Biochemistry Flashcards
What is the most likely diagnosis?
Alkaptonuria (ochronosis).
What is the biochemical defect in Alkaptonuria (ochronosis)?
Alkaptonuria is characterized by the absence of homogentisate oxidase, an enzyme of tyrosine metabolism that catalyzes the conversion of homogentisate to maleylacetoacetate (Figure 2-1). The accumulation of homogentisate in cartilage leads to arthritis as well as to the discoloration of sclerae and other areas of the body.
The metabolite that accumulates in Alkaptonuria (ochronosis) is derived from an essential amino acid. Which amino acid is this?
Homogentisate is derived from phenylalanine. Homogentisate oxidase is necessary for the metabolism of this amino acid, which is both glucogenic and ketogenic. Homogentisate is normally metabolized to acetoacetate (a ketone) and fumarate (part of the tricarboxylic acid cycle).
Given the extent of joint disease in this patient, how might his mental functioning be affected?
Alkaptonuria has no effect on cognitive functioning. Aside from its effects on joints and discoloration of the sclerae and skin, the disease is benign.
What is the appropriate treatment for Alkaptonuria (ochronosis)?
There are no known ways to prevent the build-up of homogentisate. Dietary restriction of tyrosine and phenylalanine reduces the production of homogentisate, but this approach has demonstrated no benefit on the overall condition. Treating the symptoms of the patient’s arthritis is the only recommended therapy in this case.
What is the most likely diagnosis?
This man has ingested cyanide (the “bitter almond” breath is pathognomonic). During a manic episode, patients with bipolar disorder are more likely to use illegal drugs and engage in self-injurious behavior so a toxicology screen is mandatory. Other causes of unconsciousness, including dehydration, metabolic acidosis, and diabetic ketoacidosis, should be investigated.
What biochemical process is disrupted in cyanide posioning?
Cyanide is a direct inhibitor of one step in the electron transport chain (Figure 2-2). Cyanide inhibits cytochrome oxidase.
Will a patient with cyanide posioning have a greater-than-normal or lower-than-normal proton concentration in the intermembrane space of his mitochondria?
The man has a lower proton concentration. The electron transport chain fuels the transport of protons from the mitochondrial matrix to the intermembrane space. Because this patient ingested cyanide and thus inhibited this process, his proton gradient is weakened; therefore, he has a lower concentration of protons in the intermembrane spaces of his mitochondria.
What is the appropriate treatment for cyanide posioning?
Amyl nitrite is used to treat cyanide poisoning. Amyl nitrate oxidizes hemoglobin to methemoglobin. This is normally undesirable because this form of hemoglobin binds oxygen less avidly. However, methemoglobin strongly binds cyanide, preventing it from further disrupting electron transport.
What substances, other than cyanide, inhibit the electron transport chain?
Amytal, rotenone, antimycin A, azide, and carbon monoxide also inhibit the electron transport chain.
What substances, other than cyanide, act within the mitochondria and reduce adenosine triphosphate (ATP)
synthesis?
- Oligomycin is an example of a chemical that can directly inhibit mitochondrial ATP synthase. Although the proton gradient forms, ATP is not produced. As a result, electron transport ceases.
- Uncoupling agents such as 2,4-dinitrophenol allow protons to cross the inner mitochondrial membrane. Electron transport is not disrupted, but protons are able to flow into the matrix from the intermembrane space. This reduces the proton gradient that drives ATP formation.
What is the most likely diagnosis?
This child has DiGeorge syndrome (22q11 syndrome), which is characterized by hypoparathyroidism and T-cell deficiency. Severe combined immunodeficiency may cause both B- and T-cell deficiencies or T-cell deficiency exclusively in a given host. Hyper-IgM syndrome, IgA deficiency, and Bruton agammaglobulinemia all primarily affect B cells.
What is the etiology of DiGeorge syndrome?
DiGeorge syndrome is caused by a developmental defect involving the third and fourth pharyngeal pouches. It results in a hypoplastic thymus and parathyroid glands. Laboratory tests of this patient would show hypocalcemia and low T-cell count. The hypocalcemia causes tetany and carpopedal spasm. Chvostek sign involves tapping on the facial nerve in front of the ear and observing spasm of the facial muscle; it is another indication of hypocalcemia.
This patient with DiGeorge syndrome is at risk for developing what type of infections?
Because of the aplastic thymus, patients with this disorder have ineffective T cells and are particularly susceptible to viral and fungal infections.
What abnormality may be observed on an x-ray of the chest in a patient with DiGeorge syndrome?
An x-ray of the chest in a child with DiGeorge syndrome may show a reduced thymic shadow.
What other abnormalities are associated with DiGeorge syndrome?
CATCH 22 is a mnemonic for the 22q11 syndrome, which involves a deletion in this region of chromosome 22. Clinical manifestations include Cardiac abnormalities, Abnormal facies, Thymic hypoplasia, Cleft palate, and Hypocalcemia. Velocardiofacial syndrome also arises from this gene and involves cardiac abnormalities, abnormal facies, and cleft palate.
What is the most likely diagnosis?
- This patient had familial hypercholesterolemia (FH), an inherited disorder characterized by extremely high serum cholesterol levels.
- Type I familial hyperlipidemia is caused by lipoprotein lipase deficiency and results in abdominal pain, xanthomas, and hepatosplenomegaly.
- Type III is caused by a defect in apolipoprotein E2 synthesis and results in palmar xanthomas and tubo- eruptive xanthomas.
- Type IV is caused by increased very-low- density lipoprotein (VLDL) production and decreased elimination.
What is the genetic pattern of familial hypercholesterolemia?
FH is inherited in an autosomal manner. Heterozygotes typically have high cholesterol, approximately 370 mg/dL, and are at increased risk of myocardial infarctions. Homozygotes frequently have extremely high cholesterol levels, up to 1000 mg/dL, and frequently die before 30 years of age from cardiovascular disease. Normal total cholesterol is < 200 mg/dL, and levels > 240 mg/dL are considered elevated.
What is the molecular basis of familial hypercholesterolemia?
In FH there is a mutation in the LDL receptor gene. This results in a smaller number of functional LDL receptors. Normally, LDL circulates in the blood and binds to its receptor on hepatocyte membranes and is then taken up into the liver and metabolized. In FH patients, LDL is taken up by the hepatocytes less efficiently, leading to elevated LDL levels in the blood.
What would the microscopic examination of the lesions on this patient’s arms show?
Cholesterol deposits in the skin, called xanthomas, form when there is a persistently elevated LDL level. They are composed largely of lipid-laden macrophages.
Statin drugs are frequently used to treat hypercholesterolemia. What is their mechanism of action?
Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A reductase, a hepatic enzyme that catalyzes the rate-determining step in cholesterol synthesis. They reduce the amount of endogenous cholesterol synthesized by the liver (Figure 2-4).
What is the likely diagnosis?
The child most likely has Down syndrome, which can be associated with gastrointestinal disorders such as duodenal atresia or stenosis, annular pancreas, tracheoesophageal defects, and anal atresia. Duodenal atresia below the sphincter of Oddi causes bilious vomiting as seen in this patient.
What is the most common cytogenetic abnormality in patients with Down Syndrome?
Trisomy 21, resulting from nondisjunction of chromosome 21 during meiotic anaphase 1 or anaphase 2. The risk of nondisjunction increases with maternal age.
What other medical abnormalities are seen in children with Down Syndrome?
A single palmar crease; small, folded ears; a short neck; Brushfield spots (pale yellow spots on the iris); and a gap between the first and second toes. They also suffer from heart disease, most often cardiac cushion malformations (Figure 2-5), and may have ophthalmologic problems, gastrointestinal tract malformations, poor hearing, and mental retardation. Males with Down syndrome are almost always infertile.
What screening is available in utero for Down Syndrome?
Markers of Down syndrome in maternal blood include:
1. Reduced levels of α-fetoprotein.
2. Elevated levels of β-human chorionic gonadotropin (β-hCG).
Ultrasound measurements of nuchal lucency are also used. A definitive diagnosis can be made via karyotype analysis of fetal cells obtained via amniocentesis.
Later in life, what disorders is this baby with Down Syndrome at risk of developing?
Older individuals with trisomy 21 have a high risk of developing early Alzheimer disease. This may be because the amyloid-β protein implicated in Alzheimer disease is encoded on chromosome 21. They are also at increased risk of hematologic disorders, particularly acute leukemias and most commonly acute lymphoblastic leukemia.
What is the most likely diagnosis?
Ehlers-Danlos syndrome is most likely. Although Marfan syndrome can cause joint hypermobility, it is unlikely to cause easy bruising. Most forms of Ehlers-Danlos syndrome are inherited as autosomal dominant mutations.
What is the etiology of the easy bruising in this child?
Mutations that affect the formation of type III collagen, which may prevent proper synthesis or posttranslational modification of collagen. The bruising is a direct result of defects in the collagen of vessel walls.
What other abnormalities may be present in individuals with Ehlers-Danlos syndrome?
Thin, fragile skin; abnormal scar formation; aortic aneurysms; rupture of large arteries; and rupture of the bowel and uterus (pregnancy increases the risk of uterine rupture).
What are the 6 stages of collagen synthesis?
- Protein translation on ribosomes in the rough endoplasmic reticulum.
- Hydroxylation of proline and lysine residues in the endoplasmic reticulum. This step requires vitamin C.
- Glycosylation of lysine residues to form α chains. Three α chains form a triple helix of procollagen in the Golgi apparatus.
- The procollagen is secreted by exocytosis.
- Extracellular enzymes cleave the terminal regions of the procollagen to form tropocollagen.
- Many tropocollagen units line up in a staggered arrangement and cross-link to form the final collagen
fibrils.
Where are the four major types of collagen found in the body and where?
- Type I: Bone, skin, tendons, fascia, dentin, and the cornea.
- Type II: Cartilage, nucleus pulposus, and the vitreous body.
- Type III: Reticular collagen, found in skin, blood vessels, the uterus, granulation tissue, and fetal tissue.
- Type IV: Basement membranes.
What is the most likely diagnosis?
This boy has fragile X syndrome. This disease occurs in individuals who have an expansion of a CGG trinucleotide repeat sequence on the X chromosome. This expansion results in hypermethylation of DNA in the 5′ region of the FMR1 gene, which silences the gene by inhibiting its transcription. The FMR1 protein is an RNA-binding protein.
What is the inheritance pattern of Fragile X syndrome?
Fragile X syndrome is an X-linked genetic disorder. It is the most common inherited cause of mental retardation. The hallmark of X-linked disorders is the absence of father-to-son disease transmission. These disorders are much more common in males than in females. However, mild symptoms of fragile X syndrome appear in a significant minority of female carriers. Fragile X syndrome is not fully penetrant, and many families show a maternal transmission pattern.
What physical abnormalities are associated with Fragile X syndrome?
Individuals with fragile X syndrome frequently have long, narrow faces with a large jaw, large ears, and a prominent forehead. Most postpubertal males also have macroorchidism.
What are other trinucleotide repeat disorders, aside from Fragile X syndrome, and why are they associated with “permutations”?
What are other trinucleotide repeat disorders, aside from Fragile X syndrome, and why are they associated with “permutations”?
What is the most likely diagnosis?
Fructose intolerance.
What intermediate is elevated within the liver cells in patients with Fructose intolerance?
Fructose-1-phosphate is elevated in fructose intolerance.
What enzyme is deficient in Fructose intolerance?
Aldolase B is deficient in this disorder.
How does Fructose intolerance cause hypoglycemia?
Aldolase B catalyzes the conversion of fructose-1-phosphate into glyceraldehyde and dihydroxyacetone phosphate (DHAP) (Figure 2-7). Its absence results in accumulation of fructose-1-phosphate in liver cells and a consequent depletion of adenosine triphosphate (ATP). A low cellular supply of ATP inhibits glycogenolysis and gluconeogenesis leading to very low serum glucose. Excess fructose is lost in the urine.
What is the most likely diagnosis?
Homocystinuria
What is the biochemical defect in Homocystinuria?
The most common form of inherited homocystinuria results from reduced activity of cystathionine synthase, an enzyme that converts homocysteine to cystathionine (Figure 2-8).
This boy has a marfanoid body habitus and lens subluxation, two characteristics of this condition. For which other conditions is this patient at greatly increased risk?
This child is at increased risk for cardiovascular disease. Elevated plasma homocysteine increases risk of coronary artery disease, stroke, and peripheral artery disease. He is also at risk for osteoporosis. Homocysteine inhibits collagen cross-linking and over time can cause osteoporosis.
What is the most likely diagnosis?
Hurler syndrome.
What is the significance of the consanguinity between the child’s parents?
In consanguineous relationships there is an increased risk of a child’s inheriting the same genetic mutation from both of his parents. There is therefore a higher incidence of autosomal recessive disorders in this population.
What is the most likely diagnosis?
This patient is suffering from I-cell disease, which is characterized by coarse facial features, poor tone, kyphosis, and mental retardation. These children suffer frequent upper respiratory infections, pneumonia, otitis media, and carpal tunnel syndrome. Death usually occurs in infancy or early childhood as a result of congestive heart failure or respiratory infections. I-cell disease is clinically similar to Hurler syndrome but presents with different findings at birth, including coarse facial features and restricted joint movement.
What is the most likely diagnosis? What is the cause of their infertility?
The fact that the wife has had prior children suggests that the cause of infertility lies in the husband. Given the history, Kartagener syndrome is most likely. This is a genetic disorder with an autosomal recessive inheritance pattern. Abnormality in dynein, which is an adenosine triphosphatase that acts as a molecular motor and is responsible for retrograde transport of material along microtubules. In addition, it is required for movement of cilia and flagella. If this enzyme is not functional, it results in immotile sperm.
What is the cause of the husband’s recurrent sinus infections given his diagnosis of Kartagener syndrome?
The cilia of the respiratory epithelium require functional dynein for motility. Without it, they are unable to transport bacteria and particles out of the respiratory tract. The retained particles and bacteria can lead to infections as well as a chronic cough with sputum production.
What is the most likely diagnosis?
Lesch-Nyhan syndrome.
What is the function of the deficient enzyme?
HGPRT plays a key role in the purine salvage pathway (Figure 2-10), recycling hypoxanthine and guanine to the purine nucleotide pool. In the absence of this enzyme, purine bases are degraded into uric acid, thus causing hyperuricemia. Uric acid crystals in the urine give rise to the crystalluria.
What is the most likely diagnosis?
McArdle disease (type V glycogen storage disease). Other glycogen storage diseases include Von Gierke disease, which causes severe fasting hypoglycaemia; Pompe disease, which is characterized by cardiomegaly and early death; and Cori disease, which is less severe than Von Gierke and has normal lactate levels.
What accounts for the color of her urine?
Her muscles begin to break down during exercise because of the lack of glucose. This causes myoglobinuria as well as elevated creatine kinase. Her urine will be positive for blood on urine dipstick but will be negative for RBCs.
What is the most likely diagnosis?
Phenylketonuria (PKU).
What is the pathophysiology of Phenylketonuria (PKU)?
PKU is caused by a defect in the metabolism of phenylalanine (Figure 2-11). Normally, this essential amino acid is converted to tyrosine by phenylalanine hydroxylase. However, when phenylalanine hydroxylase activity is reduced or absent, phenylalanine builds up. This leads to excess phenyl ketones in the blood, resulting in the symptoms seen in this patient. PKU is inherited in an autosomal recessive fashion.
What is the most likely diagnosis?
Pyruvate dehydrogenase deficiency.
What is the pathophysiology of Pyruvate dehydrogenase deficiency?
Glycolysis is the pathway that converts one molecule of glucose into two molecules of pyruvate. Pyruvate dehydrogenase then converts pyruvate to acetyl-CoA, which can enter the tricarboxylic acid (TCA) cycle (Figure 2-12). Without this enzyme, the cells derive much less adenosine triphosphate (ATP) from each molecule of glucose and rely more heavily on glycolysis alone. As pyruvate accumulates, some of it is converted to lactate to regenerate oxidized nicotinamide adenine dinucleotide (NAD+). The elevated lactate level is responsible for the acidemia and anion gap observed in this baby.
What is the most likely diagnosis?
Tay-Sachs disease.
What is the most likely diagnosis?
Vitamin B1 (thiamine) deficiency. Although the patient’s alcoholism presents a clear etiology, arsenic poisoning blocks thiamine utilization and can result in a clinical picture resembling thiamine deficiency; it should also be considered.
The deficient factor in Vitamin B1 (thiamine) deficiency is a cofactor for which enzymes?
Thiamine is part of thiamine pyrophosphate (TPP). TPP acts as a cofactor for transketolase (an enzyme in the hexose monophosphate shunt) (Figure 2-14A), pyruvate decarboxylase (a component of the pyruvate dehydrogenase complex), and α-ketoglutarate decarboxylase (a component of the α-ketoglutarate dehydrogenase complex) (Figure 2-14B).
What is the most likely diagnosis?
Von Gierke disease (type I glycogen storage disease).
What is the biochemical defect in Von Gierke disease (type I glycogen storage disease)?
This is a glycogen storage disease resulting from glucose-6- phosphatase deficiency. In this disease, although the liver is able to create and break down glycogen, it is unable to release glucose into the blood, because glucose-6-phosphatase (which catalyzes the final step of this process) is deficient (Figure 2-15). The result is poor glucose control and marked fasting hypoglycemia.
