a gallstone blocks the papilla of Vater, this blocks the main secretory duct from the pancreas as well as common bile duct. The pancreatic enzymes are then dummed up in the ducts and acini of the pancreas. Eventually, so much trypsinogen accumulates that it overcomes the trypsin inhibitor in the secretion, and a small quantity of trypsinogen becomes activated to form trypsin. Once this happens, the trypsin activates still more trypsinogen as well as chymotrypsinogen and carboxypolypeptidase, resulting in a vicious circle until most of the proteolytic enzymes in the pancreatic ducts and acini become activated. These enzymes rapidly digest large portion of the pancreas itself, sometimes completely and permanently destroying the ability of the pancreas to secrete digestive enzymes.

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