Biochemistry

Question 1

What is the most likely diagnosis?

Answer 1

Alkaptonuria (ochronosis).

Question 2

What is the biochemical defect in Alkaptonuria (ochronosis)?

Answer 2

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.

Question 3

The metabolite that accumulates in Alkaptonuria (ochronosis) is derived from an essential amino acid. Which amino acid is this?

Answer 3

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).

Question 4

Given the extent of joint disease in this patient, how might his mental functioning be affected?

Answer 4

Alkaptonuria has no effect on cognitive functioning. Aside from its effects on joints and discoloration of the sclerae and skin, the disease is benign.

Question 5

What is the appropriate treatment for Alkaptonuria (ochronosis)?

Answer 5

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.

Question 6

What is the most likely diagnosis?

Answer 6

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.

Question 7

What biochemical process is disrupted in cyanide posioning?

Answer 7

Cyanide is a direct inhibitor of one step in the electron transport chain (Figure 2-2). Cyanide inhibits cytochrome oxidase.

Question 8

Will a patient with cyanide posioning have a greater-than-normal or lower-than-normal proton concentration in the intermembrane space of his mitochondria?

Answer 8

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.

Question 9

What is the appropriate treatment for cyanide posioning?

Answer 9

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.

Question 10

What substances, other than cyanide, inhibit the electron transport chain?

Answer 10

Amytal, rotenone, antimycin A, azide, and carbon monoxide also inhibit the electron transport chain.

Question 11

What substances, other than cyanide, act within the mitochondria and reduce adenosine triphosphate (ATP)
synthesis?

Answer 11

• 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.

Question 12

What is the most likely diagnosis?

Answer 12

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.

Question 13

What is the etiology of DiGeorge syndrome?

Answer 13

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.

Question 14

This patient with DiGeorge syndrome is at risk for developing what type of infections?

Answer 14

Because of the aplastic thymus, patients with this disorder have ineffective T cells and are particularly susceptible to viral and fungal infections.

Question 15

What abnormality may be observed on an x-ray of the chest in a patient with DiGeorge syndrome?

Answer 15

An x-ray of the chest in a child with DiGeorge syndrome may show a reduced thymic shadow.

Question 16

What other abnormalities are associated with DiGeorge syndrome?

Answer 16

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.

Question 17

What is the most likely diagnosis?

Answer 17

• 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.

Question 18

What is the genetic pattern of familial hypercholesterolemia?

Answer 18

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.

Question 19

What is the molecular basis of familial hypercholesterolemia?

Answer 19

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.

Question 20

What would the microscopic examination of the lesions on this patient’s arms show?

Answer 20

Cholesterol deposits in the skin, called xanthomas, form when there is a persistently elevated LDL level. They are composed largely of lipid-laden macrophages.

Question 21

Statin drugs are frequently used to treat hypercholesterolemia. What is their mechanism of action?

Answer 21

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).

Question 22

What is the likely diagnosis?

Answer 22

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.

Question 23

What is the most common cytogenetic abnormality in patients with Down Syndrome?

Answer 23

Trisomy 21, resulting from nondisjunction of chromosome 21 during meiotic anaphase 1 or anaphase 2. The risk of nondisjunction increases with maternal age.

Question 24

What other medical abnormalities are seen in children with Down Syndrome?

Answer 24

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.

Question 25

What screening is available in utero for Down Syndrome?

Answer 25

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.

Question 26

Later in life, what disorders is this baby with Down Syndrome at risk of developing?

Answer 26

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.

Question 27

What is the most likely diagnosis?

Answer 27

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.

Question 28

What is the etiology of the easy bruising in this child?

Answer 28

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.

Question 29

What other abnormalities may be present in individuals with Ehlers-Danlos syndrome?

Answer 29

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).

Question 30

What are the 6 stages of collagen synthesis?

Answer 30

1. Protein translation on ribosomes in the rough endoplasmic reticulum. 2. Hydroxylation of proline and lysine residues in the endoplasmic reticulum. This step requires vitamin C. 3. Glycosylation of lysine residues to form α chains. Three α chains form a triple helix of procollagen in the Golgi apparatus. 4. The procollagen is secreted by exocytosis. 5. Extracellular enzymes cleave the terminal regions of the procollagen to form tropocollagen. 6. Many tropocollagen units line up in a staggered arrangement and cross-link to form the final collagen fibrils.

Question 31

Where are the four major types of collagen found in the body and where?

Answer 31

- 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.

Question 32

What is the most likely diagnosis?

Answer 32

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.

Question 33

What is the inheritance pattern of Fragile X syndrome?

Answer 33

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.

Question 34

What physical abnormalities are associated with Fragile X syndrome?

Answer 34

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.

Question 35

What are other trinucleotide repeat disorders, aside from Fragile X syndrome, and why are they associated with “permutations”?

Answer 35

Question 36

What are other trinucleotide repeat disorders, aside from Fragile X syndrome, and why are they associated with “permutations”?

Answer 36

Question 37

What is the most likely diagnosis?

Answer 37

Fructose intolerance.

Question 38

What intermediate is elevated within the liver cells in patients with Fructose intolerance?

Answer 38

Fructose-1-phosphate is elevated in fructose intolerance.

Question 39

What enzyme is deficient in Fructose intolerance?

Answer 39

Aldolase B is deficient in this disorder.

Question 40

How does Fructose intolerance cause hypoglycemia?

Answer 40

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.

Question 41

What is the appropriate treatment for fructose intolerance?

Answer 41

The condition is treated through the removal of fructose, sucrose (a disaccharide of glucose and fructose), and sorbitol from the diet.

Question 42

Why did the infant with fructose intolerance exhibit no symptoms while exclusively fed breast milk?

Answer 42

Carbohydrates in breast milk derive largely from lactose rather than fructose.

Question 43

What is the most likely diagnosis?

Answer 43

Homocystinuria

Question 44

What is the biochemical defect in Homocystinuria?

Answer 44

The most common form of inherited homocystinuria results from reduced activity of cystathionine synthase, an enzyme that converts homocysteine to cystathionine (Figure 2-8).

Question 45

What vitamin supplementation is appropriate in Homocystinuria?

Answer 45

Vitamin B6 (pyridoxine) is a necessary cofactor with cystathionine synthase. Vitamin B6 supplementation has been successful in many patients with this enzyme deficiency.

Question 46

In addition to vitamin supplementation, what other dietary changes should be made in patients with Homocystinuria?

Answer 46

The absence of cystathionine synthase means that cysteine cannot be formed from methionine. Therefore, cysteine becomes an essential amino acid. This child should be given a diet low in methionine and high in cysteine.

Question 47

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?

Answer 47

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.

Question 48

What enzyme deficiency is most likely to be found in a patient with increased serum homocysteine but decreased serum methionine?

Answer 48

This could be caused by a deficiency of methionine synthase. This enzyme catalyzes the conversion of homocysteine to methionine. Like patients with cystathionine synthase deficiency, these patients often have central nervous system dysfunction and vascular disease.

Question 49

What is the most likely diagnosis?

Answer 49

Hurler syndrome.

Question 50

What is the pathophysiology of Hurler syndrome?

Answer 50

This syndrome results from a defect in α-L-iduronidase, an enzyme essential to the degradation of dermatan sulfate and heparan sulfate. This disease is one of the mucopolysaccharidoses, a group of hereditary disorders characterized by defects in glycosaminoglycan (GAG) metabolism. Features that distinguish this disorder from the other lysosomal storage disorders include coarse facial features and corneal clouding. In Hurler syndrome, the GAGs are not appropriately degraded in the lysosomes and are therefore deposited in various tissues. The disease is inherited in an autosomal recessive manner.

Question 51

What disease has a similar presentation but is typically milder than Hurler syndrome?

Answer 51

Hunter syndrome is another mucopolysaccharidosis. It is due to a deficiency of iduronate sulfatase and has X-linked inheritance. Unlike Hurler syndrome, Hunter syndrome does not present with corneal clouding, but affected patients may exhibit aggressive behavior.

Question 52

What are the typical findings on electron microscopy in Hurler syndrome?

Answer 52

The lysosomal vesicles appear swollen. This is due to accumulation of partially degraded polysaccharides.

Question 53

What key modification must be made in the Golgi apparatus for lysosomal enzymes, such as α-L-iduronidase, to be properly targeted to lysosomes?

Answer 53

Lysosomal enzymes must be covalently modified with mannose-6-phosphate (M6P) as they pass through the cis Golgi network to be targeted to the lysosomes. These M6P groups are then recognized by M6P receptor proteins in the trans Golgi network.

Question 54

What is the significance of the consanguinity between the child’s parents?

Answer 54

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.

Question 55

What is the most likely diagnosis?

Answer 55

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.

Question 56

What is the fundamental molecular defect in I-cell disease?

Answer 56

In I-cell disease there is a mutation in the enzyme found in the Golgi apparatus that is responsible for adding a mannose-6-phosphate group to proteins destined for lysosomes. Instead of trafficking to lysosomes, these lysosomal enzymes are secreted from the cell, and high levels are found in the blood. Because the lysosomes lack the normal hydrolytic enzymes, material accumulates in the lysosomes and is not effectively broken down.

Question 57

What abnormalities would be evident by electron microscopy of cells in a patient with I-cell disease?

Answer 57

This patient’s cells would contain many vacuoles. These consist of lysosomes filled with nondegradable material.

Question 58

What proteins direct movement of vesicles between the endoplasmic reticulum (ER) and Golgi apparatus?

Answer 58

The Golgi apparatus is responsible for modifying many different proteins and directing their trafficking. COP I proteins mediate retrograde movement of vesicles from the Golgi apparatus to the ER, whereas COP II proteins mediate anterograde transport from the ER to the Golgi apparatus.

Question 59

What is the most likely diagnosis? What is the cause of their infertility?

Answer 59

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.

Question 60

What is the cause of the husband’s recurrent sinus infections given his diagnosis of Kartagener syndrome?

Answer 60

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.

Question 61

What abnormality might be observed on x-ray of the chest in a patient with Kartagener syndrome?

Answer 61

Situs inversus, which on the chest x-ray, the heart is found predominantly on the right side of the thorax. It may also show bronchiectasis, with signs of dilated bronchioles.

Question 62

What condition is caused by a mutation in microtubule polymerization?

Answer 62

Chédiak-Higashi syndrome is an autosomal recessive disorder caused by a defect in microtubule polymerization resulting in impaired migration of immune cells, such as neutrophils, and impaired lysosome fusion, which results in large granules visible within the cytoplasm (Figure 2-9). These both contribute to immune deficiency. Patients present with recurrent bacterial infections with staphylococci and streptococci.

Question 63

There are a number of antimicrobial drugs that inhibit microtubule function. What are some examples?

Answer 63

Mebendazole and related drugs inhibit microtubule activity in helminths. Griseofulvin is an antifungal that acts on microtubules. A number of chemotherapeutic agents also interfere with microtubule function, such as vincristine, vinblastine, and taxols such as paclitaxel.

Question 64

What is the most likely diagnosis?

Answer 64

Lesch-Nyhan syndrome.

Question 65

What is the biochemical defect in Lesch-Nyhan syndrome?

Answer 65

Lesch-Nyhan syndrome is characterized by a deficiency in hypoxanthine-guanine phosphoribosyltransferase (HGPRT).

Question 66

What is the function of the deficient enzyme?

Answer 66

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.

Question 67

What is the appropriate treatment for Lesch-Nyhan syndrome?

Answer 67

Allopurinol is a drug that inhibits xanthine oxidase, thus preventing the formation of uric acid from the more soluble hypoxanthine and xanthine. Hypoxanthine and xanthine can more easily be excreted in the urine. Doses should be titrated to normalize serum uric acid levels. To prevent self-injury, affected children often need lifelong benzodiazepine or barbiturate sedation, restraints, and behavioral therapy.

Question 68

What associated conditions are likely if Lesch-Nyhan syndrome is not treated?

Answer 68

Kidney stones, renal failure, gouty arthritis, and subcutaneous tophus deposits will result if the disorder is left untreated.

Question 69

What is the most likely diagnosis?

Answer 69

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.

Question 70

What is the biochemical defect in McArdle disease (type V glycogen storage disease)?

Answer 70

McArdle disease is caused by a deficiency of muscle glycogen phosphorylase. Although glycogen formation is not affected, glycogen cannot be broken back down to glucose (glycogenolysis) because the α-1,4-glycosidic bonds cannot be broken in the muscle to release glucose-1-phosphate.

Question 71

What are the most likely liver and muscle biopsy findings in a patient with McArdle disease (type V glycogen storage disease)?

Answer 71

A liver biopsy is normal, as the defective enzyme is present only in muscle. Muscle biopsy shows accumulation of glycogen.

Question 72

After a patient with McArdle disease (type V glycogen storage disease) completes an exercise tolerance test, her lactic acid levels do not increase normally. Why?

Answer 72

Lactic acid is a product of anaerobic glucose metabolism. Failure of lactic acid levels to elevate after exercise is an indication of a defect in the metabolism of glycogen or glucose to lactate. This response can be seen in other disorders of glycogenolysis or glycolysis as well.

Question 73

What accounts for the color of her urine?

Answer 73

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.

Question 74

What is the most appropriate treatment for McArdle disease (type V glycogen storage disease)?

Answer 74

Oral ingestion of sucrose before exercise has been demonstrated to improve exercise tolerance and reduce the risk of myoglobinuria.

Question 75

What is the most likely diagnosis?

Answer 75

Phenylketonuria (PKU).

Question 76

What is the pathophysiology of Phenylketonuria (PKU)?

Answer 76

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.

Question 77

What additional physical characteristics are common at presentation of Phenylketonuria (PKU)?

Answer 77

Affected children are normal at birth but fail to reach developmental milestones. Other physical findings include failure to thrive, mental retardation, microcephaly, large cheek and upper jaw bones, and widely spaced teeth with poorly developed enamel.

Question 78

What is the cofactor for the defective enzyme in Phenylketonuria (PKU) that, when deficient, can also lead to increased levels of phenylalanine in the blood?

Answer 78

A deficiency in tetrahydrobiopterin can also lead to increased blood levels of phenylalanine.

Question 79

What is the appropriate treatment for Phenylketonuria (PKU)?

Answer 79

PKU is treated with decreased dietary phenylalanine (which is contained in many foods, including artificial sweeteners). In patients with PKU, tyrosine cannot be derived from phenylalanine, so it becomes an essential amino acid. Therefore, patient should also receive dietary tyrosine supplementation. Currently, screening is mandatory and performed 6 days to 2 weeks after birth using high-performance liquid chromatography.

Question 80

What is the most likely diagnosis?

Answer 80

Pyruvate dehydrogenase deficiency.

Question 81

What is the pathophysiology of Pyruvate dehydrogenase deficiency?

Answer 81

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.

Question 82

Why are alanine levels high and citrate levels low in Pyruvate dehydrogenase deficiency?

Answer 82

Alanine levels are high because much of the excess pyruvate is converted to alanine in a reversible reaction by alanine aminotransferase. Citrate levels are low because there is little acetyl-CoA to combine with oxaloacetate to form citrate.

Question 83

What is the appropriate treatment for Pyruvate dehydrogenase deficiency?

Answer 83

Treatment involves increased intake of ketogenic nutrients (foods with high fat content). The breakdown of fatty acids involves reduction of flavin adenine dinucleotide (FAD) and NAD and produces one molecule of acetyl-CoA for every two carbon atoms in the fatty acid chain. The FADH2 (1-5-dihydro-FAD) and NADH (reduced NADH oxidase) can be used by the electron transport chain to produce ATP, whereas the acetyl- CoA can enter the TCA cycle. Oral citrate is also helpful for replenishing the substrates of the citric acid cycle.

Question 84

Which are the only 2 purely ketogenic amino acids?

Answer 84

Leucine and lysine are the only purely ketogenic amino acids.

Question 85

What is the most likely diagnosis?

Answer 85

Tay-Sachs disease.

Question 86

What is the biochemical defect in Tay-Sachs disease?

Answer 86

This disease, one of the sphingolipidoses, is caused by a deficiency of hexosaminidase A. This enzyme is present within the lysosomes of central nervous system cells and helps degrade a lipid called GM2 ganglioside. GM2 ganglioside accumulation within the neurons leads to progressive neurodegeneration. Children become blind and deaf before paralysis ultimately sets in. Children with Tay-Sachs disease usually die by 3 years of age.

Question 87

How is the gene responsible for Tay-Sachs disease inherited?

Answer 87

Tay-Sachs disease is inherited in an autosomal recessive fashion. Fabry disease is the only one of the sphingolipidoses that is inherited differently; it is X-linked.

Question 88

What other conditions present with similar physical examination findings to Tay-Sachs disease?

Answer 88

Niemann-Pick disease, which is caused by a deficiency of sphingomyelinase, also presents with a cherry- red spot in the macula in approximately 50% of cases. These patients often present with anemia, fever, and neurologic deterioration. The prognosis of Niemann-Pick disease is poor as well; most patients die by 3 years of age. Unlike Niemann-Pick, Tay-Sachs does not involve hepatosplenomegaly and demonstrates onion-like lysosomes on microscopy. Foam cells are characteristic of Niemann-Pick.

Question 89

Which of the other sphingolipidoses also has a higher prevalence among Ashkenazi Jews?

Answer 89

Although Tay-Sachs is considered to have a higher prevalence among Ashkenazi Jews, screening programs have significantly decreased the prevalence of Tay-Sachs in this group. Gaucher disease, which is caused by a deficiency of β-glucocerebrosidase, also has a much higher incidence in this population.

Question 90

What is the most likely diagnosis?

Answer 90

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.

Question 91

What clinical manifestations are commonly present in Vitamin B1 (thiamine) deficiency?

Answer 91

This patient has the symptoms of both wet and dry beriberi. Patients with wet beriberi present with high-output congestive heart failure and dilated cardiomyopathy. Patients with dry beriberi present with peripheral neuropathy consisting of muscular atrophy and diminished sensation and reflexes. Dry beriberi presents similarly to vitamin B12 deficiency; however, vitamin B12 deficiency is usually due to a malabsorptive process, does not cause congestive heart failure, and will cause a macrocytic anemia.

Question 92

The deficient factor in Vitamin B1 (thiamine) deficiency is a cofactor for which enzymes?

Answer 92

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).

Question 93

What other pathologies are commonly seen with Vitamin B1 (thiamine) deficiency?

Answer 93

Wernicke encephalopathy is the central nervous system manifestation of thiamine deficiency. This disease classically consists of nystagmus, ophthalmoplegia, and cerebellar ataxia. When the additional symptoms of confusion/psychosis and confabulation are seen, the disease is known as Wernicke-Korsakoff syndrome. It is standard practice to give thiamine before glucose to any patient with suspected thiamine deficiency to prevent Wernicke-Korsakoff.

Question 94

What are the most likely MRI findings in Vitamin B1 (thiamine) deficiency?

Answer 94

Although degenerative changes are often seen in the cerebellum, brain stem, and diencephalon, atrophy of the mammillary bodies is most commonly noted.

Question 95

What is the most likely diagnosis?

Answer 95

Von Gierke disease (type I glycogen storage disease).

Question 96

What is the biochemical defect in Von Gierke disease (type I glycogen storage disease)?

Answer 96

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.

Question 97

What are the most likely liver biopsy findings in a patient with Von Gierke disease (type I glycogen storage disease)?

Answer 97

Glycogen lipid droplets and significant steatosis are most likely to be found on microscopy.

Question 98

What 5 complications are commonly associated with Von Gierke disease (type I glycogen storage disease)?

Answer 98

1. Gout can develop as a result of hyperuricemia. 2. Hyperlipidemia—especially hypertriglyceridemia—is also common and can lead to xanthoma formation and pancreatitis. 3. Platelet dysfunction is common and presents as easy bruising and epistaxis. 4. Over time, patients may develop liver adenomas that occasionally undergo malignant transformation. 5. Nephropathy often develops from the accumulation of glycogen in the kidney.

Question 99

What is the appropriate treatment for Von Gierke disease (type I glycogen storage disease)?

Answer 99

Treatment consists of frequent meals to prevent hypoglycemia. Some patients make cornstarch a central part of their diet because it is absorbed slowly and provides a steady glucose supply. Allopurinol is often used for gout. Liver transplantation is curative.